Modern Surgical Care: Physiologic Foundations and Clinical Applications. Volume 1

medwedi.ru MODERN SURGICAL CARE Third Edition Volume 1 medwedi.ru Associate Editors Barbara L. Bass, M.D. Professo...

45 downloads 3342 Views 24MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

medwedi.ru

MODERN SURGICAL CARE Third Edition Volume 1

medwedi.ru

Associate Editors

Barbara L. Bass, M.D. Professor of Surgery Department of Surgery Weill Medical College of Cornell University New York, New York, USA Carolyn and John F. Bookout Chair Department of Surgery The Methodist Hospital Houston, Texas, USA

Peter J. Fabri, M.D. Professor of Surgery Associate Dean for Graduate Medical Education University of South Florida College of Medicine Tampa, Florida, USA

Carl E. Haisch, M.D. Professor of Surgery Department of Surgery East Carolina University Brody School of Medicine Director of Surgical Immunology and Transplantation Attending Surgeon Pitt County Memorial Hospital Greenville, North Carolina, USA

David W. Mercer, M.D. Professor and Vice Chairman of Surgery Department of Surgery The University of Texas Health Science Center–Houston Chief of Surgery Lyndon Baines Johnson General Hospital Houston, Texas, USA

Ronald C. Merrell, M.D. Professor of Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Richmond, Virginia, USA

Stuart I. Myers, M.D. Professor of Surgery Division of Vascular Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Attending Surgeon Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia, USA

MODERN SURGICAL CARE Physiologic Foundations and Clinical Applications

Third Edition Volume 1

editor-in-chief

Thomas A. Miller, M.D. Ammons Professor of Surgery Division of General Surgery Department of Surgery Virginia Commonwealth University School of Medicine and Medical Center Chief of Surgery Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, Virginia, USA

medwedi.ru

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-2869-6 (Hardcover) International Standard Book Number-13: 978-0-8247-2869-4 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

T&F_LOC_C_Master.indd 1

6/13/06 8:05:19 AM

Dedication

DEDICATION

To all trainees in surgery, medical students rotating on surgical services, and surgeons in practice who recognize the importance of understanding the physiologic underpinnings of treating surgical disease in order to ensure optimal patient care.

medwedi.ru

Preface

When the first edition of this book was published in 1988 under the title Physiologic Basis of Modern Surgical Care, its goal was to bridge the gap that commonly exists between basic science information regarding human disease and the ability to apply this knowledge to everyday clinical care. In teaching medical students rotating on surgery, as well as residents embarking on surgical careers, many of my colleagues and I, serving on medical school faculties across the country, were all too acutely aware that management of surgical disorders by these trainees was frequently based on memorized schemes or protocols rather than a thorough understanding of the pathophysiology underlying a particular disease. To address this issue, we published the initial edition with the intent to approach surgical disease as a derangement in normal physiology and that the best way to diagnose and treat it was to understand thoroughly this deviation from normal. We were very gratified with the acceptance of the book by the surgical community and its adoption by many program directors as essential reading to prepare residents for various examinations, such as the annual in-service training examination in surgery and the board certification examination following completion of surgical training. We also received many positive comments from established surgeons regarding its usefulness in preparing for recertification exams. Because of the wide acceptance of the first edition as an important vehicle to train house officers in the physiologic underpinnings of surgical disease, a second edition was published in 1998 under the title Modern Surgical Care: Physiologic Foundations and Clinical Applications. The title change was made to more adequately reflect the linkage between physiology and clinical care. We have been especially pleased with the continuing acceptance of the second edition as an important educational tool and were extremely grateful when Informa Healthcare (formerly Marcel Dekker, Inc.) asked us to produce a third edition. In addition to being thoroughly updated, the third edition reflects the capable assistance and counsel of a group of associate editors who have contributed greatly in streamlining chapters, minimizing repetitive material, adding new chapters to include cutting-edge material, and selecting a more diverse and mainstream authorship who are the current leaders in their fields. Their recommendations were responsible for the inclusion of 91 new authors

not involved in the previous editions. These associate editors include Drs. Barbara Bass, Jeff Fabri, Carl Haisch, Dave Mercer, Ron Merrell, and Stuart Myers. To each of them, I offer my utmost thanks and gratitude. As reflected in the previous editions, the needs of the general surgeon continue to be emphasized in the present edition. Further, the goal of this third edition remains the same, namely to approach surgical disease as a derangement in normal physiology, which needs to be corrected to as near normal as possible to effectively manage and treat the underlying disorder. This book is divided into nine parts, with the first part devoted to information pertinent to the body as a whole, and the eight remaining sections focused on specific organ systems or themes. Diseases affecting the reproductive organs, disorders of the head and neck (other than the thyroid and parathyroid glands), and disorders of the musculoskeletal system are not specifically dealt with because the current practice of surgery only rarely involves these disciplines. Finally, this book is not meant to replace standard textbooks of surgery and, accordingly, is not a comprehensive discussion of all surgical diseases. For less common types of surgical problems or those not regularly encountered in the practice of general surgery, such books should be consulted. I would personally like to offer my sincere appreciation to the folks at Informa Healthcare who have worked with us during the production of the book. I have found everyone with whom I have collaborated to be extremely professional, cordial, and helpful in making sure that this third edition meets the goals that we have set. I would especially like to recognize two people with whom I have had a very close working relationship. The first is Joe Stubenrauch who has been the project editor. He has more than met my expectations and has demonstrated unusual adaptability when I thought something should be done for which initially he and I had differing viewpoints. The second individual is Joanne Jay who was responsible for the final editing of each chapter and preparing the galley proofs. Her attention to detail has been exemplary. I have been very pleased with the outstanding quality of her editorial review. To both of these individuals I say ‘‘Thank you!’’ They made the process of finalizing this book most pleasurable.

medwedi.ru v

Thomas A. Miller, M.D.

Contents

6. Surgical Infection: Principles of Management and Antibiotic Usage / 127

Preface / v Contributors / xiii

VOLUME 1 PART ONE: GENERAL CONSIDERATIONS IN THE MANAGEMENT OF SURGICAL PATIENTS

1. Metabolic Response to Starvation, Stress, and Sepsis / 1 Joseph F. Amaral, Michael D. Caldwell, and Thomas A. Miller Introduction / 1 Body Composition / 1 Normal Metabolism: Intermediary Metabolism and Substrate Interactions / 8 Neuroendocrine Regulatory Mechanisms / 15 Metabolic Response in Starvation, Injury, and Sepsis / 21 Cytokines / 26 Summary / 28 References / 28

2. Pathophysiology of Fluid and Electrolyte Disorders / 33 Peter J. Fabri and Mark Bloomston Introduction / 33 Maintenance of the Internal Milieu / 33 Homeostatic Control Mechanisms / 35 Pathophysiology and Treatment of Specific Electrolyte and Acid/Base Abnormalities / 38 Principles of Fluid Therapy / 45 Summary / 46 References / 46

3. Surgical Nutrition / 49 Rosemary A. Kozar, Margaret M. McQuiggan, and Frederick A. Moore Introduction / 49 Metabolic Response to Stress vs. Starvation / 49 Rationale for Nutritional Support / 50 Initiation of Nutritional Support / 50 Enteral Nutrition / 53 Total Parenteral Nutrition / 56 Disease-Specific Nutrition / 60 Summary / 61 References / 61

Kathryn M. Verbanac, Lorita Rebellato, and Carl E. Haisch Introduction / 65 An Overview of the Immune System / 65 The Immunocompromised Surgical Patient / 76 Summary / 86 References / 87

Yuan Zhai and Rafik M. Ghobrial Introduction / 91 Allograft Rejection / 91 Immunosuppressive Therapy / 112 Clinical Transplant Outcomes / 120 Summary / 124 References / 124

7. Hemostasis and Thrombosis in the Surgical Patient / 157 Stuart I. Myers, Mark R. Jackson, Michael Sobel, and G. Patrick Clagett Introduction / 157 Mechanisms of Hemostasis / 157 Regulation of Hemostasis / 159 Inherited Disorders of Coagulation / 161 Inherited Qualitative Platelet Disorders / 163 Acquired Disorders of Hemostasis / 164 Acquired Disorders of Platelet Function / 164 Bleeding in the Surgical Patient / 165 Congenital Disorders of Hypercoagulability / 167 Acquired Hypercoagulable Disorders / 168 Antithrombotic Therapy / 170 Therapeutic Agents / 171 Summary / 174 References / 174

8. Pathophysiology of Shock / 181

4. The Immune System and the Immunocompromised Patient / 65

5. Physiologic Basis of Transplantation / 91

Christina Paylan and Rodney Durham Introduction / 127 Pathophysiology of Surgical Infections / 127 Systemic Inflammatory Response / 128 Overall Approach to Sepsis / 129 Definitions of Surgical Infections / 130 Evaluation of Suspected Infection in the Surgical Patient / 131 Role of the Laboratory in Infection Diagnosis / 131 Types of Postoperative Infections / 133 Pathogens Responsible for Surgical Infection / 140 Antibiotics in the Management of Infection / 141 Clinical Use of Antibiotics / 148 Summary / 153 References / 153

Ajai K. Malhotra Introduction / 181 Definition of Shock / 181 Cardiovascular Physiology and Types of Shock / 182 Pathophysiologic Response to Shock / 184 Management Considerations / 190 The Future / 193 Summary / 193 References / 194

9. Neoplastic Disease: Pathophysiology and Rationale for Treatment / 197 Gregory Kennedy and John E. Niederhuber Introduction / 197 Basic Concepts of Cancer Biology / 197 Biologic Rationale for Therapy / 202 Summary / 208 References / 208

10. The Physiology of Anesthesia and Pain / 213 Charles Williams and Denise Lester Introduction / 213 The Physiology of Anesthesia / 213 Preoperative Decisions / 213

medwedi.ru vii

viii

Contents Regional Anesthesia / 214 General Anesthesia / 215 Conscious Sedation / 217 Anesthetic Implications of Selected Disease States / 217 Anesthesia Emergencies / 218 The Physiology of Pain and Analgesia / 219 The Physiology of Nociception / 219 Pain Measurement / 221 The Management of Acute Postoperative Pain / 221 Summary / 224 References / 224

15. Gastric Physiology and Acid-Peptic Disorders / 333 Kenneth S. Helmer and David W. Mercer Introduction / 333 Normal Physiology / 333 Gastric Physiology / 338 Abnormal Physiology / 346 Summary / 362 References / 362

& Small and Large Intestine

16. Physiology of Digestion and Absorption / 369 11. Sepsis and the Syndrome of Multiple Organ Failure / 227 Lena M. Napolitano Introduction / 227 Sepsis: Definitions / 227 Incidence and Outcomes of Sepsis / 229 Pathophysiology of Sepsis / 230 Genetic Variability in Sepsis / 232 Treatment Strategies in Sepsis / 234 Multiple Organ Dysfunction and Failure: Definitions / 244 Incidence and Outcome of MODS / 244 Pathophysiology of MODS / 246 Potential Treatment Strategies for Reduction of MODS / 246 Summary / 247 References / 248

12. Application of Cellular and Molecular Biology in Modern Surgical Practice / 253 Huiping Zhou and Jian-Ying Wang Introduction / 253 Basic Genetic Mechanisms / 253 Cellular and Molecular Biological Technology: From Recombinant DNA to Transgenic Animals / 259 The Molecular Organization of the Cells / 263 Novel Treatment Strategies in Modern Surgical Care / 267 Summary / 269 References / 269

13. Physiologic Principles in Preparing Patients for Surgery / 271 Henry J. Schiller, Kara C. Kort, and Lelan F. Sillin Introduction / 271 General Aspects of Preoperative Preparation / 271 Specific Aspects of Preoperative Preparation / 273 Risks of Hematologic Disease / 286 Prophylaxis Against Thromboembolism / 289 HIV Infection and AIDS / 289 Summary / 290 References / 290

Bobby S. Glickman and Jon S. Thompson Introduction / 369 Fluid and Electrolyte Secretion and Absorption / 369 Overview of Digestion / 371 Protein Absorption / 372 Carbohydrate Absorption / 374 Fat Absorption / 376 Vitamins and Minerals / 377 Regulation / 378 Diarrhea and Malabsorption / 378 Summary / 379 References / 379

17. Circulation and Vascular Disorders of the Splanchnic Vascular Bed / 381 Stuart I. Myers and Patricia A. Lowry Introduction / 381 Normal Anatomy and Collateral Circulation / 381 Physiology of Intestinal Circulation / 384 Reperfusion Injury of the Intestine / 386 Clinical Evaluation of Intestinal Blood Flow / 392 Radiologic Evaluation of Patients with Acute Mesenteric Ischemia / 393 Intraoperative Assessment of Intestinal Viability / 396 Diseases That Affect the Visceral Vessels / 397 Miscellaneous Diseases That Affect the Viscera / 403 Summary / 406 References / 408

18. Inflammatory Disorders of the Small Bowel and Colon / 415 Douglas J. Turner and Barbara L. Bass Introduction / 415 Inflammatory Bowel Disease / 415 Appendicitis / 419 Meckel’s Diverticulum / 421 Jejunoileal Diverticuli / 421 Colonic Diverticular Disease / 422 Clostridium difficile Colitis / 423 Radiation Enteritis / 423 Summary / 424 References / 424

PART TWO: THE ALIMENTARY TRACT & Liver, Biliary Tract, Pancreas, and Spleen & Esophagus and Stomach

14. Physiologic Dysfunction of the Esophagus / 295 Nahid Hamoui and Peter F. Crookes Introduction / 295 Anatomy and Physiology / 295 Symptoms of Esophageal Disease / 296 Physical Examination / 297 Investigations / 297 Esophageal Diseases / 304 Esophageal Motor Disorders / 316 Esophageal Emergencies / 321 Esophageal Tumors / 323 Summary / 328 References / 328

19. Hepatic Physiology / 427 Jose M. Prince and Timothy R. Billiar Introduction / 427 Embryology / 427 Histology / 428 Anatomy / 429 Hepatic Functions / 431 Metabolic Homeostasis / 432 Pathophysiology / 435 Diagnostic Testing / 436 Regeneration / 438 Future / 438 Summary / 438 References / 439

Contents

20. Portal Hypertension / 443

26. The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain / 539

Alexander S. Rosemurgy and Emmanuel E. Zervos Introduction / 443 Anatomy / 443 Variceal Hemorrhage / 443 Summary / 452 References / 452

21. Calculous Disease of the Gallbladder and Common Bile Duct / 455 Lillian S. Kao and Terrence H. Liu Introduction / 455 Epidemiology / 455 Bile Physiology / 455 Pathogenesis of Gallstones / 459 Clinical Manifestations of Gallstone Disease / 461 Treatment / 463 Summary / 465 References / 465

22. Normal Exocrine Function and Inflammatory Diseases of the Pancreas / 469 David J. Bentrem and Raymond J. Joehl Introduction / 469 Embryology / 469 Gross Anatomy / 469 Acinus / 470 Pancreatic Exocrine Function / 470 Control of Pancreatic Secretion / 471 Acute Pancreatitis / 471 Treatments / 475 Summary / 479 References / 479

23. The Jaundiced Patient / 483 Attila Nakeeb and Henry A. Pitt Introduction / 483 Bilirubin Metabolism / 483 Classification of Jaundice / 483 Pathophysiology of Jaundice / 484 Diagnostic Approach / 487 Patient Management / 492 Benign Disease / 495 Malignant Disease / 497 Summary / 499 References / 499

24. The Spleen / 503 Haytham M. A. Kaafarani and Kamal M. F. Itani Introduction / 503 Gross Anatomy / 503 Embryology / 503 Histology / 504 Physiology and Function of the Spleen / 505 Hematologic Disorders and Splenectomy / 507 Malignancies and Splenectomy / 511 Miscellaneous Conditions / 513 Splenic Trauma / 515 Splenectomy / 520 References / 522

Kathryn A. Richardson, Ryan M. Wolfort, and Richard H. Turnage Introduction / 539 Types of Abdominal Pain / 539 Anatomy and Physiology of Abdominal Pain / 539 Pathophysiologic Stimuli for Somatic and Visceral Nociceptors / 541 Evaluation of Patients with Acute Abdominal Pain / 541 Prototypical Examples of Acute Abdominal Pain / 547 Abdominal Pain in Special Patient Groups / 550 Summary / 553 References / 553

27. Neoplastic Disorders of the Gastrointestinal Tract / 555 Carlos A. Murillo, Kenneth J. Woodside, Lindsey N. Jackson, and B. Mark Evers Introduction / 555 Cellular and Molecular Biology of GI Cancers / 555 Neoplastic Diseases of the Stomach, Small Bowel, and Colorectum / 562 Summary / 579 References / 580

28. Mechanical Disorders of the Stomach, Duodenum, and Intestine / 587 Sean P. Harbison and Daniel T. Dempsey Introduction / 587 Mechanical Disorders of the Stomach and Duodenum / 587 Mechanical Disorders of the Small Bowel / 590 Mechanical Disorders of the Colon / 595 Summary / 597 References / 597

29. Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor / 599 Janette Gaw and Walter E. Longo Introduction / 599 Anorectal Anatomy / 599 Normal Physiology of the Anus and Rectum / 603 Colonic Function and Anorectal Physiology Testing / 604 Disordered Anorectal Physiology / 605 Neoplasms of the Anal Canal and Anal Margin / 611 Summary / 613 References / 613

30. Derangements in Gastrointestinal Function Secondary to Previous Surgery / 617 Jeannie F. Savas, Thomas A. Miller, and David W. Mercer Introduction / 617 Gastric Dysfunction / 617 Intestinal Dysfunction / 625 Summary / 628 References / 629 Index / I-1

VOLUME 2 PART THREE: THE CARDIOTHORACIC SYSTEM

& Other Conditions

& Lung

25. Gastrointestinal Hemorrhage / 527

31. Pathobiology of Surgically Relevant Pulmonary Disease / 631

Kevin Bruen and Leigh Neumayer Introduction / 527 Initial Evaluation and Management / 527 Upper Intestinal Bleeding / 528 Lower Intestinal Bleeding / 532 Occult Bleeding / 535 Summary / 536 References / 536

ix

Daniel G. Tang, Jonathan Kiev, and Neri M. Cohen Introduction / 631 Anatomy and Physiology / 631 Perioperative Pulmonary Assessment / 636 Common Pulmonary Disorders / 637 Neoplastic Conditions / 643 Lung Transplantation / 645

medwedi.ru

x

Contents Summary / 646 References / 647

& Heart

32. Normal Cardiac Function / 649 Andrew C. Fiore and Andrew S. Wechsler Introduction / 649 Molecular Mechanisms in Contraction and Relaxation / 649 Mechanics of Isolated Muscle / 651 Function of the Intact Heart / 653 Heart Failure / 660 Summary / 661 References / 661

33. Heart Failure and Resuscitation / 663 Heinrich Taegtmeyer Introduction / 663 Heart Failure / 663 Resuscitation / 671 Summary / 673 References / 674

34. Mechanical Support for the Failing Heart: Current Physiologic Concepts of Management / 677 Sina L. Moainie and Bartley P. Griffith Introduction / 677 Cardiac Support in End-Stage Heart Failure / 677 Summary / 683 References / 683

35. Congenital Heart Lesions / 685 Ralph S. Mosca and Edward L. Bove Introduction / 685 Adjustments in the Circulation After Birth / 685 Congestive Heart Failure / 685 Obstructive Lesions / 686 Left-to-Right Shunts / 689 Right-to-Left Shunts / 691 Inadequate Mixing / 693 Hypoplastic Left Heart Syndrome / 695 Summary / 695 References / 696 Further Reading / 697

38. Urinary Tract Obstruction / 767 J. Robert Ramey and Deborah T. Glassman Introduction / 767 The Upper Urinary Tract / 767 The Lower Urinary Tract / 770 Summary / 772 References / 772

39. Neurogenic Lower Urinary Tract Dysfunction / 775 Hari Siva Gurunadha Rao Tunuguntla and Unyime O. Nseyo Introduction / 775 Anatomy and Physiology of Continence and Micturition / 775 Pathophysiology of LUT Dysfunction / 780 Definition of Common Terms in Neurogenic Voiding Dysfunction / 781 Specific Neurologic Lesions / 781 Classification of NLUTD / 783 Diagnosis of NLUTD / 783 Management of NLUTD / 787 Device Therapy / 791 Urinary Diversion / 792 Quality of Life / 792 Follow-Up / 792 Summary / 793 References / 793

PART FIVE: THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS

40. Pathophysiology and Management of Head Injury / 795 Egon M. R. Doppenberg, M. Ross Bullock, and William C. Broaddus Introduction / 795 Pathophysiology / 795 General Considerations in the Care of the Head-Injured Patient / 798 Specific Management of the Head-Injured Patient / 799 Monitoring the Injured Brain / 802 Summary / 802 References / 802

41. Spinal Cord Injury / 805 36. Acquired Cardiac Disorders / 699 Dipin Gupta, Andrew C. Fiore, and Glenn J. R. Whitman Introduction / 699 Ischemic Heart Disease / 699 Valvular Heart Disease / 709 Heart Failure / 715 Cardiac Dysrhythmias / 716 Pericardial Disease / 719 Cardiac Tumors / 721 Summary / 721 References / 722

Kangmin Lee and R. Scott Graham Introduction / 805 Epidemiology / 805 Pathophysiology / 805 Evaluation / 807 Classic Injury Patterns / 807 Imaging / 812 Management of Acute SCI / 812 Rehabilitation / 814 Advanced Therapies / 814 Restoration of Function / 814 Summary / 814 References / 814

PART FOUR: THE URINARY SYSTEM

37. Urine Formation: From Normal Physiology to Florid Kidney Failure / 725 Akinsan Dosekun, John R. Foringer, and Bruce C. Kone Introduction / 725 Overview of Renal Physiology / 725 Acute Kidney Failure / 735 Chronic Kidney Disease / 740 Renal Transplantation / 755 Summary and Conclusions / 761 References / 761

42. Injuries to Peripheral Nerves / 817 Irvine G. McQuarrie, Thomas C. Chelimsky, and Karen Bitzer Introduction / 817 Anatomy and Physiology / 817 Pathology / 820 Assessment of the Deficit / 821 Treatment Approach / 824 Rehabilitation After Neurorrhaphy / 826 Summary / 828 References / 828

Contents

PART SIX: THE PERIPHERAL VASCULAR SYSTEM

PART SEVEN: THE ENDOCRINE SYSTEM

43. Physiology of Arterial, Venous, and Lymphatic Flow / 831

49. Calcium and Phosphorus Metabolism and the Parathyroid Gland / 927

Dennis F. Bandyk and Paul A. Armstrong Introduction / 831 Peripheral Arterial System / 831 The Venous System / 841 Lymphatic System / 846 Summary / 847 References / 848 Further Readings / 848

Fiemu E. Nwariaku Introduction / 927 Calcium Homeostasis / 927 Hormonal Regulation of Extracellular Calcium Concentration / 928 Disorders of Calcium Metabolism / 931 Phosphate Metabolism / 937 The Parathyroid Glands / 938 Multiple Endocrine Neoplasia Syndromes / 944 Summary / 945 References / 945

44. Aorta and Arterial Disease of the Lower Extremity / 849 Christopher K. Zarins and Sheila M. Coogan Introduction / 849 Atherosclerosis / 849 Pathophysiologic Processes Affecting the Aorta and Lower Extremity Arteries / 851 Arterial Occlusive Disease of the Aorta and Peripheral Arteries / 852 Evaluation of Peripheral Vascular Occlusive Disease / 854 Treatment of Peripheral Vascular Occlusive Disease / 856 Aneurysmal Disease of the Aorta / 862 Peripheral Artery Aneurysms / 865 Complications of Vascular Procedures / 865 Summary / 866 References / 866

45. Cerebrovascular Disease and Upper-Extremity Vascular Disease / 869 Bruce L. Gewertz and James E. McKinsey Introduction / 869 Cerebral Blood Flow / 869 Clinical Presentation of Cerebrovascular Disease / 871 Types of Cerebrovascular Disease / 872 Upper-Extremity Vascular Disease / 876 Summary / 880 References / 880

46. Venous and Lymphatic Abnormalities of the Limbs / 883 Jose R. Parra and Julie A. Freischlag Introduction / 883 Anatomy / 883 Venous Physiology / 884 Venous Disorders of the Lower Extremity / 884 Venous Disorders of the Upper Extremity / 891 Lymphedema / 892 Summary / 894 References / 894

50. Pituitary Dysfunction / 947 Henry Ty and Kathryn Holloway Introduction / 947 Anatomy of the Pituitary Gland / 947 Physiology of the Pituitary Gland / 948 Hormones of the Adenohypophysis / 948 Hormones of the Neurohypophysis / 950 Regulation of Hormone Secretion / 950 Hypopituitarism / 952 Sellar and Parasellar Lesions / 954 Syndrome of Inappropriate Secretion of ADH / 960 Summary / 961 References / 961

51. Adrenal Glands / 965 Maria A. Kouvaraki, Douglas B. Evans, Ana O. Hoff, and Jeffrey E. Lee Introduction / 965 Embryology, Anatomy, and Histology / 965 Physiology / 966 Neoplasms of the Adrenal Gland / 968 Controversies in the Surgical Management of Adrenal Disease / 982 Adrenal Insufficiency / 983 References / 984

52. The Thyroid Gland / 989 Ronald C. Merrell and Lucian Panait Introduction / 989 Thyroid Anatomy / 989 Physiology / 990 Assessment of Patients with Thyroid Disease / 993 Sick Euthyroid Syndrome / 994 Hyperthyroidism (Thyrotoxicosis) / 995 Hypothyroidism / 997 Thyroiditis / 997 Thyroid Nodule / 998 Thyroid Cancer / 999 Summary / 1003 References / 1003

47. Diseases of the Thoracic Aorta / 897 Michael P. Macris and O. Howard Frazier Introduction / 897 Intrinsic Thoracic Aortic Disease / 897 Traumatic Pseudoaneurysms / 902 Summary / 903 References / 904

53. Endocrine Pancreas / 1005

48. Secondary Hypertension: Pathophysiology and Operative Treatment / 907 James C. Stanley and Gerard M. Doherty Introduction / 907 Adrenal Disease and Hypertension / 907 Renal Artery Occlusive Disease and Hypertension / 912 Summary / 922 References / 922

Ronald C. Merrell, Giacomo P. Basadonna, and Cristiana Rastellini Introduction / 1005 Anatomy and Embryology of the Islets / 1005 Physiology of the Islets / 1007 Islets in Health and Disease / 1010 Endocrine Tumors of the Pancreas / 1016 Summary / 1020 References / 1021

medwedi.ru

xi

xii

Contents

54. Multiple Endocrine Neoplasia: Types 1 and 2 / 1025 Frank J. Quayle and Jeffrey F. Moley Introduction / 1025 Multiple Endocrine Neoplasia Type 1 / 1025 Multiple Endocrine Neoplasia Type 2 / 1028 Summary / 1032 References / 1032

Metabolic Alterations / 1091 Organ System Alterations / 1093 Resistance to Infection / 1095 Pulmonary Consequences of Thermal Injury / 1096 Physiologic Considerations in Managing the Burn Patient / 1097 Summary / 1101 References / 1102

PART EIGHT: THE INTEGUMENT AND BODY WALL

55. The Biology of Wound Healing / 1035 Dorne R. Yager and Ashley E. Ducale Introduction / 1035 Phases of Healing / 1035 Other Aspects of Repair / 1038 Wound-Healing Pathologies / 1038 Wound Management / 1040 Summary / 1044 References / 1044

56. Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States / 1047 Rakhshanda Layeeque and V. Suzanne Klimberg Introduction / 1047 Physiology of Development / 1047 Pregnancy / 1050 Physiology of Lactation / 1051 Lactogenesis / 1052 Breast-Feeding / 1053 Physiology of Involution / 1053 Clinical Approach to Breast Pathology / 1054 Work-Up of Common Clinical Symptoms / 1055 Treatment of Benign Breast Pathology / 1057 Treatment of Malignant Breast Pathology / 1058 Summary / 1062 References / 1062

57. Hernias of the Abdominal Wall and Its Contents / 1067 Philip E. Donahue Introduction / 1067 Concepts and Definitions / 1067 Pathophysiology of Hernia Development / 1068 Types of Abdominal Wall Hernias / 1070 Summary / 1082 References / 1083

58. Pathophysiology of Thermal Injury / 1085 Ronald M. Barton, Evan R. Kokoska, David J. Wainwright, and Donald H. Parks Introduction / 1085 The Burn Wound / 1085

PART NINE: SPECIAL PHYSIOLOGIC CONSIDERATIONS

59. Physiologic Problems in the Pediatric Surgical Patient / 1107 Daniel J. Ostlie, Shawn D. St. Peter, Sheilendra S. Mehta, and George K. Gittes Introduction / 1107 Physiologic Considerations / 1107 Glucose, Fluid, and Electrolyte Management / 1107 Thermoregulation / 1109 Pulmonary and Cardiac Transitional Physiology / 1109 Nutritional Support / 1110 Specific Pediatric Surgical Conditions / 1111 Summary / 1123 References / 1124

60. Physiologic Considerations in the Elderly Surgical Patient / 1129 Ronnie Ann Rosenthal and Melissa F. Perkal Introduction / 1129 Physiology and Pathology of Aging / 1129 Preoperative Evaluation, Risk Assessment, and Outcome / 1141 Summary / 1144 References / 1145

61. Surgery for Morbid Obesity / 1149 Eric J. DeMaria, Ramzi Alami, and Robert E. Brolin Introduction / 1149 Etiology and Pathophysiology / 1149 Risks and Complications of Severe Obesity / 1150 Treatment of Severe Obesity / 1151 Patient Management / 1156 Results of Surgical Treatment / 1158 Summary / 1161 References / 1161 Index / I-1

Contributors

Ramzi Alami, MD Fellow in Advanced Laparoscopic Surgery, Department of Surgery, Stanford University Medical Center, Palo Alto, California, U.S.A. Joseph F. Amaral, MD President and CEO, Rhode Island Hospital, Professor of Surgery, Brown University Medical School, Providence, Rhode Island, U.S.A. Paul A. Armstrong, DO Clinical Assistant Professor of Surgery, Department of Surgery, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Dennis F. Bandyk, MD Professor of Surgery, Director, Division of Vascular Surgery, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Ronald M. Barton, MD Associate Professor of Surgery Emeritus, Director of the Burn Center Emeritus, Division of Plastic Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Giacomo P. Basadonna, MD Professor of Surgery, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Barbara L. Bass, MD Professor of Surgery, Department of Surgery, Weill Medical College of Cornell University, New York, New York; Carolyn and John F. Bookout Chair, Department of Surgery, The Methodist Hospital, Houston, Texas, U.S.A. David J. Bentrem, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A. Timothy R. Billiar, MD The George Vance Foster Professor and Chair, Department of Surgery, Presbyterian University Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A. Karen Bitzer, OTR/L, CHT Musculoskeletal Division Coordinator, Department of Rehabilitation Services, University Hospitals of Cleveland, Cleveland, Ohio, U.S.A. Mark Bloomston, MD Fellow in Surgical Oncology, Ohio State University Medical Center, Columbus, Ohio, U.S.A. Edward L. Bove, MD Helen and Marvin Kirsh Professor of Surgery, Professor and Section Head, Cardiac Surgery, Director, Pediatric Cardiac Surgery, University of Michigan, C. S. Mott Children’s Hospital, Ann Arbor, Michigan, U.S.A.

of Bariatric Surgery, University Medical Center at Princeton, Princeton, New Jersey, U.S.A. Kevin Bruen, MD Resident in Surgery, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, U.S.A. M. Ross Bullock, MD, PhD Reynolds Professor, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia, U.S.A. Michael D. Caldwell, MD, PhD Director of Marshfield Medical Research and Education Foundation, Director of the Wound Healing Clinic, Marshfield, Wisconsin, U.S.A. Thomas C. Chelimsky, MD Associate Professor of Neurology, Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A. G. Patrick Clagett, MD Professor and Chairman, Division of Vascular and Endovascular Surgery, Department of Surgery; Ian and Bob Pickens Distinguished Professorship in Medical Science; Director, Center for Vascular Disease, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Neri M. Cohen, MD, PhD Chief, Division of Thoracic Surgery, Greater Baltimore Medical Center Health Care, Baltimore, Maryland, U.S.A. Sheila M. Coogan, MD Assistant Professor of Surgery, Vascular Surgery Service, Palo Alto Veterans Affairs Hospital, Stanford University School of Medicine, Palo Alto, California, U.S.A. Peter F. Crookes, MD Associate Professor of Surgery, Director of Bariatric Surgery Program, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California, U.S.A. Eric J. DeMaria, MD Professor and Chief, Endoscopy and Bariatric Surgery, Vice Chair, Network General Surgery, Chief, Duke General Surgery at Durham Regional Hospital, Duke University Medical Center, Durham, North Carolina, U.S.A. Daniel T. Dempsey, MD Professor and Chairman, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Gerard M. Doherty, MD Norman W. Thompson Professor of Surgery, Head, Section of General Surgery; Chief, Division of Endocrine Surgery, University of Michigan, Ann Arbor, Michigan, U.S.A.

William C. Broaddus, MD, PhD Hord Professor, Department of Neurosurgery, Virginia Commonwealth University Health System; Chief of Neurosurgery, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Philip E. Donahue, MD Professor of Surgery, Department of Surgery, University of Illinois Medical Center at Chicago; Chairman, Division of General Surgery, John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois, U.S.A.

Robert E. Brolin, MD Adjunct Professor of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, Director

Egon M. R. Doppenberg, MD Former Chief Resident, Department of Neurosurgery, Virginia Commonwealth University

medwedi.ru xiii

xiv

Contributors

Health System, Richmond, Virginia; presently in neurosurgery private practice in Chicago, Illinois, U.S.A. Akinsan Dosekun, MD Associate Professor of Internal Medicine, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. Ashley E. Ducale, MPT, PhD Post-Doctoral Fellow, Department of Surgery, Wound Healing Laboratory, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A. Rodney Durham, MD Professor of Surgery, Department of Surgery, Division of Trauma and Critical Care, University of South Florida College of Medicine, Tampa General Hospital, Tampa, Florida, U.S.A. Douglas B. Evans, MD Professor of Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. B. Mark Evers, MD Professor and Robertson-Poth Distinguished Chair in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A. Peter J. Fabri, MD Professor of Surgery, Associate Dean for Graduate Medical Education, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Andrew C. Fiore, MD Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, St. Louis University School of Medicine; Chief of Cardiothoracic Surgery, Cardinal Glennon Children’s Hospital, St. Louis, Missouri, U.S.A. John R. Foringer, MD Assistant Professor of Internal Medicine, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. O. Howard Frazier, MD Professor of Surgery, University of Texas Health Science Center at Houston; Professor of Surgery, Baylor College of Medicine; Chief of Cardiopulmonary Transplantation; Director of Cardiovascular Surgery Research, Texas Heart Institute, Houston, Texas, U.S.A. Julie A. Freischlag, MD William Stewart Halstead Professor of Surgery, Chair, Department of Surgery; Surgeon-in-Chief, Johns Hopkins Medical Center, Baltimore, Maryland, U.S.A.

Deborah T. Glassman, MD Clinical Assistant Professor, Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Bobby S. Glickman, MD Instructor of Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A. R. Scott Graham, MD Associate Professor of Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Bartley P. Griffith, MD Professor of Surgery, Chief, Division of Cardiac Surgery, Director, Heart and Lung Transplantation, Maryland Heart Center, University of Maryland Medical Center, Baltimore, Maryland, U.S.A. Dipin Gupta, MD Fellow, Cardiovascular Surgery, New York University School of Medicine, New York, New York, U.S.A. Carl E. Haisch, MD Professor of Surgery, Department of Surgery, East Carolina University Brody School of Medicine, Director of Surgical Immunology and Transplantation; Attending Surgeon, Pitt County Memorial Hospital, Greenville, North Carolina, U.S.A. Nahid Hamoui, MD Assistant Professor of Surgery, Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, California, U.S.A. Sean P. Harbison, MD Associate Professor of Surgery, Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Kenneth S. Helmer, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Ana O. Hoff, MD Assistant Professor of Endocrinology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Kathryn Holloway, MD Professor of Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System; Neurosurgical Director of the Southeast Parkinson’s Disease Research, Education and Clinical Care Center of Excellence (PADRECC) at Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Janette Gaw, MD Former Chief Resident, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut; presently in colorectal surgery private practice, Fort Myers, Florida, U.S.A.

Kamal M. F. Itani, MD Professor of Surgery, Boston University Medical Center, Chief of Surgery, VA Boston Health Care System, Boston, Massachusetts, U.S.A.

Bruce L. Gewertz, MD Dallas B. Phemister Professor and Chair, Department of Surgery, The University of Chicago, Chicago, Illinois, U.S.A.

Lindsey N. Jackson, MD Resident in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A.

Rafik M. Ghobrial, MD, PhD Professor of Surgery, Director, Liver, Pancreas and Small Bowel Transplantation, The DumontUCLA Transplant Center, David Geffen School of Medicine of the University of California at Los Angeles, Los Angeles, California, U.S.A.

Mark R. Jackson, MD Former Associate Professor of Surgery, Division of Vascular Surgery, University of Texas Southwestern Medical School, Dallas, Texas; presently in vascular surgery private practice, St. Francis Hospital, Greenville, South Carolina, U.S.A.

George K. Gittes, MD Surgeon-in-Chief, Children’s Hospital of Pittsburgh, Professor of Surgery, Division Chief, Pediatric Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Raymond J. Joehl, MD Professor of Surgery, Program Director General Surgery Residency, Department of Surgery, Loyola University Medical Center, Maywood; Chief, Surgical Service and Manager, Surgery Service Line, The Charles B. Puestow Surgical Service, Edward Hines, Jr VA Hospital, Hines, Illinois, U.S.A.

Contributors

xv

Haytham M. A. Kaafarani, MD Resident in Surgery, Department of Surgery, University of South Florida Medical School, Tampa, Florida, U.S.A.

Walter E. Longo, MD Professor and Vice Chairman, Chief, Division of General Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

Lillian S. Kao, MD Assistant Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Patricia A. Lowry, MD Associate Professor of Radiology, Department of Radiology, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A.

Gregory Kennedy, MD Chief Resident in Surgery, Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin, U.S.A.

Michael P. Macris, MD Medical Director, Cardiovascular Surgery, Memorial Hermann Northwest Hospital, Houston, Texas, U.S.A.

Jonathan Kiev, MD Assistant Professor of Surgery, Division of Cardiothoracic Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. V. Suzanne Klimberg, MD Professor of Surgery, Department of Surgery, Director, Breast Surgical Oncology, University of Arkansas for Medical Services and the Arkansas Cancer Research Center, Little Rock, Arkansas, U.S.A. Evan R. Kokoska, MD Assistant Professor of Surgery, Department of Surgery–Pediatric Surgery Service, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A. Bruce C. Kone, MD The James T. and Nancy B. Willerson Chair, Chairman, Department of Medicine, Professor of Internal Medicine and of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas, U.S.A. Kara C. Kort, MD Assistant Professor of Surgery, Department of Surgery, State University of New York–Upstate Medical University, Syracuse, New York, U.S.A. Maria A. Kouvaraki, MD, PhD Fellow in Endocrine Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Rosemary A. Kozar, MD, PhD Associate Professor of Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Rakhshanda Layeeque, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology Section, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, U.S.A. Jeffrey E. Lee, MD Professor of Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A. Kangmin Lee Resident in Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia, U.S.A.

Ajai K. Malhotra, MD Assistant Professor of Surgery, Division of Trauma and Critical Care, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. James F. McKinsey, MD Associate Professor of Clinical Surgery and Site Chief of Vascular Surgery, Columbia University of New York Presbyterian Hospital System, New York, New York, U.S.A. Irvine G. McQuarrie, MD, PhD Associate Professor of Neurosurgery and Neuroscience, Department of Surgery, School of Medicine, Case Western Reserve University; Cleveland VA Medical Center, Cleveland, Ohio, U.S.A. Margaret M. McQuiggan MS, RD, CNSD Clinical Instructor, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Sheilendra S. Mehta Former Research Fellow in Pediatric Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. David W. Mercer, MD Professor of Surgery and Vice Chairman, Department of Surgery, The University of Texas Health Science Center–Houston; Chief of Surgery, Lyndon Baines Johnson General Hospital, Houston, Texas, U.S.A. Ronald C. Merrell, MD Professor of Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A. Thomas A. Miller, MD Ammons Professor of Surgery, Division of General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Chief of Surgery, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A. Sina L. Moainie, MD Resident in Cardiothoracic Surgery, Maryland Heart Center, University of Maryland Medical Center, Baltimore, Maryland, U.S.A. Jeffrey F. Moley, MD Professor of Surgery and Chief, Endocrine and Oncologic Surgery, Washington University School of Medicine; Associate Director, Alvin J. Siteman Cancer Center; Attending Surgeon, Barnes-Jewish Hospital, St. Louis, Missouri, U.S.A.

Denise Lester, MD Assistant Professor, Department of Anesthesiology, Virginia Commonwealth University School of Medicine and Medical Center; Director, Chronic Pain Clinic, Anesthesiology Service, McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Frederick A. Moore, MD Professor of Surgery and Vice Chairman, Department of Surgery, Medical Director, Trauma Services, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Terrence H. Liu, MD Associate Clinical Professor of Surgery, Residency Program Director, UCSF–East Bay Surgery Program, University of California San Francisco School of Medicine, East Bay Campus, Oakland, California, U.S.A.

Ralph S. Mosca, MD Associate Professor of Surgery, Columbia University College of Physicians and Surgeons; Associate Attending Surgeon, New York Presbyterian Hospital/Columbia University Medical Center, New York, New York, U.S.A.

medwedi.ru

xvi

Contributors

Carlos A. Murillo, MD Resident Instructor, Department of Surgery, Texas Tech University Health Sciences Center, El Paso School of Medicine, El Paso, Texas, U.S.A.

Jose M. Prince, MD Surgical Resident, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Stuart I. Myers, MD Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Attending Surgeon, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Frank J. Quayle, MD Resident in Surgery, Department of Surgery, Division of General Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Attila Nakeeb, MD Associate Professor of Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. Lena M. Napolitano, MD Professor of Surgery, Director, Surgical Critical Care; Associate Chair, Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, U.S.A. Leigh Neumayer, MD Professor of Surgery, Program Director, Utah Building Interdisciplinary Research Careers in Women’s Health, University of Utah Medical Center, Salt Lake City, Utah, U.S.A. John E. Niederhuber, MD Acting Director, National Cancer Institute, Bethesda, Maryland; Former Director, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, U.S.A. Unyime O. Nseyo, MD Adjunct Professor, Department of Urology, University of Florida School of Medicine; Chief, Urology Section, Malcom Randall VA Medical Center, Gainesville, Florida, U.S.A. Fiemu E. Nwariaku, MD Associate Professor and Vice Chairman, Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Daniel J. Ostlie, MD Associate Professor of Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. Lucian Panait, MD Former Postdoctoral Research Fellow, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A. Donald H. Parks, MD Professor and Chief, Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A. Jose R. Parra, MD Former Assistant Professor of Surgery, Division of Vascular Surgery, Department of Surgery, Johns Hopkins Medical Center, Baltimore, Maryland, U.S.A.

J. Robert Ramey, MD Chief Resident in Urology, Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Cristiana Rastellini, MD Associate Professor, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Lorita Rebellato, PhD Associate Professor of Pathology, Department of Pathology, East Carolina University Brody School of Medicine, Greenville, North Carolina, U.S.A. Kathryn A. Richardson, MD Assistant Professor, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Alexander S. Rosemurgy, MD Professor of Surgery and Medicine, Director, Division of General Surgery, Surgical Director, Tampa General Hospital Digestive Disorders Center, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Ronnie Ann Rosenthal, MS, MD Associate Professor of Surgery, Yale University School of Medicine, New Haven; Chief, Surgical Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, U.S.A. Shawn D. St. Peter, MD Assistant Professor of Surgery, Division of Pediatric Surgery, Children’s Mercy Hospital, Department of Surgery, University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, U.S.A. Jeannie F. Savas, MD Associate Professor of Surgery, Division of General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center; Attending Surgeon, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A. Henry J. Schiller, MD Associate Professor of Surgery, Department of Surgery, Mayo Clinic School of Medicine, Rochester, Minnesota, U.S.A. Lelan F. Sillin, MD, MS(Ed) Professor of Surgery, Vice Chair for Educational Affairs, Department of Surgery, University of Rochester Medical Center, Rochester, New York, U.S.A.

Christina Paylan, MD Former Fellow in Trauma and Critical Care, Department of Surgery, University of South Florida College of Medicine, Tampa General Hospital, Regional Trauma Center, Tampa, Florida, U.S.A; presently in plastic surgery private practice, Tampa, Florida, U.S.A.

Michael Sobel, MD Professor and Vice Chairman, Department of Surgery, University of Washington; Professor and Chief, Puget Sound Veterans Affairs Health Care System, Seattle, Washington, U.S.A.

Melissa F. Perkal, MD Assistant Professor of Surgery, Director, Veterans Affairs Hospital Surgical Intensive Care Unit, Director, Surgical Preceptor Program, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.

James C. Stanley, MD Handleman Professor of Surgery, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, U.S.A.

Henry A. Pitt, MD Professor and Vice Chairman, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

Heinrich Taegtmeyer, MD, DPhil Professor of Medicine, Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Contributors

xvii

Daniel G. Tang, MD Chief Resident in General Surgery, Department of Surgery, Virginia Commonwealth University School of Medicine and Medical Center, Richmond, Virginia, U.S.A.

Glenn J. R. Whitman, MD Professor of Surgery, Division of Cardiothoracic Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Jon S. Thompson, MD Professor and Vice Chairman, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.

Charles Williams, MD Associate Professor, Vice Chair for Veterans Affairs, Department of Anesthesiology, Virginia Commonwealth University School of Medicine and Medical Center; Chief, Anesthesiology Service, Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, U.S.A.

Hari Siva Gurunadha Rao Tunuguntla, MD, MBBS, MS (Surgery), MCh Resident, Department of Urology, University of Miami, Miller School of Medicine, Miami, Florida, U.S.A. Richard H. Turnage, MD Professor of Surgery and Chairman, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Douglas J. Turner, MD Assistant Professor of Surgery, Division of General Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A. Henry Ty, MD Former Chief Resident in Neurosurgery, Department of Neurosurgery, Virginia Commonwealth University Health System, Richmond, Virginia; presently in neurosurgery private practice, North Andover, Massachusetts, U.S.A.

Ryan M. Wolfort, MD Resident in Surgery, Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A. Kenneth J. Woodside, MD Chief Resident in General Surgery, Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, U.S.A. Dorne R. Yager, PhD Associate Professor of Surgery, Physiology and Biochemistry, Director, Wound Healing Laboratory, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A.

Kathryn M. Verbanac, PhD Professor of Surgery, Division of Transplantation, Department of Surgery, East Carolina University Brody School of Medicine, Greenville, North Carolina, U.S.A.

Christopher K. Zarins, MD Chidester Professor of Surgery, Chief, Division of Vascular Surgery, Stanford University Medical Center, Palo Alto, California, U.S.A.

David J. Wainwright, MD Associate Professor of Surgery, Division of Plastic and Reconstructive Surgery; Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, U.S.A.

Emmanuel E. Zervos, MD Assistant Professor of Surgery, Department of Surgery, Surgical Oncology, University of South Florida College of Medicine, Tampa General Hospital, Tampa, Florida, U.S.A.

Jian-Ying Wang, MD, PhD Professor of Surgery and Pathology, Associate Chair for Basic Research, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A. Andrew S. Wechsler, MD Stanley K. Brockman Professor and Chairman, Department of Cardiovascular Medicine and Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania, U.S.A.

Yuan Zhai, MD Assistant Professor of Surgery, Department of Surgery, Section of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, U.S.A. Huiping Zhou, PhD Assistant Professor, Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, U.S.A.

medwedi.ru

PART ONE: General Considerations in the Management of Surgical Patients

1 Metabolic Response to Starvation, Stress, and Sepsis Joseph F. Amaral, Michael D. Caldwell, and Thomas A. Miller

INTRODUCTION The metabolic response to stress, starvation, and sepsis should be viewed as a complex series of neuroendocrine reflexes resulting in an integrated attempt by the organism to mobilize energy substrates, to preserve oxygen and substrate delivery, and to maintain essential body functions (1). These alterations involve changes in the distribution and use of water, proteins, fats, and carbohydrates. As such, an understanding of normal body composition is essential to make discussion of the metabolic response meaningful.

BODY COMPOSITION Body composition has been defined by Moore (2) as ‘‘the study of the total mass and volume of body components in relation to body size, body configuration, age, sex, disease, and concentration changes.’’ It can be considered from several aspects, including tissue anatomy, chemical composition, and metabolic structure (Fig. 1), with the latter two being the most important with regard to energy stores and ‘‘intermediary metabolism.’’

Chemical Composition

for the relatively high boiling point of water, its relatively high freezing point, and its high specific heat (the energy required to raise the temperature of 1 g of a substance by 1 C). This latter property allows water to exert a major role in temperature regulation, because a large amount of heat is lost as water evaporates (perspiration) and a large amount of heat is required to raise the temperature of water. The extensive hydrogen bonding of water also makes it important in establishing the tertiary structure of proteins and other molecules. Total body water (TBW) is divisible into two components: intracellular water (ICW) and extracellular water (ECW). These two components are separated by cell membranes. Measurement of body fluid compartments uses dilution techniques, based on the concept that a substance that distributes itself equally and exclusively throughout a given compartment (e.g., TBW) can be used to determine the volume of that compartment. This procedure is done by injecting a known amount of the substance and measuring its concentration at steady state, as well as measuring the amount excreted during the period of time required to reach steady state. Thus: Volume ¼

All living organisms may be considered as complex and organized arrangements of fats, proteins, carbohydrates, minerals, and electrolytes in an aqueous environment. Although the percentage of each of these chemical groups varies among and within species, by far the largest component of all living organisms is water.

Amount injected Amount excreted Steady state concentration

Because the amount lost is usually negligible, the convention is to use: Volume ¼

Amount injected Steady state concentration

Water Water is an important substance involved in virtually all physiologic processes. Its physiochemical properties result largely from its electron structure. The hydrogen ions have a slightly positive charge, whereas the oxygen molecule, with its lone pair of electrons, has a negative charge. This difference allows extensive hydrogen bonding and a relatively high dipole moment (5) that causes the water molecules to orient themselves in an external electric field in such a way that they act as an electric buffer. When ionic substances are placed in water, a hydrational shell forms around the individual ions, reducing their electrochemical attraction and thus forming a solution (5). Water thus keeps electrolytes and other polar molecules in solution and allows them independent motion, which is critical to nutrient transport. The extensive hydrogen-bonding capacity of water molecules causes them to orient themselves in a highly organized structure similar to ice. This structure accounts

Numerous substances are available that allow measurement of various fluid compartments (Fig. 2). Generally, the TBW is the most accurately measured compartment. The TBW varies with age, sex, body build, physical activity, disease, and state of hydration. The TBW can be measured accurately using deuterium oxide or tritiated water. For a healthy man, TBW constitutes approximately 60% of total body weight, and for a healthy woman, it constitutes approximately 50% (Table 1). The differences in the proportion of TBW reflect the quantity of skeletal muscle and adipose tissue present in the two sexes. Adipose tissue contains little ICW, whereas skeletal muscle has one of the largest water contents of all tissues (Table 2). Women, with their larger adipose tissue stores and smaller skeletal muscle mass, have less TBW than men. Similarly, the TBW of young, lean athletes is greater than that of elderly, obese nonathletes. The TBW as a percentage of body weight decreases steadily with age (Table 1). Newborns have the highest

medwedi.ru 1

2

Part One: General Considerations

Table 1 Distribution of Total Body Water in Infants, Children, and Adults 100

CHO Mineral

Other

Other nitrogen

Protein

Vital organs

Fat

Blood Nerve

Hydrogen Carbon

Fat

Skin Adipose

% 50

Extracellular water

Extracellular mass

Intracellular water

Body cell mass

Oxygen

Bone

Muscle

0 TISSUE

CHEMICAL

METABOLIC MOLECULAR

Figure 1 Body composition in adult man. Source: From Refs. 3, 4.

percentage, with 75% to 80% of body weight representing water. This percentage decreases during the first few months after birth to approximately 65% of the body weight, where it remains for the remainder of infancy and childhood. This reduction in TBW is primarily the result of reduction in ECW (Fig. 3). Until the age of 12, no difference in TBW is noted between boys and girls. With advancing age, TBW as a percentage of body weight decreases to a low of 52% and 47% in males and females, respectively (2). This results primarily from a decrease in

ECF

ICF

PlasRBC ma ISF

RBC Plasma

Cr54

T1824

131

I ECF

Inulin Sucrose

Mannitol S2O3

TBW (%) Age

Men

Women

0–1 day 1–10 days 1–3 mo 3–6 mo 6–12 mo 1–2 yr 2–3 yr 3–5 yr 5–10 yr 10–16 yr 17–39 yr 40–59 yr 60 þ yr

79 74 72.3 70.1 60.4 58.7 63.5 62.2 61.5 58.9 60.6 54.7 51.5

79 74 72.3 70.1 60.4 58.7 63.5 62.2 61.5 57.3 50.2 46.7 45.5

Abbreviation: TBW, total body water. Source: Adapted from Ref. 7.

ICW, because ECW remains unchanged (5). The size of the ECW space depends on the method used for determining it. Large molecules such as insulin, mannitol, or sucrose appear to underestimate the ECW compartment because of the slower diffusion of these larger molecules into noncellular spaces (5). An ECW space of 15% to 16% of body weight is usually reported with these methods (5). Assessment of the ECW with small molecules such as 35SO4,82Br, and 24Na appears to overestimate the ECW space because of the ability of these small ions to diffuse into cells. An ECW space of 21% to 27% of body weight is usually reported when these methods are used (5). In general, it is estimated that the ECW occupies 20% of the body weight (and therefore 30–40% of TBW). It is divided into plasma (5% of body weight) and interstitial fluid (15% of body weight). The interstitial fluid occupies a rapidly equilibrating functional space between cells and a slowly equilibrating (or nonequilibrating) space composed of epithelial cell secretions, connective tissue, joint space, and cerebrospinal fluids, the so-called transcellular space (9). The functional interstitial fluid accounts for 90%, and the transcellular space accounts for 10% of the total interstitial fluid. The transcellular space should not be equated with the ‘‘third space.’’ The transcellular fluids are a normal component of the ECW and do not affect the functional volume of the extracellular space. The third space results

SO4 Br

Table 2 Distribution of Water in the Various Tissues of a 70 kg Man

Cl Na SCN D 2O

TBW

THO Antipyrine

RBC Plas- ISF ma ECF

Conn. tissue ICF

Figure 2 Substances used to measure the body fluid compartments. Abbreviations: ECF, extracellular fluid; ICF, intracellular fluid; ISF, interstitial fluid; RBC, red blood cell; TBW, total body water; THO, titrated water. Source: From Ref. 6.

Tissue Skin Muscle Skeleton Brain Liver Heart Lungs Kidneys Spleen Blood Intestine Adipose tissue Source: From Ref. 8.

Water (%)

Body weight (%)

Liters of water per 70 kg

72 75.6 22 74.8 68.3 79.2 79 82.7 75.8 83 74.5 10

18 41.7 15.9 2 2.3 0.5 0.7 0.4 0.2 8 1.8 10

9.07 22.1 2.45 1.05 1.03 0.28 0.39 0.25 0.1 4.65 0.94 0.7

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

3

Table 3 Electrolyte Composition of the Body Fluid Compartments Serum Serum water (mEq/L) (mEq/L)

100 90

Electrolytes

BODY WEIGHT (%)

80

Total body water (TBW)

70 60

Intracelluar fluid (ICF)

50 40

Extracellular fluid (ECF)

30 20

+

+

+

10 2 4 6 8 Birth 6 12 3yr 6yr 9yr 12yr 15yr Adult mo mo AGE

Figure 3 Distribution of body fluids in children as a function of age and sex. Source: From Ref. 6 and courtesy of Pediatrics 1961; 28:169.

Interstitial fluid (mEq/L)

Intracellular fluid (muscle) (mEq/kg of H2O)

Cations Sodium (Naþ) Potassium (Kþ) Calcium (Ca2þ) Magnesium (Mg2þ)

142 4 5 2

152.7 4.3 5.4 2.2

145 4

10 156 3.3 26

Total cations

153

165

149

195

102 26

109.7 28

114 31

2 8

2

2.2

95

1 6 16

1.1 6.5 17.2

20

Anions Chloride (Cl) Bicarbonate (HCO2 3 ) Phosphate (HPO2 4 ) Sulfate (SO2 4 ) Organic acids Protein Total anions

153

165

55 145

180þ

Source: Adapted from Ref. 7.

from abnormalities in the permeability of cells, such as the abnormalities seen after ischemia and those seen with inflammation that increases the size of the extracellular space but not, a priori, the volume of the ECW. Third-space size is proportional to the severity of the injury. Because fluid and electrolytes in the third space are derived from functional extracellular fluid, the increase in size of the space reduces the functional extracellular volume. Direct measurement of the ICW compartment is extremely difficult, because substances that equilibrate only in the intracellular space have not been defined. Consequently, the ICW space is estimated as the difference between TBW and ECW. The ICW space varies from individual to individual. In healthy normal adults, it constitutes approximately 30% to 40% of body weight (55% of TBW). Because fat has little ICW and skeletal muscle has the highest percentage of ICW, athletic muscular individuals have a higher proportion of ICW; but women, the obese, and the elderly have a smaller muscle mass and therefore have a smaller percentage of their body weight as ICW. The electrolyte composition of the various fluid compartments is noted in Table 3. The major cations are sodium and potassium, and the major anions are chloride and bicarbonate. The absolute amount of a particular ion can only be measured by cadaveric analyses, but the total exchangeable amount of an ion can be estimated by dilution with a labeled

form of the compound. Total exchangeable sodium is not equivalent to total body sodium. A large amount, approximately 1000 mEq, is present in a nonexchangeable form in bone (10). The total exchangeable potassium is more closely equivalent to the total body potassium (TBK) (less than 0.5% is nonexchangeable) (10). Sodium is the major extracellular cation, and potassium is the major intracellular cation (Table 4). The ECW space is approximated by the total body sodium, the ICW space by the TBK, and the TBW by the sum of total body sodium and TBK. Moore (10) has used this relationship to estimate TBW from total exchangeable sodium (Nae) and potassium (Ke) using the following formula: TBM ¼

ðNae þ Ke Þ þ 70 ð2LÞ 163

The differing ionic compositions of the various fluid compartments are the result of variations in the permeabilities and active transport mechanisms present great diversity among the transcellular fluids in this regard (Table 5).

Fat (Lipids) Until the 1950s, lipids, the second largest chemical constituent of the body, were considered to be relatively inert

Table 4 Total and Exchangeable Amounts of Electrolytes in Fluid Compartments of Adult Man Sodium

Potassium

Compartment Total extracellular Total intracellular Total body Total exchangeable Total body intracellular concentration (milliequivalent per liter intracellular water)

Magnesium

Chloride

Bicarbonate

27.8 5.2 33 33 14.4

6.8 5.9 12.7 12.7 16.4

(mEq/kg of body weight) 52.8 5.2 58 41 14.4

2.5 51.3 53.8 52.8 14.3

21.8 8.2 30 3.4, 4.9, 10a 22.8

a

Equilibrated for 24, 48, and 89 hours, respectively. Total exchangeable magnesium is a function of time of equilibration. Source: From Ref. 11.

medwedi.ru

4

Part One: General Considerations

Table 5 Mean Electrolyte Composition of Transcellular Fluids Fluid Saliva Gastric juice Bile Pancreatic juice Ileal fluid Cecal fluid Cerebrospinal fluid Sweat

Na (mEq/L)

K (mEq/L)

Cl (mEq/L)

HCO3 (mEq/L)

Hþ (mEq/L)

33 60 149 141

20 10 5 5

34 130 101 77

0 0 45 92

– 90 – –

129 80 141

11 21 3

116 48 127

29 22 23

– – –

45

5

58

0

–

Source: Adapted from Ref. 12.

substances that served as a source of protection and insulation. They now are recognized as essential components of energy metabolism (providing 9.3 kcal/g), hormonal synthesis (steroids), hormonal regulation and action (prostaglandins), and neural transmission (sphingomyelins). In addition, they are required for general cellular integrity and stability (cell membrane phospholipids and cholesterol). Many of the functions of lipids require fatty acids that cannot be synthesized by human beings. The three major essential fatty acids are arachidonic acid, linoleic acid, and linolenic acid. Total body fat (TBF) varies inversely with TBW in normal individuals. During the first four months of life, there is a decrease in the percentage of TBF, expressed as percent of total body weight (Table 6). After puberty, the TBF content increases, with the increase being greater in girls than in boys. In healthy men, TBF accounts for approximately 25% of body weight, and in healthy women, fat accounts for approximately 35% of body weight. With age, there is an increase in the percentage of body weight occupied by fat. However, it is of note that body weight often remains unchanged with age. Because total body weight equals body fat plus fat-free tissues, a decrease in fat-free tissue is thought to occur with aging (14). The percentage of body weight occupied by fat is also inversely related to the level of physical activity. Muscular athletic individuals have a greater muscle mass and smaller percentage of body fat than sedentary individuals of similar body weight (15). However, these changes are somewhat adaptive. For example, a long-distance swimmer benefits from the buoyancy and insulation provided by fat and often has a greater amount of fat than a long-distance runner of equivalent body build (15). This presumably results from a difference in caloric intake between these two groups. Approximately 50% of the fat in human beings is located in the subcutaneous tissue, but the distribution of the subcutaneous tissue varies with age, sex, and physical activity (14). Children have a large amount of subcutaneous

Table 6 Body Composition of Infants and Children as Function of Age

Age (mo) Birth 4 12 24 36

Whole body (g/100 g)

Body weight (kg)

Water

Protein

Lipid

Other

3.5 7 10.5 13 15

75.1 60.2 59 61 62

11.4 11.4 14.6 15.7 16.4

11 26.3 23.9 20.6 18.3

2.5 2.1 2.5 2.7 3.3

Source: From Ref. 13.

tissue over their triceps, but only a small amount of subcutaneous tissue in their abdominal walls. The distribution is reversed in adults. Changes in the body fat distribution occurring as a result of weight gain are not equally distributed (14). For this reason, serial measurement of an isolated anthropometric index may not adequately reflect body composition changes in malnourished individuals who are being repleted. However, changes in the body fat distribution occurring as a result of weight loss are equally distributed. A 10% loss in triceps skinfold is accompanied by a concomitant 10% loss in the size of the subcutaneous tissues of other areas such as the hips, abdomen, thighs, and breasts (14). TBF is defined as the difference between total body weight and fat-free mass (see the equation given below). Fat contains very little water and virtually no potassium. On the other hand, the total water content of fat-free tissue averages 73.2% of TBW (16), and the potassium content of fat-free tissues averages 68.1 mEq/kg (14). Consequently, fatfree tissue may be approximated from either TBW or total exchangeable potassium (Ke), and the TBF is estimated by inference. Equations for these calculations are: For TBW: TBF ¼ BWt ðTBW=0:732Þ

and

%TBF ¼ 1 ð%TBW=0:732Þ For Ke : TBF ¼ BWt ðKe Þ=68:1 and %TBF ¼ ½BWt ðKe =68:1Þ=BWT where BWt is body weight. It should be noted that these methods assume that the hydration and potassium content of that portion of the body that is fat free is constant. However, these assumptions are not always valid because the hydration of the fat-free tissue can vary considerably (e.g., greatest in edematous states and least in dehydrated states). A third method used in calculating TBF involves the measurement of the specific gravity of the individual by underwater weighing procedure (14,15,17,18). This method is based on the findings that normal human fat has a density of 0.9 g/mL and nonfat tissue has an average density of 1.1 g/mL at 37 C. At 37 C, the density of an average reference male containing 15.3% body fat is 1.064 g/mL (19). With the use of these values, the percentage fat in an individual can be determined by measuring the density (D) in water as indicated by the equation: %Fat ¼ ½ð4:570=DÞ 4:142 100 Although the density of human fat changes only with temperature, the density of fat-free tissue changes with age, degree of obesity, and degree of hydration (14). When estimates of TBF made by densitometric methods are compared to calculations of TBF made from TBW, the densitometric methods give a higher estimate of TBF (15,17). Densitometric methods give a lower estimate of TBF when compared to calculations of TBF made from total exchangeable potassium (17,20). A fourth method used to calculate TBF involves the measurement of the uptake of an inert, highly fat-soluble gas such as cyclopropane or krypton (21). The assumption made in this technique is that the gas will only go into fat cells. Thus it should yield a more accurate measurement of TBF than the other methods noted. When compared to measurements made by TBW determination, similar results

5

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

protein turnover per kilogram of body weight are the result of a decrease in skeletal muscle mass. TBP may be estimated by one of two methods: (i) measurement of total exchangeable potassium or (ii) measurement of total body nitrogen (TBN) by neutron activation. TBN is linearly related to total exchangeable potassium in both normal and decreased conditions (26,27). The average exchangeable potassium to nitrogen ratio in tissue is 3 mEq/g nitrogen (10). Thus:

are obtained (22). When compared to total exchangeable potassium measurements or densitometric measurements, lower values are obtained (23). However, no data are available comparing the inert gas method with cadaver analyses.

Proteins Proteins are chains of amino acids. Proteins and amino acids form essential components of all living cells and are involved in virtually all body functions. These molecules serve as enzymes, hormones, neurotransmitters, immunoglobulins, and transport molecules. They are also essential components of all cell membranes and various cellular components, including receptors, transport systems, and contractile elements. As such, they are necessary for the metabolism, growth, regulation, replication, protection, repair, communication, and motion of individual cells and the coordinated function of the entire organism. Consequently, it is somewhat remarkable that total body proteins (TBPs) account for only 15% of the body weight in a healthy man and that over 80% of the TBP is present in skeletal muscle and connective tissue. Unlike fat, there are no storage depots for protein. All the body’s protein is functional. As a result of its numerous and varied functions, protein, unlike fat, undergoes considerable daily turnover. Approximately 2.5% of the TBP (250 g in a 70 kg man) is broken down and resynthesized each day (23). More than half this turnover is accounted for by daily secretory processes, white cell turnover, hemoglobin turnover, muscle-protein turnover, and plasma protein turnover. The total turnover rate of body protein diminishes progressively with age (24). The protein synthesis rate per kilogram of body weight decreases from 25 g/kg/day in the neonate to 7 g in a one-year-old infant. In the average man and woman, protein synthesis is 3.2 and 2.6 g/kg of body weight per day, respectively; in an elderly man and woman, it is 2.6 and 1.9 g, respectively. The synthesis rate of transport protein, such as albumin, remains unchanged with increasing age, but the breakdown rate (and presumably synthesis rate) of skeletal muscle decreases (Table 7). If the total turnover rate of protein is expressed per lean body mass rather than body weight, an increase in turnover is noted with aging. Because the lean body mass decreases with aging as a result of a reduction in skeletal muscle mass and the synthesis rate of albumin is unchanged, it is apparent that the changes in

TBN ¼ Ke =3 where Ke equals exchangeable potassium. TBP is directly proportional to TBN by a factor of approximately 6.25. Thus: TBP ¼ ð6:25ÞðTBNÞ ¼ ð6:25ÞðKe =3Þ ¼ 2:08 Ke TBN can also be measured using neutron activation analysis (26,28). When tissues are irradiated with neutrons from either a cyclotron or a plutonium source, gamma rays specific for a substance capturing the neutron are emitted. For nitrogen, gamma rays of 10.83 meV are emitted. Consequently, measurement of the gamma rays produced after neutron activation allows determination of TBN. In general, the results obtained with either method correlate well with each other.

Carbohydrates Carbohydrates serve as the energy source of the body when energy is rapidly required, providing approximately 4 kcal/g. They also play important roles in cell membrane function and stability (glycoproteins and glycolipids), in hormone function (glycoproteins), and as precursors of lipid and nonessential amino acid synthesis. In addition, the brain, RBCs, WBCs, and wounds are to a large extent glucose-dependent tissues. Of the three major sugars found in the human body (glucose, fructose, and galactose), glucose is the primary carbohydrate. In addition to ingested carbohydrates, glucose is readily available from pyruvate and lactate, gluconeogenic amino acids (alanine and glutamine), the glycerol moiety of lipids, and its storage form, glycogen. Most of the body’s glycogen is stored in the liver, skeletal muscle, and cardiac muscle. Muscle glycogen is used primarily by the muscle itself, because muscle lacks

Table 7 Comparison of Whole Body Protein Breakdown with Estimates of Muscle-Protein Breakdown and Albumin Synthesis in Young and Old Adult Human Beings Whole body protein breakdowna (g/day) Group Males Young Old Females Young Old

Muscle-protein breakdownb (g/day)

Albumin synthesisc (g/day)

Mean age (yr)

Per kg body weight

Per kg BCM

Per g creatinine

Per kg body weight

Per kg BCM

Per g creatinine

Per kg body weight

Per kg BCM

Per g creatinine

22 70

2.94 2.64

6.7 7.5

115 163

0.76 0.53

1.74 1.50

30 32

0.19 0.15

0.39 0.40

7 8.4

20 76

2.35 1.94

6.1 6.6

103 166

0.64 0.31

1.69 1.05

28 26

– –

– –

a

Measured by administration of 15N-glycine. Measured as 3-methylhistidine output in urine and computed as muscle protein. c Measured by administration of 15N-glycine. Abbreviation: BCM, body cell mass. Source: From Ref. 25. b

medwedi.ru

– –

6

Part One: General Considerations

glucose-6-phosphatase. In contrast, hepatic glycogen is primarily used in providing glucose to glucose-dependent tissues. Because only a little glycogen is stored in the liver, the hepatic stores of glycogen are rapidly depleted by an overnight fast. Cahill (29) has estimated the total hepatic glycogen content of a 70 kg man to be 75 g, and the total muscle glycogen content to be 105 g. The total carbohydrate content of the body is approximately 300 g (30). Except by cadaver analysis, no method is available to measure total body carbohydrate. However, it is of note that the daily intake of carbohydrate approximates the total body stores.

Lean Body Mass and Body Cell Mass Based on densitometric measurements, Behnke (17) and Behnke and Wilmore (15) proposed the division of total body weight into fat and lean body mass. The lean body mass was defined as that portion of the body mass with the least amount of essential body fat compatible with health. The essential body fat was thought to represent 2% to 10% of the total body weight. However, because the essential body fat cannot be differentiated from the nonessential body fat, most investigators have redefined lean body mass as the portion of body mass devoid of all fat, the so-called fat-free body (14). Although ‘‘fat-free body’’ and ‘‘lean body mass’’ are often used interchangeably, there is a small (2–10%) difference between them (Table 8). This chapter subsequently refers only to the fat-free body, but it should be kept in mind that the same statements are generally true for lean body mass. Because the total body weight is equal to TBF plus the fat-free body, the size of the fat-free body can be determined by the same methods used to determine the size of the TBF.

The fat-free body is divisible into the extracellular mass, composed primarily of water, and the body cell mass (BCM), composed of all the metabolically active cells in the body (2,10). The cells in the BCM are actively involved in energy exchange, protein synthesis, enzyme replication, and morphogenesis (2). Therefore the BCM is composed of the skeletal muscle mass (60%), visceral cell mass (20%), and the peripheral cell mass (20%) (Table 8) (10). The peripheral cell mass includes blood cells and connective tissue cells. Although the BCM cannot be measured directly, it can be calculated from the exchangeable potassium, the exchangeable sodium, the TBN, or the ICW. Because more than 98% of the TBK is intracellular, a linear relationship exists between BCM, TBK, total exchangeable potassium, and ICW. Histochemical analysis has demonstrated that approximately one-fourth of the wet weight of cells is protein (31). Consequently: BCM ¼ ðTBKÞð4Þ ¼ ð2:08 Ke Þð4Þ ¼ 8:33 Ke BCM ¼ ðTBNÞð6:25Þð4Þ ¼ 25ðTBNÞ Because the average cell has 150 mEq of intracellular potassium per liter (10) and because each cell is composed of 25.8% solids (74.2% water) (31), BCM is also equivalent to: Ke ð1000=0:732Þ=150 ¼ ðKe Þð9:10Þ or ICW=0:742 Each of these methods yields a different value for the BCM of a given individual. This is most obvious when

Table 8 Comparison of Body Cell Mass, Lean Body Mass, and Fat-Free Body BCM Anatomy

All body cells Protoplasm Nucleus Membrane [ICK]av ¼ 150 mEq/LICW

LBM

g

g

Function

Composition

Cellular metabolism Respiration Oxidation Synthesis Cretion Mitosis [Ke ECK] f ¼ BCM f ¼ 7.510 or Ke 8.33 ¼ BCM 70 kg man 3200 8.33 ¼ 26.6 kg Calories 2.73.6 kcal/hr/kgBCM

FFB

All body cellsg BCM Plus: Plasma ECF ECF TCF Tendon ECT Fascia Collagen Elastin ECS Dermis Skeleton ‘‘2% ¼ 10% essential lipid’’: Fat Cellular metabolism Support Transport Circulation Protection Integument Density ¼ 1100 % LBM ¼ 100 495/d 450 70 kg man Approximately 50 kg Calories 110 kcal/hr/kgLBM

Same as LBM but no lipid at all

g

Same as LBM

FFB ¼ TBW/f f ¼ 0.695 0.735 70 kg man 36.4/0.732 ¼ 49.7 Calories (same as LBM)

Abbreviations: BCM, body cell mass; ECF, extracellular fluid; ECK, extracellular potassium; ECS, extracellular supporting structure; ECT, total extracellular space; f, coefficient; FFB, fat-free body; ICK, intracellular potassium; ICW, intracellular water; Ke, exchangeable potassium; LBM, lean body mass; TBW, total body water; TCF, total cellular fluid. Source: From Ref. 10.

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

2400

× 2100

× ×× × ×

1800 IRME (cal/day)

the two methods presented for total exchangeable potassium are used. However, any of these methods provide accurate estimates of sequential changes in an individual or differences among populations, if the same method is used throughout the study. Measurements of total exchangeable potassium by whole body 40K counting or of TBN by neutron activation are difficult to perform and require equipment that is expensive and not readily available. To avoid these practical problems, Shizgal et al. (32) developed a method to estimate total exchangeable potassium from isotope dilution measurements of TBW and total exchangeable sodium. As noted previously, TBW is approximately equal to the sum of the total exchangeable sodium and potassium. Thus:

7

×

1500 1200

×

900

× ×

× ×× × ××

= Healthy young males = Healthy young females = Healthy elderly males × = Surgical patients

× ×

600 300

TME = –8.99 = 10–5Ke + 250

Nae þ Ke =TBW ¼ R

400 800 1200 1600 2000 2400 2800 3200 3600 4000 4400 4800 Ke (mEq)

where R is constant. Total exchangeable sodium and TBW can be easily measured by isotope dilution with deuterium oxide or tritiated water and 22Na. The constant, R, can be approximated by measurement of the sodium, potassium, and water of whole blood. Thus:

Figure 4 Relationship of total body energy expenditure to the total Ke. Abbreviations: Ke, exchangeable potassium; IRME/TME, total metabolized energy. Source: From Ref. 34.

Ke ¼ ½ðRÞðTBWÞ Nae energy expenditure when compared to total exchangeable potassium because skeletal muscle at rest contributes significantly to total exchangeable potassium but not to total metabolic energy expenditure.

and BCM ¼ 8:33 Ke or 9:10 Ke As might be expected, BCM increases with age until the middle years of life. With advancing age, the percentage of body weight composed of the BCM decreases as a result of a decrease in skeletal muscle mass. In addition, men generally have a greater percentage of body weight composed of BCM than women; athletic individuals have a greater percentage of body weight composed of BCM than sedentary individuals; and lean individuals have a greater percentage of body weight composed of BCM than obese individuals. Thus the BCM varies from 20% of body weight in morbidly obese individuals to 54% in lean athletic men (33). A direct correlation exists between total energy expenditure and BCM, whereas other measurements of body composition such as total body mass and fat-free body demonstrate a variable or poor correlation (34). Kinney et al. (34) have demonstrated an oxygen consumption of 8 to 10 mL oxygen per kilogram BCM and an energy expenditure of 2.7 to 3.6 kcal/kg/hr: As noted in Figure 4, total exchangeable potassium (and therefore BCM) is linearly related to the total metabolic energy expenditure in healthy adults and surgical patients until 1800 cal/day are expended. However, when measurements of total metabolic energy expenditure greater than this are included, the relationship is parabolic. This relationship is believed to reflect the lower resting metabolic rate of skeletal muscles per milliequivalent intracellular potassium when compared to visceral tissues. Skeletal muscle, which provides approximately 50% of the TBK, accounts for only 15% of the body’s resting energy expenditure. On the other hand, visceral tissues, such as brain, heart, and kidneys, which provide only 10% of the TBK, account for 70% of the body’s resting energy expenditure (35). Consequently, individuals with a small BCM have less skeletal muscle mass and a good correlation of total exchangeable potassium with total metabolic energy expenditure. In contrast, individuals with a large BCM have a smaller increase in total metabolic

Changes in Body Composition with Stress, Sepsis, and Starvation The body composition of a human being at any given moment is influenced significantly by the individual’s age, sex, physical activity, and previous nutritional status, as well as by concurrent infections, injuries, and disease processes. Changes produced by age, sex, and physical activity have been discussed at length. Tables 9 and 10 and Box 1 provide a summary of the formulas derived from multiple body composition studies of normal individuals (2,10). These formulas can be applied to any healthy adult under normal circumstances to estimate the components of body composition. Ultimately, body composition is the net result of the total chemical constituents taken in minus the total chemical constituents used and excreted. Because carbohydrates and lipids primarily serve as a source of calories, this relationship can be estimated by: DBC ¼ ½ðCin þ Nin þ WSin Þ ½ðCout þ Nout þ WSout Þ where D is change, BC is body composition, C is calories, N is nitrogen, W is water, and S is solutes (electrolytes and Table 9 Estimation of Total Body Water by Age, Sex, and Body Weight Sex

Age (yr)

TBW (L)

95% conf. limits (%)

Males

16–30 31–60 61–90 16–30 31–90

0.4 (BWt) þ 13 0.4 (BWt) þ 11 0.34 (BWt) þ 12 0.31 (BWt) þ 11.6 0.33 (BWt) þ 8.84

16 17 16 13 21

Females

Abbreviations: TBW, total body water; BWt, body weight. Source: From Ref. 10.

medwedi.ru

8

Part One: General Considerations

Table 10 Estimation of Total Exchangeable Potassium by Age, Sex, and Body Weight Sex

Age (yr)

Exchangeable potassium (mEq)

Males

16–30 31–60 61–90 16–30 31–90 61–90

38 (BWt) þ 735 26 (BWt) þ 1383 27 (BWt) þ 723 18 (BWt) þ 1250 17 (BWt) þ 1176 18 (BWt) þ 757

23 20 16 20 23 29

20–60 61–84

97.4 (TBW) 409 2 þ 77 (TBW)

10 17

Females

By TBW Males and Females

Injury and infection

Normal

95% conf. limits (%)

+110 +100 +90 +80

Abbreviations: BWt, body weight; TBW, total body water. Source: From Ref. 10.

minerals). Under normal steady-state conditions, the quantities of these components taken in equal the quantities used or lost, and there is no net change in body composition (BC ¼ 0). If the quantity of a component taken in is greater than the quantity used, this component either is stored (BC > 0), thus changing body composition, or is lost (BC < 0). For example, if caloric intake is greater than caloric loss or expenditure, energy is stored in the body in the form of lipids and carbohydrates. If water intake is greater than output, water is retained (e.g., edema). Fortunately, regulatory mechanisms exist that protect against an increase in body water (Chapter 2) and other nutrients. Consequently, for a net increase to be seen in TBW, there must be a neuroendocrine alteration present as well. Such is the case after trauma and surgery when elevated secretion rates of aldosterone and vasopressin promote the retention of salt and water. On the other hand, excess nitrogen intake is not stored, and, as already noted, maximum rates of protein synthesis exist in each individual. When the intake of nitrogen exceeds the need, the excess nitrogen is converted into urea and is excreted. There are five basic situations in which intake does not equal output—dehydration and the four catabolic stresses defined by Moore (2) as fasting, starvation, injury, and febrile illness. In dehydration, the loss of water exceeds the intake resulting in a reduction in TBW that is distributed throughout the ICW and ECW. In fasting and in starvation (prolonged fasting), caloric and nitrogen expenditures are the same or less than those of a normal individual, but the

Box 1 Estimation of Body Composition by Sex and Body Weight TBW ¼ 0.7945 (BWt) 0.0024 (BWt)2 0.0015 (age) (BWt) (males) TBW ¼ 0.6981 (BWt) 0.0026 (BWt)2 0.0012 (age) (BWt) (females) ICW ¼ 0.623 (TBW) 0.0016 (age) (TBW) (males) ICW ¼ 0.553 (TBW) 0.0007 (age) (TBW) (females) Fat ¼ BWt TBW/0.732 ECW ¼ TBW ICW Ke ¼ 150 (ICW) þ 4 (ECW) Nae ¼ 163.2 (TBW) Ke 69 Abbreviations: BWt, body weight; ECW, extracellular water; ICW, intracellular water; Ke, exchangeable potassium; Nae, exchangeable sodium; TBW, total body water. Source: From Ref. 2.

+70 +60

Third degree burns >20% BSA

+50 +40 +30 +20 Basal

Resting 10%

+10 Normal _10 _20 _30

Severe infection

Multiple fractures Postoperative Partial starvation

_40

Figure 5 Resting energy expenditure during injury and starvation in man. Abbreviation: BSA, body surface area. Source: From Ref. 36.

intake of these substrates is markedly reduced or absent. As a result there is a loss of total body lipids, carbohydrates, and nitrogen. In patients with injury or febrile illness, caloric and nitrogen expenditures are greater than those of the normal individual. The increase in energy expenditure produced by an injury or infection is in proportion to the severity of the insult. Burns are the most severe injury, and generalized sepsis is the most severe febrile illness (Fig. 5). A healthy adult undergoing an elective operation increases the resting energy expenditure by approximately 10%, but the same individual with a severe burn increases the resting energy expenditure by 40% to 120%, depending on the size and the degree of the burn injury (37). A minor febrile illness or a minor febrile complication after an elective operation increases the resting energy expenditure by 13% for each degree Celsius of temperature elevation (38), but generalized sepsis increases the resting energy expenditure by 15% to 50% (37). The changes in body composition resulting from an increase in caloric and nitrogen expenditure during injury and febrile illness are frequently compounded by reductions in intake as a result of anorexia and ileus. However, if the increased measurements are adequately met by exogenous substrate sources (enteral or parenteral), little change in the body composition occurs (10,28,39,40).

NORMAL METABOLISM: INTERMEDIARY METABOLISM AND SUBSTRATE INTERACTIONS Body composition remains in a steady state when four essential conditions are met: (i) energy is supplied in sufficient quantities to meet the metabolic demands of all the body’s tissues, (ii) carbohydrates are supplied in sufficient quantities to meet the requirements of glucosedependent tissues, such as those of the brain, RBCs, and WBCs, (iii) nitrogen is supplied in sufficient quantities to meet the obligatory synthesis of protein, and (iv) water

Chapter 1: Metabolic Response to Starvation, Stress, and Sepsis

and solutes (electrolytes and minerals) are supplied in sufficient quantities to replace daily obligatory losses (water and electrolyte metabolism). In addition, these conditions must be met in the face of varying dietary intakes and varying daily energy requirements. This achievement is possible as a result of numerous substrate-to-substrate interactions (e.g., conversion of protein to carbohydrates) and the neuroendocrine regulation of intermediary metabolism.

Energy Metabolism All metabolic processes in cells either produce energy (exergonic reactions) or use energy (endergonic reactions). The energy required for the operation of all biologic processes in mammalian cells is derived from the inherent energy present in the structure of organic molecules (41). The chemical energy produced by the processing of these organic molecules is transferred to the phosphate bonds of purine nucleotides and other molecules with phosphate bonds such as phosphagens. As noted in Table 11, the hydrolysis of the phosphate bonds of adenosine triphosphate (ATP) or its precursors releases a considerable amount of energy that can be used to drive other biologic processes. The formation of these compounds with high-energy phosphate (HEP) group transfer potential is usually a result of the transfer of reducing equivalents from the substrate by reduction of nicotinamide adenine dinucleotide (oxidized form) (NADþ), flavoproteins, and other coenzymes followed by coupled oxidative phosphorylation of adenosine diphosphate (ADP) in the mitochondria (42). Although ATP serves as a carrier of chemical energy in all living cells, it is not a reservoir of energy (41). The intracellular concentrations of ATP are small, highly regulated, and rapidly depleted. Reservoirs of energy (phosphagens), such as phosphocreatine, do exist in some cells (41). These reservoirs accept HEP bonds when the intracellular concentration of ATP is high and transfer a phosphate group to ADP nucleotides when the availability of ATP is low (41). The intracellular concentrations of adenine nucleotides also provide the cell with a sensitive control mechanism for regulating energy-producing and energy-using processes in cells. Atkinson (43) has introduced the concept of energy charge to explain this regulatory mechanism. Adenylate energy charge (EC) represents the balance between energyusing processes and energy-producing processes. It is defined by the equation: EC ¼ ðATP þ 0:5ADPÞ=ðATP þ ADP þ AMPÞ A normal energy charge signals that energy-producing processes and energy-using processes are in balance. If the 0

Table 11 Energy Released (Go ) During Hydrolysis of High-Energy Phosphate Compounds 0

Reaction

Go (J/mol)

ATP þ H2O ! ADP þ Pi ADP þ H2O ! AMP þ Pi ATP þ H2O ! AMP þ PPi PPi þ H2O ! 2Pi AMP þ H2O ! A þ Pi

36,800 36,000 40,600 31,800 12,600

Abbreviations: A, adenine; ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate; PPi, inorganic pyrophosphate. Source: From Ref. 41.

9

energy charge is increased, energy-producing processes are exceeding energy-using processes, and a resultant reduction of energy-producing processes occurs. If the energy charge is decreased, energy-using processes are exceeding energyproducing processes, resulting in a decrease in energy-using processes that may jeopardize cell survival. The major energy-producing processes include the catabolism of carbohydrates, proteins, and lipids. Each of these substrate groups can provide part of the energy present in their structure through cytoplasmic catabolic reactions (e.g., glycolysis). The remainder of the available energy present in these substrates is released during oxidation of the remaining carbon fragments in the intramitochondrial tricarboxylic acid (TCA) cycle. The final common pathway into the TCA cycle for carbohydrates, proteins, and lipids is through the formation of acetyl coenzyme A(CoA) (Figs.6–8). Foreachmolecule ofacetylCoA completely oxidized in the TCA cycle, two molecules of carbon dioxide, three molecules of nicotinamide adenine dinucleotide (reduced form) (NADH), one molecule of flavin adenine dinucleotide (FADH), and one molecule of guanosine triphosphate (GTP) are produced. In total, 12 HEPs are formed primarily by way of transfer of the reducing equivalents from NADH and FADH to oxygen in the electron transport system with the subsequent phosphorylation of ADP linked to this oxidative process (oxidative phosphorylation). Unlike carbohydrates and lipids, amino acids may directly enter the TCA cycle at one of the intermediate reactions (Fig. 6).

Carbohydrate Metabolism In the cytoplasm of all cells, one molecule of glucose is catabolized to pyruvate through the Embden–Meyerhof pathway to yield two molecules of pyruvate, two molecules of ATP, and one molecule of NADH (Fig. 7). The completion of glycolysis (i.e., glucose to lactate) uses one molecule of NADH in the conversion of pyruvate to lactate. Conversely, the conversion of pyruvate to acetyl-CoA produces one molecule of NADH. Because the oxidation of acetyl-CoA in the TCA cycle produces 15 HEPs, the complete oxidation of one molecule of glucose to carbon dioxide and water produces 26 HEPs [(2 12) þ 2] and four molecules of NADH. The latter molecules produce 12 HEPs (three HEPs per molecule of NADH) through coupled oxidative phosphorylation. Consequently, the total energy produced in the complete oxidation of one molecule of glucose to carbon dioxide and water is equivalent to 38 HEPs. This result is in contrast to glycolysis where only two HEPs are produced in the conversion of glucose to lactate. As noted in Fig. 7, there are two nonreversible reactions in glycolysis: (i) the conversion of glucose to glucose 6-phosphate, catalyzed by hexokinase, and (ii) the conversion of phosphoenolpyruvate to pyruvate, catalyzed by pyruvate kinase. These reactions are irreversible because they lose a considerable amount of energy as heat. It is the presence of these two nonreversible reactions that drives glucose to pyruvate. In addition, phosphofructokinase (PFK) and pyruvate kinase act as the major regulators of glycolysis (45). Once the catabolism of glucose has begun, it rapidly proceeds to pyruvate. Under aerobic conditions, most tissues oxidatively decarboxylate pyruvate to acetyl-CoA and then oxidize the acetyl-CoA in the TCA cycle. Under an anaerobic condition, pyruvate cannot be decarboxylated, and it is converted instead to lactate. As a result, elevated tissue and plasma concentrations of lactate (and pyruvate) are characteristic of ischemia and anoxia. Some tissues with a paucity of mitochondria, such as erythrocytes and leukocytes, are capable of glycolysis only. These cells lack

medwedi.ru

10

Part One: General Considerations

Protein Glycogen

Proteolysis

Glucose Lactate

Glycolysis Pyruvate

Beta-oxidation

Fatty acyl-CoA

Phenylalanine Tyrosine Leucine Lysine Tryptophan

Cystine Glycine Alanine Serine Threonine

Fatty acid

Acetoacetyl-CoA

Acetyl-CoA

Cholesterol Oxaloacetate Malate Fumarate Succinate

Citrate

TCA cycle (15 ATP/TURN)

Ketone bodies

Isocitrate Alpha-ketoglutarate

Succinyl-CoA Glutamate

Phenylalanine Tyrosine

Isoleucine Methionine Valine

Aspartate Asparagine

the ability to oxidize pyruvate and acetyl-CoA even under aerobic conditions. Therefore they derive all their energy from conversion of glucose to pyruvate and lactate. Carbohydrates other than glucose can also be metabolized through glycolysis. For example, fructose, galactose, mannose, and triose sugars can enter glycolysis after modification by endergonic reactions. Similarly, pentose sugars may also enter the glycolytic pathway. As noted earlier, the total carbohydrate stores of the human body are limited and are rapidly depleted (31). In addition, RBCs, WBCs, and the brain are glucose-dependent tissues that are unable to use nonglucose energy substrates. Thus glucose must be made continuously available. The synthesis of glucose through a process called gluconeogenesis can proceed from lactate, pyruvate, and amino acids. Gluconeogenesis is not simply the reversal of glycolysis, because the unidirectional reactions make glycolysis irreversible. However, gluconeogenic tissues, such as the liver and the kidney, contain four enzymes that essentially allow glycolysis to proceed in reverse fashion from pyruvate (and lactate) to glucose (Fig. 8). The first of these enzymes, pyruvate carboxylase, in the presence of ATP, carbon dioxide, and biotin, converts pyruvate to oxaloacetate in the mitochondria. [Although it does not act as a cofactor, acetyl-CoA must be present in excess for this reaction to proceed (46).] Oxaloacetate is then converted to phosphoenolpyruvate by the cytoplasmic enzyme phosphoenolpyruvate carboxylase and GTP. Because the oxaloacetate is found in the mitochondria and phosphoenolpyruvate carboxylase in the cytoplasm, oxaloacetate must cross the mitochondrial membranes into the cytoplasm. However, because the mitochondrial membranes are relatively impermeable to oxaloacetate, it is thought that oxaloacetate leaves the mitochondria as either malate or aspartate, which

Arginine Histidine Glutamine Proline

Figure 6 Pathways for production and use of acetyl-CoA. Abbreviations: TCA, tricarboxylic acid; CoA, coenzyme A. Source: From Ref. 44.

can be transported through the mitochondrial membranes and then reconverted to oxaloacetate in the cytoplasm (47). Once phosphoenolpyruvate is formed, glycolysis can easily proceed in reverse fashion to fructose-1,6-biphosphatase. The enzyme fructose-1,6-bisphosphatase is required to form fructose 6-phosphate. This enzyme is present in the liver and kidney and to a lesser extent in skeletal muscle. However, it is not present in adipose tissue, smooth muscle, or cardiac muscle (48). Fructose 6-phosphate can then proceed to glucose 6-phosphate by the reversible glycolytic reaction catalyzed by glucose phosphate isomerase, but the conversion of glucose 6-phosphate to glucose requires the last of the gluconeogenic enzymes, glucose 6-phosphatase. This enzyme is present in the liver and kidney but not in skeletal, smooth, or cardiac muscle. Any glucose 6-phosphate that might be formed in skeletal muscle must be converted to glycogen, be used in glycolysis, or be used in the hexose monophosphate shunt, because skeletal muscle cannot release free glucose as a result of the absence of glucose 6-phosphatase. The glucose 6-phosphate formed in the liver and kidney can be converted to glucose and released into the circulation. Because there is a constant production of lactate and pyruvate in aerobic glycolytic tissues, in all tissues during anaerobic conditions, and from the reticuloendothelial system during sepsis and locally inflamed tissues, a constant source of lactate and pyruvate is available to gluconeogenic tissues such as the liver and kidney. In the liver and kidney, these substrates can be converted back to glucose and released into the circulation. The newly formed glucose is then available to glucose-dependent tissues for reconversion to lactate in the so-called Cori cycle (Fig. 9). However, it should be noted that this reconversion does not result in a net increase in glucose carbon, because lactate is itself derived from glucose (49).

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

Glycogen

11

Pyruvate + CO2 ATP Pyruvate carboxylase ADP

Glucose 1-phosphate

Oxaloacetate

ATP ADP

GTP Glucose

Glucose 6-phosphate Hexokinase

Phosphoenolpyruvate carboxylase

GDP

Glucose phosphate isomerase

Phosphoenolpyruvate

Fructose 6-phosphate ATP Phosphofructokinase

ADP

Fructose 1,6-diphosphate

Glyceraldehyde 3-phosphate NAD

Pi

NADH

Triose phosphate

Triose phosphate isomerase Dihydroxyacetone phosphate

Phosphoglycerate kinase Phosphoglyceromutase Enolase

ADP

Lactate dehydrogenase

Phosphoenolpyruvate ATP Pyruvate kinase ADP

Lactate

Pi Fructose 1,6-bisphosphate

Glyceraldehyde phosphate dehydrogenase

3 phospho-glycerol phosphate ATP

H 2O

Fructose-bisphosphatase Fructose 6-phosphate H2O Pi Glucose 6-phosphatate Glucose 6-phosphatase

Pyruvate NAD Pyruvate dehydrogenase

NADH NAD NADH

Glucose

TCA cycle

Figure 8 Gluconeogenic pathway in the liver and the kidney. Source: From Ref. 44.

CO2

Figure 7 Catabolism of glucose and major carbohydrate precursors. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; NAD, nicotinamide adenine dinucleotide; NADH, reduced form of NAD; Pi, inorganic phosphate; TCA, tricarboxylic acid. Source: From Ref. 44.

Protein and Amino Acid Metabolism Energy and glucose can also be derived from the metabolism of amino acids. Although the partial catabolism and transformation of all a-amino acids to their a-keto acid derivatives can occur in most tissues, the complete oxidation of a-amino acids to urea and carbon dioxide occurs primarily in the liver and secondarily in the kidney (50). In general, the catabolism of all amino acids (except lysine) involves the removal of the a-amino acid group from the carbon skeleton to form ammonia and an a-keto acid. This is followed by the conversion of ammonia to urea and by the conversion of the a-keto acids to TCA-cycle intermediates or precursors (51,52). Removal of the a-amino group can occur by one of three processes: (i) transamination, (ii) oxidative deamination, and (iii) nonoxidative deamination (47,48). The most common mechanism is transamination. Transaminases (aminotransferases) interconvert a pair of amino acids and a pair of a-keto acids (Fig. 10). This process requires the presence of pyridoxal phosphate (vitamin B6) for the transfer of the amino group. These reactions are freely reversible and function both in synthesis and in catabolism. At least 12 of the amino acids undergo transaminations, including the branched-chain amino acids, valine, leucine, and

isoleucine. The most notable transaminases are glutamineoxaloacetic transaminase (or aspartate transaminase) and glutamic-pyruvic transaminase (or alanine transaminase). Through the collective action of all the transaminases, the a-amino groups are usually collected in the form of glutamate or alanine. Because a-ketoglutarate can accept the a-amino group of all the amino acids that are transaminated, including alanine, it serves as the final common amino group acceptor to form glutamate. Mallette et al. (53) have proposed and Felig (54) has expanded the concept of an alanine–glucose cycle similar to the Cori cycle (Fig. 9). In peripheral tissues, amino acids are transaminated with pyruvate to form alanine and an a-keto acid. The alanine is then transported to the liver, where it is transaminated with a-ketoglutarate to form pyruvate and glutamate. The pyruvate can then be converted back to glucose and released into the circulation, where it may be taken up by peripheral tissues and converted to pyruvate and lactate. The oxidative deamination of glutamate by glutamate dehydrogenase is an important mechanism in the liver for the removal of the amino group (Fig. 10). Because a-ketoglutarate is the common acceptor for all transaminases, substantial amounts of glutamate are formed. Consequently, the oxidative deamination of glutamine allows for the regeneration of a-ketoglutarate and the removal of free ammonia. Oxidative deamination of other amino acids is also possible through the action of a-amino

medwedi.ru

12

Part One: General Considerations

Figure 9 Glucose–lactate (Cori) cycle and glucose–alanine cycle. Source: From Ref. 1.

acid oxidases that are present in the liver and kidney. However, with the exception of glutamate dehydrogenase, these enzymes do not appear to exert a major physiologic role in humans (50,52). Three amino acids, serine, threonine, and histidine, are primarily deaminated nonoxidatively (Fig. 10) (47). The former two amino acids undergo nonoxidative deamination by dehydration, whereas histidine undergoes direct deamination. The non–a-amino groups of glutamine and asparagine are removed by hydrolytic deamination (47). Free ammonia, even in small concentrations, is poorly tolerated by cells. Four mechanisms exist to handle the free

OXIDATIVE DEAMINATION Alpha-amino acid

Amino acid oxidase [Alpha-imino acid]

Flavin Flavin

H2O

H2

Alpha-Keto acid

ammonia produced by oxidative or nonoxidative deamination, thereby keeping the intracellular (and extracellular) concentration of this substance low. Free ammonia can be added to glutamate by glutamine synthetase to form glutamine. This is the primary mechanism for the elimination of ammonia in brain cells and muscle cells. The free ammonia may also be added to a-ketoglutarate, forming glutamate in the freely reversible reaction catalyzed by glutamate dehydrogenase. The resulting glutamate may be used as an amino acid in protein, as a precursor in arginine and citrulline syntheses, or as an a-amino group donor in transaminase reactions. A third mechanism for ammonia elimination is through its excretion by the kidney. Two-thirds of the ammonia excreted by the kidney is derived from the amide nitrogen of glutamine from renal arterial blood and one-third from the a-amino nitrogen of renal arterial amino acids (55). Although these three mechanisms remove a substantial amount of the ammonia formed, most of it is cleared by the liver, after which it enters into the urea cycle (Krebs– Henseleit cycle) (50). As noted in Figure 11, the urea cycle essentially involves the cleavage of a molecule of urea from arginine. The ammonia is first combined with carbon dioxide in the presence of ATP to form carbamylphosphate. Carbamylphosphate then condenses with ornithine to form citrulline, which, through a series of reactions, forms arginine. The arginine is then cleaved into urea and ornithine, thereby reestablishing the cycle. The net energy cost of this cycle is four HEPs, derived from three molecules of ATP. Atkinson and Bourke (56) have suggested an important role for ureagenesis in the maintenance of pH homeostasis. Because the oxidation of amino acids yields both bicarbonate and ammonium ions, the urea cycle promotes the neutralization of the bicarbonate ion by the proton of the ammonium ion during the formation of carbonyl phosphate. The remaining carbon skeletons of amino acid deamination or transamination are converted either to intermediates of the TCA cycle or to precursors of acetyl-CoA, such as pyruvate and acetoacetate. Consequently, all the carbon skeletons of amino acids can be oxidized in the TCA cycle to carbon dioxide and water. The carbon skeletons of all the amino acids may also be converted to glucose or fat. As such, they may be classified as glucogenic, ketogenic, or glucogenic and ketogenic (Table 12). Seven (alanine, serine, glycine, cysteine, cystine, proline, and hydroxyproline) of the 22 most common amino

NH3

NONOXIDATIVE DEAMINATION BY DEHYDRATION H2 O Amino acid oxidase Serine [Intermediates] Pyruvate H 2O

NH3

Pi Citrulline

2 ADP+Pi

DIRECT NONOXIDATIVE DEAMINATION Histidase Serine

CO2+NH4 ATP

[Histidine-enzyme]

Pyruvate

Aspartate ATP

Carbamyl phosphate

AMP+PPi Ornithine

UREA CYCLE

Argininosuccinate

NH3 HYDROLYTIC DEAMINATION OF NONALPHA AMINO GROUP Arginine

Asparaginase Asparagine

Aspartate

Urea

Fumarate

H2O NH 3

Figure 10 Mechanisms for removal of the amino group. Source: From Ref. 44.

Figure 11 Urea cycle. Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; PPi, inorganic pyrophosphate. Source: From Ref. 44.

Chapter 1:

Table 12 Pathways for the Use of Amino Acid Carbon Fragments Gluconeogenesis Alanine Arginine Aspartic acid Asparagine Cystine Glutamic acid Glycine Histidine Hydroxyproline Methionine Proline Serine Threonine Valine

Ketogenesis Leucine

Gluconeogenesis and ketogenesis Isoleucine Lysine Phenylalanine Tyrosine Tryptophan

acids in proteins are converted to pyruvate. Depending on the redox state of the cell, the pyruvate can either be used for gluconeogenesis or converted to acetyl-CoA. Five amino acid carbon skeletons (phenylalanine, tyrosine, tryptophan, leucine, and lysine) form acetoacetate that may be converted to acetyl-CoA and either oxidized in the TCA cycle or used in fatty acid–synthesis. In addition, in the process of producing acetoacetate, phenylalanine and tyrosine are also cleaved to fumarate, and tryptophan is cleaved to alanine. Thus, phenylalanine, tyrosine and tryptophan may be used both in glucogenesis and in ketogenesis. Lysine may also be used both in glucogenesis and ketogenesis, but its precursor for gluconeogenesis is not known. In contrast, leucine forms one molecule of acetyl-CoA and one molecule of acetoacetate. Because neither acetyl-CoA nor acetoacetate can be converted to pyruvate, the carbon skeleton of leucine can only be used for ketogenesis or oxidation.

Metabolic Response to Starvation, Stress, and Sepsis

13

It should be apparent that any compound that enters the TCA cycle as acetyl-CoA cannot be used as a precursor of glucose. This relates to the fact that by the time it reaches malate, the acetyl-CoA that entered the TCA cycle has been completely oxidized. However, the carbon skeletons of amino acids that are TCA-cycle intermediates can be used for gluconeogenesis. In addition to phenylalanine and tyrosine, which enter the TCA cycle as fumarate, three amino acids enter as succinyl-CoA (isoleucine, methionine, and valine), and two other amino acids enter as oxaloacetate (aspartate and asparagine) and give amino acids that enter as a-ketoglutarate (glutamate, glutamine, proline, histidine, and arginine) (Fig. 12). Consequently, all these amino acids may be used either in gluconeogenesis or in oxidation. Quantitatively, in the isolated perfused liver, only alanine, serine, threonine, and glycine are used in significant amounts for gluconeogenesis (57). As noted previously, excess nitrogen cannot be stored. When the protein intake is excessive, the amino acids resulting from proteolysis are catabolized to nitrogen and a carbon skeleton. The nitrogen is converted to urea, and the carbon skeleton is converted to glucose, lipid, or carbon dioxide, depending on the needs of the cell and the redox state present. Similarly, when glucose is needed but unavailable, excess ingested proteins or existing body proteins are degraded. Although it may be imperceptible, the use of existing body protein for energy or gluconeogenesis always results in the loss of some cellular function.

Lipid Metabolism The final and greatest source of energy in the body is lipid. Stored in adipose tissues as triglycerides, lipids can be released on demand and transported to most tissues for use as an energy source. Tissues capable of using lipids include the liver, kidney, heart, and skeletal muscle; such use,

Figure 12 Pathways through which the carbon skeletons of a-amino acids enter the tricarboxylic acid cycle.

medwedi.ru

14

Part One: General Considerations

however, must occur under aerobic conditions. Non–lipidusing tissues include erythrocytes, leukocytes, and nerve cells. Triglycerides are composed of three fatty acid–chains linked together by a glycerol molecule. During lipolysis, the fatty acids are sequentially cleaved off the glycerol moiety by lipases. The remaining glycerol moiety can then be used for glucose synthesis or converted to pyruvate (Fig. 7). In contrast, fatty acids themselves cannot be used as substrate for gluconeogenesis, because they are ultimately broken down to acetyl-CoA. The catabolism of fatty acids can be divided into two stages. These stages include b-oxidation in the outer mitochondrial membrane to produce molecules of acetyl-CoA, and the processing of acetyl-CoA in the mitochondria to produce carbon dioxide and energy or ketone bodies (Fig. 13) (58,59). Only the first step in fatty acid–catabolism requires energy. In this step, the enzyme thiokinase adds CoA to a fatty acid, producing a fatty acetyl-CoA (Fig. 13). After a sequence of reactions, the final two carbons on the fatty acetyl-CoA are cleaved, resulting in the production of one molecule of acetyl-CoA and a new fatty acetyl-CoA that is two carbon atoms shorter than the parent fatty acetyl-CoA. This process of b-oxidation yields five HEPs per acetyl-CoA formed and, with even-numbered fatty acid chains, continues until the entire fatty acid has been cleaved to acetyl-CoA. In the case of odd-numbered fatty acid chains, b-oxidation continues until a three-carbon fatty acetyl-CoA (propionyl-CoA) remains. The latter substance may then be converted to succinyl-CoA and enter the TCA cycle. The acetyl-CoA that results from the oxidation of fatty acids can be used in one of the three available pathways (Fig. 13) (58,60). The first involves the intramitochondrial oxidation of acetyl-CoA through the TCA cycle to two molecules of carbon dioxide and 12 HEPs. Thus the total

oxidation of a 20-carbon fatty acid, for example, yields: 169 HEPs ¼ ½ð10 5Þ þ ð10 12Þ 1 The second pathway involves the ketogenic pathway in the liver (Fig. 14). Through the action of the enzyme thiolase, two molecules of acetyl-CoA combine to form acetoacetyl-CoA in a freely reversible reaction. AcetoacetylCoA can then be converted to 3-hydroxy-3-methylglutaryl CoA, the precursor in cholesterol synthesis and ketone body formation. The three ketone bodies, acetoacetate, b-hydroxybutyrate, and acetone, are normally produced and released by the liver. Under conditions in which there is an abundance of hepatic glycogen, b-hydroxybutyrate predominates; under conditions in which the liver glycogen is low, acetoacetate predominates. The ketone bodies that are released by the liver can then be used by a variety of peripheral tissues, such as cardiac and skeletal muscle, as a source of energy by conversion back to acetyl-CoA. The final pathway for use of acetyl-CoA is in the synthesis of fatty acids and triglycerides (Fig. 13). This pathway is stimulated by neuroendocrine mechanisms and low cytoplasmic concentrations of fatty acids. Lipogenesis is a cytoplasmic process that requires malonyl-CoA. MalonylCoA is formed from acetyl-CoA by acetyl-CoA carboxylase. When fatty acid–levels are low, the rate-limiting enzyme in malonyl-CoA formation, acetyl-CoA carboxylase, is stimulated, leading to increased intracellular concentrations of malonyl-CoA (61). In turn, the elevated concentration of malonyl-CoA inhibits carnitine acetyl transferase, the enzyme necessary for transport of acetyl-CoA into the mitochondria (62), resulting in an increased concentration of cytoplasmic acetyl-CoA that can then be used for malonyl-CoA synthesis and ultimately for the synthesis of triglycerides and other lipids. In contrast, when the intracellular concentrations of

Figure 13 Metabolic pathways of fatty acid metabolism in the liver. Abbreviations: GAA, gossypol acetic acid; TCA, tricarboxylic acid. Source: From Ref. 1.

Chapter 1:

Acetyl-CoA Thiolase CoA

SH

Acetoacetyl-CoA H 2O HMG-CoA synthetase

Acetyl-CoA CoA

SH

3-Hydroxy-3-methylglutaryl CoA Acetyl CO2 CoA Acetone

HMG-CoA lyase

Acetoacetate

Beta-hydroxybutyrate dehydrogenase

Steroids

Cholesterol NADH NAD+

Beta-hydroxybutyrate

Bile salts

Cholesterol esters

Figure 14 Ketogenic pathway and cholesterol pathway in the liver. Abbreviations: CoA, coenzyme A; HMG, 3-hydroxy-3-methylglutaryl; NADH, reduced nicotinamide adenine dinucleotide. Source: From Ref. 44.

fatty acids are elevated, the rate-limiting enzyme in malonylCoA synthesis (acetyl-CoA carboxylase) is inhibited. Malonyl-CoA concentrations decrease, thereby stimulating carnitine acetyl transferase and increasing the transport of acetyl-CoA into the mitochondria for oxidation and ketogenesis (62). The inhibition of acetyl-CoA carboxylase also results in the accumulation of cytoplasmic citrate that in turn inhibits glycolysis through inhibition of PFK, the so-called Randle effect (45).

NEUROENDOCRINE REGULATORY MECHANISMS Stimuli and Mechanism of Action of the Neuroendocrine System The pathways of intermediary metabolism and substrateto-substrate interactions noted previously are under the local control of substrate availability, cellular redox potential, and cellular energy availability. The integration of this control is governed by the neuroendocrine system. This system may be thought of as a reflex physiologic network in which alterations in homeostasis are perceived by specialized receptors that are located both peripherally and centrally. The receptors

Metabolic Response to Starvation, Stress, and Sepsis

15

transmit their information to the central nervous system (CNS), where the afferent signals are processed and modulated, resulting in release or inhibition of numerous neuroendocrine effectors that produce physiologic changes aimed at correcting the alterations in homeostasis. In the absence of significant injury, sepsis, or starvation, alterations in homeostasis are small, and the responses of the neuroendocrine system to stimuli are directed at fine tuning and integrating the functioning of the organism. In the presence of significant injury, sepsis, or starvation, the stimuli are multiple and intensified, and the reflexes are directed at an integrated attempt by the organism to preserve oxygen delivery, mobilize energy substrates, and minimize pain (Fig. 15) (1). The major stimuli affecting neuroendocrine reflexes include (i) changes in the circulating body fluids; (ii) changes in the oxygen, hydrogen ion, and carbon dioxide concentrations in tissues and blood; (iii) changes in ambient and core temperature; (iv) changes in substrate availability; (v) emotional arousal; (vi) pain; and (vii) infection. Critical to the initiation of the neuroendocrine response is the perception of the stimulus. Paraplegics do not respond to stimuli below the level of cord transection. This lack of response is thought to be the result of the absence of afferent impulses reaching the brain (63). However, conscious perception of the stimulus is not required. An individual responds to a stimulus in the presence of anesthesia, but the response may not be the same as that in the absence of anesthesia. Changes in the circulating body fluids may result from the direct loss of blood (as in hemorrhage), from the loss of plasma volume (as in third-space losses and dehydration), or from the inability of the body fluids to circulate (as in cardiac failure or pulmonary embolism). The changes in circulating body fluids are sensed by high-pressure baroreceptors in the carotid arteries and aorta and by low-pressure stretch receptors in the right atrium. Under normal conditions, the afferent signals from these receptors exert a tonic inhibition of the release of many hormones and of the activities of the CNS and autonomic nervous system (64). When baroreceptor or stretch-receptor activities decrease (e.g., a decrease in blood pressure or blood volume), the tonic inhibition is released, resulting in the increased secretion of adrenocorticotropic hormone (ACTH), vasopressin, b-endorphin, and growth hormone through central pathways and resulting in the increased secretion of epinephrine, norepinephrine, renin, and glucagon through peripheral

Infection Pain

+

Hemorrhage plus ECF loss

Peripheral nerves

Baroreceptors + +

Hypoxemia

+

Fear and anxiety + + + Central _ nervous system +

+ Endocrine glands + + Sympathetic nervous system

Chemoreceptors – + Cardiac stimulation Vascular resistance Fluid shifts + Respiratory stimulation

medwedi.ru

Figure 15 Overview of the neuroendocrine reflexes induced by shock and trauma. Abbreviation: ECF, extracellular fluid. Source: From Ref. 1.

16

Part One: General Considerations

autonomic neural pathways. These responses bring about further neuroendocrine changes such as the inhibition of insulin secretion by epinephrine (65) and the stimulation of aldosterone secretion by renin and ACTH (66). Changes in blood concentrations of oxygen, hydrogen ion, and carbon dioxide initiate neuroendocrine responses through the activation of peripheral chemoreceptors. The chemoreceptors, which are located in the aortic and carotid bodies, have an extremely high–blood flow rate (67). Under normal conditions, these receptors are not activated. However, changes primarily in oxygen and secondarily in carbon dioxide and in hydrogen ions are sensed by these receptors, which result in the activation of neuroendocrine pathways. Because of the high blood flow through the chemoreceptors, the partial pressure of oxygen (PO2) of arterial blood, chemoreceptor tissue, and venous blood is nearly the same. However, a drop in blood flow increases the oxygen extraction by the chemoreceptor tissue, decreases the venous PO2, and through an unknown mechanism, activates the chemoreceptor (67). Consequently, a decrease in circulating volume or pressure not only inhibits baroreceptors and stretch receptors, but also activates chemoreceptors. Pain and emotion also activate the neuroendocrine system. The former acts through the projections of peripheral nociceptive receptors to the CNS, and the latter acts through projections from the limbic areas of the brain to the hypothalamus and lower brain stem nuclei (68). Through these pathways, pain and emotional arousal bring about increased hypothalamic, autonomic, adrenomedullary, and adrenocortical activities, the so-called fight- or-flight reaction of Cannon (69). Abnormalities in core and ambient temperatures, as well as infection, also stimulate neuroendocrine reflexes. Changes in the core temperature of the body are sensed in the preoptic area of the hypothalamus. These changes may result from alterations in ambient temperature, a loss of the normal insulating barrier of the skin (e.g., burns), or a reduction in hepatic thermogenesis produced by inadequate blood flow or substrate supply or in response to inadequate peripheral vasoconstriction or vasodilation. Infection may also decrease the core temperature through the action of endotoxin. Infection may further stimulate neuroendocrine reflexes through a direct action of endotoxin on the hypothalamus (70) or through secondary changes in blood volume, oxygen concentration, substrate concentrations, and pain. The primary substrate alterations that activate the neuroendocrine system are those induced by changes in the plasma glucose concentration. Plasma glucose alterations are sensed by receptors in the hypothalamus and the pancreas. A decrease in plasma glucose concentration stimulates the release of catecholamines, cortisol, growth hormone, and vasopressin through central mechanisms and stimulates the release of glucagon both by central pathways (autonomic nervous system) and peripheral pathways (direct pancreatic activation) (71). In addition, the secretion of insulin is inhibited through central pathways (autonomic nervous system) and directly by the pancreas itself (65). All these stimuli are commonly produced by injury, sepsis, and starvation. Furthermore, these stimuli rarely occur singly. Generally, the individual perceives multiple stimuli that occur both simultaneously and sequentially. Thus the neuroendocrine response is the summation of all the stimuli the individual perceives and processes. According to classic endocrine feedback mechanisms, the

elevation of serum cortisol resulting from one set of stimuli would be expected to inhibit the release of ACTH by a new set of stimuli. Following most injuries, this is not true. The secretion of ACTH is unchanged or increased (potentiated), and the secretion of cortisol may also increase. The mechanism of action of this physiologic facilitation is incompletely understood, but it appears to take 60 to 90 minutes to be of sufficient magnitude to offset the inhibition, and lasts for at least 24 hours (72). Physiologic facilitation and potentiation have been demonstrated with sequential hemorrhages (73) and repeated operations (74), in response to hypoxia and surgery (75), with pain and hemorrhage (20), and with elevated core temperature and hemorrhage (76). Consequently, the response to an injury or an alteration in homeostasis may be modified by previous stimuli, and the response to a second set of stimuli may be different if they had occurred first. The efferent limb of the neuroendocrine system arises from two primary areas, the hypothalamic–pituitary axis and the autonomic regions of the brain stem. The output from the former region involves the release of numerous pituitary hormones, and the output from the latter region involves changes in the neural activities of the sympathetic and parasympathetic nervous systems. Both sets of output either may cause direct changes in physiologic functions or may stimulate or inhibit the secretion of peripheral endocrine organs. The hormones secreted by endocrine organs and the autacoids produced by tissues fall into one of five chemical classes. These include the fatty acid–derivatives of cholesterol (cortisol and aldosterone) or arachidonic acid (prostaglandins), proteins (insulin and glucagon), glycoproteins [thyroid-stimulating hormone (TSH) and corticotropin], small polypeptides (vasopressin and enkephalin), and the amines (catecholamines and serotonin). All these agents act on cellular receptors that are either on the surface of cell membranes or in the cytoplasm of the cell. These cellular receptors are neither fixed nor unchangeable. Instead, they are in a dynamic state in which the number of receptors on cells can be increased (up regulation) or decreased (down regulation) according to need. Furthermore, the affinity of these receptors for their specific hormone can also be changed (77). Steroid hormones (and possibly thyroxine), which are freely permeable to cell membranes, bind to cytosolic receptors in target cells (78,79). The hormone–receptor complex migrates to the cell nuclei, where it interacts with DNA to modulate the transcription of messenger RNA and ultimately the synthesis of enzymatic, structural, and regulatory proteins (Fig. 16A) (78). This may, in part, explain the one- to two-hour delay in the action of steroid hormones. In contrast, the action of most peptide and amine hormones, which generally bind to cell surface receptors, is faster and of shorter duration. In general, these hormones act either through alterations in the intracellular concentrations of cyclic adenosine monophosphate (cAMP) or calcium, the so-called second messengers (81,82), or through other intermediates (growth hormone through somatomedins). The second messenger system of hormonal action operates primarily through the activation and inactivation of regulatory proteins and enzymes rather than through the synthesis of new proteins. This difference explains the faster onset of action and shorter duration of effect of hormones that operate through this system in contrast to those of steroid and other lipid-soluble hormones. The adrenergic receptor system may be considered the prototype for examining the mechanisms of second

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

17

Figure 16 (A) Proposed mechanism of action of steroid hormones. (B) Proposed mechanism of action of peptide hormones through the second messenger system. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; m, molecular; MW, molecular weight. Source: From Refs. 1, 80.

messengers, because all the second messenger pathways known are represented in the four adrenergic receptors (a1, a2, b1, and b2) (Fig. 16B). b1- and b2-receptors (differentiated on the basis of radioligand-binding affinity) both function through the activation of membrane-bound adenylate cyclase, which in turn leads to the production of cAMP (81). The increased intracellular concentration of cAMP activates an inactive protein kinase by attaching to a binding protein on the protein kinase molecule. The attachment of cAMP to the regulatory subunit protein results in the release of an active protein kinase that in turn phosphorylates an inactive phosphorylase kinase to an active form. The active phosphorylase kinase then phosphorylates dephosphoregulatory enzymes, possibly resulting in the activation of the regulatory enzyme (e.g., glycogen phosphorylase) or in its inactivation (e.g., glycogen synthetase) (Fig. 17) (83). In addition, active protein kinase may directly act on dephosphoregulatory enzymes without the activation of phosphorylase kinase. In contrast, a2-receptor activation inhibits membrane-bound adenylate cyclase, thereby decreasing the concentration of cAMP and active protein kinase. Activation of a1-adrenergic receptors results in an increase in phosphatidylinositol turnover that then mediates an increase in intracellular

calcium from intracellular and extracellular sources (81,84). The increase in intracellular calcium activates a calciumbinding protein kinase or phosphorylase kinase (Fig. 16B). The actions of intracellular cAMP and calcium in the coupling of receptor activation with hormonal action (stimulus–response coupling) are not independent. Instead, there is a duality to this system in which the actions of calcium and cAMP are highly interrelated, termed synarchic control by Rasmusen (81). As noted in Fig. 18 and Box 2, there are five basic patterns to the synarchic control of hormone-response coupling through cAMP and calcium. In co-ordinate control, a hormone activates both a calciumactivating receptor and a cAMP-activating receptor, either one of which may produce the response alone. In hierarchal control, separate stimuli activate independently the calcium and cAMP pathways that are both necessary for a given response. In sequential control, the activation of one of the two lines of the system leads to the activation of the other limb. Although the first limb can produce the response, activation of the second limb augments the response. In redundant control, two separate stimuli independently activate the two different limbs of the messenger system, either one of which can produce the response. Finally, in

medwedi.ru

18

Part One: General Considerations

Box 2 Calcium–Cyclic AMP Interactions in Stimulus-Response Coupling

Figure 17 Activation of protein kinase leading to enzymatic or physiologic response. Activation of the dephosphoenzyme by phosphorylation may be brought about either directly by the active protein kinase or indirectly through the activation of a phosphorylase kinase by the active protein kinase. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate. Source: From Ref. 80.

antagonist control, one stimulus activates one limb of the messenger system that leads to the response, and a second stimulus activates the second limb, which inhibits the ability of the first limb to produce the response. Although each of these control mechanisms can occasionally be found in cells in pure form, most of the presently known hormone– response coupling mechanisms involve mixed patterns (81).

1. Effects of calcium on cAMP messenger systems a. Stimulates cAMP production—brain, adrenal cortex, pancreatic islets, adrenal medulla, slime mold b. Stimulates cAMP hydrolysis—brain, heart, liver, kidney, fly salivary gland, many other tissues c. Activates phosphoprotein product of cAMP-dependent protein kinase, glycogenolysis in many tissues 2. Effects of cAMP on calcium messenger system a. Increases calcium entry across plasma membrane—heart, synapse b. Increases calcium release from mitochondria—kidney, liver, fly salivary gland, others c. Increases calcium uptake by microsomes—heart, uterus, liver, smooth muscles d. Increases calcium efflux across plasma membrane—smooth muscle, heart e. Decreases sensitivity of response elements to calcium—smooth muscle, heart f. Increases sensitivity of response element to calcium—phosphorylase beta kinase, liver, muscle 3. Interrelated activities a. cAMP-dependent and calcium-dependent protein kinases act upon same protein substrate—liver, brain, adrenal cortex b. Regulate sequential steps in metabolic or transport process—secretion in fly salivary gland, glycogenolysis Abbreviation: cAMP, cyclic adenosine monophosphate. Source: From Ref. 81.

Hormonal Regulation of Metabolism The neuroendocrine system is able to regulate metabolic reactions through three basic processes. First, it may increase substrate availability so that by simple stoichiometry (mass action), reactions proceed in a desired direction. This process can be brought about either by an increase in the plasma

COORDINATE CONTROL ++

R1

Ca

R2

cAMP

Response

H

HIERARCHICAL CONTROL H1

R1

++

Ca

+

Response

SEQUENTIAL CONTROL H

R

Ca

H2

R2

++

Response

+

cAMP

cAMP H

cAMP

R +

Ca

REDUNDANT CONTROL H1

R1

++

Ca

Response

++

ANTAGONISTIC CONTROL ++

H1

R1

Ca

H2

R2

cAMP

–

Response

Response H2

R2

cAMP

Figure 18 Patterns of synarchic regulation by calcium and cyclic adenosine monophosphate. Source: From Ref. 81.

concentration of a substrate or by alterations in blood flow and its distribution. Second, the neuroendocrine effectors can alter the membrane transport properties of cells for a given substrate so that more or less of the substrate enters or leaves the cell. Third, the neuroendocrine effectors can alter the activity or synthesis of key regulatory enzymes that are necessary for reactions to proceed. Most hormones operate through more than one of these processes. For example, insulin stimulates both glycogen synthetase and the transport of glucose into cells. In this manner, insulin not only activates the enzymatic mechanisms necessary for glycogenesis, but also increases the availability of the necessary substrates. It would be futile for a hormone to stimulate opposing processes in a given cell. If a hormone stimulated both glycogenesis and glycogenolysis, there would be no net effect. As a result, most hormones not only activate the enzymes necessary for one metabolic pathway, they also inhibit the enzymes necessary for the opposing process. Thus epinephrine, through an a-mechanism, activates glycogen phosphorylase and inactivates glycogen synthetase, whereas insulin inactivates glycogen phosphorylase and activates glycogen synthetase. The coordinated control of metabolism also requires that a hormone not have opposing actions in different tissues. Thus by increasing amino acid uptake in skeletal muscle and decreasing amino acid degradation in the liver, insulin promotes the availability of an abundant substrate supply for the enzymes of protein synthesis it activates. Cortisol produces an inhibition of amino acid uptake in skeletal muscle, increases amino acid uptake by the liver, and stimulates hepatic gluconeogenic enzymes. These processes ensure that an abundant supply of amino acids is available to the liver for cortisol-stimulated gluconeogenesis.

Chapter 1:

The primary hormones involved in the regulation of metabolism include insulin, cortisol, epinephrine, glucagon, growth hormone, vasopressin, and somatostatin. Insulin is the primary anabolic hormone promoting the synthesis of glycogen, proteins, and lipids. Cortisol, epinephrine, glucagon, and vasopressin are the primary catabolic hormones promoting the breakdown of glycogen, proteins, and lipids and the synthesis of glucose from gluconeogenic amino acids, lactate, and pyruvate. In contrast, the actions of growth hormone initially are anabolic, but its late effects are primarily catabolic.

Insulin, Glucagon, and Somatostatin Insulin, composed of two polypeptide chains, one containing 21 amino acids and the other 30 amino acids, and glucagon, a 29–amino acid polypeptide, are produced and secreted by the pancreatic B cells (beta islets of Langerhans) and A cells (alpha islets of Langerhans), respectively. The secretion of both of these hormones is under the control of at least three mechanisms: (i) circulating substrates (glucose, amino acids, and free fatty acids); (ii) the autonomic nervous system; and (iii) other circulating hormones. Under normal physiologic conditions, glucose is the most important regulator of insulin and glucagon secretion. When the plasma concentration of glucose increases, the secretion of insulin increases, and the secretion of glucagon decreases. When the plasma concentration ofglucosedecreases, the secretion of insulin decreases, and the secretion of glucagon increases. These changes are probably the result of a direct action of glucose on pancreatic islet cells and not a result of neuroendocrine modulation of the pancreas by other neuroendocrine effectors (85). The direct action of glucose on islet cell function may be mediated either through a glucoreceptor on the surface of the islet cell or through the intracellular metabolism of glucose in the islet cells (86). Elevations in the plasma concentration of amino acids stimulate the release of both insulin and glucagon. Most, if not all, of the amino acids increase insulin secretion, but the potency of amino acids in stimulating glucagon secretion is variable (87). In general, more gluconeogenic amino acids appear to stimulate glucagon secretion (87). High concentrations of fatty acids stimulate the secretion of insulin and inhibit the secretion of glucagon. Conversely, low concentrations of free fatty acids inhibit the secretion of insulin and stimulate the secretion of glucagon. The potency of fatty acids in regulating insulin and glucagon secretion is substantially less than that of glucose (87). The stimulation of insulin secretion and the inhibition of glucagon secretion after the administration of an oral glucose load are greater than that following the intravenous administration of glucose (88). Similarly, the stimulation of both insulin and glucagon secretion is greater after an oral protein or amino acid load than it is after the intravenous administration of amino acids and protein (89). This effect is thought to be the result of the higher concentrations of substrate in the pancreas, the potentiation by gastrointestinal hormones of the substrate effect on the pancreas, and the effect of neural input to the pancreas that has been stimulated by eating (87). The gastrointestinal hormones, cholecystokinin, gastrin, vasoactive intestinal peptide, substance P, neurotensin, and gastric inhibitory peptide (GIP), increase the secretion of both insulin and glucagon in pharmacologic concentrations (87,90). Although gastrin does appear to potentiate the release of glucagon and insulin induced by amino acids and GIP in physiologic concentrations and

Metabolic Response to Starvation, Stress, and Sepsis

19

appears to augment the release of insulin by glucose (87), and the physiologic role of gastrointestinal hormones is not certain. The pancreatic A cells and B cells both have a- and b-adrenergic receptors that alter the secretion of insulin and glucagon. a-Adrenergic stimulation of the pancreas inhibits the secretion of both insulin and glucagon, whereas b-adrenergic stimulation of the pancreas stimulates the secretion of both insulin and glucagon (91,92). However, the a- and b-adrenergic receptor density of A cells and B cells is not the same. The b-adrenergic receptor density of A cells is greater than that of B cells (92). As a result, increased sympathetic stimulation of the pancreas or increased circulating concentrations of epinephrine or norepinephrine increase the secretion of glucagon but decrease the secretion of insulin (91,92). In contrast, isoproterenol infusion increases the secretion of both insulin and glucagon (92). In addition to sympathetic stimulation, the parasympathetic limb of the autonomic nervous system alters pancreatic hormone secretion. Both acetylcholine infusion and direct parasympathetic stimulation of the pancreas increase the secretion of both insulin and glucagon (87). In addition to the gastrointestinal hormones and the autonomic nervous system, other hormones alter the secretion of insulin and glucagon. b-Endorphin appears to directly increase the secretion of insulin and glucagon (93), insulin inhibits the release of insulin and stimulates the release of glucagon (87), and glucagon inhibits the release of glucagon and stimulates the release of insulin (87,94). Insulin and glucagon appear to exert their action both directly on islet cells and by the alterations they produce in circulating substrates (87). Cortisol stimulates the release of insulin and glucagon, but it appears to have no direct activity on the secretory ability of A cells and B cells. Instead, cortisol is believed to increase glucagon secretion through an increase in plasma amino acids and to increase insulin secretion by an increase in plasma glucose. In this regard, both cortisol and epinephrine are able to inhibit the peripheral actions of insulin, and both are thought to exert a major role in insulin resistance (95,96). Somatostatin, a tetradecapeptide, is a potent inhibitor of both insulin and glucagon secretion (90,97). In addition to its location in pancreatic D cells, somatostatin is found in the hypothalamus, limbic system, brain stem, spinal cord, other neural tissue, salivary glands, parafollicular thyroid cells, kidneys, and gastrointestinal tissue (90). Although somatostatin was originally named for its ability to inhibit growth hormone secretion, somatostatin is now recognized to inhibit the secretion of TSH, renin, calcitonin, gastrin, secretin, cholecystokinin, insulin, and glucagon (90). In addition, somatostatinergic nerve fibers are involved in the projection of impulses from peripheral sensory organs to the neuroaxis (90). The role somatostatin exerts in the physiologic regulation of insulin and glucagon secretion is not known precisely. The A, B, and D cells have somatostatin receptors that, when activated, inhibit the secretion of glucagon, insulin, and somatostatin, respectively. Although the mechanism of action of somatostatin is thought to be mediated primarily by the local diffusion of somatostatin from D cells to A cells and B cells (90,97), current evidence suggests that somatostatin reaching the pancreas through the blood stream may be more important (98). The effects of somatostatin on A cells are transient, but the effects on B cells are persistent (97). This persistence may account for the relative hyperglycemia that occurs in patients with somatostatinomas or after the longterm administration of somatostatin (97).

medwedi.ru

20

Part One: General Considerations

The physiologic actions of glucagon occur primarily in the liver and are mediated through an increase in intracellular cAMP. The activation of glycogen phosphorylase and the inhibition of glycogen synthetase by glucagon promote the breakdown of glycogen to glucose (glycogenolysis) (45). In addition, glucagon stimulates gluconeogenesis through the stimulation of phosphoenolpyruvate carboxykinase, amino acid transport, and amino acid transamination (45,99). The net result is an increase in hepatic production and release of glucose that under basal conditions accounts for 75% of the glucose produced by the liver (100). Glucagon also exerts an important influence over hepatic lipid metabolism. In addition to stimulating lipolysis in adipose tissue and the liver, glucagon inhibits acetyl-CoA carboxylase, the enzyme that converts acetyl-CoA to malonyl-CoA (87). In turn, the reduction in malonyl-CoA produces inhibition of triglyceride synthesis and activation of carnitine acyl transferase. The latter increases fatty acid transfer to the mitochondria and therefore increases the oxidation of acetyl-CoA and ketogenesis (58,87). Peripheral actions of glucagon include the stimulation of lipolysis in adipose tissue, of glycogenolysis in skeletal muscle, and of myocardial contractility (101–103). However, these actions do not appear to be of physiologic significance in human beings (101–103). As a result of glucagon’s ability to increase hepatic glucose production, mobilize fat, and increase ketogenesis, glucagon is important in normal metabolism and more so in the metabolism of altered states. However, the effects of glucagon are evanescent (104). After 30 to 60 minutes, the activity assigned to glucagon decreases even if plasma glucagon concentrations remain elevated. Therefore it appears that an increase in glucagon concentration rather than the absolute amount of glucagon present is a key determinant of glucagon activity (104). This effect also appears to be true of other cAMP-mediated hormones (the burst effect). The physiologic activity of insulin is primarily in the liver, skeletal muscle, and adipose tissue, but insulin does affect many other peripheral tissues. Notable exceptions include erythrocytes and wounded tissue. Insulin promotes the entry of glucose into cells by stimulating the membrane transport of glucose. The increased intracellular concentrations of glucose are used in glycogen synthesis (stimulation of glycogen synthetase and inhibition of glycogen phosphorylase) and in glycolysis (stimulation of glucokinase, PFK, and pyruvate kinase) to produce energy (45). In addition, insulin inhibits gluconeogenesis through the inhibition of phosphoenolpyruvate carboxylase and the stimulation of PFK and pyruvate kinase (45). Insulin also increases the membrane transport of amino acids into the liver and peripheral tissues. The increased intracellular concentrations of amino acids are used in protein synthesis (stimulation of protein synthesis and inhibition of proteolysis). By inhibiting gluconeogenesis and amino acid oxidation, insulin further directs the intracellular amino acids to protein synthesis (99). In adipose tissue, insulin stimulates lipogenesis and inhibits lipolysis, as it does in the liver. By stimulating lipoprotein lipase, insulin also makes triglycerides more available for uptake from the plasma by adipose tissue. Glycerol synthesis and the action of the pentose-phosphate shunt also are increased by insulin in adipose tissue and the liver. Thus insulin is the primary anabolic hormone promoting the storage of lipid, glucose, and protein.

Although insulin and glucagon oppose each other in the metabolic processes each stimulates, a bihormonal response is necessary for maintenance of glucose homeostasis after a protein meal (90). If insulin were secreted alone in response to a protein meal, the increase in protein synthesis and decrease in hepatic glucose production would result in hypoglycemia. Conversely, if glucagon were secreted alone, the decrease in protein synthesis and the increase in hepatic gluconeogenesis would result in hyperglycemia. However, when a rise in glucagon is accompanied by an increase in insulin, hepatic glucose production remains unchanged and euglycemia is maintained. In this regard, Unger (105) has proposed the insulin/glucagon (I/G) ratio as a quantitative measure of hepatic glucose balance. When the I/G ratio is greater than 5, anabolism and protein synthesis are favored. When the I/G ratio is less than 3, glycogenolysis, gluconeogenesis, and lipolysis are favored. However, the validity of this relationship has been questioned (86).

ACTH, Cortisol, and Epinephrine The primary hormones released in response to any physiologic or psychologic stress are the glucocorticoids and catecholamines. These hormones are in large part responsible for the ‘‘fight-or-flight reaction.’’ The release of cortisol is under the control of ACTH, a 39–amino acid polypeptide released from the chromophobe cells in the anterior pituitary gland. In turn, the release of ACTH is itself under the inhibitory influence of cortisol and the stimulatory influence of corticotropin-releasing factor (CRF) produced by the hypothalamus. The release of CRF (and ACTH–cortisol) is stimulated by all the stimuli noted previously and is potentiated by vasopressin, oxytocin, and angiotensin II (106,107). ACTH acts directly on cells of the adrenal zona fasciculata, stimulating the production and release of cortisol through a cAMPmediated conversion of cholesterol to pregnenolone (108). The catecholamines (epinephrine, norepinephrine, and dopamine) are the prototypical neuroendocrine effectors that act as neurotransmitters and hormones (109). Epinephrine, produced almost exclusively by the adrenal medulla, functions primarily as a hormone, whereas norepinephrine and dopamine function primarily as neurotransmitters (109). Although the adrenal medulla may be viewed as a collection of postganglionic sympathetic neurons without axons that release their neurotransmitters into the general circulation, the activation of the sympathetic nervous system does not occur in an all-or-none fashion, and it is not synonymous with adrenomedullary secretion (110). Similarly, adrenomedullary stimulation is not synonymous with the complete activation of the sympathetic nervous system. Numerous stimuli have been identified that lead to increased secretion of catecholamines from the adrenal medulla (e.g., hypotension, hypoxia, hypoglycemia, pain, and fear), but the exact mechanisms involved in adrenomedullary control remain poorly understood (110). Both cortisol and epinephrine function as ‘‘counterregulatory’’ hormones, mediating catabolic processes throughout the body. In the liver, cortisol inhibits several key glycolytic enzymes (glucokinase, PFK, and pyruvate kinase), the pentose-phosphate shunt, and the actions of insulin (45,108). In addition, cortisol stimulates the hepatic uptake of amino acids, transaminases, and several gluconeogenic enzymes (pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase), as well as potentiating the actions of glucagon and epinephrine (45,95,111). As a result, the production of glucose, lactate, and pyruvate by the liver is increased.

Chapter 1:

The metabolic effects of epinephrine are similar to those of glucagon but are more widespread, affecting peripheral tissues and the liver. In the liver, epinephrine stimulates glycogenolysis (a1-mediated stimulation of glycogen phosphorylase and inhibition of glycogen synthetase) (81), lipolysis (b1-mediated activation of triacylglycerol lipase) (112), ketogenesis (b1-mediated inhibition of acetylCoA carboxylase leading to decreased malonyl-CoA and increased carnitine acyl transferase) (68), and gluconeogenesis (b1-mediated inhibition of PFK and hexokinase by the products of glycolysis and glycogenolysis) (113). Thus epinephrine serves to increase hepatic glucose production and lipid breakdown. Although both glucagon and epinephrine increase glucose production by the liver, glucose use by peripheral tissues is not the same in the presence of epinephrine as it is in the presence of glucagon (99). Glucagon promotes the use of glucose by peripheral tissues through the stimulation of insulin secretion. In contract, epinephrine inhibits both the release and the action of insulin, thereby decreasing glucose use in insulin-dependent peripheral tissues. However, epinephrine serves to increase glucose availability to insulin-insensitive tissues such as the brain, whereas glucagon does not shunt glucose to insulininsensitive tissues (99). In adipose tissue, epinephrine increases lipolysis (b-mediated activation of triacylglycerol lipase). In peripheral tissues, epinephrine stimulates glycogenolysis (a1) and inhibits stimulated glucose uptake through a b2- and a1-mechanism (114,115). As a result of increased substrate availability, glycolysis is increased in skeletal muscle, and large amounts of lactate are produced and released into the circulation. The lactate can then be taken up by the liver for subsequent gluconeogenesis (Cori cycle). Therefore during stressful conditions, epinephrine and cortisol both promote a rise in blood glucose and make glucose more available to glucose-dependent tissues. Both of these hormones also promote the breakdown of lipid and thereby its use as a source of fuel. Whereas the actions of epinephrine are direct, many of the actions of cortisol occur as a result of the potentiation or inhibition of other hormones, the so-called permissive action of cortisol.

Growth Hormone and Vasopressin Growth hormone is a 191–amino acid polypeptide that is released from acidophilic cells in the anterior pituitary gland. Its secretion is under the control of a releasing factor (growth hormone–releasing factor) and by an inhibiting factor (somatostatin) (116). Elevation of blood glucose or free fatty acids stimulates the release of growth hormone (116). In addition, the release of growth hormone is stimulated by vasopressin, ACTH, a-melanocyte–stimulating hormone, and estrogen; release of growth hormone is inhibited by cortisol, thyroxine, and growth hormone itself. In addition to its ability to promote protein synthesis and RNA synthesis and to increase linear growth, growth hormone exhibits an important role in the regulation of metabolic processes. Its effects are biphasic, composed of early effects of three to four hours duration and late effects of longer duration (116). In muscle and liver, growth hormone increases amino acid uptake and protein synthesis (117). In addition, growth hormone stimulates glucose uptake in skeletal muscle and antagonizes the lipolytic effects of catecholamines in adipose tissue while increasing protein synthesis (117). Therefore the early effects of growth

Metabolic Response to Starvation, Stress, and Sepsis

21

hormone are similar to insulin. In fact, growth hormone directly stimulates the secretion of insulin by pancreatic B cells during its early phase (66). The late effects of growth hormone include an increased mobilization of fatty acids and ketone bodies by adipose tissue as a result of increased lipolysis. This action of growth hormone occurs only in the presence of cortisol (118). In addition, growth hormone inhibits insulin-stimulated glucose uptake and use, thereby producing a profound stimulation of insulin release by hyperglycemia (66). Arginine vasopressin (antidiuretic hormone) is a nonapeptide that is released by the posterior pituitary gland. Although released primarily in response to an increase in plasma osmolality and to a reduction in effective circulating volume (98,119), vasopressin release is also stimulated by hypoglycemia through nonosmotic pathways (120). Vasopressin is a powerful stimulator of hepatic glycogenolysis (a-receptor) and also stimulates hepatic gluconeogenesis (121,122). As such, it may exert an important role in elevating the blood glucose after injury and during hypoglycemia.

METABOLIC RESPONSE IN STARVATION, INJURY, AND SEPSIS Fasting and Starvation In the absence of food, fasting humans must supply the energy required for daily activities, glucose for glucosedependent tissue, essential amino acids (Table 12), and essential fatty acids from existing body stores. Cahill (29) has estimated that the average resting 70 kg man using 1800 kcal of energy per day requires 180 g of glucose daily—for the metabolism of nervous tissue (144 g) and for other glycolytic tissue (RBCs, WBCs, and the renal medulla) (36 g) (Fig. 19). Because the available glycogen in the liver is only 75 g (Table 13), this amount will not suffice for either the energy requirements or the glucose needs of a fasting man. Although an additional 150 g of glucose is in skeletal muscle as glycogen, as noted previously, it cannot be released from skeletal muscle as free glucose as a result of the absence of glucose 6-phosphatase. Thus, it is apparent that the energy requirements and glucose requirements of fasting human beings must be supplied from noncarbohydrate sources and by gluconeogenesis. The daily energy requirements can be met by the mobilization of approximately 160 g of triglycerides from adipose tissue in the form of free fatty acids (19). The free fatty acids, as well as ketone bodies produced by the liver, are used throughout the body by nonglycolytic tissues such as the heart, kidney, muscle, and liver. In the liver, energy derived from b-oxidation of fat and from oxidation of acetyl-CoA is used to drive the necessary gluconeogenic processes. Gluconeogenic substrates are available from three sources (Table 14). First, the lipolysis of 160 g of triglycerides releases 16 g of glycerol that can be converted by the liver to glucose. Second, some glucose-dependent tissues (i.e., RBCs and WBCs) convert glucose to lactate and pyruvate that may then be reused in the liver by the Cori cycle to produce new glucose. In addition to the 36 g of lactate and pyruvate produced in this manner, skeletal muscle can also release lactate and pyruvate by the breakdown of glycogen and glucose. Third, approximately 75 g of skeletal muscle protein is degraded daily during starvation, and the resulting amino acids are used in the liver for gluconeogenesis. Consequently, the energy required during brief fasting is derived primarily from adipose tissue. In contrast, the

medwedi.ru

22

Part One: General Considerations

FASTING MAN (24 hours, basal: –1800 calories) FUEL CONSUMPTION

ORIGIN OF FUEL

Nerve Muscle protein 75 g

Amino acids Glycerol 16 g

Adipose tissue Triglyceride 160 g

40 g Fatty acid 160 g

144 g Glucose 180 g 36 g 36 g

Liver Glycogen Gluconeo genesis O2 H2O _P

Ketone 60 g

(Fatty acid) 120 g

glucose required is supplied from lactate, pyruvate, glycogen, and amino acids. During the first two to four days of fasting, there is a rapid increase in the urinary nitrogen excretion from 5 to 7 g/day to approximately 8 to 11 g/day (123). This increase is associated with the previously noted breakdown of 50 to 75 g of protein per day. The rapid proteolysis of skeletal muscle protein does not continue during more prolonged fasting. During the next 20 to 40 days of fasting, the urinary nitrogen excretion begins gradually to decline and eventually reaches its nadir of 2 to 4 g of nitrogen per day (123). This decline is the result of ketoadaptation to starvation. In this process, the brain, which does not normally use ketone bodies for fuel, adapts its metabolism and transport systems to use ketone bodies (124). This adaptation results in a significant reduction in the amount of glucose needed by this glucose-dependent tissue and consequently in the amount of amino acid substrate necessary for gluconeogenesis (Fig. 20). Protein conservation follows with only 20 to 30 g of protein catabolized per day (29). The molecular mechanisms responsible for these adaptive responses are incompletely understood. With respect to skeletal muscle proteolysis, an ATP-ubiquitin-proteasome pathway seems to be involved (125,126). Early in the starvation process, this pathway is activated so that muscle-protein degradation occurs during fasting. As the starvation is prolonged, down-regulation of this process occurs so as to conserve muscle protein stores. Concurrent with these adaptations to starvation is a reduction in the resting energy expenditure by as much as 31% (120). In part, the reduction in resting energy expenditure is the result of a reduction in BCM produced by the breakdown of muscle and other proteins. However, the reduction in body size is less than the reduction in resting energy expenditure (120,127). Other factors that may contribute to the reduction in resting energy expenditure include a reduction in voluntary work, a decrease in body temperature, a decrease in cardiac work, a decrease in sympathetic nervous system activity, and a decrease in muscle activity. The changes in metabolism accompanying fasting and starvation are primarily regulated by decreased concentrations of insulin and increased concentrations of glucagon in response to decreasing glucose concentrations (29,58,123). The decreased insulin concentrations promote an increase in lipolysis in adipose tissue and a decrease in glucose uptake

_P

CO2 + H2O

RBC, WBC, etc. _P Lactate and pyruvate O2 Heart, kidney, muscle, etc.

~P

CO2 + H2O

Figure 19 Flow diagram of fuel metabolism in normal fasted man. Abbreviations: RBC, red blood cell; WBC, white blood cell. Source: From Ref. 29.

in insulin-dependent tissues. The increased concentrations of glucagon promote hepatic gluconeogenesis. These changes (including the decreased secretion of insulin and increased secretion of glucagon) may be further augmented by slight increases in the concentrations of epinephrine, ACTH, cortisol, and growth hormone (103,128). However, an actual increase in these hormones is not necessary, because basal concentrations of the counter-regulatory hormones are unopposed by the reduced secretion of insulin that is stimulated by hypoglycemia. Thus through four major adaptive mechanisms, a reduction in resting energy expenditure, the use of protein for gluconeogenesis, the use of fat for energy, and ketoadaptation of the brain, a human is able to survive for prolonged periods of time without food. As a result of the decreased excretion of urea and nitrogen during prolonged starvation, water intake is also reduced. However, it is apparent that this condition cannot be maintained indefinitely. In the average 70 kg man, there are approximately 170,000 calories and 6000 g of protein (Table 13). If it could all be used, starvation for up to 100 days would be tolerated. However, this is not possible because of the loss of essential body functions as body protein is consumed and not replenished. In fact, acute weight losses of 30% to 40% of body weight are usually fatal and associated with a rapid increase in urinary nitrogen excretion and a rapid decline in plasma glucose (123,129,130).

Table 13 Fuel Composition of Normal Humans Fuel Tissues Fat (adipose triglyceride) Protein (mainly muscle) Glycogen (muscle) Glycogen (liver) Total Circulating fuels Glucose (extracellular fluid) Free fatty acids (plasma) Triglycerides (plasma) Total Source: From Ref. 29.

Weight (kg)

Calories

15 6 0.15 0.075

141,000 24,000 600 300 165,900

0.02 0.0003 0.003

80 3 30 113

Chapter 1:

Metabolic Response to Starvation, Stress, and Sepsis

23

Table 14 Amount of Glucose Produced from Lactate, Glycerol, and Amino Acids During Starvation Grams of glucose produced per day Glucose precursor Glycerola Lactate þ pyruvateb Amino acidsc Total glucose produced from above precursors by liver and kidney cortexd Maximum glucose available for oxidation by the brain (i.e., glycerol and amino acid as precursors)e Fuel requirement of brain (glucose equivalents)f Suggested alternative fuel to glucose for braing

3 or 4 days of starvation

Several weeks of starvation

19 39 41 99

19 39 16 74

60

35

120 Ketone bodies

120 Ketone bodies

a

Amount of glucose produced from glycerol is estimated from the amount of triglyceride hydrolyzed per day. In starvation, 190 g of triglyceride is required to satisfy the caloric needs of the subject. Because glycerol represents 10% of triglyceride, it can provide 19 g of glucose per day. This amount is confirmed by measurement of glycerol uptake by liver and kidney using catheterization techniques. b Amount calculated from glucose 1-C turnover studies in man that gives values between 27 and 58 g/day, and this is not affected by the dietary state. Also, the measurement of lactate and pyruvate uptake by the liver and kidney in man by catheterization techniques estimates glucose formation as 39 g/day. c Amount calculated from nitrogen excreted in urine (100 g protein produces 57 g glucose; 1 g nitrogen is equivalent to 6–25 g protein). In early stages of starvation approximately 12 g nitrogen is excreted per day, but this is decreased in prolonged starvation to 4 to 7 g/day. Catheterization studies in subjects undergoing prolonged starvation indicate an uptake of amino acids by liver and kidney that could theoretically produce 26 g glucose per day. d In prolonged starvation, the hepatic–renal glucose production as measured by catheterization techniques provides an estimate of 86 g glucose per day, which is in good agreement with the 74 g obtained in this calculation. e Catheterization techniques have been used to measure the arterio–venous (A–V) differences across the brain. In prolonged starvation, glucose oxidation by the brain (excluding glucose converted to lactate, which is converted back to glucose in the liver and kidney) is estimated as 24 g/day. f Oxygen uptake or total fuel use is measured by catheterization techniques. g The rate of ketone body uptake by the brain has been estimated from A–V differences using catheterization techniques. These studies strongly suggest that ketone bodies are the alternative fuel to glucose during starvation. Source: From Ref. 45.

Injury and Sepsis Cuthbertson (131,132), in his classic studies of the metabolic response to long-bone fractures, defined two phases of the metabolic response to injury—an ebb or shock phase and a flow phase. Moore (133) subsequently divided the flow phase into catabolic and anabolic stages. The ebb phase, constituting the first several hours after injury, is characterized by hyperglycemia and the restoration of circulatory

volume and tissue perfusion. Once perfusion is restored, the flow phase begins. It is characterized by generalized catabolism, negative nitrogen balance, hyperglycemia, and heat production. The flow phase is the best-studied phase and may last from days to weeks, depending on the severity of the injury, the previous health of the individual, and medical intervention. Finally, once volume deficits have been corrected, pain has been eliminated, wounds have been

FASTING MAN, ADAPTED (5_6 weeks) (24 hours, basal: – 1500 calories) FUEL CONSUMPTION

ORIGIN OF FUEL

O2

47g

Muscle Protein 20 g

Glycerol 15 g Adipose tissue Triglyceride 150 g

O2 30 g

Fatty acid 150 g

H 2O –P

–P CO2 + H2O

44 g

Liver, kidney Glycogen Gluconeogenesis

Amino acids

Nerve

Glucose 80 g 50 g

Ketone 57g

(Fatty acid) 112 g

36 g

RBC, WBC, etc. –P 14 g

Lactate and pyruvate O2 Heart, kindly muscle, etc.

–P CO2 + H2O

Urine 10 g ketone = ~100 mEq

medwedi.ru

Figure 20 Flow diagram of fuel metabolism in starved man after adaptation. Source: From Ref. 29.

24

Part One: General Considerations

closed, infection has been controlled, and complete oxygenation has been restored, the anabolic phase begins (1). This phase can be divided into a slow but progressive reaccumulation of protein, followed by the reaccumulation of body fat. Because protein synthesis cannot exceed 3 to 5 g of nitrogen per day, the protein repletion phase may be considerably longer than the catabolic phase in which protein is broken down. The posttraumatic state is characterized by starvation, immobilization, and repair. Although starvation and immobilization are both associated with decreased energy requirements, reparative processes increase energy needs. As a result, the overall energy requirements of traumatized and septic individuals are increased. The increase in energy need varies directly with the severity of injury and the complications that develop. In this regard, the most severe injury is the burn, and the most severe complication is sepsis (Fig. 5). Despite the use of protein and carbohydrate for calories, most of the energy used after trauma and after sepsis is derived from fat. This use is reflected in the low respiratory quotients noted after injury and sepsis. For example, Wilmore et al. (134) found respiratory quotients of 0.70 to 0.76 after severe burns. In addition, septic injury appears to have a greater lipid dependence for energy than nonseptic injury (100,135). Increased lipolysis is seen in both the ebb phase and the flow phase of the metabolic response to injury. During the ebb phase, elevated concentrations of cortisol, catecholamines, glucagon, growth hormone, ACTH, increased sympathetic nervous system activity, and depressed concentrations of insulin favor lipolysis. The presence of cortisol appears to be necessary for the remainder of the hormonal agents to be effective (136,137). Elevated concentrations of glycerol and free fatty acids during the ebb phase are well documented (138–140). However, Kovach et al. (141) have noted that elevation of plasma free–fatty acids may not occur after severe hemorrhage as a result of intense vasoconstriction in adipose tissue, producing minimum blood flow. During the flow phase, net lipolysis persists despite an increase in the concentration of insulin. Increased free fatty acids have been documented after trauma, burns, and sepsis (100,133,142–146). The fatty acids are used throughout the body for energy. In both the ebb and flow phases, the high concentration of intracellular fatty acids and the elevated concentration of glucagon inhibit acetyl-CoA carboxylase, thereby decreasing malonyl-CoA concentrations and fatty acid synthesis. In hepatocytes, the decreased concentration of malonyl-CoA also stimulates carnitine acyl transferase, thereby increasing the transport of acetyl-CoA into the mitochondria for oxidation and ketogenesis. However, the activity of ketogenesis after shock, injury, and sepsis is variable and correlates with the severity of injury (144–146). After major injury and sepsis, ketogenesis is low or absent, whereas after minor injury and sepsis, it is increased but to a lesser extent than is seen during nonstressed starvation (142,147). During starvation, the inhibition of acetyl-CoA carboxylase also results in the accumulation of cytoplasmic citrate that in turn inhibits glycolysis through PFK inhibition (Randle effect) (45). However, after shock and major injury, citrate does not accumulate (148,149). This lack of accumulation may play a role in the persistence of glycolysis after injury. Unlike fasting and starvation, hyperglycemia is a hallmark of the response to injury, sepsis, and stress. An increase in blood glucose occurs during both the ebb and

flow phases and is proportional to the severity of the injury (150,151). There is also an increased concentration of lactate, pyruvate, organic phosphates, total amino acids, glycerol, and free fatty acids. Changes in lactate, pyruvate, and alanine have also been found to correlate with the severity of injury (144). The rise in the concentrations of glucose and other solutes contributes to an elevated plasma osmolality after hemorrhage and injury that is thought to be critical in the complete restitution of blood volume and plasma proteins (119,152–155). The hyperosmolality appears to augment the transcapillary refill phase and the plasma protein– restoration phase of blood volume–restitution by mediating the movement of water from cells to the interstitium and ultimately to the plasma (153–155). The metabolic changes in carbohydrate metabolism arise primarily as the result of the actions and interactions of catecholamines, cortisol, glycogen, insulin, growth hormone, and somatostatin (65,95,96,150,156,157). It is apparent that the elevated blood glucose concentration results from increased hepatic production and from impaired peripheral uptake that are under endocrine control. Both the ebb and the flow phases are associated with hyperglycemia, increased gluconeogenesis, and hepatic and peripheral insulin resistance. However, the mechanisms involved in these carbohydrate ‘‘abnormalities’’ are different. During the ebb phase, plasma insulin is clearly depressed in relationship to the degree of hyperglycemia (111,150,158,159). This results from decreased B-cell sensitivity to glucose that is secondary to catecholamines, somatostatin, reduced pancreatic blood flow, and the increased activity of the sympathetic nervous system (92,115,139,160,162). However, during the flow phase, B-cell sensitivity returns to normal, and insulin concentrations rise to more appropriate values. Nevertheless, hyperglycemia persists (111,163). In both the ebb and the flow phases, there is a delayed rate of assimilation of a glucose load, glucosuria, and a resistance to exogenously administered insulin (156,160,164). Despite this ‘‘diabetes of injury,’’ glucose uptake and use by peripheral tissues in both the ebb and the flow phases have been demonstrated consistently to be greater than that under normal circumstances (111,165–169). The resistance to insulin is manifested in a decreased glucose clearance. Consequently, the high plasma glucose concentration and the attendant increase in plasma–tissue glucose concentration gradient appear to overcome the resistance of peripheral tissues to glucose entry. The insulin resistance that develops appears to result from the action of catecholamines, cortisol, and other factors (65,95,96,115,157). Hepatic carbohydrate metabolism is also affected by insulin resistance. During the ebb phase, elevated concentration of catecholamines, cortisol, and glucagon and a decreased concentration of insulin result in rapid glycogenolysis and an outpouring of glucose from the liver. In addition, these hormonal alterations stimulate gluconeogenesis from alanine, lactate, and pyruvate. Growth hormone also is involved in these processes by inhibiting glucose uptake through inhibition of glucokinase. During the flow phase, gluconeogenesis persists despite nearnormal concentrations of insulin. This persistence appears to result from insulin resistance and produces a continued flow of glucose from the liver. Therefore the hyperglycemia that occurs after injury results from a combination of increased glucose production and glucose release and from a peripheral resistance to the entrance of glucose. After injury and during sepsis, glucose must be provided not only to RBCs, WBCs, renal medulla, and

Chapter 1:

neural tissues, but also to wounded tissue (162,170,171). Glucose uptake in wounded tissue is increased by up to 100%. Wounds demonstrate a lack of insulin sensitivity and do not increase their glucose uptake or glycogenesis in response to insulin (60,172,173). The accelerated glucose uptake in wounded tissue and possibly in septic tissue appears to correlate with the degree of inflammatory cellular infiltrate (171). In addition, it has been demonstrated that the accelerated glycolysis of wounded tissue may be aerobic and not anaerobic, as thought previously (170). The aerobic glycolysis proceeds to lactate in the presence of adequate oxygen. Thus oxygen consumption and carbon dioxide production are normal, but lactate production is accelerated. Increased lactate production may be related to an inability of the NADH shuttle to transfer reducing equivalents from the cytoplasm to the mitochondrion (85,174). Metabolic derangements suggestive of aerobic glycolysis have also been seen in septic tissue (175). In this regard, it is of note that aerobic glycolysis is characteristic of the cellular infiltrate (176). As one might expect, negative nitrogen balance and net proteolysis are characteristic of the posttraumatic and the septic states (177,178). However, only 20% of the protein broken down is used for calories (71). The remainder is used in gluconeogenesis. As noted previously, the production of lactate in the presence of oxygen primarily results from the actions of cortisol, glucagon, catecholamines, and the decreased effectiveness of insulin. The rise in urinary nitrogen is associated with an increased excretion of urea, sulfur, phosphorus, potassium, magnesium, and creatinine, suggesting the breakdown of intracellular material (131,179). Isotope dilution studies suggest that this loss of protein results from the loss of cell mass rather than cell number (131). The nitrogen-to-sulfur and nitrogen-to-potassium ratios suggest that this loss occurs mainly from muscle (131). The marked increase in the urinary excretion of 3-methylhistidine during trauma, sepsis, and burns also suggests the importance of skeletal muscle in response (180,181). Analysis of the protein content and the incorporation of radiolabeled amino acids in visceral tissues and skeletal muscle confirm that it is skeletal muscle that is depleted and the visceral tissue (liver and kidney) is spared (182). This is the opposite of nonstress starvation in which visceral protein is used before muscle protein and has been termed visceral translocation of protein (37,182). In fact, one of the molecular tragedies associated with trauma, burns, and especially sepsis is that the proteolytic suppression accompanying prolonged starvation is not observed. Consequently, continued breakdown of protein results. The alterations in plasma amino acids are not well defined during the ebb and flow phases. During the ebb phase, little change in total amino acid concentrations were noted by Elwyn et al. (183) until the late phases of shock. In addition, it appears that these changes result primarily from a decreased hepatic uptake (183) and not an increased peripheral release as was thought previously (184). During the flow phase, alterations in plasma amino acids appear to be related to the severity of injury and the specific type of injury (121,185–187). Alanine, the major gluconeogenic amino acid, appears to be released from peripheral tissues and taken up by the liver for gluconeogenesis. Early in the flow phase, the concentration of alanine in plasma is increased; but as the injury persists, serum alanine decreases, presumably as a result of its lack of availability in peripheral tissues and its continued hepatic uptake.

Metabolic Response to Starvation, Stress, and Sepsis

25

Branched-chain amino acids and aspartate and asparagine are transaminated in peripheral tissues, and their remaining carbon fragments are used in the TCA cycle. Nonetheless, muscle concentrations of amino acids generally reveal normal or elevated concentrations of all amino acids except alanine, glutamine, and arginine (188). The net catabolism of protein can result from increased catabolism, decreased synthesis, or a combination of the two. Available data on TBP turnover suggest that after injury the net changes in catabolism and synthesis depend on the severity of the injury (189). Elective operations and minor injury appear to result in a decreased rate of synthesis with a normal rate of protein catabolism (118,140). Severe trauma, burns, and sepsis appear to be associated with increases in both synthesis and catabolism but with a greater increase in the latter, resulting in net catabolism (122,189–191). In this regard, it is important to note that the accelerated proteolysis and a high rate of gluconeogenesis persist after injury and during sepsis (185,192). This persistence appears to result from an inhibition of ketoadaptation after injury and sepsis. Unlike starvation, ketogenesis is not prominent, and it does not fuel the brain in significant amounts. Therefore a high requirement for glucose and therefore gluconeogenesis persist. The mechanism for this inhibition of ketoadaptation is not understood presently. Clowes et al. (193) have presented evidence suggesting the involvement of a circulating peptide containing 33 amino acids in this response. In addition, Baracos et al. (194) have proposed that interleukin-1 (IL-1) (a human leukocyte pyrogen) may be responsible for the accelerated proteolysis that accompanies fever and sepsis (see section on ‘‘Cytokines’’). As noted previously, activation of an ubiquitin-proteasome pathway appears to be involved in skeletal muscle degradation during starvation (125,126). In septic states, rates of ubiquitination of muscle proteins are profoundly increased (125,195,196). Further, inhibition of this process significantly reduces proteolysis in septic conditions (197). The net catabolism of protein that occurs after any injury is dependent on the prior nutritional status and intake, sex and age of the individual, and the severity of the injury. Young healthy males lose more protein in response to an injury than do women or the elderly (40). In addition, the urinary excretion of nitrogen is less after a second operation if it closely follows the first (145,178). This decline is presumably the result of a reduction in available protein stores. Finally, negative nitrogen balance can be reduced or virtually eliminated by high caloric and nitrogen supplementation (34,156,191,198,199). Together, these facts suggest that the loss of protein that occurs after injury is not entirely obligatory to the injury, but is also a manifestation of acute starvation (146).

Local Wound Metabolism Injury is associated with a negative bodily balance of many substrates (200–203). Despite injury-induced abnormalities in cofactors and substrates known to be important in wound healing, most wounds heal after injury (203–205). The ability of the wound to heal in the face of varying hormone and substrate supply suggests that the wound has a biologic priority over the host. This concept of biologic priority of healing wounds was described by Moore and Brennan (206), who stated that 75% of wounds or surgical incisions healed to the point of tensile integrity during a period of negative energy and nitrogen balance. The other 25% healed in patients who returned to eating so rapidly that the

medwedi.ru

26

Part One: General Considerations

period of negative balance was of minimal duration (206). It is therefore evident that during a period of postinjury hormonal alterations and general catabolism, the wound has a favored status. This concept suggests that the metabolic and functional determinants of normal wound repair are inherent within the local wound environment. This further suggests that the local wound environment is differently sensitive to substrate and hormonal alterations than are other organ systems.

Cellular Infiltrate as a Determinant of Biologic Priority Following injury, there is a local ordered infiltration of inflammatory cells and a characteristic pattern of cellular predominance within the wound over time. This ordered sequence of cellular predominance leads to characteristic alterations in extracellular substrate concentrations, temporal effects of wound fluid on wound cell function, an altered sequence of expression for peptide growth factors, and degradation of classical peptide hormones. It appears that the metabolism of the wound is determined by the cellular infiltrate and is independent of systemic hormonal and substrate alterations. This is supported by the following findings: 1. 2.

3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13.

A direct relationship exists between DNA content of wounded tissue and the cellular infiltrate (207). Wounded tissue metabolizes glucose rapidly through aerobic glycolysis. This unusual form of glycolysis is characteristic of the leukocytes that comprise the cellular infiltrate (170). A time course for glucose uptake and lactate production by wounded tissue appears to correlate with the development of the cellular infiltrate (207). Autoradiographic studies using [3H]-2-deoxyglucose reveal that the majority of the glucose uptake in wounded tissue occurs in the cellular infiltrate (208). Both wounded tissue and macrophages increase their glucose uptake in response to increasing glucose concentrations in the environment, and this glucose clearance is concentration independent. Thus the lack of saturation of glucose uptake of wounded tissue appears to be determined by the macrophages in the cellular infiltrate (209). A high PFK activity of wounded tissue can be explained by the PFK activity of the cellular infiltrate as measured by 5-[3H]-glucose (208). Macrophage glucose uptake and lactate production are independent of local epinephrine concentrations (208). Macrophages have a stimulatory effect on the HEP content of resident host tissue (210). A decreased HEP content of wounded tissue appears to be secondary to the dilutional effect of the cellular infiltrate (211). The presence of macrophages seems to explain the pattern of purine release from wounded muscle (212). Glutamine utilization by the cellular infiltrate appears to explain the decrease in glutamine content of wounded tissue (213). In the isolated perfused system, hormone and substrate profiles similar to those found following injury do not affect wound metabolism. A prior adrenalectomy does not affect wound metabolism despite substantial effects on noninjured tissue.

In addition, other investigators have shown a lack of effect of exogenous insulin on local wound metabolism in an incubated system (171). Thus there are substantial data to support the position of the wound as independent of circulating hormone and substrate concentrations. Yet it is known that several of the more common clinical examples of impaired wound healing involve systemic hormonal and substrate changes. Specifically, diabetes mellitus (214– 217), steroid therapy (218–220), amino acid deprivation (221,222), and hypophysectomy (223) have been shown to impair wound healing. In summary, generalized catabolism, hyperglycemia, persistent gluconeogenesis, protein wasting, negative nitrogen balance, heat production, and loss of the body mass that parallel the severity of the injury are characteristic after trauma and during sepsis. Most of the energy necessary for biologic processes to proceed is derived from fat. The net catabolism of 300 to 500 g of lean body mass per day is apparently required as a source of amino acids for gluconeogenesis. The persistence of the injury, particularly sepsis, through unknown mechanisms produces inhibition of the usual adaptive mechanisms that occur in starvation, resulting in the persistence of a highly catabolic state. This state in turn leads to protein wasting and malnutrition and ultimately in multiple organ failure (224) and death if the stimuli are not eliminated. (For further information on wound healing, the reader is referred to the chapter 55).

CYTOKINES In addition to the important role that neurohumeral mediators have been shown to play in the metabolic response to stress and injury, emerging evidence is also defining a role for cytokines (225,226). Often these two systems appear to work in tandem to carry out a particular response. Because cytokines are primarily proinflammatory agents, the magnitude of their involvement is related to the severity of the underlying stress or injury. For example, in an elective surgical procedure, the wound is the primary locus of the inflammatory response. Thus, cytokines involved in this response are targeted toward healing this wound; accordingly, their access to the systemic circulation is minimal and the resultant systemic response is modest or nonexistent. In a more traumatic situation in which massive tissue destruction has occurred (e.g., motor vehicle accident and blast injury), the local production of cytokines may be profound with an equally excessive egress of these substances into the systemic circulation. In this situation, the systemic response may result in hemodynamic instability and even distant organ failure. Cytokines comprise a family of small proteins or glycoproteins that alter the function of a target cell through an autocrine or paracrine process; rarely this targeting may be accomplished in an endocrine fashion. Many different cells may secrete cytokines but those commonly involved include lymphocytes, macrophages, Kupffer cells of the liver, and various components of the intestinal epithelium. The biologic response induced by cytokines is considerably diverse and will depend upon the particular cytokine secreted and the target cell affected. Since first being discovered in the 1970s, dozens of cytokines have been identified, and it is likely that many more will become recognized in the years to come. Accordingly, a comprehensive review of cytokines and their physiology is beyond the scope of this chapter [the reader is referred to several excellent references for this information

Chapter 1:

(225–228)]. This discussion will focus on those cytokines that have been shown to influence the metabolic response to stress. These include interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor [(TNF)/cachectin], and interferon-gamma. Cytokines are commonly categorized as being proinflammatory, anti-inflammatory, or both. This is based on their ability to invoke local or systemic inflammation and alter the immune response. The four cytokines involved in the metabolic response to stress are primarily proinflammatory, with the exception of IL-6, which possesses both proinflammatory and anti-inflammatory characteristics. Their effects on the immune response will not be discussed in this context, because this function is extensively covered in the chapter on immunity and the immunocompromised patient (Chapter 4). As mentioned above, cytokines can elicit both local and systemic effects. Because they are produced at the site of injury, their major action will be targeted to that site if the wound is uncomplicated. Thus, in situations such as setting a simple fracture, repairing an inguinal hernia, or removing a diseased gallbladder (particularly if done laparoscopically), a systemic response is highly unlikely. Rather, locally released cytokines will be confined to the site of injury to both induce and modulate the healing process. Important healing factors such as enhancement of blood flow through vasodilation, recruitment of neutrophils, monocytes, and other blood elements to the wound site to prevent or contain infection, maintenance of hemostasis through alterations in coagulation, and induction of angiogenesis and cell proliferation to issue adequate healing may all be cytokine mediated (226). TNF, for example, has been shown to induce microvascular angiogenesis, bone remodeling, and fibroblast proliferation (226). IL-1 induces procoagulant activity, collagenase activity, and collagen synthesis. Further, it has been shown to stimulate osteoclastic activity, which may be important in bone remodeling during injury (226). In situations where the injury is more severe, and particularly if extensive devitalization is present, excessive production of cytokines at the wound site results in their entrance into the systemic circulation that can often be measured. When this situation occurs, a variety of metabolic aberrations have been shown to occur. Release of IL-6 into the circulation appears to play a prominent role in many of these metabolic effects. Paramount among them is its induction of the acute phase response (229). This response is characterized by the reprioritization of hepatic synthesis and release of certain proteins into the blood during inflammation and sepsis and following severe injury (230). Thus, albumin and transferrin, which are normally important proteins synthesized by the liver, are reduced in favor of a number of acute phase proteins whose plasma concentrations increase substantially (sometimes as much as 10–1000-fold) (231). Examples of such proteins include C-reactive protein, a2 macroglobulin, a1 acid glycoprotein, amyloid, and fibrinogen. The physiologic role of many acute phase proteins is unknown, while emerging evidence has shown that others act as opsonins, influence coagulation mechanisms, and contain generalized tissue destruction. Acute phase proteins that possess antiprotease activity can significantly reduce tissue destruction from dead or dying cells. Similarly, fibrinogen can elicit thrombus formation to prevent bleeding in wounded tissue. It would appear, therefore, that an important role for the acute phase response is to set into motion a variety of survival mechanisms to contain the injury and/or associated infection and restore homeostasis (232).

Metabolic Response to Starvation, Stress, and Sepsis

27

Other cytokines that also have been shown to induce the acute phase response in the liver include TNF and IL-1 (226,233,234). Their role appears to be less important, and certainly less sustained, than that of IL-6. An explanation for this is the different half-lives of these cytokines. The half-life of TNF is 20 minutes or less whereas that of IL-1 is approximately six minutes (225). In contrast, IL-6 levels in the circulation are detectable within an hour after injury, reach peak levels within four to six hours, and can be sustained for a week or more (225). It may be that these three cytokines interact to initially induce the acute phase response and that IL-6 keeps it sustained. Because glucocorticoids also regulate hepatocyte biosynthetic activity, it has been proposed that such substances may be important cofactors to IL-6 and other cytokines in inducing and modulating the acute phase response (232). In support of this hypothesis is the finding that IL-6, TNF, and IL-1 stimulate the hypothalamic–pituitary–adrenal axis to secrete ACTH and glucocorticoids (235). Thus, there is likely to be a feedback mechanism involving glucocorticoids and cytokines (236,237). It is well known that injury and inflammation induce a metabolic response in skeletal muscle that results in net catabolism. Thus, amino acids released from skeletal muscle catabolism are preferentially taken up by the liver for gluconeogenesis and protein synthesis (especially acute phase proteins), as needed. Although the preponderance of evidence suggests that glucocorticoids are the major mediator of muscle proteolysis, various cytokines may also be involved (232). In differing models of sepsis, IL-1, TNF, and IL-6 have all been shown to stimulate muscle-protein breakdown (238–240). It would appear, therefore, that regulation of muscle-protein degradation following stress or injury is a multifaceted response. Conceivably, glucocorticoids may orchestrate the primary role, but cytokines may modulate this response in specific settings (232,241). During massive tissue destruction or endotoxemia, for example, cytokines may play a key role, whereas in other conditions such as starvation or differing forms of stress, glucocorticoids play the central role. An interesting effect of cytokines on protein catabolism is that induced by TNF. Chronic excessive production of this cytokine can lead to a state of profound cachexia (hence, its other name, cachectin). Administration of TNF to rodents induces nitrogen loss, decreased food intake, depletion of body lipid stores, and excessive weight loss (242–244). In a mouse model, tumors secreting TNF can cause profound weight loss and cachexia (245). IL-1 has also been shown to induce cachexia (242). Whether TNF or IL-1 are responsible, either alone or in combination, for the cachectic state observed in many cancer patients remains to be elucidated. TNF is also thought to be the primary mediator of many of the systemic manifestations of endotoxemia. In various animal models, administration of this cytokine in high doses can induce fever, tachypnea, tachycardia, hypotension, and death, not dissimilar to that observed in patients in septic shock (226). Pathologic findings are also characteristic of those reported in human septic shock, including pulmonary congestion, intestinal infarction, and adrenal necrosis (246). Other effects of cytokines include reductions in iron and zinc levels, which are commonly observed in septic patients. Both TNF and IL-1 have been shown to elicit these effects, which may actually confer a survival benefit by inhibiting the growth of various microorganisms and limiting the production of oxygen radical formation, both of which

medwedi.ru

28

Part One: General Considerations

depend on trace metals (226). Finally, interferon-gamma can upregulate the number of TNF receptors on various cells, particularly monocytes. Although this interferon is primarily an immune modulator with antiviral activity, its TNF-related action may enhance cytotoxicity of devitalized tissue and thereby aid in the hearing of wounded tissue (226). It seems clear that cytokines play a major role in the metabolic response to injury and stress that is just now being unraveled. As our knowledge of this role is clarified, modulation of these substances and their physiologic and pathophysiologic mechanisms should prove beneficial in altering responses that are detrimental to recovery and survival.

SUMMARY Starvation, stress from injury or surgical procedures, and sepsis induce a series of metabolic changes that are regulated by neuroendocrine reflexes and cytokines and result in mobilization of substrates from endogenous tissue stores. These metabolic changes ensure that energy is available for vital functions, oxygen delivery is maintained, and reparative processes take place. An understanding of these complex metabolic interactions depends on an appreciation of normal homeostasis and the distribution of body water, proteins, fat, and carbohydrates. The role of each component of body tissue is important in periods of starvation, stress, and sepsis, especially when the ability to replenish endogenous food stores is impaired as a result of either the inability to consume adequate nutrients or the excessive consumption of tissue stores. The mechanisms described in this chapter illustrate the complexity of the metabolic response to stress, the interrelationships between the neuroendocrine responses, cytokine release and substrate mobilization and use, and the importance of adequate energy and tissue stores for survival and repair of the organisms under conditions of nutrient deprivation.

REFERENCES 1. Gann DS, Amaral JF. The pathology of trauma and shock. In: Zuidema GD, Rutherford WF, Ballinger WF, eds. The Management of Trauma. Philadelphia: WB Saunders, 1984. 2. Moore FD. The Body Cell Mass and its Supporting Environment. Philadelphia: WB Saunders, 1963. 3. Shizgal HM. Body composition. In: Fischer JE, ed. Surgical Nutrition. Boston: Little Brown, 1983. 4. Bell GH, Davidson JN, Emslie-Smith D. Textbook of Physiology and Biochemistry. London: Churchill Livingstone, 1972. 5. Maxwell MH, Kleeman CR. Dynamics of body water and electrolytes. In: Clinical Disorders of Fluid and Electrolyte Metabolism. 4th ed. New York: McGraw-Hill, 1987. 6. Winters RW. The Body Fluids in Pediatrics. Boston: Little, Brown, 1973. 7. Maxwell MH, Kleeman CR. Clinical Disorders of Fluid and Electrolyte Metabolism. 3rd ed. New York: McGraw-Hill, 1979. 8. Skeleton H. Arch Intern Med 1927; 40:140. 9. Edelman IS, Leibman J. Anatomy of body water and electrolytes. Am J Med 1959; 27:256. 10. Moore FD. Energy and the maintenance of the body cell mass. JPEN 1980; 4:228. 11. Ruch TC, Patton HD. Physiology and Biophysics. Philadelphia: WB Saunders, 1974. 12. Rose BD. In: Clinical Physiology of Acid–Base and Electrolyte Disorders. New York: McGraw-Hill, 1977.

13. Fomon SJ. Infant Nutrition. 2nd ed. Philadelphia: WB Saunders, 1974. 14. Grande F, Keys A. Body weight, body composition, and calorie status. In: Goodhart RS, Shihs ME, eds. Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger, 1980. 15. Behnke AR, Wilmore JH. Evaluation and Regulation of Body Build and Composition. Englewood Cliffs, NJ: Prentice Hall, 1974. 16. Pace H, Rathbun EN. Studies in body composition. III. The body water and chemically combined nitrogen content in relation to fat content. J Biol Chem 1945; 158:685. 17. Behnke AR. Physiologic studies pertaining to deep sea diving and aviation, especially in relation to the fat content and composition of the body. Harvey Lect 1941; 37:198. 18. Brozek J, et al. Densitometric analysis of body composition: revision of some quantitative assumptions. Ann NY Acad Sci 1963; 110:113. 19. Baylis PH, Zerbe RL, Robertson GL. Arginine vasopressin response to insulin-induced hypoglycemia in man. J Clin Endocrinol Metab 1981; 53:935. 20. Bereiter DA, Plotsky PM, Gann DS. Tooth pulp stimulation potentiates the ACTH response to hemorrhage in cats. Endocrinology 1982; 111:1127. 21. Lesser GT, Deutsch S, Markofsy T. Use of independent measurement of body fat to evaluate overweight and underweight. Metabolism 1971; 20:792. 22. Norris AH, Lundry T, Shock NW. Trends in selected indices of body composition in men between the ages 30 and 80 years. Ann NY Acad Sci 1963; 110:623. 23. Vaglcirsdottir K, Munro HN. Protein and ammo acid metabolism. In: Fischer JE, ed. Surgical Nutrition. Boston: Little Brown, 1983. 24. Munro HN, Young VR. Protein metabolism in the elderly: observations relating to dietary needs. Postgrad Med 1978; 63:143. 25. Valgeirsdottir K, Munro HN. Protein and amino acid metabolism. In: Fischer JE, ed. Surgical Nutrition. Boston: Little, Brown, 1983:129. 26. Harvey TC, et al. Measurement of whole body nitrogen by neutron activation analysis. Lancet 1973; 2:359. 27. Tarso PJ, Spafford MS, Blaw M. The metabolism of water and electrolytes in congestive heart failure. J Lab Clin Med 1953; 41:280. 28. Hill GL, et al. Multi-element analysis of the living body by neutron activation analysis—application to critically ill patients receiving intravenous nutrition. Br J Surg 1979; 66:868. 29. Cahill GF. Starvation in man. N Engl J Med 1970; 668–675:282. 30. Kinney JM, Gump FE. The metabolic response to injury. In: American College of Surgeons, eds. Manual of Pre and Post Operative Care. Philadelphia: WB Saunders, 1983. 31. Hastings AB. The electrolytes of tissue and body fluids. Harvey Lect 1940–1941; 36:91. 32. Shizgal HM, et al. The indirect measurement of total exchangeable potassium. Am J Physiol 1977; 233:F253. 33. Randall HT. Water, electrolytes and acid base balance. In: Goodhart RS, Shils ME, eds. Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger, 1980. 34. Kinney JM, Lister J, Moore FD. Relationship of energy expenditure to total exchangeable potassium. Ann NY Acad Sci 1963; 110:711. 35. Drabkin DL. The distribution of the chromoproteins, hemoglobin, myoglobin and cytochrome C, in the tissue of different species, and the relationship to the total content of each chromoprotein to body mass. J Biol Chem 1950; 182:317. 36. Kinney JM. The application of indirect calorimetry to clinical studies. In: Kinney JM, ed. Assessment of Energy Metabolism in Health and Disease. Report of the First Ross Conference on Medical Research. Columbus, Ohio: Ross Laboratories, 1980:48. 37. Kinney JM. Energy requirements in injury and sepsis. Acta Anaesthesiol Scand 1974; 55:15. 38. Dubois EF. The Mechanism of Heat Loss and Temperature Regulation. Lane Medical Lectures. Stanford University Press, 1937.

Chapter 1: 39. Clowes GHA, Randall H, Cha C. Effects of parenteral alimentation on metabolism in septic patients. Surgery 1980; 88:531. 40. Shizgal HM, Milne CA, Spainer HA. The effect of nitrogensparing intravenously administered fluids on postoperative body composition. Surgery 1979; 86:60. 41. Lehninger AL. Biochemistry: The Molecular Basis of Cell Structure and Function. 2nd ed. Menlo Park, CA: Worth Publishing, 1975. 42. Lehninger AL. Bioenergetics. 2nd ed. Menlo Park, CA: Benjamin/Cummings Publishing, 1972. 43. Atkinson DE. The energy charge of the adenylate pool as a regulator parameter interaction with feedback modifiers. Biochemistry 1966; 7:4030. 44. Gann DS, Amaral JF, Caldwell MD. Metabolic response to injury, stress, and starvation. In: Davis JH, et al., eds. Clinical Surgery. St. Louis: Mosby, 1987. 45. Newsholme EA, Start C. Regulation in Metabolism. New York: John Wiley, 1973. 46. Bie P. Osmoreceptors, vasopressin, and control of renal water excretion. Physiol Rev 1980; 60:961. 47. McGilvery RW. Biochemistry—A Functional Approach. Philadelphia: WB Saunders, 1970. 48. Harper HA, Rodwell VW, Mayes PA. Review of physiological chemistry. 16th ed. Los Altos, CA: Lange Medical Publications, 1977. 49. Exton JH. Gluconeogenesis. Metabolism 1972; 21:945. 50. Krebs HA. The metabolic fate of amino acids. In: Munro HN, Allison JB, eds. Mammalian Protein Metabolism. New York: Academic Press, 1964. 51. Munro HN. Biochemical aspects of protein metabolism. In: Munro HN, Allison JB, eds. Mammalian Protein Metabolism. New York: Academic Press, 1964. 52. Munro HN, Crim MC. The proteins and amino acids. In: Goodhart RS, Shils ME, eds. Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger, 1980. 53. Mallette LE, Exton JH, Park CR. Control of gluconeogenesis from amino acids in the perfused rat liver. J Biol Chem 1969; 244:5713. 54. Felig P. The glucose–alanine cycle. Metabolism 1973; 22:179. 55. White A, Handler P, Smith EL. Principles of Biochemistry. New York: McGraw-Hill, 1973. 56. Atkinson DE, Bourke E. The role of ureagenesis in pH homeostasis. Trends Biochem Sci 1984; 9:297. 57. Ross BD, Hems R, Krebs HA. The rate of gluconeogenesis from various precursors in the perfused rat liver. Biochem J 1967; 102:942. 58. Cahill GF. Ketosis. JPEN 1981; 5:281. 59. Masoro EJ. Lipids and lipid metabolism. Annu Rev Physiol 1977; 39:301. 60. Nelson KM, Turinsky J. Analysis of postburn insulin unresponsiveness in skeletal muscle. J Surg Res 1981; 31:404. 61. Korchak HM, Masoro EJ. Changes in the level of the fatty acids synthesizing enzymes during starvation. Biochem Biophys Acta 1962; 58:354. 62. McGarry JD, Foster DW. Hormonal control of keto genesis: bio-chemical considerations. Arch Intern Med 1977; 137:495. 63. Egdahl RH. Pituitary–adrenal response following trauma to the isolated leg. Surgery 1959; 46:9. 64. Gann DS, Ward DG, Carlson DE. Neural control of ACTH: a hemostatic reflex. Recent Prog Horm Res 1978; 35:357. 65. Rizza RA, et al. Adrenergic mechanism for the effect of epinephrine on glucose production and clearance in man. J Clin Invest 1980; 65:682. 66. Kaplan NM, Bartter FC. The effect of ACTH, renin angiotensin II and various precursors on biosynthesis of aldosterone by adrenal slices. J Clin Invest 1962; 41:715. 67. Guyton AC. Textbook of Medical Physiology. 6th ed. Philadelphia: WB Saunders, 1981. 68. Gann DS, Dallman MF, Engeland WC. Reflex control and modulation of ACTH and corticosteroids. In: McCann SM,

Metabolic Response to Starvation, Stress, and Sepsis

69. 70.

71. 72.

73.

74.

75.

76.

77.

78. 79. 80.

81. 82. 83. 84.

85.

86.

87.

88.

89.

90. 91.

92. 93. 94.

29

ed. Endocrinology Physiology. III. International Review of Physiology. Vol. 24. Baltimore: University Park Press, 1981. Cannon WB. The Wisdom of the Body. New York: WW Norton, 1939. Egdahl RH. The differential response of the adrenal cortex and medulla to bacterial endotoxin. J Clin Invest 1959; 38:1120. Duke JH, et al. Contribution of protein to caloric expenditure following injury. Surgery 1970; 68:168. Gann DS, Cryer GL, Pirkle JC Jr. Physiological inhibition and facilitation of adrenocortical response to hemorrhage. Am J Physiol 1977; 232:R5. Lilly MP, Engeland WC, Gann DS. Adrenal response to repeated hemorrhage: implications for studies of trauma. J Trauma 1982; 22:809. Lilly MP, Gann DS. The effect of repeated operation on the response of the adrenal cortex to infused ACTH. Surg Forum 1982; 33:10. Raff H, Shinsako J, Dallman MF. Surgery potentiates adrenocortical responses to hypoxia in dogs. Proc Soc Exp Biol Med 1983; 172:400. Wood CE, et al. Hormonal and hemodynamic responses to 15 ml/kg hemorrhage in conscious dogs: responses correlate to body temperature. Proc Soc Exp Biol Med 1981; 167:15. Roth J, Grunfeld C. Endocrine systems: mechanisms of disease, target cells, and receptors. In: William RH, ed. Textbook of Endocrinology. Philadelphia: WB Saunders, 1981. O’Malley BW, Schrader WT. The receptors of steroid hormones. Sci Am 1976; 234:32. Oppenheimer JH. Thyroid hormone action at the cellular level. Science 1979; 203:971. Gann DS, Amaral JF, Caldwell MD. Neuroendocrine response to injury, stress, and starvation. In: Davis JH, et al., eds. Clinical Surgery. St. Louis: Mosby, 1987. Rasmusen H. Calcium and cAMP as Synarchic Messengers. New York: John Wiley, 1981. Sutherland EW. Studies on the mechanism of hormone action. Science 1972; 177:401. Greengard P. Phosphorylated proteins as physiological effectors. Science 1978; 199:146. Fain JN. Involvement of phosphatidylinositol breakdown in elevation of cytosol Ca2þ by hormones and relationship to prostaglandin formation. In: Kohn LD, ed. Hormone Receptors. Vol. 6. New York: John Wiley, 1982. Needham AE. Regeneration of wound healing. In: Albercrombie M, ed. Methuen’s Monographs on Geological Subjects. New York: John Wiley, 1952. Felig P. The endocrine pancreas: diabetes mellitus. In: Felig P, et al., eds. Endocrinology and Metabolism. New York: McGraw–Hill, 1981:p. 761. Porte D Jr, Halter JB. The endocrine pancreas and diabetes mellitus. In: Williams RH, ed. Textbook of Endocrinology. Philadelphia: WB Saunders, 1981. Mcintyre N, Holdsworth CD, Turner DS. Intestinal factors in the control of insulin secretion. J Clin Endocrinol Metab 1965; 25:1317. Raptis S, et al. Differences in insulin, growth hormone, and pancreatic enzyme secretion after intravenous and intraduodenal administration of mixed amino acids in man. N Engl J Med 1973; 288:1199. Reichlin S. Somatostatin. N Engl J Med 1983; 309:1495. Kaneto A, Kajinuma H, Kosaka K. Effect of splanchnic nerve stimulation on glucagon and insulin output in the dog. Endocrinology 1975; 96:143. Porte D Jr, Smith PH, Ensinick JW. Neurohumoral regulation of the pancreatic islet A and B cells. Metabolism 1976; 25:1453. Feldman M, et al. Beta-endorphin and the endocrine pancreas. N Engl J Med 1983; 208:350. Felig P, Wahren J, Hendler R. Influence of physiologic hyperglucagonemia on basal and insulin inhibited splanchnic glucose output in normal man. J Clin Invest 1976; 58:961.

medwedi.ru

30

Part One: General Considerations

95. Eigler N, Sacca L, Sherwin RS. Synergistic interactions of physiologic increments of glucagon, epinephrine, and cortisol in the dog. J Clin Invest 1979; 63:114. 96. Felig P, et al. Hormonal interactions in the regulation of blood glucose. Recent Prog Horm Res 1979; 35:501. 97. Unger RH, Dobbs RE, Orci L. Insulin, glucagon, and somatostatin secretion in the regulation of metabolism. Ann Rev Physiol 1978; 40:307. 98. Kawai K, et al. Circulating somatostatin acts on the islet of Langerhans by way of a somatostatin poor compartment. Science 1982; 218:417. 99. Kraus-Friedmann H. Hormonal regulation of hepatic gluconeogenesis. Physiol Rev 1984; 64:170. 100. Nanni G, et al. Increased lipid fuel dependence in the critically ill, septic patient. J Trauma 1983; 24:14. 101. Parmley WW, Glick G, Sonnenblick EH. Cardiovascular effects of glucagon in man. N Engl J Med 1968; 12:279. 102. Posefsky T, et al. Metabolism of forearm tissues in man: studies with glucagon. Diabetes 1976; 25:128. 103. Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology. N Engl J Med 1981; 304:1518. 104. Fradkin J, et al. Evidence for an important role of changes in relative rather than absolute concentrations of glucagon in the regulation of glucose production in humans. J Clin Endocrinol Metab 1980; 50:698. 105. Unger RH. Diabetes and the alpha cell. Diabetes 1976; 25:136. 106. Gibbs DM. Measurement of hypothalamic corticotrophinreleasing factors in hypophyseal-portal blood. Fed Proc 1985; 44(1 Pt 2):203. 107. Makara G. Mechanisms by which stressful stimuli activate the pituitary-adrenal system. Fed Proc 1985; 44:149. 108. Yates FE, Marsh DJ, Maran JW. The adrenal cortex. In: Mountcastle VB, ed. Medical Physiology. 14th ed. St. Louis: Mosby, 1980. 109. Cryer PE. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980; 303:436. 110. Gann DS, Lilly MP. The neuroendocrine response to multiple trauma. World J Surg 1983; 7:101. 111. Wilmore DW, Mason AD, Pruitt BA. Insulin response to glucose in hypermetabolic burn patients. Ann Surg 1976; 183:314. 112. Fain JN, Garcia-Sainz JA. Adrenergic regulation of adipocyte metabolism. J Lipid Res 1983; 24:945. 113. Altszuler N, et al. Glucose metabolism and plasma insulin level during epinephrine infusion in the dog. Am J Physiol 1967; 212:677. 114. Chaisson JL, et al. Inhibitory effect of epinephrine on insulin stimulated glucose uptake by rat skeletal muscle. J Clin Invest 1981; 68:706. 115. Palmer BQ, et al. Epinephrine acutely mediates skeletal muscle insulin resistance. Surgery 1983; 94:172. 116. Goodman HM. The pituitary gland. In: Mountcastle VB, ed. Medical Physiology. 14th ed. St. Louis: Mosby, 1980. 117. Frohman LA. Diseases of the anterior pituitary. In: Felig P, et al., eds. Endocrinology and Metabolism. New York: McGraw-Hill, 1981. 118. Crane CW, et al. Protein turnover in patients before and after elective orthopedic operations. Br J Surg 1977; 64:129. 119. Kenney PR, Allen-Rowlands CF, Gann DS. Glucose and osmolality as predictors of injury severity. J Trauma 1983; 23:712. 120. Keys A, et al. The Biology of Human Starvation. Minneapolis: University of Minnesota Press, 1950. 121. Freund HR, Ryan JA, Fischer JE. Amino acid derangements in patients with sepsis: treatment with branched chain amino acid rich infusions. Ann Surg 1978; 188:423. 122. Kien CL, et al. Increased rates of whole body protein synthesis and breakdown in children recovering from burns. Ann Surg 1978; 187:383. 123. Moore FD, Brennan ME. Surgical injury: body composition, protein metabolism and neuroendocrinology. In: Ballinger WF,

124. 125.

126.

127. 128.

129. 130. 131. 132.

133. 134. 135. 136.

137.

138.

139.

140. 141.

142.

143. 144. 145. 146.

147.

148. 149.

150.

et al., eds. Manual of Surgical Nutrition. Philadelphia: WB Saunders, 1975. Owen OE, et al. Brain metabolism during fasting. J Clin Invest 1967; 46:1589. Jagoe RT, Goldberg AL. What do we really know about the ubiquitin-proteosome pathway in muscle atrophy? Curr Clin Nutr Metab Care 2001; 4:183. Bodine SC, Latres E, Baumhueter S. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 2001; 294:1704. Crowley CV, et al. Effects of environmental temperature and femoral fracture on wound healing in rats. J Trauma 1977; 17:436. Palmblad J, et al. Effect of total energy withdrawal (fasting) on the levels of growth hormone, thyrotropin, cortisol, adrenaline, norepinephrine, T4, T3 and rT3 in healthy males. Acta Med Scand 1977; 201:15. Levenson SM, Seifter E. Starvation. In: Fischer JE, ed. Metabolic and Physiologic Responses. Boston: Little Brown, 1982. Studley HO. Percentage of weight loss, a basic indicator of surgical risk. JAMA 1936; 106:458. Cuthbertson DP. Observations on the disturbance of metabolism by injury to the limbs. Q J Med 1932; 1:233. Cuthbertson DP. Further observations on the disturbance of metabolism caused by injury, with particular reference to the dietary requirements of fracture cases. Br J Surg 1936; 23:505. Moore FD. Bodily changes in surgical convalescence. Ann Surg 1953; 137:289. Wilmore DW, et al. Effect of injury and infection on visceral metabolism and circulation. Ann Surg 1980; 192:491. Askanazi J, et al. Respiratory distress secondary to a high carbohydrate load. Surgery 1980; 86:596. Fain JN, Kovacev VP, Scow RO. Effect of growth hormone and dexamethasone on lipolysis and metabolism in isolated fat cells of the rat. J Biol Chem 1965; 240:3522. Shafnr E, Steinberg D. The essential role of the adrenal cortex in the response of plasma free fatty acids, cholesterol, and phospholipids to epinephrine injection. J Clin Invest 1960; 39:310. Coran AG, et al. Fat and carbohydrate metabolism during hemorrhagic shock in the unanesthetized baboon. Surg Forum 1971; 9:10. Halmagyi DFJ, Irving MH, Varga D. Effect of adrenergic blockade on the metabolic response to hemorrhagic shock. J Appl Physiol 1968; 25:384. O’Keefe SJD, Sender PM, James WPT. Catabolic loss of body nitrogen in response to surgery. Lancet 1974; 2:1035. Kovach AGB, et al. Blood flow, oxygen consumption, and free fatty acid release in subcutaneous adipose tissue during hemorrhagic shock in control and phenoxybenzamine-treated dogs. Circ Res 1970; 26:733. Birkhain RH, et al. A comparison of the effects of skeletal trauma and surgery on the ketosis of starvation in man. J Trauma 1981; 21:513. Mays ET. The effect of surgical stress on plasma-free fatty acids. J Surg Res 1970; 10:315. Oppenheim W, Williamson D, Smith R. Early biochemical changes and severity of injury in man. J Trauma 1980; 20:135. Smith R, et al. Initial effect of injury on ketone bodies and other blood metabolites. Lancet 1975; 1:1. Stoner HB, et al. The relationships between plasma substrates and hormones and the severity of injury in 277 recently injured patients. Clin Sci 1979; 56:563. Miller JDB, Bistran BR, Blackburn GL. Failure of postoperative infection to increase nitrogen excretion in patients maintained on peripheral amino acids. Am J Clin Nutr 1977; 30:1523. Drucker WR, et al. Citrate metabolism during surgery. Arch Surg 1962; 85:557. Morris AS, et al. The role of effectors of phosphofructokinase on the regulation of aerobic glycolysis in a A-carrageenan wounded muscle. Metabolism. In press. Carey LC, Lowery BD, Cloutier CT. Blood sugar and insulin response in human shock. Ann Surg 1970; 172:342.

Chapter 1: 151. Meguid MM, et al. Hormone-substrate interrelationships following trauma. Arch Surg 1974; 109:776. 152. Byrnes GJ, Pirkle JC Jr, Gann DS. Cardiovascular stabilization after hemorrhage depends upon restitution of blood volume. J Trauma 1978; 18:623. 153. Drucker WR, Chadwick CDJ, Gann DS. Transcapillary refill in hemorrhage and shock. Arch Surg 1981; 116:1344. 154. Gann DS. Endocrine control of plasma protein and volume. Surg Clin North Am 1976; 56:1135. 155. Gann DS, et al. Role of solute in the early restitution of blood volume after hemorrhage. Surgery 1983; 94:439. 156. Carey LC, Cloutier CT, Lowery BD. Growth hormone and adrenal cortisol response to shock and trauma in the human. Ann Surg 1971; 174:451. 157. Rizza RA, Mandarino LJ, Gerich JE. Cortisol induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor defect of insulin action. J Clin Endocrinol Metab 1982; 54:131. 158. Cryer PE, Herman CM, Sode J. Carbohydrate metabolism in the baboon subjected to gram-negative septicemia. I. Hyperglycemia with depressed plasma insulin concentrations. J Lab Clin Med 1972; 79:622. 159. Moss GS, et al. Serum insulin response in hemorrhagic shock in baboons. Surgery 1970; 68:34. 160. Black PR, et al. Mechanisms of insulin resistance following injury. Ann Surg 1982; 196:420. 161. Drucker WR, et al. The effect of persisting hypovolemic shock on pancreatic output of insulin. In: Kovach AGB, Stoner HB, Spitzer JJ, eds. Neurohumoral and Metabolic Response to Injury. New York: Plenum Publishing, 1978. 162. Hiebert JM, et al. Insulin response to hemorrhagic shock in the intact and adrenalectomized primate. Am J Surg 1973; 125: 501. 163. Kahn CR. Insulin resistance, insulin insensitivity and insulin unresponsiveness: a necessary definition. Metabolism 1973; 27:1893. 164. Allison SP, Hinton P, Chamberlain JJ. Intravenous glucose tolerance insulin and free fatty acid levels in burn patients. Lancet 1968; 2:1116. 165. Drucker WR, Dekieweit JC. Glucose uptake by diaphragm from rats subjected to hemorrhagic shock. Am J Physiol 1964; 206:317. 166. Long CL, et al. Carbohydrate metabolism in men: effect of elective operations and major injury. J Appl Physiol 1971; 31:110. 167. Randle PJ, Smith GH. Regulation of glucose uptake by muscle. I. The effect of insulin, anaerobosis and cell poisons on the uptake of glucose and release of potassium by isolated rat diaphragm. Biochem J 1958; 70:409. 168. Russel JA, Long CNH, Engel FL. Biochemical studies of shock: peripheral tissues on the metabolism of protein and carbohydrate during hemorrhagic shock in the rat. J Exp Med 1944; 79:1. 169. Swerlick RA, Drucker NA, McCoy S. Insulin effectiveness in hypovolemic dogs. J Trauma 1981; 21:1013. 170. Caldwell MD, et al. Evidence for aerobic glycolysis in A-carrageenan wounded skeletal muscle. J Surg Res 1984; 37:63. 171. Turinsky J. Glucose metabolism in the region recovering from burn injury. Endocrinology 1983; 113:1370. 172. Nelson KM, Turinsky J. Local effect of burn on skeletal muscle insulin responsiveness. J Surg Res 1981; 31:288. 173. Wilmore DW, et al. Influence of the burn wound on local and systemic responses to injury. Ann Surg 1977; 186:444. 174. Hochachka PN. Living Without Oxygen. Cambridge, MA: Harvard University Press, 1980. 175. Romanosky AJ, et al. Increased muscle glucose uptake and lactate release after endotoxin administration. Am J Physiol 1980; 239:E311. 176. Ross R. The fibroblast and wound repair. Biol Rev 1968; 43:51. 177. Abbott WE, Anderson K. The effect of starvation, infection, and injury on the metabolic processes and body composition. Ann NY Acad Sci 1963; 110:941.

Metabolic Response to Starvation, Stress, and Sepsis

31

178. Siegel JH, et al. Physiological and metabolic correlations in human sepsis. Surgery 1979; 86:163. 179. Frawley JP, Artz CP, Howard JM. Muscle metabolism and catabolism in combat casualties. Arch Surg 1955; 71:612. 180. Bilmazer C, et al. Quantitative contribution by skeletal muscle to elevated rates of whole-body protein breakdown in burned children as measured by 3-MEH output. Metabolism 1978; 27:671. 181. Williamson OH, et al. Muscle-protein catabolism after injury in man, as measured by urinary excretion of 3-methyl histidine. Clin Sci Mol Med 1977; 52:527. 182. Ryan NT. Metabolic adaptations for energy production during trauma and sepsis. Surg Clin North Am 1976; S6:1073. 183. Elwyn DH, et al. Interorgan transport of amino acids in hemorrhagic shock. Am J Physiol 1976; 231:377. 184. Engel FL. The significance of the metabolic changes during shock. Ann NY Acad Sci 1956; 55:383. 185. Clowes GHA, Randall H, Cha C. Amino acid and energy metabolism in septic and traumatized patients. JPEN 1980; 4:195. 186. Dale G, et al. The effect of surgical operation on venous plasma free amino acids. Surgery 1977; 81:295. 187. Woolfe LI, Groves AC, Moore JP. Arterial plasma amino acids in patients with serious postoperative infections and in patients with major fractures. Surgery 1976; 79:283. 188. Askanazi J, et al. Muscle and plasma ammo acids following injury. Ann Surg 1980; 192:78. 189. Birkhain RH, et al. Effects of major skeletal trauma on whole body protein turnover in man measured by L-[l,14C]-leucine. Surgery 1980; 88:294. 190. Long CL, et al. Muscle protein catabolism in the septic patient as measured by 3-methyl histidine excretion. Am J Clin Nutr 1977; 30:1349. 191. Stein TP, et al. Changes in protein synthesis after trauma: importance of nutrition. Am J Physiol 1977; 233:E348. 192. O’Donnell TF, et al. Proteolysis associated with a deficit of peripheral energy fuel substrates in septic man. Surgery 1976; 80:192. 193. Clowes GHA, et al. Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma. N Engl J Med 1983; 308:545. 194. Baracos V, et al. Stimulation of muscle protein degradation and prostaglandin E2 release by leukocyte pyrogen (interleukin-1). N Engl J Med 1983; 308:553. 195. Tiao G, Fagan J, Roegner V, et al. Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids. J Clin Invest 1996; 97:339. 196. Hobler SC, Williams AB, Fischer D, et al. Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis. Am J Physiol 1999; 277:R434. 197. Tawa NE Jr, Odessey R, Goldberg AL. Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying not skeletal muscles. J Clin Invest 1997; 100:197. 198. Schrier RW, Berl WT, Anderson RJ. Osmotic and nonosmotic control of vasopressin release. Am J Physiol 1979; 236:F321. 199. Stephens RV, Randall HT. Use of a concentrated, balanced, liquid elemental diet for nutritional management of catabolic states. Ann Surg 1969; 170:642. 200. Levenson SM, Green RW, Taylor FH. Ascorbic acid, riboflavin, thiamine and nicotinic acid in relation to severe injury, hemorrhage and infection in the human. Ann Surg 1946; 124:840. 201. Lund CC, Levenson SM, Green RW. Ascorbic acid, thiamine, riboflavin and nicotinic acid in relation to acute burns in man. Arch Surg 1947; 55:557. 202. Cuthbertson DP. Interrelationships of metabolic changes consequent to injury. Br Med Bull 1954; 10:33–37. 203. Moore FD. Metabolic Care of the Surgical Patient. Philadelphia: WB Saunders, 1959. 204. Hunt TK, Van Winkle W. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management. New York: AppletonCentury-Crofts, 1979:2. 205. Levenson SM, Seifter E, Van Winkle W. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management. New York: Appleton-Century-Crofts, 1979:286.

medwedi.ru

32

Part One: General Considerations

206. Moore FD, Brennan ME. Manual of Surgical Nutrition, by the Committee on Pre- and Post-operative Care of the American College of Surgeons. Philadelphia: WB Saunders, 1975:169. 207. Daly JM, et al. Does wounded tissue regulate hepatic glucose production. Surg Forum 1987; 38:23. 208. Forster J, et al. Glucose uptake and flux through phosphofructokinase in wounded rat skeletal muscle. Am J Physiol (Endocrinol Metab 19) 1989; 256:E788. 209. Caldwell MD. Carbohydrate and energy metabolism in healing wounds. In: Barbul A, et al., eds. Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications. New York: Alan R Liss, 1988:183. 210. Morris A, et al. A macrophage-mediated factor that increases the high energy phosphate content of skeletal muscle. J Surg Res 1985; 38:373. 211. Morris A, et al. Macrophage interaction with skeletal muscle: potential role of macrophages in determining the energy state of healing wounds. J Trauma 1985; 25(8):751. 212. Morris AS, et al. The role of purine metabolism in the macrophage mediated increase in high energy phosphates in skeletal muscle. J Surg Res 1986; 41:339. 213. Caldwell MD. Local glutamine metabolism in wounds and inflammation. Metabolism 1989; 38(suppl 1):34. 214. Goodson WH, Hunt TK. Studies of wound healing in experimental diabetes mellitus. J Surg Res 1977; 22:221. 215. Spanheimer RG, Umpierrez GE, Stumpf V. Decreased collagen production in diabetic rats. Diabetes 1988; 37:371. 216. Yue EK, et al. Effects of experimental diabetes, uremia, and malnutrition on wound healing. Diabetes 1987; 36:295. 217. Rosenberg CS. Wound healing in the patient with diabetes mellitus. Nurs Clin North Am 1990; 25:247. 218. Ehrlich HP, Hunt TK. Effects of cortisone and vitamin A on wound healing. Ann Surg 1968; 167:324. 219. Hunt TK, et al. Effects of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animal and man. Ann Surg 1969; 170:633. 220. Salmela K, et al. The effect of local methylprednisolone on granulation tissue formation. Acta Chir Scand 1980; 146:541. 221. Seifter E, et al. Arginine: an essential amino acid for injured rats. Surgery 1978; 84:224. 222. Barbul A. Arginine: biochemistry, physiology and therapeutic implications. J Parenter Enter Nutr 1986; 10:227. 223. Skottner A, et al. Anabolic and tissue repair functions of recombinant insulin-like growth factor l. Acta Paediatr Scand (Suppl) 1990; 367:63. 224. Hassett J, Border JR. The metabolic response to trauma and sepsis. World J Surg 1983; 7:125. 225. Lin E, Lowry SF, Calvano SE. Mediators of inflammation and injury. In: Norton JA, Bollinger RR, Chang AE, et al., eds. Surgery: Scientific Basis and Evidence-Based Practice. New York: Springer-Verlag, 2001:69–94. 226. Fong Y, Lowry SF. Cytokines and the cellular response to injury and infection. In: Wilmore DW, et al., eds. ACS Surgery: Principles and Practice. New York: Wed MD, 2002:1603–1622. 227. Fink MP. The role of cytokines as mediators of the inflammatory response. In: Townsend CM Jr, ed. Sabiston Textbook, of Surgery. Philadelphia: Elsevier Saunders, 2004:45–66.

228. Bessey PQ. Metabolic response to critical illness. In: Wilmore DW, et al., eds. ACS Surgery: Principles and Practice. New York: Wed MD, 2002:1495–1520. 229. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265:621. 230. Koj A. Definition and classification of acute phase proteins. In: Gordon AH, Koj A, eds. The Acute Phase Response to Injury and Infection. New York: Elsevier, 1985:139–147. 231. Kushner I. The acute phase response: an overview. Methods Enzymol 1988; 163:373. 232. Hasselgren PO. Protein metabolism in surgery. In: Norton JA, Bollinger PR, Chang AE, et al., eds. Surgery: Scientific Basis and Evidence-Based Practice. New York: Springer-Verlag, 2001:105–121. 233. Enayati P, Brennan MF, Fong Y. Systemic and liver cytokine activation. Arch Surg 1994; 124:1159. 234. Lin E, Calvano SE, Lowry SF. Cytokine response in abdominal surgery. In: Schein M, Wise L, eds. Cytokines and the Abdominal Surgeon. Austin: Landes, 1998:17–34. 235. Del Rey A, Besedovsky HO. Metabolic and neuroendocrine effects of pro-inflammatory cytokines. Eur J Clin Invest 1992; 22:10. 236. Besedovsky H, Del Rey A, Sorkin E, et al. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986; 233:652. 237. Hocke GM, Barry D, Fey GH. Synergistic action of interleukin6 and glucocorticoids is mediated by the interleukin-6 response element of the A2-macroglobulin gene. Mol Cell Biol 1992; 12:2282. 238. Zamir O, Hasselgren PO, Higashiguchi T, et al. Tumor necrosis factor (TNF) and interleukin-l (IL-1) induce muscle proteolysis through different mechanisms. Mediat Inflamm 1992; 1:247. 239. Zamir O, Hasselgren PO, Kunkel S, et al. Evidence that tumor necrosis factor participates in the regulation of muscle proteolysis during sepsis. Arch Surg 1992; 127:170. 240. Goodman MN. Interleukin-6 includes skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 1994; 205:182. 241. Mealy K, van-Lanschot JJ, Robinson BG, et al. Are the catabolic effects of tumor necrosis factor mediated by glucocorticoids? Arch Surg 1990; 125:42. 242. Fong YM, Moldawer LL, Marano MA, et al. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 1989; 256:R659. 243. Tracey KJ, Wei H, Manogue KR, et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med 1988; 167:1211. 244. Moldawer LL, Anderson C, Gelin J, et al. Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 1988; 254:G450. 245. Oliff A, Defeo-Jones D, Boyer M, et al. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 1987; 50:555. 246. Tracy KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470.

2 Pathophysiology of Fluid and Electrolyte Disorders Peter J. Fabri and Mark Bloomston

INTRODUCTION The human body can be likened to a sac of electrolyte-rich fluids in which is suspended or dissolved a complex network of solids known collectively as ‘‘organs.’’ The common medium of these fluids is water; the electrolytes are a mixture of primarily monovalent and divalent ions. The total volume of water, known as total body water, accounts for approximately 60% of total body mass. Substances are continually added to and excreted from this aqueous environment, and only through a system of homeostatic, protective mechanisms is the composition and distribution of this fluid-based system maintained. Disease, pharmaceuticals, and medical interventions all have the potential to disrupt the balance of this fluid medium and result in clinically evident fluid and electrolyte disturbances. To achieve the desired goal of preventing or treating such disturbances, the nature, composition, and interrelationships of these fluids and the homeostatic mechanisms that maintain them must be clearly understood.

MAINTENANCE OF THE INTERNAL MILIEU Total Body Water Water is the universal solvent of the human body. The total volume of this substance is subdivided into discrete parts known as intracellular, extracellular, and transcellular water (Fig. 1). These parts are separated by semipermeable membranes equipped with energy-consuming, work-producing pumps that are usually based on an adenosine triphosphatase (ATP-ase) enzyme system. These pumps are able to maintain electrochemical and concentration gradients across membranes, which result in a marked difference in composition between the intracellular and extracellular spaces. Water, on the other hand, passively follows the laws of osmotic and ionic equilibrium. It traverses these membranes freely to maintain an equal number of solute molecules (osmolality) and ionic particles (tonicity) per unit volume on each side of such semipermeable membranes. This difference between the control of solutes/ions and that of water results in marked differences in volume and electrolyte composition of the two spaces. The normal balance can be disturbed by changing the number of solute molecules on either side of the membrane (e.g., hypoalbuminemia and hyperglycemia) or by disrupting its enzyme-based pumps (e.g., shock and digitalis). The extracellular space can be considered an open system in that the alimentary tract serves as a mode of entrance and exit of water and solute, as shown in Figure 1. Similarly, the lungs, kidneys, and skin also serve as excretory conduits. Entrance and excretion of water and solute are

controlled by active systems that are under homeostatic (nervous or hormonal) control. Thus the composition of this open, extracellular system can be maintained within relatively tight limits (1). Nonstandard entrance routes, such as the administration of fluids intravenously, bypass the normal entry control mechanisms and directly add water and solute to the extracellular space. In this circumstance, the intrinsic ability of the excretory systems to maintain osmotic and ionic stability becomes the limiting factor in maintaining ionic stability and composition of the extracellular space. Failure of these excretory control mechanisms, by inability to either conserve or increase loss, threatens the chemical stability of the extracellular fluids. The intracellular space, on the other hand, is a closed space and is represented by the numerous cells floating within the extracellular water in Figure 1. The only route of entrance and exit is across the semipermeable cellular membrane and its contained enzyme systems. Therefore, extracellular space can be thought of as a conduit and buffer zone to the intracellular space. Only by transfer from or to the extracellular water can intracellular composition be changed. This complex system, richly furnished with active transport mechanisms and buffer zones, rigidly protects the stability of the body fluids and maintains constancy of

Figure 1 Conceptualized model of the human body. Note that everything enters into, is excreted from, and is sampled in extracellular water.

medwedi.ru 33

34

Part One: General Considerations

Table 1 Normal Distribution of Body Water as Percent of Body Weight

Total body water Extracellular water Intracellular water a

a

Men (%)

Women (%)

60 15 45

55 15 40

Values are less than equivalent for men because women have a relatively greater amount of adipose tissue.

the internal milieu. Although not depicted accurately in our model, two-thirds of total body water is intracellular and one-third is extracellular. This translates to about 40% and 20% of total body weight for the intracellular and extracellular compartments, respectively (Table 1).

Extracellular Water The extracellular space is composed of the intravascular space (blood cells plus plasma) (comprising about 8% of total body weight) and the extravascular space (interstitial fluid and lymph). Cerebrospinal fluid is a specialized subspace of extracellular fluid. The vascular and extravascular spaces are in relative continuity, separated only by the rather permeable basement membranes of the blood vessel walls. When these vessels are intact, the formed cellular elements of the blood remain contained in the intravascular space, whereas the aqueous, noncellular plasma undergoes continuous ‘‘filtration’’ through the relatively leaky vessel walls into the extravascular space. The extravascular space, however, is continuously ‘‘drained’’ by a system of lymphatic channels that return protein-rich extracellular fluid to the vascular space through the lymphatic ducts. This continuous-cycle system results in moment-to-moment renewing of the interstitial, pericellular space, bringing fresh nutrients from and carrying waste products to the vascular space, which is in direct continuity with normal routes of intake and excretion. The volume of intravascular fluid (blood) is determined by the oncotic effect of blood cells and large molecules such as albumin, as well as the rate of return of lymph. The volume of the extravascular fluid space depends on the balance between ‘‘filtration’’ of plasma and ‘‘drainage’’ of lymph. Plasma is continuously filtered across the vascular pores, particularly at the capillary level. The rate of filtration is governed by Starling’s law, which takes into account net hydrostatic pressure, net oncotic pressure, and pore size (reflectance and permeability). Fluid shifts across the vascular membrane are controlled by the summed effect of hydrostatic and oncotic pressures. Hydrostatic pressure exists in both the vessel (mean capillary pressure) and the tissue (mean tissue pressure). The difference results in a vector force that typically acts to drive fluid into the extravascular space. Simultaneously, this vector is offset by an oncotic pressure vector, which is the net difference between plasma oncotic pressure and tissue oncotic pressure adjusted for a permeability factor (reflectance) that varies as the ‘‘size’’ of the pores changes. Ordinarily, these vectors, on the average, tend to cancel, and there is only a small flux of fluid across the membrane. However, alteration in any of the main forces can lead to marked derangement in fluid distribution and the development of increased interstitial fluid, a condition recognized as clinical edema. The balanced forces in Starling’s equation result in the passage of fluid across the vascular membrane into the interstitial (extravascular) space. Not addressed in Starling’s equation is the ‘‘drainage’’ effect of the lymphatic system that tends to remove filtered plasma

from the interstitium. Obstruction of lymphatics by conditions such as tumor and infection can further impair fluid clearance and result in localized edema or lymphedema.

Osmolality and Tonicity The composition of extracellular water is reflected by the concentration of solutes. Ordinarily, extracellular composition is maintained within narrow limits by accurate renal control mechanisms [e.g., antidiuretic hormone (ADH) and aldosterone]. These control mechanisms, however, tend to respond to the concentration of a given substance rather than to the total amount of all substances. Concentration represents the combined effect of the amount of a given substance (numerator) dissolved in a given amount of water (denominator). Thus abnormalities in concentration may represent changes in the amount of solute, amount of water, or both. The concentration of total solute is most easily measured by plasma osmolality (mOsm/kg). This value indicates the ratio of solute to water in the plasma and in the extravascular space. Because extracellular water is in equilibrium with intracellular water, shifts of membrane permeable water result in maintenance of osmotic equality throughout total body water. In other words, accumulation of intracellular solute is compensated by a shift in water from the extracellular space to the intracellular space until osmolality is equal and vice versa. The concentration of total ions, indicating ionic strength, is approximated by assessing the concentration of the principal extracellular cation, sodium. Changes in sodium concentration represent changes in tonicity, a term related to but not synonymous with osmolality. Typically, tonicity and osmolality change together, and hyperosmolality usually includes hypertonicity (2). However, any substance that has a low molecular weight and a sizable concentration will contribute to serum osmolality. Thus conditions such as hyperglycemia, azotemia, hyperlactatemia, and accumulation of ethanol, which add solute but not ions, will raise osmolality without a change in tonicity. The contributing factors to osmolality can be understood more clearly by determining the osmolal gradient. This represents the difference between calculated (Osm[c]) and measured (Osm[m]) osmolality. Calculated osmolality is estimated by the formula Osm½c ¼ 1:86½Na þ Glu=18 þ BUN=2:8 where Na is serum sodium concentration in mequiv/L, Glu is serum glucose in mg/100 mL, and BUN is blood urea nitrogen in mg/100 mL. [1.86 is twice the osmotic activity coefficient of a monovalent ion; 18 is the molecular weight of glucose divided by 10 (a correction factor to convert mg/dL to mg/L); and 2.8 is the molecular weight of urea nitrogen divided again by the correction factor 10.] Ordinarily the osmolal gradient is less than 10 mOsm/kg where Osmolal gradient ¼ Osm½m Osm½c A gradient greater than 10 mOsm/kg represents the accumulation of some unmeasured, osmotically active (low molecular weight) substance such as lactate, ethanol, or mannitol. A common error in clinical practice is to assume that a change in measured osmolality represents an increase or decrease in water. As might be anticipated, osmolality is a concentration term and therefore can be disrupted by a change in amount of solute (e.g., azotemia) or amount of water (e.g., dehydration) or both (e.g., hyperosmolar coma).

Chapter 2:

Table 2 Electrolyte Composition

Total body content (mequiv/kg) Exchangeable content (mequiv/kg) Intracellular concentration (mequiv/L) Plasma water concentration (mequiv/L) Serum concentration (mequiv/L)

Na

K

Cl

Ca

Mg

67

58

42

940

32

41

44

30

–

–

10

160

3

2

26

152

5

110

5

3

142

5

103

5

–

Because measured osmolality equals the ratio of solute molecules to water: Osm ¼ solute=water

Pathophysiology of Fluid and Electrolyte Disorders

35

only part of the system that is able to ‘‘control’’ its output. Accepting that fact, it is helpful to think of renal homeostasis as ‘‘throwing the baby out with the bath water, and catching the baby before it goes down the drain.’’ In other words, glomerular filtration, the frontline initiator of renal excretion, is relatively nonspecific. It only limits excretion of substances that are associated with large proteins and therefore too big to pass through the renal vascular pores. Glomerular filtrate, therefore, is an ultrafiltrate of plasma. This ultrafiltrate passes through the proximal tubule where approximately 95% of most solutes and water are reabsorbed. In effect, control of excretion to this point is really a question of ‘‘what isn’t reabsorbed.’’ Final modification of urinary composition takes place in the distal tubule and collecting duct, where sodium is, in a matter of speaking, ‘‘exchanged’’ for hydrogen or potassium and the remaining water is either reabsorbed or not (8–11).

Sodium and Water Homeostasis

By rearrangement, the amount of solute determines the osmolality multiplied by total body water (which can be estimated as 60% of total body weight), as shown by the formula: Solute ¼ Osm 0:6 wt Estimation of this variable allows assessment of changes in total body solute, and, by comparison, permits an appraisal of relative changes in body water versus body solute.

Electrolyte Composition As previously indicated, intracellular and extracellular fluids vary in concentration of electrolytes. The total body content of each electrolyte (3) has been estimated by direct assay (4) and by radionuclide exchange (exchangeable ion) (5–7). The distribution of these electrolytes is unequal and results in marked concentration differences throughout the body (Table 2). Most of the difference between total body content (gravimetric) and exchangeable content is accounted for as substance in bone. As a glance at Table 2 will confirm, and contrary to the impression gained from evaluating serum electrolytes, the content of total exchangeable sodium (Na) is roughly equal to the content of total exchangeable potassium (K). The sum of these ions (exchangeable Na þ K) validly estimates total body cations that are roughly equally divided between intracellular and extracellular water. Accordingly, the serum sodium concentration (or conversely the intracellular potassium concentration) represents the ratio of total body cations to total body water, as shown below: Na ðserumÞ ¼ ðNa þ KÞ=ð0:6 wtÞ By a process analogous to osmolality, cross-multiplying serum sodium concentration by an estimate of total body water yields total body exchangeable cations. An estimate, therefore, of total body water, total body solute, and total body cations allows a more detailed serial assessment of fluid and electrolyte balance for patients in whom derangements are suspected.

HOMEOSTATIC CONTROL MECHANISMS General Concepts The kidney is the cornerstone of the homeostatic mechanisms controlling fluid and electrolyte balance. Although it is true that fluid losses from the skin, lungs, and gastrointestinal (GI) tract may be impressive, the kidney is the

Intracellular water is in equilibrium with extracellular water through osmotic and ionic neutrality. A small gradient is accounted for by anion proteins, which results in a concentration inequality referred to as the Gibbs–Donnan distribution. Extracellular water is controlled largely by plasma volume and serum sodium concentration. Sodium and water conservation must be considered together because their control mechanisms are inseparable. Water deficits or excesses are compensated by changes in ADH release from the pituitary, and its effects within the renal collecting duct (12–14). Changes in sodium composition are accompanied by both ADH and mineralocorticoid responses. A decrease in plasma volume stimulates baroreceptors located in sites such as the right atrium and carotid body, as well as in the juxtaglomerular apparatus and macula densa of the kidney (15). The baroreceptor response results in an increase in ADH release from the posterior pituitary and causes decreased loss of solute-free water in the collecting duct of the kidney. Conversely, as the serum sodium concentration falls, ADH release will be inhibited, and further water conservation will be blunted. The simultaneous effects of decreased glomerular filtration leading to decreased sodium delivery to the juxtaglomerular apparatus results in renin release, which subsequently causes cleavage of angiotensinogen into the decapeptide angiotensin I. This latter substance is converted in the lung to the octapeptide angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is a very potent vasoconstrictor that also directly stimulates aldosterone release from the zona glomerulosa of the adrenal cortex. The resultant increase in circulating aldosterone increases sodium reabsorption in the distal tubule of the kidney, in exchange for potassium and/or hydrogen ions. As serum sodium concentration changes, release of ADH from the posterior pituitary is altered by osmoreceptors in the hypothalamus. Very small changes (e.g., 2 mOsm) can predictably result in a measurable change in plasma ADH levels. Corresponding changes in thirst perception and in the permeability of the collecting duct of the kidney to water also occur. In the case of hypernatremia, thirst increases, and maximum retention of solute-free water occurs in the kidney. This can be corroborated by a high measured urine osmolality (usually >500 mOsm). During hyponatremia, ADH release is inhibited, the stimulus for water conservation in the collecting duct ceases, and solute-free water (‘‘free water’’) is excreted, resulting in hypotonic (< 280 mOsm/kg) urine and a return of serum sodium to normal. In addition, the zona glomerulosa

medwedi.ru

36

Part One: General Considerations

of the adrenal appears to be sensitive to changes in serum sodium concentration, resulting in feedback control of aldosterone release.

Potassium Homeostasis Control of serum potassium levels is quite unlike that of sodium. Sodium is controlled at both the intake and excretion level, whereas potassium intake is unregulated. Potassium, then, is controlled entirely by excretion. Potassium is primarily an intracellular ion, with a concentration many fold greater than plasma. Yet, the extracellular concentration is extremely important in maintaining electrochemical gradients across cell membranes that facilitate depolarization of electrically active cells such as cardiac muscle and specialized conduction cells. Therefore control of extracellular potassium is vitally important. Typically, mammalian diets contain very large amounts of potassium, such that conservation of potassium is not usually a problem unless losses are excessive (diuresis and diarrhea) or renal mechanisms are abnormal (hyperaldosteronism). Potassium conservation and excretion tends to be a direct contrast to sodium conservation. Excess potassium, for example, stimulates the release of aldosterone from the adrenal, whereas too little sodium would result in the same response (16,17). While the majority of potassium reabsorption (like sodium) occurs in the proximal tubule, it is excreted in the distal tubule in response to the aldosterone stimulus. Sodium can be reabsorbed almost entirely within the nephron, whereas potassium conservation is less complete until profound body deficits occur. Distal tubular flow rate is also a major factor in potassium homeostasis. As flow rates increase, potassium excretion becomes inappropriately high. Although total body potassium distribution is greatly affected by renal mechanisms, it is also subject to exchange mechanisms at the cell surface of all cells such that, as sodium (or hydrogen) is transported out, potassium reenters the intracellular fluid (probably insulindependent). Likewise, in severe acidosis or alkalosis, plasma potassium levels may change as a result of the fluxes of potassium that are consequent to the hydrogen ion shifts.

Calcium Homeostasis The majority of calcium in the human body is complexed within the rigid crystal lattice of bone. This phase of calcium hydroxyapatite and phosphate is in equilibrium with three other forms of calcium: protein-bound, ionic complex, and ionic. Only the latter, ionic calcium, is physiologically active. In normal physiology, this very small amount of calcium is responsible for a large number of functions, including extracellular, transcellular, and intracellular communication; coordination of protein structure, including clotting factors; electrical triggering of active cells, such as myocytes; second messenger function together with calmodulin; activation of enzymes; and many others. Because of the many life-critical functions of calcium, its concentration is very tightly controlled and the cell is capable of functioning normally in an environment with little calcium intake. Consequently, normal homeostatic mechanisms do an admirable job at maintaining calcium-dependent physiologic processes in a wide variety of situations. Said another way, clinical abnormalities of calcium metabolism are very rare except in specific circumstances. Normal laboratory measurement of calcium assays all three components of nonbone calcium, yet only the ionized fraction is active. Numerous nomograms and algorithms have attempted to allow the physiologic fraction to be estimated based on serum protein concentrations, but

recent studies suggest that such estimates have little clinical utility and that ionized calcium must be measured to identify clinical hyper- or hypocalcemia. Calcium in the serum is regulated by the interplay of two hormones, parathyroid hormone (parathormone, PTH) and 1,25 dihydroxyvitamin D3. Calcitonin, which is important in other animal species, has not been identified as being of importance in calcium homeostasis in humans. PTH is produced as a very large macropeptide, undergoes posttranslational cleavage to the smaller 84–amino acid peptide, and is released by the parathyroid glands. The parathyroid glands, in turn, have calcium receptors (CaR), which recognize the level of ionized calcium in the extracellular fluid within the parathyroids. Even a small decrease in ionized calcium produces an immediate increase in PTH release and, if of long duration, hyperplasia of the parathyroids themselves. Similarly, a small increase in ambient calcium turns off PTH release and, if of long duration, regression of the parathyroids. This increase in PTH increases the mobilization of calcium from bone, increases the resorption of calcium in the renal tubule, and enhances excretion of phosphate in the renal tubule. Additionally, prolonged increase in PTH elevation induces an increase in hydroxylation of vitamin D in the kidney. 1,25 dihydroxyvitamin D3 increases the absorption of both calcium and phosphate from the intestine. A second hormone, parathyroid hormone–related peptide, homologous with PTH, is often produced in tumors, particularly squamous cell neoplasms, and leads to tumoral hypercalcemia. This must be distinguished from an alternative form of malignancy-related hypercalcemia seen in advanced disease where the tumor is actively invading the bone, leading to osteoclast and osteoblast mobilization and subsequent hypercalcemia. Hypercalcemia can also be produced by diseases that cause an increase in active vitamin D, such as lymphoma, granulomatous diseases including sarcoidosis, and excessive intake of vitamin D in the diet or supplements. When a patient is identified with hypercalcemia, the urgency of correction must be established. Mild hypercalcemia or intermittent hypercalcemia rarely produces physiologically important abnormalities or even symptoms and therefore does not require management. Calcium levels above 12 mg/dL have traditionally been considered urgent, requiring aggressive treatment, and above 14 mg/dL, as a medical emergency (hypercalcemic crisis). Saline diuresis and inhibition of bone resorption with biphosphonates or calcitonin is the mainstay of treatment. Hypercalcemia, if persistent, produces a physiologic equivalent of nephrogenic diabetes insipidus, resulting in volume loss and hypernatremia, with the symptoms of polydypsia and polyuria. Treatment with fluids alone will correct the electrolyte abnormalities but will not correct the underlying cause of the hypercalcemia (18). Hypocalcemia is often seen in critically ill individuals and in individuals who have hypoalbuminemia. Because serum calcium levels are often measured in the basic metabolic panel used in hospitalized patients, the treatment of hypocalcemia as an electrolyte problem is often considered. Current evidence suggests that the hypocalcemia seen in hospitalized patients (except hypoparathyroidism following thyroid or parathyroid surgery) is almost never of clinical significance and does not require treatment. Furthermore, evidence is accumulating that PTH release and responsiveness of the CaR are altered as part of the acute injury response, suggesting that hypocalcemia is actually a programmed component of acute injury (19).

Chapter 2:

In the final analysis, ionized calcium is very tightly controlled and is not often a fluid and electrolyte issue. Treatment of asymptomatic hypocalcemia does not appear to be needed and may even be detrimental. Although the discovery of hypercalcemia clearly requires the establishment of a diagnosis, mild hypercalcemia also does not usually require treatment as a fluid and electrolyte issue unless the calcium level is greater than 12 mg/dL.

Acid/Base Conservation With the exception of several specialized body fluids, the pH of body water is very closely guarded in a narrow range. Normal plasma pH (7.4 0.05) generally is representative of the pH of total body water, although the pH of fluids such as cerebrospinal fluid and intracellular fluid may transiently diverge from that of plasma because of differing controlling factors and influences. For practical purposes, however, the pH of all compartments of body water can be assumed to be equal. To appreciate the intricacies of acid/base balance, a solid understanding of the basic chemical concepts of acids, bases, and dissociation is essential. Acids are substances that have the capability of donating protons (hydrogen ions and hydronium ions). Bases, conversely, are substances that have the ability to accept protons during chemical reactions. Both acids and bases are ionic compounds that, when dissolved in water, have the ability to dissociate into cationic and anionic species. For most organic acids and bases in the body, dissociation is only partial, and the ratio of dissociated to nondissociated forms is determined by the dissociation constant. Acids, when dissociated, contribute hydrogen ions (Hþ) and a corresponding anion (An) to the total ionic composition of the solution. Bases typically contribute a cation and a hydroxyl (OH) ion. A typical acid (or base) dissociation can be described by the chemical reaction: HAn ¼ Hþ þ An: The dissociation constant is determined by the ratio of products to reactants; therefore: K ¼ ½Hþ ½An=½HAn; where the brackets represent concentration in solution. Taking the logarithm of both sides of this equation results in a useful and familiar form of the dissociation equation: logK ¼ log Hþ þ logð½An=HAnÞ pK ¼ pH logð½An=½HAnÞ pH ¼ pK þ logð½An=½HAnÞ: The dissociation constant (and consequently the pK) takes into account the simultaneous equilibrium of water. In the human, many acid/base pairs (buffer pairs) exist in simultaneous equilibrium. This means that the ambient pH of the body determines the ratio of anion to dissociated acid for a number of acids present in the body. Although substances such as phosphoric acid, proteins, and amino acids are all present in abundance and could be used as estimates of acid/base status, the carbonic acid/bicarbonate buffer system is most commonly used for this purpose. Bicarbonate is not the major buffer in the human body (pKa ¼ 6.1). In fact, hemoglobin and proteins make up the bulk of the buffering capacity (maintenance

Pathophysiology of Fluid and Electrolyte Disorders

37

of pH within narrow limits). The reason for measuring the bicarbonate/carbonic acid component of the buffer system is clear. Again, the organic acids and bases in extracellular water are in equilibrium with each other, so any pair could be used to evaluate acid/base status. The major homeostatic mechanisms of acid/base control are pulmonary (the excretion of carbon dioxide) and renal (the conservation of bicarbonate and excretion of hydrogen ions). Consequently, this buffer pair reflects the efficacy of the homeostatic mechanisms that are operative in compensating for changes in the gain or loss of acid or base. In addition, bicarbonate and carbon dioxide (pCO2) are easily measured in plasma. The general dissociation equation, when applied to the bicarbonate/carbonic acid buffer system, is known as the Henderson–Hasselbach equation: pH ¼ 6:1 þ logð½HCO 3 =½H2 CO3 Þ; where [HCO 3 ] is the concentration of bicarbonate and [H2CO3] is the concentration of carbonic acid. Because the concentration of carbonic acid is determined by the partial pressure of carbon dioxide, and the solubility of carbon dioxide in water is 0.03 pH ¼ 6:1 þ logð½HCO 3 =0:03 pCO2 Þ and ½Hþ ¼ 24ðpCO2 =½HCO 3 Þ: Current technology allows the direct measurement of pH and pCO2 in arterial (or venous) blood, enabling the estimation of bicarbonate concentration by the above equation. Alternatively, measurement of bicarbonate concentration and pH would enable calculation of pCO2. In normal circumstances, the ratio of [HCO 3]/0.03 pCO2 is 20/L. Other electrolytes enter the body pool only by ingestion (or injection), but acids (and bases) are rarely present in the diet. Acid is a product of metabolism of other substances and is added to total body water as a function of the rate of metabolism and the fractional use of acidproducing metabolites (Table 3). In general, net acid production is approximately 1 mequiv/kg/day (2 to 3 mequiv/kg/day in infants) and is primarily caused by the production of sulfuric acid from metabolism of thiols; phosphoric acid from metabolism of organic phosphates; and other organic acids from the metabolism of proteins, carbohydrates, and fats. Any addition of base (e.g., antacids) or compounds that generate base (e.g., citrate and lactate) will tend to offset the daily endogenous acid load. Table 3 Physiologic Factors Affecting Plasma Acidity Through plasma bicarbonate changes Rate of hydrogen ion input Rate of hydrogen ion or bicarbonate loss (gastrointestinal) Availability of buffers Bicarbonate space of distribution Rate of net renal acid excretion

medwedi.ru

Through plasma pCO2 Rate of carbon dioxide production Rate of alveolar ventilation

38

Part One: General Considerations

To maintain acid/base equilibrium, the body must excrete a quantity of acid equal to endogenous production (plus any exogenous acid and minus any exogenous base). This is accomplished primarily by renal excretion of fixed acid in the form of phosphates and ammonia. Ammonia is actively produced by metabolism of glutamine in the kidney and subsequently excreted into the renal tubular lumen. Simultaneously, monohydrogen phosphate is filtered at the glomerulus. Hydrogen ions, filtered or secreted, are trapped by the buffering capability of these two proton acceptors and excreted. In addition, through a carbonic anhydrase– dependent system, the tubular epithelial cell is capable of generating a hydrogen ion and a bicarbonate ion from carbonic acid (dissolved carbon dioxide) and reabsorbing the bicarbonate while the hydrogen ion is excreted. This regenerates the bicarbonate pool and facilitates acid/base stability. If the bicarbonate pool becomes excessive, renal excretion of bicarbonate is increased by a complex mechanism dependent on the decreased hydrogen ion in the tubular fluid. In effect, therefore, the kidney is able to directly influence acid excretion by three mechanisms: excretion of phosphate (affected by glomerular filtration and parathyroid hormone), synthesis of ammonia, and control of the directional flow of bicarbonate. The last of the three mechanisms just enumerated requires further comment. Because of the ready availability of carbon dioxide and water (and consequently carbonic acid), the kidney, through carbonic anhydrase, can control the abundance of hydrogen ions and bicarbonate. By directing the excretion of hydrogen ions into the tubular lumen and the return of bicarbonate to plasma, the kidney has a great capacity to excrete acid and control base levels. Only when the renal mechanisms responsible for reabsorption of base or excretion of acid are compromised does the renal contribution to acid/base balance become limited. In normal circumstances, the rate at which the kidney returns bicarbonate to the body is equivalent to the rate of sodium/hydrogen exchange in the distal tubule. Although the proximal tubule is quantitatively the most important site of bicarbonate reabsorption in the kidney, with a small contribution from the loop of Henle, the distal segment is capable of ‘‘fine-tuning’’ the acid/base excretory balance.

Acute Injury Response Since the discovery of interleukin-1 in 1981, we have continued to learn about the system of cytokines and chemokines, which mediates what is often called the ‘‘acute injury response.’’ Current evidence suggests that the macrophage reacting to surface receptor signals from infectious agents, allergens, trauma, chemokines, and other agonists initiates a vigorous biochemical response leading to a cascade of interrelated events that alter metabolism, body temperature, cellular response, hepatic protein synthesis, and renal handling of fluid and electrolytes (20). More recent evidence suggests that many, if not all, of the observations usually referred to as ‘‘sepsis’’ can actually be explained by the human response to activation of a cell receptor (toll-like receptor). This would imply that what historically has been considered to be an effect of gram-negative endotoxin may actually be the host response to the presence of chemical substances (lipopolysaccharide from the cell wall) rather than a toxic effect of the substances themselves. The impact on fluid and electrolyte balance appears to be primarily mediated by a ‘‘nonphysiologic’’ release of ADH and mineralocorticoids. This increase in the substances that control the reabsorption of salt and water in the distal portion of

the nephron results in decreased renal excretion (often manifested as oliguria) in an attempt to protect the volume and composition of extracellular water. The recognition of the importance and ubiquity of this acute injury response may result in a change in our methods of intravenous fluid therapy as we more fully understand the significance of this hormonal response to injury.

Effect of Medications It is beyond the scope of this chapter to address specific effects of drugs used in clinical practice. It is nevertheless important to recognize that commonly used pharmaceutical agents can produce significant fluid and electrolyte abnormalities. One hundred fifty-two separate drugs are identified as having hyponatremia as a major side effect. These are broadly categorized as agents that cause loss of sodium in the kidney (e.g., diuretics) or that enhance the retention of water in the renal collecting duct [e.g., syndrome of inappropriate antidiuretic hormone (SIADH)]. Hypokalemia is also commonly produced by drugs. Loop-active diuretics, amphotericin B, and drugs producing metabolic alkalosis are commonly responsible. It is prudent to consider the possibility of an adverse drug effect early in the course of evaluating new onset fluid and electrolyte abnormalities (21–24).

PATHOPHYSIOLOGY AND TREATMENT OF SPECIFIC ELECTROLYTE AND ACID/BASE ABNORMALITIES To understand abnormalities of electrolyte homeostasis, some attention must be given to normal daily requirements (Table 4) (25). Although it is true that a state of electrolyte balance requires that intake be equal to losses (and losses can be minimized), realistically there will be daily excretion of electrolytes of a fairly predictable magnitude, allowing a range of estimated daily needs. Under normal conditions, water losses occur primarily through urinary excretion, evaporation from the skin, and water losses through the lungs. The latter two sources are referred to as insensible losses because they are not visible or readily measurable and amount to 500 to 800 mL [300 mL/m2 body surface area (BSA)] of water daily, with almost negligible amounts of sodium and chloride. Urine is the major sensible loss (one that is visible and measurable) and averages between 1200 and 1500 mL of water daily, with 10 to 30 mequiv of sodium and 20 to 60 mequiv of potassium. Another sensible loss is water loss through the feces, which is usually quite minimal. Losses greater than those routinely encountered (e.g., diarrhea) will result in corresponding increases in requirements; increases in normal excretion rates (e.g., renal failure) will necessitate a reduction in intake.

Abnormalities of Water Balance Disturbances in the amount and distribution of total body water are common in clinical practice. Because water Table 4 Adult Daily Requirements Normal Water (total) Water (insensible) Sodium Potassium Chloride Calcium Magnesium Source: From Ref. 25.

2

1500 mL/m 500 mL/m2 0.7–3.6 mequiv/kg 0.7–2.1 mequiv/kg 0.7–3.6 mequiv/kg 0.4–1.1 mequiv/kg 0.3–0.7 mequiv/kg

Minimal 870 mL/m2 – 0.3 mequiv/kg 0.3–0.5 mequiv/kg 0.3 mequiv/kg 0.2 mequiv/kg 0.2–0.4 mequiv/kg

Chapter 2:

distributes throughout the body, restricted in its movement only by osmotic and ionic barriers, abnormalities in amount, with maintenance of normal electrolyte concentrations (i.e., isotonic), are frequent. An isotonic increase in total body water results in edema, whereas an isotonic decrease produces clinical dehydration. Because electrolyte conservatory mechanisms are extremely efficient, deviation from isotonicity is uncommon except at the extremes of age, when compensatory mechanisms are less adequate or access to water or salt is restricted. In infants and the elderly, therefore, hypertonic (sodium > 145 mequiv/L) and hypotonic (sodium < 135 mequiv/L) abnormalities are more common and require that attention be given to the volume as well as the concentration problems. It is important to realize that isotonic abnormalities in total body water are more prevalent than other fluid derangements in adults, only because compensatory mechanisms maintain the concentration of important solutes. In circumstances where a coexistent problem compromises these compensatory mechanisms (e.g., renal disease, inappropriate ADH secretion, diuretic use, and adrenal insufficiency), a superimposed fluid loss or gain may very well not be isotonic. Dehydration is an absolute decrease in total body water and usually represents a balanced loss between intracellular and extracellular volume. Dehydration can be assessed on clinical grounds alone, and in fact, there is no readily available ‘‘test’’ that identifies dehydration unless there is a coexistent abnormality of concentration. Blood urea nitrogen and consequently osmolality are frequently elevated, however, and may be supportive of the diagnosis when the creatinine concentration is normal and the blood urea nitrogen/creatinine ratio is greater than 20. Up to a 5% decrease in total body water can escape clinical detection, without appropriate suspicion by history. Thirst is usually present, however, and is an accurate sign of water deficit. Losses greater than 5% usually lead to conditions such as sunken eyes, loss of skin turgor with tenting of presternal skin, and dry mucous membranes. Greater than 10% dehydration will commonly demonstrate hemodynamic changes with tachycardia and postural hypotension. Treatment of dehydration requires an understanding of the composition of the fluid deficits. Isotonic dehydration reflects a loss of all fluid compartments (and their contained electrolytes) and is corrected by intravenously infusing a balanced salt solution such as Ringer’s lactate (Table 5). Concomitant abnormalities in concentration or tonicity are best assessed by the serum sodium concentration; such electrolyte abnormalities should be treated simultaneously with management of the volume deficit. For example, in hypernatremic dehydration (Table 5), water alone as 5% dextrose in water is used for replacement of the water deficit and a balanced salt solution, for volume restoration. The appropriate intravenous fluid should be administered to correct one-half of the estimated abnormality over 24 hours. This

39

Pathophysiology of Fluid and Electrolyte Disorders

approach is used because most deficits develop over a period of days or weeks and the patient has usually adjusted to them. Rapid replacement of losses may actually impose a greater risk than the deficit itself. Edema can be related to an underlying disease (cardiac, renal, or hepatic) or, as is common in modern practice, to abundant or excessive intravenous fluid administration. Excesses in extracellular fluid typically are susceptible to gravity and hence are most pronounced in dependent areas. Conditions such as pretibial and ankle edema are common in the upright patient. Presacral edema or pitting of the skin overlying the iliac crest is more likely in the recumbent patient. Water intoxication represents a specific abnormality of water balance. Ordinarily, large amounts of ingested or administered water can be excreted quantitatively, without a resultant volume excess or ionic dilution. Very marked amounts, however, particularly in a setting of compromised homeostatic mechanisms, can result in edema, hyponatremia, and dilution of other electrolytes as well (for a further discussion, refer to section on hyponatremia). Treatment of fluid excess requires an understanding of the cause and an assessment of the integrity of homeostatic mechanisms, particularly renal, hepatic, and central nervous system (CNS) function. In the setting of normal compensation, simple fluid restriction or decreased administration is likely to be effective. When simultaneous abnormalities in renal, hepatic, adrenal, or cardiac physiology exist, careful attention to intake and output (an ‘‘accountant’’ approach) is indicated. Only by specific accounting of all volumes, concentrations, and amounts can aggravation or creation of abnormalities be prevented.

Abnormalities of Sodium Because sodium is the major cation within extracellular water and is regularly analyzed in the laboratory, it is surprising that abnormalities in sodium concentration are not discovered more frequently. Although hypernatremia and hyponatremia are seen, they are rigorously prevented by compensatory mechanisms within the kidney. In fact, very small changes in sodium concentration (and subsequently osmolality) result in a measurable change in ADH release in the same direction. When renal concentrating mechanisms are defective (2) (e.g., wash out of renal medullary concentration gradient as with diuretics, partial tubular dysfunction from incipient or resolving acute tubular necrosis, or massive sodium loss in interstitial nephritis), abnormalities in serum sodium are more common.

Hyponatremia Virtually all acute, stressful situations (e.g., infection, anesthesia, and surgery) are accompanied by release of ADH and conservation of free water (26,27). This homeostatic mechanism is very effective in preserving extracellular volume, when combined with sodium conservation, which

Table 5 Composition of Common Solutions Used for Intravenous Therapy Solutions 5% Dextrose and water 0.9% Sodium chloride (normal saline) 0.45% Sodium chloride (half-normal saline) 3% Sodium chloride (hypertonic saline) Lactated Ringer’s solution

Glucose (g/L)

Na (mequiv/L)

Cl (mequiv/L)

HCO3 (mequiv/L)

K (mequiv/L)

Ca (mequiv/L)

50 – – – –

– 154 77 513 130

– 154 77 513 109

– – – – 28a

– – – – 4

– – – – 2.7

Exists in solution as lactate and is ultimately metabolized to bicarbonate (HCO3).

a

medwedi.ru

40

Part One: General Considerations

depends on a decrease in perfusion pressure or delivered sodium at the juxtaglomerular apparatus (28,29). Consequently, hyponatremia in adult patients at the time of admission for elective surgery is distinctly uncommon. However, once a patient has received intravenous administration of hypotonic fluids (e.g., 0.45% saline), the inability to excrete the ‘‘free’’ water due to an obligatory ADH release will frequently result in a dilutional decrease in serum sodium to some degree. When hyponatremia is present, spurious causes must be excluded. This is accomplished most simply by evaluating the serum osmolality. Because osmolality measures the amount of solute per ‘‘mass’’ of water instead of volume, it is independent of the amount of water in a volume of serum. Normally, serum is 94% water. Increases in protein or lipid concentrations can, however, alter the amount of water and lead to an analytic error in sodium determination. Osmolality is not affected so. Consequently, hyponatremia in the setting of normal osmolality would raise the suspicion of paraproteinemia (e.g., multiple myeloma and macroglobulinemia) or hyperlipidemia. Alternatively, an increase in an extracellular solute such as glucose (or mannitol) causes a shift in water from the intracellular to extracellular space, to conserve osmotic equality. This results in a subsequent ‘‘dilution’’ of extracellular sodium, but a maintained osmolality because of the presence of another osmotically active substance, glucose. Identification of hyperglycemia in the setting of normal osmolality will explain a fall in sodium levels of approximately 1.6 mequiv/L for each 100 mg/100 mL rise in blood sugar above normal. When true hyponatremia does occur (low sodium plus low osmolality), evaluating how the kidney is behaving allows a rational interpretation of the probable pathophysiology. A careful assessment of overall fluid and electrolyte status (weight change, input and output summaries, presence or absence of edema, etc.) is essential (30). Characterizing the patient as ahead or behind in volume by clinical assessment allows appropriate interpretation of the renal response, which is best ascertained by measuring the urinary osmolality and sodium concentration. During active sodium conservation, urinary sodium is typically low (< 5 mequiv/L). This indicates either that there is a true deficit in sodium or that the kidney ‘‘thinks’’ there is one. The latter occurs when circulating substances (e.g., aldosterone) are inappropriately present in edematous states such as cirrhosis and chronic congestive heart failure (28,31). In each of these settings, however, the patient is edematous and probably has ascites. In the absence of either of these findings, true sodium depletion is probably present. Sodium administration should be guided by an estimate of the deficit, which must be considered independently of (added to) volume deficits that are isotonic (Na ¼ 140 mequiv/L). The sodium deficit approximates 0.6 mequiv/kg per milliequivalent fall in serum sodium. Unless neurologic symptoms are present, which would mandate urgent treatment, the sodium replacement should take 24 to 48 hours. After one-half of the deficit has been replaced, serum electrolyte levels should be rechecked. When urinary sodium is increased (>20 mequiv/L), simple sodium depletion can be excluded. Sodium conservation either will not or cannot take place. This occurs in the setting of abnormal ADH release, adrenal insufficiency, severe hyperthyroidism, recent use of diuretics, or intrinsic renal tubular dysfunction as in renal failure or interstitial nephritis. This can be clarified by measuring urinary osmolality.

Because the normal response to hyponatremia and hypo-osmolality is excretion of solute-free water (or dilute urine), the finding of a urine osmolality above that of serum, plus hyponatremia, indicates an abnormal ADH response (27,32). This implies a continued release of ADH in spite of a hypo-osmolar state. If this is present at the time of admission or in the absence of intravenous fluids, it implies a CNS abnormality (e.g., head trauma and intracranial tumor) or an ectopic site of production (e.g., bronchogenic carcinoma). In the patient receiving hypotonic fluids, this finding more commonly reflects the release of ADH associated with a central ‘‘acute phase response’’ or ‘‘systemic inflammatory response’’ to stress or illness. In either event, fluid balance will be ‘‘ahead’’ as is the total amount of sodium in the body. The hyponatremia means that water is ‘‘more ahead’’ than sodium. This paradoxic increased total sodium in the face of decreased serum sodium concentration results in a high urinary sodium excretion (>20 mequiv/L) and a high salt excretion fraction (>5%) (33). The finding of isosthenuria (urine osmolality equals serum osmolality) implies intrinsic renal dysfunction or pharmacologic dysfunction from diuretics. The finding of low urine osmolality and high urine sodium, however, suggests that ADH release is appropriately terminated, but that sodium is not being conserved. This situation is seen in mineralocorticoid insufficiency. Laboratory evaluation of the renal response to hyponatremia can be enlightening but does not replace clinical assessment. Because hyponatremia means either a decrease in sodium or an increase in water, appropriate interpretation of readily available data should allow discrimination. A decrease in sodium requires the presence of a route of loss and usually is associated with weight loss. Alternatively, an increase in water should be manifested by a gain in weight and excess fluid intake over output. In the patient who is not receiving intravenous fluids, a serum sodium below 135 mequiv/L constitutes hyponatremia and deserves investigation. In the patient who is receiving hypotonic fluids, however, mild hyponatremia is common enough to be expected. Although it is not normal, mild hyponatremia down to 130 mequiv/L can probably be ignored. A sodium level of 125 to 130 mequiv/L justifies vigorous diagnostic efforts to identify the cause. A serum sodium level of 120 to 125 mequiv/L necessitates vigorous institution of appropriate therapy. A sodium level of less than 120 mequiv/L is a medical emergency and frequently requires careful administration of hypertonic saline for correction. It is not the low sodium per se that is detrimental, but rather the increase in the intracellular fluid compartment, which accompanies this circumstance. This intracellular volume increase is especially detrimental to brain cells because the brain is contained within a fixed space with little or no room for expansion. When brain cells swell, an increase in intracranial pressure ultimately develops and presents clinically as a variety of manifestations, including apathy, confusion, weakness, nausea, and occasionally vomiting. If this water intoxication is not corrected, it will ultimately lead to convulsions, stupor, and possibly even death. When hyponatremia occurs in the setting of brain injury or intracranial surgery (particularly for cerebral aneurysms), the term ‘‘cerebral salt wasting’’ is often applied (34). The hypothesis is that humoral substances are released from the injured brain, either directly or as a result of the injury, which leads to an excessive loss of sodium in the kidney (35). More recent studies question whether this is actually a specific syndrome, or whether it is a manifestation

Chapter 2:

of increased ADH release in patients who have received very large amounts of isotonic crystalloid solutions. Although it is not clear which explanation is correct, it is certainly true that hyponatremia occurs in neurosurgical patients and that this hyponatremia may be multifactorial. Central to appropriate treatment is the assessment of actual fluid status (hypervolemia vs. hypovolemia) and a decision whether to administer fluids containing a high concentration of sodium or to restrict the amount of water being administered. In the absence of objective evidence of a sodium deficiency, it may be more appropriate to restrict water intake, as in the syndrome of increased ADH release, seen both in SIADH and in the acutely injured patient.

Pathophysiology of Fluid and Electrolyte Disorders

41

the very narrow range of normal potassium concentration in plasma and the relatively massive adjacent intracellular pool (5) (with exchange influenced by variables such as pH and drugs) make control of serum potassium both important and tenuous. This importance is underscored by the critical nature of severe potassium abnormalities on the cardiac, neural, and muscular systems and evidenced by the diligent monitoring of potassium concentrations, which occurs in operating suites and intensive care units. An understanding of the common circumstances leading to potassium abnormalities will facilitate maintenance of normal homeostasis and simplify treatment of abnormalities (16).

Hyperkalemia Hypernatremia The body rigorously defends itself against hyperosmolality. Even a small rise results in increased ADH release and subsequent free-water retention by the kidney, unless, of course, ADH release cannot occur (e.g., diabetes insipidus), ADH is ineffective (e.g., nephrogenic diabetes insipidus), or the patient is denied access to water (e.g., infants, geriatric patients, and unconscious or restrained patients). A simple review of the clinical situation will often identify the cause. Because hypernatremia implies either an increase in sodium or a decrease in water, both must be considered. An increase in sodium can result from aggressive administration of normal saline or sodium bicarbonate. A decrease in water can occur by renal or extrarenal mechanisms. Nonrenal causes should be clinically apparent and include such symptoms as diarrhea and excessive sweating. In addition to the forms of diabetes insipidus (pituitary dysfunction or nephrogenic), renal sources must include osmotic diuresis with obligatory ‘‘free-water’’ loss. In all cases, treatment is simple. Administration of hypotonic solutions will restore sodium concentration, and, when sodium excess is a component, judicious diuretic use will hasten sodium excretion. Care in treating hypernatremia must be exercised, however, because a rapid change in sodium concentration is of greater clinical importance than the actual sodium concentration (36). Too rapid a correction of sodium abnormalities can result in dramatic CNS effects, including seizures secondary to rapid changes in intracellular volume. Accordingly, treatment should be planned to correct one-half of the estimated deficit over 24 hours. In the case of hypernatremia, this usually translates into the administration of 2 mL of free water/kg over 24 hr for each milliequivalent of planned decrease in serum sodium concentration. In the patient with head injury or recent neurosurgical intervention with accompanying diabetes insipidus, unless actual hypophysectomy has been performed, early administration of vasopressin should be avoided. Careful replacement of losses will maintain fluid and electrolyte balance until the usually transient abnormality resolves. Accordingly, hypernatremia should be avoidable. If permanent diabetes insipidus is anticipated, however, administration of vasopressin or its synthetic analog, desmopressin acetate (DDAVP), should be instituted. Serious complications of diabetes insipidus (or inappropriate ADH secretion) are not a function of difficulty in treatment, but rather failure of recognition. Anticipation of such problems will greatly simplify their subsequent management.

Abnormalities of Potassium Because mammals usually ingest large amounts of potassium, it is not surprising that most abnormalities in potassium balance are the result not of intake, but of excretion. Further,

Because the kidney is the major site of potassium excretion, compromised renal function is almost always a factor contributing to hyperkalemia (9,11,13). Although increased potassium levels can occur from either excess intake or decreased excretion, the former is quite rare, is usually iatrogenic, and occurs in the setting of administering very large intravenous doses of potassium (or potassium-containing drugs such as penicillin) or giving potassium to a patient receiving a drug that inhibits potassium excretion (e.g., spironolactone, triamterene, and ACE inhibitors). Abnormalities of excretion are common and can be caused by intrinsic abnormalities of renal function (acute oliguric renal failure), disturbances in hormonal control of potassium exchange (hypoaldosteronism, adrenal insufficiency, etc.), or alterations in the potassium exchange mechanism per se (drugs, acidosis, etc.). Occasionally serum potassium is factitiously elevated (compared to plasma potassium) because of in vitro Kþ release from platelets during phlebotomy, in the setting of thrombocytosis (37). Hyperkalemia produces predictable clinical consequences that affect neuromuscular function (weakness, irritability, etc.) and cardiac conduction (peaking of T waves, prolongation of PR and QT intervals, widening of QRS complexes, and eventual heart block). Monitoring of the electrocardiogram provides a simple, noninvasive method of assessing change in the hyperkalemic or potentially hyperkalemic patient. Predictable changes, beginning with T-wave peaking, are the harbingers of subsequent complications, which are evidenced by alterations in the shape and duration of the major electrocardiogram complexes. Because hyperkalemia poses a life-threatening problem, urgent and definitive correction is imperative (17). A transient decrease in serum potassium can be accomplished by translocating extracellular potassium back into cells with glucose and insulin, and the membrane effects of hyperkalemia can be offset by the administration of calcium. In the rare patient with reasonable renal function and the need for a rapid decrease in serum potassium, a potassium diuresis can be induced by the use of loop-active diuretics. More commonly, potassium is removed from the body by the use of potassium-exchanging resins [sodium polystyrene sulfonate (Kayexalate)] that can be given by mouth or rectum and will predictably lower serum potassium. This is accomplished, however, through exchange with sodium and may alter fluid and sodium balance. Institution of peritoneal or hemodialysis is clearly the most effective, long-term approach to potassium control in the patient with renal compromise. It is important to remember, however, that continued administration of hypertonic glucose, as in parenteral nutrition, will result in a predictable and sustained fall in serum potassium because the egress of potassium associated with catabolism is prevented.

medwedi.ru

42

Part One: General Considerations

Hypokalemia Hypokalemia is a common electrolyte abnormality in both hospitalized and ambulatory patients (16,38). Although it may be precipitated by an underlying disease (mineralocorticoid excess as in Cushing’s syndrome, potassium loss from a colonic villous adenoma, potassium wasting in renal disease, etc.) or by decreased potassium intake (low-potassium diet), most hypokalemia is iatrogenic in that it is induced pharmacologically by agents having potassium wasting as a side effect (36,39,40). Most notable are the diuretic agents currently used in the management of hypertension and fluid overload. The loop-active agents in particular are associated with a substantial potassium loss in the urine. Other classes of drugs, however, can also induce hypokalemia (21,41). The recent increased use of amphotericin B in the treatment of immune-compromised patients has uncovered a profound and difficult-to-manage hypokalemia (42). Use of newer synthetic penicillins in ultrahigh concentration is also associated with increased renal potassium loss and subsequent hypokalemia. Hypokalemia may manifest itself in various ways (e.g., muscle weakness and paralysis). More frequently, however, hypokalemia produces myocardial irritability and subsequent arrhythmias such as frequent premature contractions, sustained tachycardias, and potentiation of digitalis toxicity. Although these complications are more feared than common, they are serious complications and justify both respect and careful monitoring. Treatment is simple. Administration of potassium as the chloride salt will correct the usual associated chloride-dependent alkalosis, decrease renal potassium loss, and correct the hypokalemia. Beware, however, because the degree of hypokalemia is very poorly correlated to the magnitude of potassium deficit. Therefore, strict guidelines for replacement are dangerous. Because the hazards of hypokalemia appear to be virtually eliminated by institution of treatment rather than total correction, the identification of the abnormality and institution of treatment are more important than the rapidity of treatment. Frequently, discontinuation of the offending drug or control of the underlying disease will be necessary for long-term potassium control.

Abnormalities of Chloride Because chloride is the most abundant anion in plasma and extracellular water, it is not surprising that its range of variation is large and its mechanism of variation somewhat passive. The high concentration of chloride in gastric juice accounts for the hypochloremia that accompanies the metabolic alkalosis of conditions such as gastric outlet obstruction, repetitive vomiting, and pyloric stenosis. Chloride is absorbed in large quantities from the gut, and its level is controlled by urinary excretion. Most reabsorption of chloride occurs in the proximal tubule of the kidney, in association with sodium reabsorption. A considerable component is also actively reabsorbed in Henle’s limb (43). Alterations in proximal tubule absorption (osmotic diuretics) or Henle’s limb (loop-active diuretics) can lead to hypochloremia and metabolic alkalosis. In addition, in the presence of ‘‘hormone-dependent’’ (e.g., aldosterone) alkalosis, the fraction of chloride that is reabsorbed is decreased. This interaction of chloride and bicarbonate is important in the evaluation of the patient with metabolic alkalosis. Chloride is present in abundance in GI secretions. Substantial chloride loss can result from GI fluid losses from the upper tract (e.g., gastric outlet obstruction) or lower tract

(e.g., diarrhea). Assessment of the chloride deficit provides complementary information in the evaluation of volume depletion, secondary to GI losses.

Abnormalities of Calcium The most important factor in assessing calcium as an electrolyte is that clinically important abnormalities are very, very rare and easily categorized into hypocalcemia caused by hypoparathyroidism and hypercalcemia caused by hyperparathyroidism, tumors, systemic diseases, and medications. Hypocalcemia is rarely of clinical importance, except following parathyroid and thyroid surgery, and therefore infrequently requires treatment. Hypercalcemia, when the serum calcium is greater than 12, can be treated with aggressive saline administration, loop-active diuretics to minimize the fluid overload, and biphosphonates to reduce resorption of calcium from bone. Identification of the specific cause of the hypercalcemia (by measurement of ionized calcium, PTH, parathyroid hormone related peptide (PHRP), and 1,25-dihydroxyvitamin D3) is necessary to effect long-term control of the calcium level (18).

Isolated Acid/Base Abnormalities The availability of routine measurement of ‘‘arterial blood gases’’ has resulted in a much clearer understanding of the nature and treatment of acid/base disturbances in clinical practice. On the basis of the normal physiologic determinants previously described and the pathophysiologic mechanisms that will be enumerated, acid/base disturbances can be classified into acidosis or alkalosis. Both of the categories can be further subdivided into metabolic and respiratory, as well as combined metabolic/respiratory. Tables, nomograms, and algorithms have been developed for the assessment of the excess or deficit of acid (or base) to assist the clinician in management. Unfortunately, all of these aids are of only limited practical value because of the concurrent and efficient efforts of the compensatory mechanisms of the body to correct the acid/base disturbance. In other words, the onset of a disturbance in pH (by change in either HCO3 or pCO2) results in very rapid initiation of respiratory and/or metabolic compensatory mechanisms to partially correct the pH. It is essential in planning the treatment of acid/base disturbances to keep this compensation in mind, lest overaggressive management result in new, iatrogenic acid/base disturbances in the opposite direction.

Acidosis As described previously, acidosis can occur by the absolute gain in acid or loss of base from the body. Because the buffering system of the body is ‘‘open’’ in the sense that the CO2/HCO 3 system uses both respiratory and renal control systems, all but the most acute form of acidosis will be combined with compensatory adjustments. Consequently, all respiratory disturbances will have a metabolic compensatory component, and metabolic imbalances will stimulate respiratory compensation. Frequently, the pH is remarkably well corrected, and only a careful review of the historical facts associated with the illness will allow a clear analysis of the inciting cause. Occasionally, the cause is so elusive that only by disturbing the system with exogenous alkali and observing the respiratory response (or lack thereof) will the primary problem become apparent.

Respiratory Acidosis Pure respiratory acidosis is the simplest of the acid/base disturbances conceptually, because it results from a decrease

Chapter 2:

in effective alveolar ventilation (relative to carbon dioxide production). Normal carbon dioxide production from metabolic processes is approximately 450 L/day (20,000 mmol). Whenever carbon dioxide elimination lags behind production, respiratory acidosis ensues. The consequent laboratory abnormalities include a decrease in pH and an increase in pCO2. It is important to consider the pH first, because compensatory hypercapnea (increase in serum pCO2) in the setting of profound metabolic alkalosis is not uncommon, particularly in patients receiving mechanical ventilation by an intermittent (synchronized intermittent mandatory ventilation, pressure support ventilation, etc.) modality. Once respiratory acidosis is identified, a differential consideration of causes must include central respiratory depression (e.g., narcotics and intrinsic CNS disease), mechanical causes of decreased ventilation and/or increased dead space (e.g., tension pneumothorax, hemothorax, and massive pleural effusions), or pathophysiologic causes of increased carbon dioxide production. The common causes of acute or chronic respiratory acidosis are summarized as follows: & & & & & &

Airway obstruction Respiratory center depression Neuromuscular defects Restrictive lung diseases Smoke inhalation Inadequate mechanical ventilation

Appropriate treatment logically follows identification of the underlying mechanism and may include ventilatory assistance to enhance alveolar ventilation to eliminate the retained carbon dioxide and thereby correct the acidic pH. Occasionally, respiratory acidosis is produced by an increase in carbon dioxide production, because of either marked increase in oxygen consumption (active rewarming after heart surgery) or alteration in the respiratory quotient (excessive administration of carbohydrate-based parenteral nutrition). Because the pCO2 is proportional to the ratio of carbon dioxide production and minute alveolar ventilation, pCO2 ¼ kðV CO2 Þ=ðV AlvÞ; recognition of a high pCO2 and a high minute ventilation should assist in identifying patients with excessive carbon dioxide production.

Metabolic Acidosis In marked contradistinction to respiratory acidosis, metabolic acidosis can result from a variety of causes that include the gain of metabolic acids above excretion rates or the loss of bicarbonate greater than its rate of regeneration (44–47). Again, clinical evaluation and elucidation of the underlying mechanism greatly simplifies the task of evaluating the data. Also, it is important to avoid jumping to a conclusion of acidosis on the basis of only a decrease in the bicarbonate concentration of the serum, because this finding may also represent a normal metabolic compensation for a respiratory alkalosis. As is true with all biologic systems, electrical neutrality is maintained in all fluid compartments throughout the body by balancing the total number of cations with the total number of anions. In the extracellular compartment under normal conditions, the concentration of the cation sodium roughly equals the sum of the concentrations of the anions, chloride and bicarbonate, except for a small anion gap of

Pathophysiology of Fluid and Electrolyte Disorders

43

12 2 mequiv/L. An increase in this gap can give an important clue concerning the cause of acidosis. Thus it is helpful to subdivide metabolic acidosis into those categories that manifest an increase in unmeasured anions (increased anion gap) and those that do not and subsequently have a normal anion gap (nonanionic gap). As a generality, metabolic acidosis associated with the accumulation of organic acid will have an associated increased anion gap, whereas that caused by a loss of bicarbonate will have a normal or decreased anion gap. The distinction is important. Although both causes may require replacement of bicarbonate to correct the acidosis, the former group will require correction of an associated metabolic abnormality, and the latter will require attention to the site of bicarbonate loss (e.g., fistula).

Increased Gap Acidosis Any metabolic acidosis that is caused by the accumulation of organic acid (which is not measured by routine electrolyte analysis) will have a calculated anion gap that is greater than normal (uremia, diabetic ketoacidosis, lactic acidosis, and drug ingestion/poisoning). In some circumstances, e.g., diabetic ketoacidosis, combined mechanisms are operative, and the component caused by ketoacids is proportional to the anion gap. The presence of an acidosis with an anion gap greater than 14 mequiv/L implies either ingestion of an organic substance or an endogenous metabolic abnormality. Of the four commonly ingested ‘‘toxins’’ (methanol, ethylene glycol, ethanol, and isopropanol) only methanol (formic acid) and ethylene glycol (oxalic acid) produce a metabolic acidosis. Ethylene glycol also produces oxaluria, whereas methanol ingestion usually produces rapid retinal blindness. Acetylsalicylic acid (aspirin) and paraldehyde can also produce metabolic acidosis if ingested in large amounts, although paraldehyde is no longer available in the United States. Endogenous production of organic acid in excess of excretory capacity is seen in uremia, diabetic ketoacidosis, and lactic acidosis. Each is usually identifiable by the company it keeps: acidosis caused by renal failure is associated with the clinical and metabolic abnormalities of uremia; diabetic ketoacidosis is usually seen in known diabetics and is associated with hyperglycemia, dehydration, and ketosis in urine and serum (48); lactic acidosis can be caused by a variety of clinical states, but usually represents some form of hypoperfusion, such as sepsis or trauma (49). Lactic acidosis is associated with an increase in lactate in the blood (>4 mequiv/L) and an altered ratio of lactate to pyruvate (>30:1) and other oxidation–reduction pairs [e.g., acetoacetate/ betahydroxybutyrate and reduced nicotinamide adenine dinucleotide (NAD)/oxidized nicotinamide adenine dinucleotide (NADH)]. The actual cause of the increased lactic acid concentration is impairment of electron-to-oxygen transfer and subsequent accumulation of NADH, which shifts the equilibrium of pyruvate and lactate in the direction of lactate. Lactate serves as a reservoir or ‘‘cul de sac’’ during periods of deficient electron-to-oxygen transfer. Restoration of NADþ levels results in a prompt conversion of lactate back to pyruvate. It is often erroneously assumed that lactic acid is part of the pathophysiology of ‘‘lactic acidosis,’’ whereas it is actually only a secondary biochemical consequence of the underlying oxidation–reduction disorder. It is a quantitatively useful test to confirm the diagnosis and estimate the magnitude, however. Because it is often included in the battery of tests known as ‘‘blood gases,’’ it is important to confirm that a metabolic acidosis with an increased anion gap is

medwedi.ru

44

Part One: General Considerations

present before suggesting a diagnosis of lactic acidosis, because lactate levels may be elevated in the absence of lactic acidosis. When lactic acidosis is present, attention needs to be paid to the underlying cause of the inadequate delivery of oxygen to tissues. It is also important to recognize that lactic acid may also be a component of the metabolic acidosis caused by diabetic ketoacidosis, methanol poisoning, and salicylate intoxication. Treatment of all forms of anion gap acidosis is both supportive (restore circulation, correct acidosis with bicarbonate, etc.) and specific (correct underlying abnormality). Bicarbonate should be given in adequate quantities to keep the pH above 7.2 and/or the bicarbonate level above 15 mequiv/L. Situations with ongoing tissue hypoxia may require substantial replacement, whereas transient problems such as postictal lactic acidosis usually correct themselves spontaneously. When bicarbonate is required, the bicarbonate deficit can be determined by a variety of formulas. An easy-toremember fact is that the bicarbonate space (apparent volume of distribution of the effective buffering system) corresponds roughly to one-half of total body water (approximately 30% of total body weight in kilograms). Thus: HCO 3 deficit ¼ 0:3 wt ð24 HCO3 Þ:

Usually one-half of the calculated deficit is replaced to avoid overcorrection, following which blood gases are repeated before infusing additional bicarbonate. In patients with compromised renal function and metabolic acidosis, it is important to remember that disorders associated with levels of potassium, magnesium, and phosphate are commonly found and should be sought. In lactic acidosis produced by hypovolemic shock, the treatment should focus on restoring circulation and perfusion, rather than on correcting the acidosis itself.

in conditions such as sepsis and hypovolemia) can be estimated by the following formula: pCO2 ¼ 1:5ðHCO 3 Þ þ D; where HCO3 is mequiv of HCO 3 and D is 8 2 mequiv/L. Recognition of this compensatory phenomenon will assist in preventing iatrogenic metabolic alkalosis from overtreatment with bicarbonate. It is also helpful to test whether the change in pCO2 is of an appropriate amount, because each increase or decrease of pCO2 of 10 torr should result in a change in pH in the opposite direction of 0.08.

Alkalosis As is the case with acidosis, alkalosis may be either respiratory or metabolic in origin. In contradistinction to acidosis, it is the metabolic component that is rather simple to define and correct, whereas respiratory alkalosis may have a myriad of causes.

Respiratory Alkalosis Respiratory alkalosis is probably the most common acid/ base disturbance in clinical medicine and can be induced by a multitude of underlying conditions. The pathophysiologic mechanism is excess alveolar ventilation above the requirements of carbon dioxide production. This abnormality typically represents some form of CNS overstimulation but may include as causes the factors summarized below: & & & & & &

Nonanion Gap Acidosis (Hyperchloremic) Causes of metabolic acidosis with a normal anion gap include bicarbonate loss, inability to excrete hydrogen ion, or administration of exogenous HCl or NH4Cl. Most commonly, there is either a recognized source of bicarbonate loss or an abnormality in the kidney (or adrenal). Recognized bicarbonate loss is usually from the GI tract distal to the pylorus and may include duodenal fistula, biliary drainage, pancreatic fistula, small intestinal fistula, ureterosigmoidostomy, and diarrhea. Intrinsic renal losses of bicarbonate include interstitial nephritis, renal tubular acidosis, adrenal insufficiency, hypoaldosteronism, and acetazolamide administration (50). Treatment of nonanion gap acidosis requires correction of the existing acidosis plus routine administration of a bicarbonate source on a regular basis. The dosage of bicarbonate required will depend on the underlying disease, its magnitude, and the need for dialysis. Guidelines for acute correction are the same as for anion gap acidosis: calculate the bicarbonate deficit (base deficit), estimate the bicarbonate space, and administer only as much as should correct one-half of the predicted deficit over a period of 24 hours. As indicated previously, compensation for metabolic acidosis is usual and is manifested as hyperpnea, tachypnea, nasal flaring, or even Kussmaul’s respiration. The degree of compensatory hyperventilation in a stable, chronic metabolic acidosis (as opposed to the acute changes seen

& & & &

Anxiety Fever Salicylate intoxication CNS disorders Intrathoracic processes Hypoxemia Hepatic insufficiency Gram-negative septicemia Pregnancy Mechanical hyperventilation

Treatment of respiratory alkalosis must be directed at correcting the underlying cause (e.g., correct fever with antipyretics). In patients requiring assisted ventilation, use of intermittent or partial ventilation systems will tend to minimize the overventilation that is often seen with controlled or assist/controlled ventilation. Other attempts at increasing pCO2, such as inspired carbon dioxide, rebreathing devices, and added mechanical dead space, are relatively ineffective.

Metabolic Alkalosis The fundamental abnormality in pure metabolic alkalosis is an absolute or relative excess of base (primarily bicarbonate) in extracellular fluid (44,51,52). This excess tends to be offset by a compensatory decrease in minute alveolar ventilation with subsequent hypercarbia. The mechanisms underlying metabolic alkalosis include the loss of hydrogen ion (with chloride), gain of exogenous base, or extracellular fluid–volume contraction. Identification of the latter two mechanisms should be straightforward by clinical evaluation, although gain of exogenous base may be masked as in blood or fresh frozen plasma transfusions (citrate is converted to bicarbonate) or excessive infusion of lactated Ringer’s solution.

Chapter 2:

The most common, clinically important forms of metabolic alkalosis are a result of loss of hydrogen ion and chloride from the stomach or hydrogen ion alone from the kidney. These two varieties can be separated by attention to the amount of chloride measured in the urine. Low urinary chloride (<10 mequiv/L) indicates a ‘‘chlorideresponsive’’ alkalosis. When there is insufficient chloride in the proximal nephron to maintain electroneutral reabsorption of sodium, bicarbonate is reabsorbed, leading to alkalosis, but with no chloride in the urine (53). When the abnormality occurs in the distal tubule (caused by hyperaldosteronism, increased plasma desoxycorticosterone, exogenous corticosteroids, licorice ingestion, or carbenoxolone therapy) the urine chloride will be greater than 20 mequiv/L, which confirms that chloride depletion is not the cause and therefore will not correct the abnormality by itself (54). More specifically, chloride-resistant alkalosis of renal origin can be thought of as excessive stimulation of the distal tubular, mineralocorticoid-mediated cation exchange mechanism resulting in increased excretion of Hþ and Kþ (55). This latter variety is perpetuated by (although not initiated by) hypokalemia, and correction of the potassium deficit is essential to restoration of acid/base balance (56,57). Active reabsorption of potassium (initiated by hypokalemia-induced hyperaldosteronism) in the distal renal tubule in ‘‘exchange’’ for Hþ, leads to the paradox of acid urine in the face of hypokalemic alkalosis (paradoxic aciduria). Occasionally, massive doses of potassium are required to achieve equilibrium; so the kidney does not have to work so hard reabsorbing it. When clinically significant hypoventilation develops as compensation for metabolic alkalosis, more rapid treatment may be needed (58). Two approaches are effective, including administration of acid and inducing renal tubular acidosis with acetazolamide, but neither will correct the underlying cause of the alkalosis. Recent experience with 0.1N HCl infusions (or as high as 0.2N) has shown this form of treatment to be quite safe if administered through a central venous line. The dose of Hþ should be calculated by determining base excess (or increase in bicarbonate above 28 mequiv/L), and multiplying it by one-half of estimated total body water (0.3 weight in kg). One-half of this calculated amount is then administered over 24 hours. Although repeated acetazolamide administration is effective in the treatment of severe metabolic alkalosis, correction of the excessive mineralocorticoid stimulation or maintenance of a high serum potassium is required to prevent recurrence.

Pathophysiology of Fluid and Electrolyte Disorders

45

Table 6 Identification of Isolated Acid-Base Disturbances Disturbance Metabolic acidosis Metabolic alkalosis Respiratory acidosis (acute) Respiratory acidosis (chronic) Respiratory alkalosis (acute)

Respiratory alkalosis (chronic)

Effect pCO2 should fall by 1 to 1.5 times the fall in HCO3 PCO2 should rise by 0.5 to 1 times the rise in HCO3 Plasma HCO3 should be <30 mequiv/L Plasma HCO3 should rise by 4 mmol/10 mm Hg rise in pCO2 Plasma HCO3 should fall by 2.5 mmol/10 mm Hg fall in pCO2 (usually >18 mequiv/L) Plasma HCO3 should fall at least as much as acute but not <15 mequiv/L

Abbreviations: HCO3, Bicarbonate; pCO2, carbon dioxide partial pressure. Source: From Ref. 59.

clinical settings in which they are likely to occur are summarized below: Respiratory acidosis and metabolic alkalosis occur in patients with chronic respiratory acidosis with coexistent congestive heart failure, requiring diuretics. b. Respiratory acidosis and metabolic acidosis occur in patients with cardiopulmonary arrest, chronic lung disease in shock, or chronic renal failure with respiratory insufficiency. c. Respiratory alkalosis and metabolic acidosis may occur in hepatic failure with respiratory overstimulation or renal failure in sepsis. d. Respiratory alkalosis and metabolic alkalosis occur in hepatic cirrhosis with hyperventilation associated with vomiting or in chronic respiratory failure following institution of vigorous mechanical ventilation. e. Metabolic acidosis and metabolic alkalosis can be sequential rather than simultaneous abnormalities, although this may not be obvious. This situation is identified when the anion gap is numerically greater than the estimated HCO3 deficit and occurs with progressive contraction alkalosis caused by vomiting when hypovolemia becomes manifest. a.

PRINCIPLES OF FLUID THERAPY

Combined Acid/Base Disorders It is crucial to realize that acid/base disorders are in no way limited to a single pathophysiologic derangement at a time. Consequently, combinations of abnormalities are common. To distinguish single from combined disturbances, an objective approach is essential. Most standard texts contain graphs (e.g., Goldberg graphs) that indicate the 95% probability range for single acid/base disorders, i.e., the laboratory values that are 95% likely to represent a single pathophysiologic abnormality. In addition, numerous empiric equations have been developed to identify compensatory changes as opposed to coexistent abnormalities. Characteristics of isolated acid/base disturbances are listed in Table 6 (59). Certain combinations of acid/base disturbances are encountered commonly enough clinically to also justify listing. The components of these combinations and the

In any patient requiring intravenous fluid therapy, three categories of fluid loss must be taken into consideration. These include losses related to normal body maintenance (insensible plus urine), continuing losses of fluid and electrolytes, and preexisting fluid deficits resulting from the patient’s underlying disease. These should be thought of as a combination of maintenance and replacement fluids. As indicated in an earlier section of this chapter, all patients have normal maintenance requirements related to daily sensible and insensible losses. These losses will vary somewhat depending on the person’s age, body build, and sex, but generally average between 2000 and 2500 mL of fluid every 24 hrs (1500 mL/m2/day). The major sensible loss is urine, and the major insensible loss is related to evaporative losses from the skin and water losses through the lungs. All of these are primarily water losses, containing only small

medwedi.ru

46

Part One: General Considerations

Table 7 Composition of Gastrointestinal Secretions

Stomach Pancreas Bile Intestine (primarily small)

Volume (mL/24 hr)

Na (mequiv/L)

K (mequiv/L)

Cl (mequiv/L)

HCO3 (mequiv/L)

1000–2000 300–800 300–600 2000–4000

60–100 135–145 135–145 120–140

10–20 5–10 5–10 5–10

100–130 70–90 90–130 90–140

– 95–120 30–40 30–40

amounts of electrolytes. If an individual patient requires intravenous therapy for only short periods of time, replacement of electrolyte losses is generally unnecessary, and maintenance volume losses can be replaced with solutions of 5% dextrose and water (Table 5) or 5% dextrose and half normal saline. If prolonged intravenous therapy is expected, the small but consistent daily electrolyte losses will need to be taken into account and can generally be managed by giving 2 mequiv/kg of body weight of sodium, chloride, and 1 mequiv/kg of potassium daily. Thus if a patient requires 2500 mL of fluid to meet normal maintenance needs, 1500 mL could be provided as dextrose and water, and the remaining 1000 mL could be given as half normal saline with the addition of appropriate amounts of potassium chloride (Table 5). Losses arising from the patient’s underlying disease must also be replaced. In surgical patients, these losses are almost always from some portion of the GI tract. As a general rule, intestinal secretions, bile, or pancreatic juice can be replaced on a volume-to-volume basis with a balanced salt solution such as Ringer’s lactate (although pancreatic replacement may require additional bicarbonate). Losses from an actively secreting stomach (emesis or nasogastric (NG) losses) require significant amounts of chloride (normal saline or half normal saline with potassium chloride added) (Table 5). The actual amount of potassium loss from GI secretions is small, although alkalosis can result in significant potassium loss from the kidney. Generally, vomiting or NG losses produce this abnormality (Table 7). To prevent the development of problems with hypokalemia, 20 to 40 mequiv of potassium for every liter of fluid loss from any of these sites should be administered. If long-term intravenous therapy is required, these requirements may increase and should be monitored by the determination of serum electrolyte values periodically. Another source of abnormal losses is an increased evaporative loss from the skin and respiratory tract in patients who are febrile. Loss of as much as 1000 mL daily may occur over and above normal insensible losses, if the body temperature is markedly elevated. In patients with persistent temperature elevations above 101 F (38.4 C), 500 to 1000 mL of additional fluid may be required daily (10% per C increase). Because such fluid loss is primarily water, it can generally be replaced with a ‘‘dextrose and water’’ intravenous solution or as water through a feeding tube. In critically ill patients receiving ventilatory support, respiratory losses (one-third of insensible loss) are no longer present because of the use of warm, humidified air, and fluid replacement should be reduced accordingly. Finally, preexisting solute or volume deficits must also be corrected. Again, such deficits generally arise from the GI tract and are the result of such problems as vomiting, diarrhea, or sequestration of fluid as may occur in patients with bowel obstruction. A correct estimate of these losses is often difficult, but careful attention to physical findings and important historical information from the patient, summarizing the duration of disease and the

frequency and amount of fluid losses (e.g., through vomiting or diarrhea), are usually helpful in deriving an appropriate estimate of the magnitude of underlying deficits. As emphasized previously, only one-half of this calculated estimate should be replaced in a given 24-hour period, and the patient reassessed clinically and with supporting laboratory data before attempting any further deficit replacement. If the principles just enumerated are followed, the large majority of patients requiring intravenous therapy can be managed without difficulty. Especially pertinent in such management is the frequent reassessment of the patient clinically and daily review of the patient’s input and output records to ensure that the proper amount and type of fluid is being given. Daily weight assessment are especially helpful in this regard and can give valuable clues as to whether abrupt or even subtle changes in fluid balance (either fluid overload or fluid deficit) are occurring. Further, attention to such detail helps prevent the development of any major imbalances that may occur insidiously before they become clinically obvious.

SUMMARY Plasma is a subset of the total fluid (extracellular fluid) that bathes the cells. As such when sampled, it allows an indirect look at the cellular events and the interaction between the cells and the extracellular fluid. Fluid and electrolyte disorders are legion and commonplace. The correct, critical interpretation of laboratory parameters to identify the pathophysiologic mechanisms underlying these abnormalities requires a willingness to go beyond the obvious. A logical analytic approach to the meaning of the observed laboratory disturbances should lead to an insight into the significance of the observation. A cookbook approach to ‘‘correct’’ the abnormal test result may actually worsen the situation. It is critical to appreciate that a concentration actually represents a ratio of the amount of a substance to the amount of fluid in which it is dissolved or suspended. Abnormalities in concentration can be caused by a change in either component. Attention to a variety of clinical factors (weight changes, vital signs, nursing notes, even history and physical examination, etc.) often provides the insight necessary to identify the true problem and chart its solution.

REFERENCES 1. Pitts R. Physiology of the Kidney and Body Fluids: Volume and Composition of the Body Fluids. Chicago: Year Book Medical Publishers, 1968. 2. Halperin ML, Bohn D. Clinical approach to disorders of salt and water balance. Emphasis on integrative physiology. Crit Care Clin 2002; 18:249–272.

Chapter 2: 3. Gruber UMA. Water and electrolyte balance. In: Diem K, ed. Documenta Geigy, Scientific Tables. Ardsley, NY: Geigy Pharmaceuticals, 1970. 4. Forbes R, Mitchell H, Cooper A. Further studies on the gross composition and mineral elements of the adult human body. J Biol chem 1956; 223:969. 5. Corsa L, et al. Measurement of exchangeable potassium in man by isotope dilution. J Clin Invest 1950; 29:1280. 6. Moore F. Determination of total body water and solids with isotopes. Science 1946; 104:157. 7. Moore F, et al. Body composition: total body water and electrolytes: intravascular and extravascular phase volumes. Metabolism 1956; 5:447. 8. Prough DS. Physiologic acid-base and electrolyte changes in acute and chronic renal failure patients. Anesthesiol Clin North Am 2000; 18:809–833, ix. 9. Beck LH. The aging kidney. Defending a delicate balance of fluid and electrolytes. Geriatrics 2000; 55:26–28, 31–32. 10. Miller M. Fluid and electrolyte homeostasis in the elderly: physiological changes of ageing and clinical consequences. Baillieres Clin Endocrinol Metab 1997; 11:367–387. 11. Jorgensen PL. Sodium and potassium ion pump in kidney tubules. Physiol Rev 1980; 60:864–917. 12. Kreimeier U. Pathophysiology of fluid imbalance. Crit Care 2000; 4:S3–S7. 13. Samson WK. Adrenomedullin and the control of fluid and electrolyte homeostasis. Annu Rev Physiol 1999; 61: 363–389. 14. Frazier SK. Neurohormonal responses during positive pressure mechanical ventilation. Heart Lung 1999; 28:149–165; quiz 166–167. 15. Cadnapaphornchai MA, Gurevich AK, Weinberger HD, Schrier RW. Pathophysiology of sodium and water retention in heart failure. Cardiology 2001; 96:122–131. 16. Gennari FJ. Disorders of potassium homeostasis. Hypokalemia and hyperkalemia. Crit Care Clin 2002; 18:273–288, vi. 17. Williams ME. Endocrine crises. Hyperkalemia. Crit Care Clin 1991; 7:155–174. 18. Kinder B, Stewart A. Hypercalcemia. Curr Probl Surg 2002; 39:349–448. 19. Fulop M. Algorithms for diagnosing some electrolyte disorders. Am J Emerg Med 1998; 16:76–84. 20. Ward P. Role of complement, chemokines, and regulatory cytokines in acute lung injury. Ann N Y Acad Sci 1996; 796:104–112. 21. Polderman KH, Girbes AR. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002; 28:520–522. 22. Madhusoodanan S, Bogunovic OJ, Moise D, et al. Hyponatraemia associated with psychotropic medications. A review of the literature and spontaneous reports. Adverse Drug React Toxicol Rev 2002; 21:17–29. 23. Liberopoulos EN, Alexandridis GH, Christidis DS, Elisaf MS. SIADH and hyponatremia with theophylline. Ann Pharmacother 2002; 36:1180–1182. 24. Fanestil DD, Park CS. Steroid hormones and the kidney. Annu Rev Physiol 1981; 43:637–649. 25. Goodenough RD, Burke JF. Fluid, electrolyte, and acid-base homeostasis in surgery. In: Burke JF, ed. Surgical Physiology. Philadelphia: WB Saunders, 1983. 26. Patel GP, Kasiar JB. Syndrome of inappropriate antidiuretic hormone-induced hyponatremia associated with amiodarone. Pharmacotherapy 2002; 22:649–651. 27. Diringer MN. Sodium disturbances frequently encountered in a neurologic intensive care unit. Neurol India 2001; 49(suppl 1): S19–S30. 28. Porcel A, Diaz F, Rendon P, et al. Dilutional hyponatremia in patients with cirrhosis and ascites. Arch Intern Med 2002; 162:323–328. 29. Oh MS, Carroll HJ. Disorders of sodium metabolism: hypernatremia and hyponatremia. Crit Care Med 1992; 20: 94–103.

Pathophysiology of Fluid and Electrolyte Disorders

47

30. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ 2002; 166:1056–1062. 31. Milionis HJ, Alexandrides GE, Liberopoulos EN, et al. Hypomagnesemia and concurrent acid-base and electrolyte abnormalities in patients with congestive heart failure. Eur J Heart Fail 2002; 4:167–173. 32. Wong LL, Verbalis JG. Systemic diseases associated with disorders of water homeostasis. Endocrinol Metab Clin North Am 2002; 31:121–140. 33. Espinel CH. The FENa test. Use in the differential diagnosis of acute renal failure. JAMA 1976; 236:579–581. 34. Qureshi AI, Suri MF, Sung GY, et al. Prognostic significance of hypernatremia and hyponatremia among patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 2002; 50: 749–755; discussion 755–766. 35. Singh S, Bohn D, Carlotti AP, et al. Cerebral salt wasting: truths, fallacies, theories, and challenges. Crit Care Med 2002; 30:2575–2579. 36. Riggs JE. Neurologic manifestations of electrolyte disturbances. Neurol Clin 2002; 20:227–239, vii. 37. Johnson C, Hughes K. Pseudohyperkalemia secondary to postsplenectomy thrombocytosis. Am Surg 2001; 67:168–170. 38. Kapoor M, Chan GZ. Fluid and electrolyte abnormalities. Crit Care Clin 2001; 17:503–529. 39. Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci 2002; 970:134–144. 40. Elisaf M, Liberopoulos E, Bairaktari E, Siamopoulos K. Hypokalaemia in alcoholic patients. Drug Alcohol Rev 2002; 21:73–76. 41. Preuss H, Burris J. Adverse metabolic effects of antihypertensive drugs. Implications for treatment. Drug Saf 1996; 14: 355–364. 42. Ural A, Avcu F, Cetin T, et al. Spironolactone: is it a novel drug for the prevention of amphotericin B-related hypokalemia in cancer patients? Eur J Clin Pharmacol 2002; 57:771–773. 43. Rocha AS, Kokko JP. Sodium chloride and water transport in the medullary thick ascending limb of Henle. Evidence for active chloride transport. J Clin Invest 1973; 52:612–623. 44. Sirker AA, Rhodes A, Grounds RM, Bennett ED. Acid-base physiology: the ’traditional’ and the ’modern’ approaches. Anaesthesia 2002; 57:348–356. 45. Story DA, Poustie S, Bellomo R. Estimating unmeasured anions in critically ill patients: anion-gap, base-deficit, and strong-iongap. Anaesthesia 2002; 57:1109–1114. 46. Hatherill M, Waggie Z, Purves L, et al. Correction of the anion gap for albumin in order to detect occult tissue anions in shock. Arch Dis Child 2002; 87:526–529. 47. Frangiosa A, De Santo LS, De Santo NG, et al. Acid-base state in patients after cardiac transplantation. Am J Nephrol 2002; 22:332–337. 48. Felig P. Diabetic ketoacidosis. N Engl J Med 1974; 290: 1360–1363. 49. Mizock B, Falk J. Lactic acidosis in critical illness. Crit Care Med 1992; 20:80–93. 50. Rothstein M, Obialo C, Hruska K. Renal tubular acidosis. Endocrinol Metab Clin North Am 1990; 19:869–887. 51. Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg 2001; 93: 811–816. 52. Hodgkin JE, Soeprono FF, Chan DM. Incidence of metabolic alkalemia in hospitalized patients. Crit Care Med 1980; 8: 725–728. 53. Wesson D, Dolson G. Enhanced HCO3 secretion by distal tubule contributes to NaCl-induced correction of chronic alkalosis. Am J Physiol 1993; 264:F899–F906. 54. Hanna J, Scheinman J, Chan J. The kidney in acid-base balance. Pediatr Clin North Am 1995; 42:1365–1395.

medwedi.ru

48

Part One: General Considerations

55. Gill JR Jr., Bartter FC. Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter’s syndrome. Am J Med 1978; 65: 766–772. 56. Jacobson H, Seldin DW. On the generation, maintenance, and correction of metabolic alkalosis. Am J Physiol 1983; 245:F425–F432.

57. Khanna A, Kurtzman NA. Metabolic alkalosis. Respir Care 2001; 46:354–365. 58. Palmer B, Alpern R. Metabolic alkalosis. J Am Soc Nephrol 1997; 8:1462–1469. 59. Schrier RW, ed. Renal and Electrolyte Disorders. Boston: Little Brown, 1980.

3 Surgical Nutrition Rosemary A. Kozar, Margaret M. McQuiggan, and Frederick A. Moore

INTRODUCTION It has been said that outward appearances do not always convey things as they really are. This is certainly true with respect to surgical nutrition. In our society, where fast food diets have become the norm and a sedentary lifestyle is all too commonplace, protein-calorie malnutrition is being increasingly recognized in patients requiring hospitalization, despite how healthy a patient appears outwardly. Failure to identify this problem prior to embarking on a surgical procedure can have devastating effects on the outcome, not only from the standpoint of postoperative complications, but also, unfortunately and all too frequently, whether survival is impacted as well. Thus, it behooves the surgeon to have a thorough understanding of those factors that contribute to both good health and malnutrition and an understanding of how an operation or other stressful events can alter the adequacy of nutritional balance, and what strategies need to be employed to ensure that a healthy nutritional environment is maintained to minimize postoperative morbidity and mortality. The present chapter addresses these issues.

METABOLIC RESPONSE TO STRESS VS. STARVATION Endogenous supplies of carbohydrates, fat, and protein, are used to supply energy needs during starvation. In acute starvation, carbohydrates are initially utilized but stores are limited and quickly depleted. The body then depends heavily upon the breakdown of protein to provide amino acids as a primary energy source and as a source of new glucose for glucose-dependent tissues. These pathways provide about 85% of energy needs in this setting. Fat is a major fuel source available for gluconeogenesis and may also be oxidized to ketone bodies for use by the liver and other tissues. During brief starvation (approximately 72 hours), this process may be easily interrupted by providing exogenous substrate. After this, adaptive changes favor the mobilization of fat and reduce the breakdown of protein to a low level (30% of energy requirements). Fat, rather than protein, becomes the principal source of energy. With longer starvation, protein is further protected by a fall in total energy requirements. As with brief starvation, the process is quickly and easily reversed by providing exogenous glucose alone (which returns the patient to the brief starvation pattern) or exogenous glucose and amino acids. A variety of conditions, such as trauma, major elective surgery, burns, or sepsis, lead to a metabolic response called the ‘‘injury stress response.’’ This is an endocrinemediated response that increases circulating levels of

the counter-regulatory hormones, catecholamines, corticosteroids, and glucagon, and alters the metabolism of carbohydrates, protein, and fat. More recent evidence suggests that the systemic inflammatory response syndrome (SIRS) and its associated mediators [e.g., tumor necrosis factor (TNF)a, interleukin (IL)-1, IL-2, IL-6] also play an important role in the injury stress response. The best option to control the initiating insult is to provide high-risk patients exogenous substrates that support the metabolic environment. The injury stress response increases resting energy expenditure (REE). The increase in REE is dependent upon the type as well as the severity of the insult. It can increase as much as 100% after burns, 50% after sepsis, 40% after trauma, and 30% after major surgery (1–3). Similar to what occurs in starvation, endogenous substrates are mobilized. Glucose stores are quickly depleted and gluconeogenesis (principally in liver, but also in kidney) produces glucose that is shunted to glucose-dependent tissues (brain, erythrocytes, inflammatory cells, and wound tissue). Adipose tissue is stimulated to release free fatty acids and glycerol. The rate of lipolysis, however, exceeds lipid oxidation. As a result, plasma triglyceride levels increase and considerable reesterification occurs in the liver. This requires energy and creates futile cycles. The increase in protein catabolism is the most dramatic effect. Skeletal muscle proteins and later constitutive protein stores (such as albumin) are broken down and the released amino acids become the substrate for acute-phase protein synthesis, gluconeogenesis, and energy production. Metabolic differences between chronic starvation and the injury stress response are summarized in Table 1. Nutritional support needs to be tailored to the metabolic environment of the patient. The stressed intensive care unit (ICU) patient requires more nonprotein calories (25 kcal/kg/day) and more protein (1.3 g/kg/ day) compared to the starved patient (20 kcal/kg/day and 1.0 g/kg/day, respectively). As stress increases, patients become more catabolic and less tolerant to glucose. Therefore the amount of protein administered is increased (1.5–2.0 g/kg/day) and the percent of nonprotein calories delivered as glucose is decreased

Table 1 Metabolic Response of Starved vs. Stressed Patients Metabolic response

Prolonged starvation

Injury stress

Resting energy Primary fuel Proteolysis Gluconeogenesis Ketone production

Decreased Fat Increased (þ) Increased (þ) Increased (þþþ)

Increased Mixed Increased (þþþ) Increased (þþþ) Increased (þ)

medwedi.ru 49

50

Part One: General Considerations

(80–70%). Thus the nonprotein calories to gram of nitrogen ratio is decreased from 120:1 to 80:1 with increasing metabolic stress.

RATIONALE FOR NUTRITIONAL SUPPORT The rationale for providing nutritional support is threefold: first, to prevent acute protein malnutrition, second, to modulate the immune response, and third, to promote vital gut function.

Prevention of Acute Protein Malnutrition Persistent hypercatabolism dominates the metabolic response to critical illness. Initially, amino acids demands are met by skeletal muscle proteolysis. However, in a short period of time, this depletes crucial constitutive structural elements as well as circulating proteins. The resulting acute protein malnutrition is associated with cardiac, pulmonary, hepatic, gastrointestinal, and immunologic dysfunction. Delayed infections then extend hypercatabolism with the progression to full-blown multiple-organ failure (MOF). A number of clinical studies have clearly demonstrated that early enteral nutrition improves outcome, as measured by improved nitrogen balance and constitutive protein levels, improved immune function, decreased incidence of infections, and decreased length of stay (4–7). However, these studies were performed in trauma and burn patients, an easily identified and cohesive group of patients who also tend to be young and free of comorbid disease. Whether these observations can be generalized to other ICU patient populations is not clear.

Modulation of Immune Response Despite tremendous advances in ICU care, nosocomial infections continue to be an unsolved problem. In large part, these late infections occur due to failure of local and systemic host defenses. While exact causes of late immunosuppression are not clear, it is now believed to occur in part as a result of dysfunctional regulation of inflammation (8). An initial insult, whether secondary to sepsis, trauma/burns, or major operation, can precipitate early systemic hyperinflammation (i.e., SIRS), which when intense can precipitate early MOF. Certain components of this early SIRS response are endogenously downregulated to prevent unnecessary, potentially auto-destructive inflammation. This is referred to as the compensatory anti-inflammatory response syndrome (i.e., CARS). The resulting delayed immunosuppression, however, sets the stage for secondary infection, which can either worsen early MOF or trigger late MOF. While no strategy can prevent or eliminate this dysfunctional inflammatory response, the delivery of specific immune-enhancing nutrients (generally via the gut) may prove beneficial.

Promotion of Vital Gut Function The dysfunctional gut is believed to be the ‘‘reservoir for pathogens’’ that cause late MOF-associated infections. The initial insult (via ischemia/reperfusion, sepsis, or inhibitory neuroendocrine reflexes) and emergency laparotomy (via anesthesia and bowel manipulation) cause an early ileus. Disuse (parenteral instead of enteral nutrition) and common ICU therapies (e.g., H2-antagonists, narcotics, and broadspectrum antibiotics) promote further gut dysfunction, characterized by progressive ileus, colonization of the upper gut, increased permeability, and decreased gut-associated lymphoid tissue function. Consequently, the upper gut becomes

a reservoir for pathogens, and local and systemic defense mechanisms that prevent the spread of these organisms become impaired; the primary route of dissemination (i.e., aspiration vs. translocation) is not clear. Although there is good epidemiologic evidence for this sequence of events, prospective randomized controlled trials (PRCT) of gutspecific therapies such as early enteral nutrition and, recently, immune-enhancing enteral formulas have consistently demonstrated a reduction in nosocomial infections and provide the most convincing evidence (7,9). Thus, the provision of early enteral nutrition to promote more normal gut function is believed to prevent the occurrence of this cascade of events.

INITIATION OF NUTRITIONAL SUPPORT Nutritional Assessment A nutritional assessment is completed early in the hospital stay. Physical assessment of the patient includes evaluation of body composition, edema, wound healing, nutrient composition of fluid losses through wounds or drains, and review of the laboratory and medication profile. A recording of the height and preadmission weight is obtained and information on chronic disease, activity level, medications, previous dietary restrictions, psychosocial data, and drug and tobacco patterns is elicited. A history of 10% weight loss over three months is considered significant. However, weight loss combined with physiologic impairment may be clinically more important, as this can be associated with more septic complications, pneumonia, and a longer hospital stay (10). Functional impairment may be assessed by crude measures such as physical assessment of muscle bellies and triceps skinfold, decreased prehospital activity, perception of fatigue, strength of handshake, strength of cough, and skin integrity. More sophisticated measures such as caliper measurements of skin folds, bioelectrical impedance analysis, indirect calorimetry, and dual-energy X-ray absorptiometry for bone mineral density, hand-grip dynamometry, and respiratory muscle strength may also be performed. Body protein stores as assessed by muscle mass and serum proteins correlate more closely with survival than adipose stores. The normal age-related loss of skeletal muscle is well recognized. Protein-energy malnutrition is a major predictor of mortality in elderly patients (11). Beginning in the second decade, there is a reduction in the total muscle fiber numbers that, with advancing age, produces a 40% reduction in muscle cross-sectional area (12). The malnourished, elderly patient undergoing a catabolic illness may reach a critical cardiac or respiratory threshold earlier than expected (13). Loss of lean body mass, predominately skeletal muscle, in the ICU after stress or sepsis may approach 1% daily (14). Thus, a healthy young person might approach a lethal decline in lean body mass (40%) in 40 days, while a 60-year-old would reach that level in 30 days, and a person over 70 years in 20 days. Reduced immunocompetence accompanies loss of lean body mass. Assessment of serum protein status is conducted upon admission and periodically throughout the hospital stay. Acute-phase proteins, such as C-reactive protein, rise markedly within 48 to 72 hours after sepsis, injury, or surgery, while the constitutive proteins—albumin, prealbumin, and transferrin—all decline (Table 2). Measuring both categories of proteins concurrently helps to determine the degree of physiologic stress and the return of anabolism.

Chapter 3: Surgical Nutrition

Table 2 Serum Proteins that Aid in Nutritional Assessment Protein

Site of synthesis

Half-life

Liver Liver Liver Liver

21 days 2–4 days 8–10 days 48–72 hours

Albumin (g/dL) Prealbumin (mg/dL) Transferrin (mg/dL) C-reactive protein

Table 4 Urinary Nitrogen Loss as a Function of Stress Type of protein Constitutive Constitutive Constitutive Acute-phase reactant

Once the acute-phase response has resolved, the constitutive proteins should rise on provision of adequate nutrition.

Energy Requirements The Harris–Benedict equation is a common method to estimate energy expenditure and thus determine caloric requirements. This equation was derived using healthy males and estimates basal energy expenditure (BEE) based on age, sex, height, and weight. The Harris–Benedict equations are as follows: Men : BEE ¼ 66 þ ð13:7 weightÞ þ ð5 heightÞ ð6:8 ageÞ Women : BEE ¼ 665 þ ð9:6 weightÞ þ ð1:9 heightÞ ð4:7 ageÞ where weight is actual or adjusted (kg), height is in cm, and age is in years. The BEE represents energy requirements in the fasted, resting, nonstressed state. In the presence of metabolic stress, the BEE must be multiplied by an empirically derived stress factor to obtain an estimate of the caloric requirement. The usual stress multiplication factors range from 1.2 to 1.6 times the BEE. Current recommendations for estimated caloric support are reviewed in Table 3. In general, most patients should receive 25 to 30 kcal/kg/day and 1.5 to 1.75 g/kg/day of protein. Needs may decrease as patients move farther from the initial surgery or trauma.

Monitoring Response to Therapy Urinary Urea Nitrogen Urinary urea nitrogen (UUN) is measured as an indicator of the protein catabolic rate (i.e., stress) and is used to determine the nitrogen balance. It represents 60% to 90% of the nitrogen excreted in the urine, and therefore, is a rough approximation of total urinary nitrogen. As the stress level increases, the concomitant increase in protein catabolism results in an increase in urinary nitrogen. Estimated urinary losses for various clinical conditions are reviewed in Table 4. However, in patients with compromised renal function (creatinine clearance <50 mL/min), measurement of UUN is not Table 3 Estimated Caloric Requirements in Surgical Patients by Body Weight Weight class Underweight Normal Overweight Obesitya Extreme obesitya a

BMI (kg/m2) < 18.5 18.5–24.9 25–29.9 30–34.9 35–39.9 40

Use adjusted body weight.

51

Obesity class

Caloric intake (kcal/kg/day)

I II III

40 25–30 25–30 20–25 20–25 10–20

Level of stress Nonstressed Mild stress Moderate stress Severe stress

Clinical condition

Urinary nitrogen loss (g/day)

Starvation Elective surgery Trauma Sepsis

<8 8–12 13–18 > 18

valid and calculations of protein catabolism rates are necessary. These require serial measurements of blood urea nitrogen and weights, and calculations of interdialytic time period and urinary losses of nitrogen. Additionally, UUN is not useful in patients with spinal cord injury because obligatory losses due to disuse muscle wasting are generally extraordinary regardless of the level of support and persist for up to seven weeks postinjury (15). Nitrogen balance is the difference between nitrogen intake and nitrogen output. Nitrogen intake is determined from dietary intake per day, while nitrogen output per day is determined by measuring UUN in a 24-hour urine collection and adding 4 g to approximate nonurea nitrogen loss in the urine plus other insensible N2 losses. Ideally patients should be in positive nitrogen balance (3–5 g/day). Nitrogen balance is calculated as follows: Nitrogen balance ¼ ðg protein intake=6:25Þ ðg nitrogen in UUN þ 4Þ

Metabolic Gas Analysis Also known as indirect calorimetry, metabolic gas analysis is a tool that can measure REE. Oxygen consumption ðVO2 Þ and carbon dioxide production ðVCO2 Þ are measured, and the REE is then calculated from the Weir equation: REE ¼ 3:9 þ VO2 þ 1:1 VCO2 2:8 UUN Care, however, must be taken to ensure that a steady state (less than 10% change in VO2 and VCO2 during five consecutive minutes of the test) was achieved before relying on results (16). The REE obtained should then be used as the patient’s nutritional goal. No activity factor or thermogenesis factor (unless the patient is fasted or on intermittent feeds) needs to be added. Indirect calorimetry may be helpful when (i) overfeeding would be undesirable [as in diabetes, obesity, or chronic obstructive pulmonary disease (COPD)], (ii) underfeeding would be especially detrimental (renal failure, or large wounds), (iii) physical or clinical factors promote energy expenditure deviant from normal, (iv) drugs are used that may significantly alter energy expenditure (paralytic agents, beta-blockers, or corticosteroids), (v) patient response to calculated regimens is suboptimal, and (vi) body habitus makes energy expenditure predictions challenging (morbid obesity or quadriplegia). Although more commonly utilized in ventilated patients, indirect calorimetry can also be performed on spontaneously breathing patients. The second variable obtainable from indirect calorimetry is the respiratory quotient (RQ). This is calculated as follows: RQ ¼ VO2 =VCO2 ¼ CO2 production=O2 consumption RQ is a gross measurement of substrate utilization (Table 5) and should be used to verify the accuracy of the study (17).

medwedi.ru

52

Part One: General Considerations

Table 5 Respiratory Quotient (RQ) for Various Substrates RQ 0.7 0.8 0.85 1.0 > 1.0

Substrate Fat Protein Mixed Carbohydrate Lipogenesis

Any test with an RQ value outside of the physiologic range (less than 0.67 or greater than 1.3) should be checked for accuracy. When an RQ value 1 is obtained and the patient is on total parenteral nutrition (TPN), CO2 production may be increased by one of two mechanisms: either a high proportion of nonprotein calories are being supplied as glucose (carbohydrates have RQ of 1) or the patient is being provided excess calories. With overfeeding, excess glucose is converted to fat and lipogenesis (RQ > 1) occurs.

Body Proteins that Aid in Nutritional Assessment Serum proteins that correlate with nutritional status should be assessed (Table 2). The liver normally produces a number of constitutive proteins that are helpful in nutritional assessment. Albumin is useful for evaluation of chronic malnutrition, but not in the acute setting as it has a long half-life. To determine if nutritional support is having an impact, proteins such as prealbumin and transferrin are more useful due to their shorter half-life. However, during the acutephase response, the liver undergoes reprioritization and downregulates the constitutive proteins and upregulates acute-phase proteins such as C-reactive protein. Measurement of proteins such as albumin and prealbumin are therefore not helpful as indicators of the adequacy of the nutrition support during the acute stress response. C-reactive protein is a sensitive acute-phase reactant that increases from a normal level near zero up to 20 to 30 mg/dL within 48 to 72 hours of injury. It can be used as an indicator of the severity of injury, inflammation, and sepsis. Only when this level begins to decline, can the liver begin to again synthesize constitutive proteins. Once C-reactive protein falls below 10 to 15 mg/dL, a prompt increase in prealbumin typically occurs (0.5–1.0 mg/dL daily). If not, then the adequacy of the support regimen should be reevaluated and other factors that are preventing anabolism should be investigated.

Impact of Nutritional Status on Surgical Outcome Clinical studies have clearly documented the predictive value of preoperative serum albumin levels on postoperative morbidity and mortality. In fact, albumin was the single best predictor of postoperative outcome in several large studies conducted by the Department of Veteran Affairs (18–20). Recently Kudsk et al. (21) demonstrated that albumin as well as the operative site was important in predicting postoperative complications. Patients undergoing colectomy and gastrectomy tolerated greater degrees of malnutrition than those patients undergoing pancreatectomy and esophagectomy. Interestingly, patients with the lowest preoperative albumin levels sustained the longest delays in resuming oral intake postoperatively, compounding the preexisting malnutrition. Despite these findings, preoperative malnutrition remains under-recognized and under-treated and suggests that additional prospective preoperative nutritional studies should be conducted with high-risk patients.

Special Considerations in the Obese Patient Overview of Obesity and Nutrition Obesity affects one-third of Americans and is associated with a number of comorbid conditions. Obesity and morbid obesity are increasingly encountered in the surgery patient and may increase risk for morbidity and mortality. Trauma patients with a body mass index (BMI) > 31 were found to have an eightfold higher rate of mortality following blunt trauma, frequently due to pulmonary complications (22). While controversial, hypocaloric feeding in the obese patient has also been suggested to lessen infectious complications secondary to hyperglycemia. Comparable nitrogen balance is achieved in this patient population when hypocaloric feeds are administered (23). Monitoring for clinical evidence of overfeeding (hypercapnea, hyperglycemia, insulin resistance, hypertriglyceridemia, diarrhea, and distention) is used to refine predictions. Obesity is defined as a BMI 30 (Table 3). Energy needs should be based on adjusted body weight (ABW) when actual body weight exceeds 120% of the ideal body weight (IBW) and is calculated as: ABW ¼ 0:25 ðactual body weight IBWÞ þ IBW: The ABW takes into account the increased lean body mass seen in obese patients and should be used in the Harris–Benedict equation or in caloric predictions (kcal/kg) of energy needs. Obese patients experience a similar metabolic response to critical illness but tend to be more resistant to insulin. Obese patients should be started on nutritional support as early as their nonobese counterparts. Hypocaloric feeding provides the obese individual with high protein (1.5–1.75 g/kg ABW) but low total calories (20–25 kcal/kg ABW).

Nutrition After Bariatric Surgery Nutritional treatment for uncomplicated bariatric procedures is somewhat standardized across the country, although little evidence-based research has been performed in this patient population. Immediately after surgery, most programs begin clear liquids for several days, which are consumed in 30 cc/hr increments. This is followed by a progressive diet (advanced every two weeks) of full liquids, then pureed, soft foods, and finally a regular diet as tolerated. Maintenance goals are set at 1000 to 1200 kcal daily. Protein goals are typically 60 to 80 g protein/day, which may deliver as little as 0.48 g protein/kg ABW, which is less than the recommended daily intake of 0.8 g/kg body weight of protein. Liquid multivitamins with mineral supplements, iron, vitamin C, vitamin B12, and calcium may also be added. The amount of nutritional follow-up and level of expertise varies greatly between programs. For the majority of patients, a standard bariatric diet can be followed. However, patients who develop postoperative complications necessitating admission to the ICU will generally require an alternative feeding regimen. If the complication is intra-abdominal, particularly if secondary to an anastomotic leak, nutrition will usually be provided by the parenteral route, as enteral access (to the small bowel) will generally require operative placement. An initial goal of adjusted weight at 10 to 20 kcal/kg and protein at 1.5 g/kg can be instituted, depending on the degree of insulin resistance. Indirect calorimetry is helpful and, if performed, feeds should be instituted at 60% to 75% REE. A UUN can then be used as a guide to achieve positive nitrogen balance. Type 2 diabetes is a

Chapter 3: Surgical Nutrition

frequent comorbidity and strict glycemic control (glucose < 110 mg/dL) should be employed in all patients. Intravenous lipids are not provided in the first one to two weeks, and then provided sparingly to prevent essential fatty acid deficiency. Enteral support typically requires a specialized combination of a high-protein polymeric formula with the addition of a protein modular product. A liquid multivitamin and mineral supplement may also be added. Bariatric patients who experience delayed complications or significant remote illnesses can pose a challenge. Many of these patients have been on the bariatric diet for a prolonged period of time and may have some degree of protein malnutrition from a low-calorie, low-protein diet. Due to malabsorption, micronutrient deficits may be present and the refeeding syndrome is likely to occur. Organ function may also be compromised through body cell mass depletion, and immunocompetence decreased via protein malnutrition. Kilocalorie and protein requirements can be extraordinary, especially with large wounds such as necrotizing fasciitis or decubiti. However, the approach is similar to that taken with early postoperative complications. Indirect calorimetry, 24-hour UUN, and sequential monitoring of C-reactive protein and prealbumin should be employed. If renal failure occurs, continuous dialysis is typically employed to facilitate adequate feeding. Depending on the length of time since the original surgery and the adequacy of postoperative nutritional follow-up, the patient may exhibit varying degrees of protein, iron, zinc, calcium, folate, and B12 deficiency.

ENTERAL NUTRITION Benefits of Enteral Nutrition Three prospective randomized controlled trials (PRCTs) performed in the 1980s had significant impact on clinical practice in surgical, and particularly trauma ICUs (4–6). These single-institution trials all randomized trauma patients to early enteral nutrition or TPN and all demonstrated that patients receiving early enteral nutrition had significantly fewer infectious complications. A meta-analysis that

53

combined data from eight PRCT (six published, two not published) was then conducted to assess the nutritional equivalence of enteral nutriton compared to TPN in highrisk trauma and/or postoperative patients (24). Similar to the single-institution trials, fewer infectious complications developed in patients receiving enteral nutrition. Even when patients with catheter-related sepsis were removed from the analysis, a significant difference in infections between groups remained. Taken together, these trials provide convincing evidence that enteral nutrition is preferred to TPN in patients sustaining major torso trauma. A recent meta-analysis evaluating the effect of early versus delayed enteral nutrition in acutely ill (medical and surgical) patients also confirmed a decrease in infectious complications in patients receiving early enteral nutrition (25).

Role of Immune-Enhancing Agents in Surgical Patients Recent basic and clinical research suggests that the beneficial effects of enteral nutrition can be amplified by supplementing specific nutrients that exert pharmacologic immune-enhancing effects beyond the prevention of acute protein malnutrition. There are at least 18 PRCT (Table 6) and three meta-analyses (24,26,27) where an immuneenhancing enteral diet is compared with a standard enteral diet or no diet, and where the patient outcome was a predetermined end point. Of the 18 PRCTs, 11 trials demonstrated improved outcome, four trials were highly suggestive of improved outcome, and three trials did not demonstrate any clinical outcome advantage. The majority of trials are in trauma and cancer patients, though a few trials include mixed ICU and septic ICU patients. The proposed immune-enhancing agents include glutamine, arginine, omega-3 polyunsaturated fatty acids (PUFA), and nucleotides, though the individual contributions of each have not been well investigated. Glutamine is actively absorbed across the intestinal epithelium and then metabolized in the small bowel to ammonia, citrulline, alanine, and proline, and serves as an energy source for the

Table 6 Patient Outcome in Prospective Randomized Controlled Trials Comparing IEDs vs. Standard Enteral Diets Author

Year, Journal

Patient type (Number)

Gottschlich Daly Brown Moore

1990, 1992, 1994, 1994,

JPEN Surgery Pharmacotherapy J Trauma

Burns (50) Cancer (77) Trauma (37) Trauma (98)

Bower Daly Kudsk Senkel Mendez Saffle Heslina Braga Atkinson Weimann Senkel Braga Snyderman Galban

1995, 1995, 1996, 1997, 1997, 1997, 1997, 1998, 1998, 1998, 1999, 1999, 1999, 2000,

Crit Care Med Ann Surg Ann Surg Crit Care Med J Trauma J Trauma Ann Surg Crit Care Med Crit Care Med Nutrition Arch Surg Arch Surg Laryngoscope JPEN

Mixed ICU (296) Cancer (60) Trauma (35) Cancer (154) Trauma (43) Burns (50) Cancer (154) Cancer (154) Mixed ICU (369) Trauma (32) Cancer (154) Cancer (206) Cancer (129) Septic ICU (181)

Results with IED (decrease in) Wound infection, LOS Wound complication, infections Infections Intra-abdominal infection, multiple organ failure Infections, LOS Wound complications, infections, LOS Antibiotics, infection, LOS Late infections * ARDS

Infections, LOS Ventilator days, LOS SIRS, multiple organ failure Late infections Infections Infections Late infections

a

Improved outcome Yes Yes Yes Yes ? Yes Yes Yes Yes No No No Yes ? Yes ? Yes Yes Yes Yes Yes

Compared IED to no diet. Abbreviations: ARDS, adult respiratory distress syndrome; ICU, intensive care unit; IED, immune-enhancing diet; SIRS, systemic inflammatory response syndrome; LOS, length of stay.

medwedi.ru

54

Part One: General Considerations

enterocyte. Glutamine is therefore acknowledged to be the preferred fuel of the enterocyte, and stimulates lymphocyte and monocyte function. The demand for glutamine is increased during stressed states and supplementation at pharmacologic doses may be required. It also promotes protein synthesis, is a precursor for nucleotides as well as glutathione, and is thought to play a role in maintaining gut integrity. In a recent meta-analysis, glutamine (parenteral and enteral) administered to critically ill and surgical patients resulted in a lower mortality, less infectious complications, and shorter hospital stays (28). High-dose and parenteral glutamine had the greatest effect, though the study was not designed to examine these parameters. Additionally, a mixed patient population was included with limited (randomized) studies and clinical end points. A randomized trial of glutamine-enriched enteral nutrition in severely injured patients demonstrated a decrease in pneumonia, sepsis, and bacteremia (29). Arginine is a semiessential amino acid that is important for T-cell function and wound healing. Endogenous production is insufficient during periods of metabolic stress (such as illness) and exogenous supplementation is required for maximal function of the immune system. It is also a powerful secretagogue, increasing the production of growth hormone, prolactin, somatostatin, insulin, and glucagon. Additionally, arginine is the chief precursor of nitric oxide and has been shown to increase protein synthesis and improve wound healing (30). It is the association with nitric oxide production that has led to speculation that arginine may enhance the systemic inflammatory response and, therefore, be potentially harmful, particularly in septic patients (31). Sepsis increases levels of inducible nitric oxide synthetase (iNOS). Arginine is a substrate for iNOS, and in its presence arginine combines with molecular oxygen to produce citrulline and nitric oxide. The resulting nitric oxide could have numerous adverse effects in sepsis, including vasodilation, cardiac dysfunction, and direct cytotoxic injury by generating potent reactive oxygen species. Increased mortality has been demonstrated in some critically ill septic patients when receiving an immune-enhancing diet, and arginine has been implicated as the causative agent (32,33). Although traditional enteral products contain a high proportion of omega-6 PUFA, diets with a low omega-6 PUFA and high omega-3 PUFA content more favorably alter the fatty acid composition of membrane phospholipids toward reduced inflammation (34). Finally, nucleotides (purines and pyrimidines) are needed for DNA as well as RNA synthesis and may be necessary in stressed states to maintain rapid cell proliferation and responsiveness (35). In the setting of increased demand, most tissues can increase intracellular de novo synthesis of nucleotides. Lymphocytes, macrophages, and enterocytes, however, rely on increased salvage from the extracellular pool, which may be depleted during stress.

Contraindications to enteral nutrition can be divided into absolute and relative. Absolute contraindications would include functional complications such as bowel obstruction, peritonitis, progressive ileus, massive gastrointestinal hemorrhage, and gastrointestinal ischemia associated with shock and vasopressors. Relative contraindications include proven intolerance to enteral nutrition and intolerance associated with short-gut syndrome, high-output fistula, pancreatitis, and inflammatory bowel disease. A recent bowel anastomosis is not a contraindication. Laboratory data in fact suggests that healing may be hastened by early feeding (36).

Gastric Feeding Controversy exists as to the optimal site for delivery of enteral nutrients. Although there is a trend toward decreased ventilator-associated pneumonias with jejunal feeding, no significant differences have been demonstrated between postpyloric and gastric feeding (37–40). None of these studies, however, have been appropriately powered to demonstrate statistical significance. Additionally, a greater percentage of caloric goals are reached (37,41) and gastrointestinal complications are less frequent with postpyloric feeding. The stomach, but not the small bowel, commonly exhibits an ileus after surgery, major trauma, or other critical illnesses. Ritz et al. demonstrated that up to 45% of ventilated patients had delayed gastric emptying, impeding adequate delivery of gastric feeds (42). Several studies have shown that this can be modulated by the use of prokinetic agents (43,44). Erythromycin has a direct effect on the motilin receptors of the stomach and has been shown to improve the effectiveness of gastric feedings. Gastric feeding is appropriate for some surgical patients, particularly those farther out from their initial injury or insult. Prior to starting gastric feeds, however, patients should be screened for risk of aspiration (Table 7) (45). Aspiration is the second most common cause of nosocomial infection in hospitalized patients (46). The presence of an inflated endotracheal cuff does not preclude aspiration in intubated patients, as there is as high as a 50% to 75% incidence of aspiration in patients with endotracheal tubes and/or tracheostomies (47,48). Altered mental status, whether from dementia, sedation, or a closed head injury poses a risk as do neuromuscular disorders and stroke. Recent major abdominal surgery and the need for prolonged supine position can also increase the risk of aspiration. Persistently high gastric residual volumes have also been sited as a risk factor. What constitutes a high volume, however, has not been well defined. Approximately 1.5 L of saliva and 3 L of gastric secretions are produced daily and the stomach empties about a third to one-half of its contents hourly (49). Therefore, residual volumes approaching 500 cc/4 hr should be safe. To minimize the risk of aspiration, the head of the bed should remain elevated, oral care should be diligent,

Indications and Contraindications for Enteral Nutrition

Table 7 Factors Posing a Major Risk of Aspiration

Hospitalized patients who cannot adequately meet their nutritional goals by oral intake alone for a period of seven days should be considered for enteral supplementation. Additionally, early enteral nutrition should be considered for all acutely ill patients, such as patients with major torso trauma, chronically malnourished patients, and patients with limited physiologic reserve.

Endotracheal intubation Decreased level of consciousness Neuromuscular disorders or anatomical abnormalities of the upper gastrointestinal tract Recent stroke Recent major abdominal surgery Persistently high gastric residual volumes

Chapter 3: Surgical Nutrition

55

tolerance should be regularly assessed, narcotics minimized, electrolyte abnormalities corrected, and glucose control optimized. Numerous strategies have been employed to identify occurrences of aspiration. Use of food, drug, and cosmetic (FD&C) blue No. 1 and methylene blue as means of visual detection for aspiration has been associated with clinically significant toxicity and this practice is discouraged (50). Furthermore, the presence of glucose in the tracheal aspirate has been found to be neither a reliable nor specific indicator of enteral feeding aspiration.

more partially digested macronutrients or combinations of nutrients and can be absorbed in patients with compromised gastrointestinal tracts), and modular formulas (which are composed of individual nutrients or combinations of nutrients, but are nutritionally incomplete and intended for use as supplements or in combination with other products). Unfortunately, with the exception of the immune-enhancing formulas, very little comparative data exists to guide clinicians in selecting the most appropriate formula. A recommended formula selection is reviewed in Table 9.

Obtaining Enteral Access

Administration of Feeds

Access can be divided into gastric (and duodenal) and jejunal with push, endoscopic, radiologic, and surgical options available (Table 8). For patients to be fed through an intragastric approach, a soft, nonsump nasogastric tube can be placed. For patients known to require long-term feeding access, a percutaneous endoscopic gastrostomy (PEG) can be obtained. For those patients identified as candidates for jejunal feeds, access can be obtained at the time of initial laparotomy, or at subsequent laparotomy if damage control is initially performed. The needle catheter jejunostomy (NCJ) is the preferred method of access and a commercially available kit containing a silastic 7 French catheter is available. Patients not undergoing laparotomy could have a ‘‘push’’ nasojejunal tube (Corpak Medsystems, Wheeling, Illinois) placed. If this is unsuccessful, an endoscopically placed nasojejunal tube can be placed through the biopsy channel of a flexible endoscope that has been advanced into the duodenum (51). Nasojejunal feeding may be done indefinitely, but if the need for long-term access becomes apparent, a PEG with a jejunal extension limb (PEG-J) can be placed.

Once enteral access has been obtained, feeds are begun at 15 cc/hr of full-strength formula and advanced by 15 cc/hr every 12 hours to a set goal of 60 cc/hr. To assure tolerance, this rate is maintained for 24 hours and then advanced by 15 cc/hr every 12 hours to a patient-specific targeted goal.

Formula Selection Many of the early clinical trials were performed using elemental formulas that were low in fat and surmised to be better tolerated. However, more recent studies suggest other formulas to be equally well tolerated. The numerous available formulas may be categorized into polymeric formulas (which contain nutrients in high-molecular-weight form, moderate fat loads, and require normal digestive and absorptive ability), predigested formulas (which contain one or

Complications of Enteral Nutrition Overview of Complications Technical complications that can be associated with the administration of enteral nutrition include aspiration, bowel perforation, clogged tubes, and tube malposition/dislodgement. Tube clogging can be prevented by routine saline irrigation of the tube and by administering only liquid medications through smaller bore tubes such as NCJs. Functional complications are the gastrointestinal manifestations frequently associated with intolerance and include emesis, nausea/ vomiting, cramping pain or distention, and diarrhea.

NCJ-Related Complications NCJs, although an ‘‘invasive’’ technique, are a safe and effective means to deliver jejunal feeds. Myers et al. reported only a 1% incidence of major complications and a 1.7% incidence of minor complications in a large study examining the safety of NCJs in patients undergoing major elective and emergency abdominal operations (52). The jejunostomyrelated complication rate in trauma patients has been reported to be slightly higher, with a major complications rate of 4% (53). However, the majority of these complications (10%) occurred in patients with a standard, open

Table 9 Formula Selection for Delivery of Enteral Nutrition Table 8 Options for Enteral Access Gastric tubes Manual Endoscopic Radiographic Surgical Jejunal tubes Manual Endoscopic

Radiographic

Nasogastric/nasoduodenal PEG Endoscopically placed nasoenteric (nasoduodenal tube) Fluoroscopy-guided nasoenteric tube PRG Open: Stamm, Witzel, or Janeway gastrostomy Laparoscopic gastrostomy ‘‘Push’’ nasojejunal tube PEJ PEG/JET Endoscopically placed nasojejunal tube PRG/PRJ PRG/JET

Abbreviations: JET, jejunal extension tube; PEG, percutaneous endoscopic gastrostomy; PRG, percutaneous radiographic gastrostomy; PEJ, percutaneous endoscopic jejunostomy; PRG/PRJ, percutaneous radiographic gastrostomy/jejunostomy.

Immune-enhancing diet Patients who have sustained major torso trauma, undergone major upper gastrointestinal surgery, or have limited physiologic reserve and who are at known risk for septic complications and multiple organ failure Polymeric high-protein formula Patients who do not meet the criteria for an immune-enhancing diet, have normal gut function, and are believed to have increased nitrogen requirements due to major injury, illness, or surgery. A modular protein component may be used in addition to the polymeric high-protein formula for use in the morbidly obese patient or in any patient that requires protein supplementation Elemental formula Patients who are intolerant to a polymeric formula or are acutely ill and who have not received enteral feeds for prolonged period of time Renal failure formula A concentrated, reduced electrolyte formulation is selected for use only in patients requiring intermittent hemodialysis. Often a modular protein component is used in addition to the commercially available renal formula to meet the increased nitrogen demands of the critically ill patient

medwedi.ru

56

Part One: General Considerations

jejunostomy (typically a 14 French catheter), rather than with a NCJ (5–7 French, 2% incidence of complications). Major complications reported included volvuli with infarction, small bowel perforation, intraperitoneal leaks, and nonocclusive small bowel necrosis.

Nonocclusive Bowel Necrosis A rare but devastating complication of bowel necrosis has been associated with the administration of enteral feeds. The clinical presentation is similar to that of neonatal necrotizing enterocolitis, though the consistent association with enteral nutrition suggests that the inappropriate administration of nutrients into a dysfunctional gut plays a pathogenic role. The incidence is less than 1%, but the mortality frequently exceeds 50% (54,55). Most cases of nonocclusive bowel necrosis occur in a delayed fashion in critically ill patients with a complicated course (pneumonia, sepsis, renal failure, etc.) that requires progressively higher acuity care. Gastrointestinal signs and symptoms tend to occur late and, as a result, clinical monitoring fails to detect this entity early in its course. Computed tomography scan may reveal pneumatosis intestinalis or thickened bowel. Although most cases will require exploratory laparotomy, less advanced presentations may be managed with cessation of feeds, broadspectrum antibiotics, and aggressive fluid resuscitation.

Enteral Nutrition Protocol Rationale for an Enteral Nutrition Protocol An enteral feeding protocol can assist in providing a systematic, evidence-based approach to enteral nutrition and in minimizing complications. Assessing tolerance parameters are an important part of any enteral protocol. Frequently identified indicators of intolerance are vomiting, abdominal distention or cramping/tenderness, diarrhea, and high nasogastric tube output (56). Symptoms can be graded as mild, moderate, or severe. Mild symptoms of intolerance, such as mild abdominal distention or diarrhea, can just be monitored by repeat physical examinations with no change in the current rate of feeding. Moderate symptoms are managed based on the particular symptom. For distention, enteral feeds should be stopped and the patient assessed for evidence of a mechanical obstruction. If distention remains moderate, an elemental formula should be considered. Moderate diarrhea can be managed by maintaining but not increasing the current feeding rate and repeat examinations. Finally, for severe distention, enteral feeds should be stopped, intravenous hydration begun, and the possibility of nonocclusive bowel necrosis should be considered. For severe diarrhea, tube feeds can be reduced and the patient should be evaluated for possible Clostridium difficile infection. Vomiting is managed by ensuring adequate gastric decompression and either stopping gastric feeds or decreasing the tube feed infusion rate by half for jejunal feeds. Additionally, high nasogastric output in patients fed into the small bowel can be managed by verifying postpyloric placement of the feeding tube and checking the nasogastric aspirate for glucose. Any amount of glucose is considered abnormal and enteral feeds should be withheld. In general, enteral feeds should be discontinued if vasopressors are instituted.

Results of an Enteral Nutrition Protocol The incidence of enteral tolerance while using a protocol was analyzed in a prospective multi-institutional study

(57). Early tolerance (during advancement of enteral feeds to a goal of 60 cc/hr) was good in 84% (41/49) of patients and moderate in 16% (8/49). No patients experienced poor tolerance or complete intolerance. Late tolerance (after standard goal rate was met) was good in 80% (39/49), moderate in 16% (8/49), and poor in 4% (2/49) of patients. The site of feeding (gastric vs. jejunal) was not dictated by the protocol. Moderate intolerance was primarily due to high gastric output in patients fed via the stomach. All patients were successfully maintained on early enteral nutrition using this standardized protocol.

Specialized Enteral Diets Formulas with reduced carbohydrate and increased fat loads are available for use in patients with diabetes to potentially improve glycemic control. These products have not, however, undergone PRCT to demonstrate superior outcome in ICU patients. The use of standard high-protein formulas in an isocaloric or hypocaloric load, combined with aggressive insulin therapy, may be the most effective treatment for insulin resistance in the stressed, diabetic patient as opposed to carbohydrate restriction. Additionally, gastric feedings in the diabetic patient with gastroparesis may be associated with delayed gastric emptying and increased risk of aspiration, especially when high in fat content. There is one PRCT that demonstrated superior outcome, as demonstrated by reduced days on the ventilator, reduced ICU length of stay, and decreased incidence of organ failure in patients with adult respiratory distress syndrome (ARDS) when provided a high omega-3 fatty acid enteral product versus a high omega-6 ‘‘pulmonary’’ formula (58). However, the control diet was not the standard of care and may worsen ARDS. High omega-6 fatty acids increase inflammation and production of lipid mediators, which can worsen V/Q mismatch and thus worsen oxygenation in these patients. Although an enteral diet high in omega-3 fatty acids may be beneficial in early ARDS (59), prior to recommending such a diet, additional studies need to be performed.

TOTAL PARENTERAL NUTRITION Indications for TPN Whenever possible, the gastrointestinal track should be utilized for nutritional support. Table 10 reviews the basic indications for the administration of TPN. In general, TPN should not be started for at least seven days postoperatively if the patient is well nourished at baseline. Critically ill patients should be started on TPN if they are unable to achieve adequate caloric intake by postoperative day 6. Unlike with enteral feeding, there is no benefit to early TPN. Patients with persistent ileus, bowel obstruction, short gut, high-output fistulas, and malabsorption, may all benefit from TPN. Additionally, patients unable to tolerate enteral Table 10 Indications for TPN Persistent or progressive ileus Bowel obstruction Massive bowel resection refractory to enteral diet High-output fistula refractory to elemental diet Malabsorption High risk for nonocclusive bowel necrosis if fed enterally (shock resuscitation, a-agonists, persistent severe distention, or cramping) Documented intolerance to enteral nutrition Abbreviation: TPN, total parenteral nutrition.

Chapter 3: Surgical Nutrition

nutrition or who are at high risk for nonocclusive bowel necrosis (hypoperfusion or high vasopressor requirements) may benefit from TPN.

Table 11 Trace Element Deficiencies Trace element Iron Zinc

Preoperative and Perioperative TPN It is well documented that malnourished patients are at an increased risk for septic complications, problems with wound healing, longer hospital stays, and increased mortality (60). The unproved contention is that preoperative TPN can improve nutritional status and thereby reduce postoperative morbidity and mortality. However, studies evaluating preoperative TPN and outcome are variable. Results of randomized trials and a meta-analysis suggest that preoperative TPN for 7 to 10 days in severely malnourished patients may be beneficial in reducing the rates of infectious complications (61–65). For the mild to moderately malnourished patients, however, the risks of preoperative TPN (increase in septic morbidity) appear to outweigh the potential benefits. One of the confounding variables in preoperative TPN trials is that many of the patients were undergoing resection of a gastrointestinal cancer. Cancer patients in general, and particularly those with gastrointestinal malignancies, have cancer-associated weight loss, which can be very difficult to reverse. Prospective randomized trials of patients undergoing gastrointestinal surgery also failed to demonstrate any benefit, with the TPN group experiencing higher complication rates. Thus, routine postoperative TPN is not indicated and should be reserved for patients who cannot resume a diet by postoperative day 6 (66).

Initiation of TPN Components of TPN Components of TPN include (i) dextrose, (ii) fatty acids, (iii) amino acids, (iv) electrolytes, (v) vitamins, (vi) trace minerals, and (vii) fluids. Protein is provided based on grams per kilogram body weight, lipid is provided to deliver approximately 10% of total kilocalories needed, and dextrose provides the balance of kilocalories. Dextrose monohydrate (caloric density 3.4 kcal/g) is the carbohydrate. Fat emulsions (caloric density 2.0 kcal/cc of 20%) made from either soybean oil or a mixture of soybean oil and safflower oil provide fat calories and are the source of essential fatty acids (linoleic, linolenic, and arachidonic acids). Protein (caloric density 4 kcal/g) is provided as crystalline amino acids. Standard amino acid solutions contain a balance of essential and nonessential amino acids. The electrolyte cations, which include sodium, potassium, magnesium, phosphorus, and calcium, are admixed into the TPN solution using one of several anions. Acid–base status may be affected by the amount of chloride or acetate used in providing sodium and potassium. The concentrations of calcium and phosphorus are limited to avoid precipitation of a calcium phosphate salt. Multivitamin products that meet American Medical Association recommendations contain vitamins A, C, D, and E and the B vitamins, including folate, but not vitamin K, which must be added separately. A multi–trace mineral product is added to provide copper, chromium, manganese, zinc, and selenium. Symptoms of trace mineral deficiencies are reviewed in Table 11. TPN solutions are hyperosmolar and must be delivered through a large-lumen vein. When central access is unavailable or undesirable, peripheral parenteral nutrition (PPN) with a dilute solution (less than 800 mOsm/L) may be delivered through a peripheral vein for 7 to 10 days. Infusion sites must be rotated often to

57

Copper Chromium Selenium Manganese Molybdenum

Symptom of deficiency Anemia Maculopapular rash, poor wound healing, cutaneous anergy, alopecia Anemia unresponsive to iron, pancytopenia Sudden glucose intolerance during TPN Proximal neuromuscular weakness and cardiac failure Weight loss, altered hair pigmentation, nausea Nausea/vomiting, tachycardia, central nervous system disturbances

Abbreviation: TPN, total parenteral nutrition.

reduce the incidence of thrombophlebitis. This therapy is best reserved for younger patients with easy peripheral access. PPN is seldom utilized. The combination of amino acids, dextrose, and lipids is referred to as total nutrient admixture (TNA) or a 3-in-1 solution. Typically an 8.5% or 10% amino acid solution is employed, although a 15% solution is available for patients requiring fluid restriction, such as those with congestive heart failure, renal failure, or hepatic failure. Dextrose 50% is the usual carbohydrate solution, although 70% solution may be used to restrict volume. Lipids are available in 10%, 20%, and 30% and are needed to prevent essential fatty acid deficiency. Ten percent of total kilocalories will accomplish this goal. Additional lipids can be given to provide an alternative calorie source in patients intolerant of high glucose loads. If lipids are administered separately, they must be infused for no greater than over 12 hours to prevent bacterial growth. Lipids are stable in TNA for 24 hours because the osmolarity and pH are less favorable to bacterial growth. The following is an example of TPN in an 80 kg male patient with significant injuries requiring 2400 kcal (30 kcal/kg) and 140 g protein (1.75 g/kg). A typical institutional TPN form is shown in Table 12.

Calculations (see Table 13): 1. 2.

Establish the kilocalories and protein desired: 2400 kcal, 140 g protein. Select the appropriate amino acid formula and quantity: using 10% amino acids 10 gm=100 mL 140 gm ¼ 1400 mL

3.

Calculate 10% of kcal as lipid emulsion: using 20% lipids 10% 2400 ¼ 240 kcal 240 kcal 1 mL=2 kcal ¼ 120 mL

4.

Add the kcal from amino acids and fat and subtract from goal:

medwedi.ru

acids ¼ 140 g protein 4 cal=g ¼ 560 kcal kcal from fat ¼ 240 kcal goal kcal ðamino acid þ fatÞ kcal ¼ 2400 ð800 þ 240Þ ¼ 1600 kcal

58

Part One: General Considerations

Table 12 Example of a Standard TPN Order Sheet

This is the amount of dextrose kcal needed. To determine the volume, 1600 kcal=3:4 kcal=g glucose ¼ 470 g glucose 470 g glucose=50 g=100 mL ¼ 940 mL The patient’s electrolyte profile is reviewed. If it is relatively normal, infusion is started with standard electrolyte requirements.

Complications Complications of TPN can be divided into technical, infectious, and metabolic. Administration of TPN requires central venous access due to its hypertonicity. Administration

through a large, central vein allows rapid dilution and therefore prevention of venous sclerosis and thrombophlebitis, which will occur with peripheral venous administration. The insertion of a central venous line, however, is not without risk. More than 15% of patients receiving central lines have some type of complication (67). Technical complications range from injury to major veins, arteries, or nerves, and violation of the pleural space. Complications can be minimized by strict observation of well-established guidelines for insertion, including adequate supervision. If a major artery is punctured, the needle should be withdrawn and pressure applied. If the vessel has been cannulated and it is unclear into which vessel (artery or vein) the catheter has been inserted, the catheter should be transduced. A venous tracing should be seen and the measured pressure should be approximately 4 to 10 mmHg.

Chapter 3: Surgical Nutrition

Table 13 Sample TPN Order Nonstandard TPN solution Base solution Standard amino acid (10 g/100 mL) Dextrose 50% (50 g/100 mL:3.4 kcal/g) Volume of base solution to be delivered in 24 hr Electrolytes Sodium chloride Sodium phosphate Potassium acetate Calcium gluconate Magnesium sulfate Multivitamins Trace elements Fat emulsion 20% (1 kcal/mL) Infusion rate

1400 mL 940 mL 2300 mL

35 mEq/L 8.3 mEq/L 35 mEq/L 4.16 mEq/L 3.3 mEq/L 10 mL 1 mL 120 mL 101 mL/hr

Abbreviation: TPN, total parenteral nutrition.

The pathogenesis of infectious complications most commonly stems from colonization of the skin and catheter hub. Short-term, noncuffed catheters (such as single- or triple-lumen catheters) become colonized from skin flora that migrate from the insertion site along the external surface of the catheter to the catheter tip and lead to catheterrelated bloodstream infections. Long-term catheters such as cuffed, tunneled, silicone catheters (Hickmans or Broviacs) or implanted catheters (ports) become colonized as bacteria migrate through the lumen of the hub, which becomes contaminated by skin flora. Other less frequent sources of contamination include infusion of contaminated solutions or hematogenous seeding from a distal site of infection. Preventative measures can be broken down into three categories: (i) catheter insertion, (ii) catheter care, and (iii) catheter removal. Important components of catheter insertion include skin preparation (chlorhexidine is more efficacious than alcohol or povidone iodine) and the use of

59

maximal sterile barriers (68). Although it is commonly believed that multiple-lumen catheters have a higher rate of catheter-related sepsis compared to single-lumen catheters, randomized studies have not confirmed this practice (69). Recent randomized trials indicate that catheter-related sepsis can be reduced by the use of antibiotic- or antisepticbonded catheters (70). However, these catheters are considerably more expensive, can be associated with anaphylaxis, and have the potential to cause resistant organisms. Therefore, they should be used in select patients whose catheters are going to be in place for extended periods of time. With regard to catheter care, dressings may be either a transparent, semipermeable, polyurethane dressing or gauze. Insertion site antibiotic or antiseptic ointments are not recommended because of the potential to promote antibiotic resistance and fungal colonization. A meta-analysis of 12 randomized trials of catheter replacement did not support scheduled exchange of catheters over a guide wire or scheduled, routine replacement at a new site (71). Metabolic complications can include hyper- or hypoglycemia, electrolyte abnormalities, acid/base abnormalities, liver function abnormalities, and trace mineral deficiencies (Table 14) (72). Critical illness is accompanied by increased plasma counter-regulatory hormone levels, which have multiple effects on glucose homeostasis. The end result is hyperglycemia with resistance to insulin. Other factors that contribute include obesity, inflammatory cytokines associated with the SIRS (such as TNFa, IL-1, IL-2, and IL-6), advanced age, exogenous steroid or catecholamines, increased free fatty acids, and nutritional support (parenteral route greater than enteral route). The resulting hyperglycemia can adversely affect outcome through several mechanisms, including glycosuria with inappropriate diuresis, increase risk of infection by impairing neutrophil and immunoglobulin function, and exacerbation of cerebral edema. Van Den Berghe et al. (73) have recently demonstrated in a prospective randomized fashion a reduction of mortality in critically ill surgical patients, from 8% to 4.6%,

Table 14 Metabolic Complications Associated with TPN Abnormality Electrolyte Hyperkalemia Hypokalemia Hyperphosphatemia Hypophosphatemia Hypercalcemia Hypocalcemia Hypermagnesemia Hypomagnesemia Glucose Hyperglycemia Hypoglycemia Amino acids Hypercholeremia Metabolic acidosis Fatty acid deficiency Bleeding Abnormal liver functions

Etiology

Correction # " # " # "

Renal insufficiency/failure Inadequate intake, diuresis, diarrhea, refeeding Renal insufficiency/failure Inadequate administration, refeeding Excessive administration Inadequate administration, hypoalbuminemia, refeeding, rapid phosphorus repletion Excessive administration, renal failure Inadequate intake, diuresis, refeeding

# Administration " Administration

Excessive administration, sepsis, inadequate secretion of insulin Abrupt cessation of TPN, liver dysfunction

Strict glucose control with exogenous insulin, consider reducing glucose calories Taper TPN rate, administer 5% or 10% dextrose

Excessive chloride administration Excessive chloride administration Sepsis, inadequate perfusion, renal failure Inadequate administration Vitamin K deficiency Excessive fat or glucose administration, amino acid imbalance

# Administration Administer acetate Reassess patient " Administration " Administration Reassess patient

Abbreviation: TPN, total parenteral nutrition.

medwedi.ru

Administration Administration Administration Administration Administration Administration

60

Part One: General Considerations

when glucose levels were strictly controlled between 80 and 110 mg/dL versus conventional therapy (120–180 mg/dL). In a follow-up analysis, the same investigators demonstrated that the reduction in critical illness polyneuropathy, bacteremia, inflammation, and mortality was related to the lowering of blood glucose levels and not the amount of infused insulin per se (74). These data strongly support the maintenance of normoglycemia. The refeeding syndrome is a dramatic example of a metabolic complication that can be associated with TPN administration. It occurs with rapid and excessive feeding of patients with severe malnutrition due to conditions such as starvation, alcoholism, delayed nutritional support, anorexia nervosa, hyperemesis gravidarum, and massive weight loss after bariatric surgery (75). As a result of ion fluxes into the cell with refeeding, serum phosphate, magnesium, potassium, and calcium levels can drop rapidly. In the case of blunted basal insulin secretion, severe hyperglycemia may arise. Symptoms include cardiac arrhythmias, confusion, respiratory failure, and even death. This can be prevented by initiating TPN at a rate lower than the required goal, primarily by reducing dextrose calories. Exogenous insulin is frequently required.

patients have poor response to chemotherapy, radiation, and surgery as well as increased morbidity and mortality. When feasible, use of the gastrointestinal tract is the preferable mode of feeding. Immune-enhanced enteral diets in patients with gastrointestinal cancers have been shown to decrease postoperative infections (78,79). A recent metaanalysis that carried out a separate analysis of patients with gastrointestinal cancer, similarly demonstrated a reduction in major infectious complications but not death in the postoperative period (26). Traditionally, concern exists that perioperative TPN may promote tumor growth, i.e., feed the tumor not the patient. However, many studies supporting this theory were performed in animals whose life span is much shorter than humans (80). Thus, a 10-day course of TPN would represent a far greater segment of an animal’s life. Furthermore, the tumor size in these studies was large, representing up to 30% to 40% of the animal’s body weight. Nonetheless, the use of TPN in this patient population offers little benefit and may increase infection rates (81). Severely malnourished patients receiving a bone marrow transplant may be one subset of patients who can benefit from perioperative TPN.

Monitoring TPN

Short Gut

This is done to (i) determine the efficacy of the TPN therapy; (ii) determine changes in metabolic status (stress level); and (iii) detect complications associated with TPN. Measurements of efficacy in the acute-care setting include weight, constitutive protein status (e.g., albumin, transferrin, and prealbumin), nitrogen balance, and wound healing. Metabolic status should be viewed first from the clinical perspective. The presence of SIRS, infection, or high ventilation requirements all indicate a high metabolic rate. Metabolic status can be further assessed by laboratory variables that evaluate substrate tolerance (e.g., blood glucose and serum triglyceride concentrations) as well as protein catabolic rate (24-hour UUN).

Specialized Amino Acid TPN Solutions These formulas are designed to meet organ-failure specific requirements and include high-branched-chain, hepatic failure (low aromatic amino acid), and renal failure (high essential amino acids) formulations. The use of these specialty formulas remains controversial because of the expense and lack of outcome data. Studies comparing high-branchedchain amino acid solutions with standard formulas in stressed patients have shown improvements in nitrogen retention, constitutive protein levels, and immune function, but have failed to demonstrate reduced morbidity or mortality (76). One recent trial in Europe was able to demonstrate a reduced mortality in septic patients receiving a high-branched-chain formula (77). The use of hepatic and renal formulas has also not shown any proven benefit.

DISEASE-SPECIFIC NUTRITION Nutrition and Cancer Many forms of cancer are associated with weight loss and wasting or cachexia. Intake can be impaired due to the disease process, physical anomalies related to surgery or to the cancer itself, side effects of therapy, and psychosocial factors. Utilization of nutrients may be altered by malabsorption, cytokine activity, or the preponderance of inefficient cycles for energy metabolism. Malnourished cancer

Mesenteric infarction, Crohn’s disease, radiation enteritis, tumors, and trauma are the leading causes of short gut in adults (82). Factors that influence the management of short bowel syndrome include (i) the extent of resection; (ii) the site of resection; (iii) the presence or absence of the ileocecal valve; (iv) the residual function of the remaining small bowel; (v) the adaptive capacity of the intestinal remnant; (vi) the primary disease that precipitated the bowel loss; and (vii) the amount and the activity of the residual disease in the remnant (83). The average adult has 25 cm duodenum, 240 cm jejunum, and 360 cm ileum (84). In adults, the minimal length of small intestine (distal to the Ligament of Treitz) required for adequate digestive function is approximately 75 cm, although there are interindividual differences (85). For lesser amounts, patients will require long-term TPN. Additionally, patients requiring TPN three months after surgical resection can be considered as having short gut regardless of the extent of resection. The small bowel is the site of absorption for a variety of nutrients and electrolytes. Duodenectomy results in malabsorption of calcium, folate, and iron. Although the proximal jejunum is the usual site for protein, carbohydrate, and fat absorption, jejunectomy usually results in no major change in macronutrient and electrolyte absorption because the ileum can take over this role (86). Because the jejunum is the site of hormones that inhibit gastric secretion such as gastric inhibitory peptide and vasoactive intestinal polypeptide, gastric hypersecretion begins within 24 hours after jejunal resection. This produces a high sodium load in the stomach and reduces pH downstream, thus inactivating digestive enzymes and increasing diarrhea. The ileum plays an important role in slowing intestinal transit and concentrating luminal contents. Both vitamin B12 and bile salts are normally absorbed from the ileum. Following resection, the liver increases production of bile salts to compensate for the loss of absorption. However, this production can never be fully compensated for and bile salt depletion occurs, leading to steatorrhea and cholelithiasis. Cholestyramine is sometimes employed to treat the ensuing diarrhea and cholecystectomy is commonly required within two years after

Chapter 3: Surgical Nutrition

bowel resection. Steatorrhea promotes calcium binding to fatty acids rather than oxalate and allows more oxalate to be absorbed, leading to oxalate stones. Three stages of intestinal adaptation after resection have been identified (84): Stage I is characterized by fluid and electrolyte loss and lasts for approximately two weeks. It is treated with electrolyte replacement, an H2 blocker (to minimize hypersecretion), and parenteral nutrition. Hypersecretion of gastrin may result in peptic ulcer disease, gastroesophageal reflux disease, and proximal small bowel inflammation, so that H2 antagonists are a mainstay of therapy after intestinal resection. Stage II is a period of adaptation where oral intake begins and lasts from a few months up to one year. Feedings are advanced as stool and/or ostomy output becomes manageable. Stage III is maximal adaptation where normal home life may resume, although some patients may still require TPN. The residual small bowel as well as the colon undergo dilatation, lengthening, and mucosal proliferation along the course of adaptation. Experiments in rats have demonstrated superior adaptation in animals fed TPN and complex enteral diets as opposed to elemental diets (87). Aggressive use of enteral nutrition is thought to maximize gut adaptation (88). Although somatostatin may slow intestinal transit and reduce fluid and electrolyte loss acutely, it may also decrease enteroglucagon release, which exerts beneficial effects in bowel adaptation after resection. Octreotide is a synthetic analog of somatostatin with a longer half-life (three hours vs. three minutes). Octreotide reduces splanchnic blood flow and inhibits gastric, pancreatic, and small bowel secretions. These mechanisms may limit intestinal adaptation after bowel resection and reduce dietary fat digestion. Bowel output is reduced due to decreased secretions rather than improved absorption. Octreotide is generally recommended for use in patients with severe diarrhea/ostomy output (greater than 4 L daily) that is intractable to antidiarrheal agents. The use of antimotility agents may prove helpful in this circumstance. Although glutamine has been recommended, its role in morphological adaptation after bowel resection remains to be elucidated. Administering probiotics, the addition of live bacteria to the gastrointestinal tract, may also be beneficial in short gut. Healthy bacteria may be altered due to antibiotics, antimotility agents, H2 blockers, proton-pump inhibitors, and narcotics. Growth of healthy flora decreases growth of enteropathogens that may adhere to the mucosa and initiate inflammatory or immune sequelae (89). Structured programs have emerged that are geared toward decreasing TPN dependence after intestinal resection (90). Therapy consists of TPN (when necessary), peptide-based enteral nutrition, a low-fat, low-oxalate, high-protein, high–dietary fiber oral diet, and enteral glutamine in dipeptide form. Recombinant human growth hormone is provided for a specified period. Long-term follow-up of patients after intestinal resection should consist of monitoring sodium, potassium, chloride, zinc, copper, magnesium, iron, B12, folic acid, and fat-soluble vitamins. Zinc losses in diarrhea are substantial and may require supplementation above the quantity provided by intravenous multi–trace element products. Intramuscular vitamin B12 should be given if more than 60 cm of terminal ileum is resected. Chronic complications of short bowel syndrome include liver failure, gallstones, nutrient deficiencies, osteopenia, catheter-related sepsis, and small bowel bacterial overgrowth. Surgical approaches to increase functional bowel, including transplantation, remain an option.

61

Enterocutaneous Fistula Abdominal operations account for over 80% of enterocutaneous fistulae. The remainder are due to Crohn’s, cancer, radiation, and infection. The nutritional management depends on the location of the fistula, the health of the bowel distal to the fistula, and the amount of fistula output. The advent of TPN in the 1960s greatly reduced mortality from fistulae. Spontaneous closure depends on location, comorbid factors, and nutritional state. Ninety percent of fistulae that are likely to close spontaneously will do so in the first 30 days (91). If fistulae are in the proximal bowel, full enteral feeds may be delivered distally.

Pancreatitis Acute pancreatitis induces severe hypercatabolism and without exogenous nutritional support, acute protein malnutrition can quickly occur. Due to concerns that enteral feeding would stimulate further secretion of pancreatic enzymes and worsen autolysis, TPN has been the mainstay of nutritional therapy. However, recent studies have indicated that enteral feeding into the jejunum in patients with acute pancreatitis is both safe and effective. Initial trials of enteral support recommended low-fat, elemental formulas (92–95), again due to concerns over pancreatic stimulation. However, Duerksen et al. demonstrated that, in patients who underwent partial pancreatectomy with exteriorization of pancreatic stents, there was no statistically significant difference in pancreatic secretion between polymeric and elemental formulas (96). When compared with TPN, enteral nutrition is associated with an attenuation of the acute-phase response (97), reduced septic complications (94), and markedly decreased cost.

SUMMARY Protein-calorie malnutrition has become increasingly recognized in hospitalized patients and has been shown to be present in as many as 50% of patients requiring surgical procedures. Understanding the metabolic response to starvation and surgical stress, and how a suboptimal nutritional environment can adversely affect this response is mandatory if postoperative morbidity and mortality are to be lessened. Fortunately, the last several decades have unraveled an enormous amount of new knowledge regarding the role that malnutrition plays in altering fundamental metabolic pathways that are essential to good patient care. Further, the ability to provide nutritional support by way of enteral or parenteral routes has enabled the provision of optimal nutritional therapy in even the patient with profound malnutrition requiring surgical intervention. Such advances have greatly minimized the attendant negative effects that suboptimal nutrition would otherwise have on patient outcome and survival following operation.

REFERENCES 1. Hart DW, Wolf SE, Micak R, et al. Persistence of muscle catabolism after severe burn. Surg 2000; 128:312–319. 2. Plank LD, Hill GL. Sequential metabolic changes following induction of systemic inflammatory response in patients with severe sepsis or major burn trauma. World J Surg 2000; 24:630–638. 3. Plank LD, Connolly AB, Jill GL. Sequential changes in the metabolic response in severely septic patients during the first

medwedi.ru

62

4.

5.

6.

7.

8.

9.

10. 11.

12.

13. 14. 15.

16.

17. 18.

19.

20.

21.

22. 23.

24.

25. 26.

Part One: General Considerations 23 days after the onset of peritonitis. Ann Surg 1998; 28: 146–158. Moore EE, Jones TN. Benefits of immediate jejunal feeding after major abdominal trauma – a prospective randomized study. J Trauma 1986; 26:874–881. Moore FA, Moore EE, Jones TN. TEN versus TPN following major abdominal trauma-reduced septic morbidity. J Trauma 1989; 29:916–922. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding: effects on septic morbidity following blunt and penetrating abdominal trauma. Ann Surg 1992; 215:503–511. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications – the results of a meta-analysis. Ann Surg 1992; 216:172–183. Moore FA, Sauaia A, Moore EE, Haenel JB, Burch JM, Lezotte DC. Postinjury multiple organ failure: a bimodal phenomenon. J Trauma 1996; 40:501–512. Moore FA. Effects of immune-enhancing diets on infectious morbidity and multiple organ failure. J Parenter Enteral Nutr 2001; 25:S36–S42. Windsor JA, Hill GL. Weight loss with physiologic impairment: a basic indicator of surgical risk. Ann Surg 1988; 207(3):290–296. Heymsfield SB, McManus C, Stevens V, Smith J. Muscle mass: reliable indicator of protein-energy malnutrition severity and outcome. Am J Clin Nutr 1983; 35:1192–1199. Lexell J, Taylor CC, Sjostrom M. What is the cause of the aging atrophy? Total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year old men. J Neurol Sci 1988; 84:275–294. Griffiths RD. Muscle mass, survival and the elderly ICU patient. Nutrition 1996; 12:456–458. Finn PJ, Plan LD, Clark MA. Progressive cellular dehydration and proteolysis in critically ill patients. Lancet 1996; 347:654–656. Rodriguez DJ, Clevenger FW, Osler TM, Demarest GB, Fry DE. Obligatory negative nitrogen balance following spinal cord injury. J Parenter Enteral Nutr 1991; 15:319–322. McClave SA, Spain DA, Slolnick JL, et al. Achievement of steady state optimizes results when performing indirect calorimetry. J Parenter Enteral Nutr 2003; 27:16–20. Wooley JA, Sax HC. Indirect calorimetry: application to practice. Nutr Clin Pract 2003; 18:434–439. Gibbs J, Cull W, Henderson W, Daley J, Hur K, Khuri SF. Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National Surgical Risk Study. Arch Surg 1999; 134:36–42. Daley J, Khuri SF, Henderson W, et al. Risk adjustments of the postoperative morbidity rate for the comparative assessment of the quality of surgical care. Results of the National Veterans Affairs Surgical Risk Study. J Am Coll Surg 1997; 185: 325–338. Khuri SF, Daley J, Henderson W, et al. The Department of Veterans Affairs NSQIP. The first national, validated, outcomebased risk-adjusted and peer-controlled program for the measurement and enhancement of the quality of surgical care. Ann Surg 1998; 228:491–507. Kudsk KA, Tolley EA, DeWitt RC, et al. Preoperative albumin and surgical site identify surgical risk for major postoperative complications. J Parenter Enteral Nutr 2003; 27:1–9. Smith-Choban P, Weireter LJ, Maynes C. Obesity and increased mortality in blunt trauma. J Trauma 1991; 31:1253–1257. Smith-Choban P, Burge JC, Scales D. Hypoenergetic nutrition support in hospitalized obese patients: a simplified method for clinical application. Am J Clin Nutr 1997; 66:546–550. Heyland DK, Novak F, Drover JW, Jain M, Su X Suchner U. Should immunonutrition become routine in the critically ill patient? JAMA 2001; 286:944. Marik PE, Zaloga P. Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 2002; 29:2264–2270. Heys SD, Walker LG, Smith I, Eremin O. Enteral nutrition supplementation with key nutrients in patients with critical illness and cancer. Ann Surg 1999; 229:467–477.

27. Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 1999; 27:2799. 28. Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002; 30:2002–2029. 29. Houdijk APJ, Rijnsburger ER, Jansen J, et al. Randomized trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998; 352: 772–776. 30. Barbul A, Lazarou SA, Efron DT. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990; 108:331–336. 31. Suchner U, Heyland DK, Peter K. Immune-modulatory actions of arginine in the critically ill. Br J Nutr 2002; 87(suppl 1):S121. 32. Bower RH, Cerra FB, Bershadsky B, et al. Early administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care patients: results of a mulitcenter, prospective, randomized, clinical trial. Crit Care Med 2001; 23:436–449. 33. Bruzzone R, Radrizzani D. Early enteral immunonutrition in patients with severe sepsis. Results of an interim analysis of a randomized multicenter clinical trial. Intensive Care Med 2003; 29:834–840. 34. Alexander JW, Saito H, Ogle CK, Trocki O. The importance of lipid type in the diet after burn injury. Ann Surg 1986; 204:1–8. 35. Van Buren CT, Kulkarni A, Fanslow WC, Rudoph FB. Dietary nucleotides, a requirement for helper/inducer T lymphocytes. Transplantation 1985; 40:694–697. 36. Khalili TM, Navarro A, Middleton Y, Margulies DR. Early postoperative enteral feeding increases anastomotic strength in a peritonitis model. Am J Surg 2001; 182:621–624. 37. Montecalvo MA, Steger KA, Farber HW, et al. Nutritional outcome and pneumonia in critical care patients randomized to gastric versus jejunal tube feedings. The Critical Care Research Team. Crit Care Med 1992; 20:1377–1387. 38. Montejo JC, Grau T, Acosta J, et al. Nutritional and Metabolic working group of the Spanish Society of Intensive Care Medicine and Coronary Units. Multicenter, prospective, randomized, single-blind study comparing the efficacy and gastrointestinal complications of early jejunal feeding with early gastric feeding in critically ill patients. Crit Care Med 2002; 30(4):796–800. 39. Kearns PJ, Chin D, Mueller L, Wallace K, Jensen WA, Kirsch CM. The incidence of ventilator-associated pneumonia and success in nutrient delivery with gastric versus small intestinal feeding: a randomized clinical trial. Crit Care Med 2000; 28(6):1742–1746. 40. Kortbeek JB, Haigh PI, Doig C. Duodenal versus gastric feeding in ventilated blunt trauma patients: a randomized controlled trial. J Trauma 1999; 46(6):992–996; discussion 996–998. 41. McClave SA, Sexton LK, Spain DA, et al. Enteral tube feeding in the intensive care unit: factors impeding adequate delivery. Crit Care Med 1999; 27(7):1252–1256. 42. Ritz MA, Fraser R, Edwards N, et al. Delayed gastric emptying in ventilated critically ill patients: measurement by 13 C-octanoic acid breath test. Crit Care Med 2001; 9(9):1744–1749. 43. Chapman MJ, Fraser RJ, Kluger MT, Buist MD, De Nichilo DJ. Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Crit Care Med 2000; 28(7):2334–2337. 44. Boivin MA, Levy H. Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill. Crit Care Med 2001; 29(10):1916–1919. 45. McClave SA, DeMeo MT, DeLegge MH, et al. North American Summit on Aspiration in the Critically Ill Patient: consensus statement. J Parenter Enteral Nutr 2002; 26(suppl 6):S80–S85. 46. DeLegge MH. Aspiration pneumonia: incidence, mortality, and at-risk populations. J Parenter Enteral Nutr 2002; 26(suppl 6): S19–S24; discussion S24–S25.

Chapter 3: Surgical Nutrition 47. Elpern EH. Pulmonary aspiration in hospitalized adults. Nutr Clin Pract 1997; 12(1):5–13. 48. Seegobin RD, van Hasselt GL. Aspiration beyond endotracheal cuffs. Can Anaesth Soc J 1986; 33(3 Pt 1):273–279. 49. Lin HC, Van Citters GW. Stopping enteral feeding for arbitrary gastric residual volume may not be physiologically sound: results of a computer simulation model. J Parenter Enteral Nutr 1997; 21(5):286–289. 50. Maloney JP, Ryan TA. Detection of aspiration in enterally fed patients: a requirement for bedside monitors of aspiration. J Parenter Enteral Nutr 2002; 26(suppl 6):S34–S42. 51. Reed RL, Eachempati SR, Russell MK, Fahky C. Endoscopic placement of jejunal feeding catheters in critically ill patients by a ‘‘push’’ technique. J Trauma 1998; 45:388–393. 52. Myers JG, Page CP, Stewart RM, Schwesinger WH, Sirinek KR, Aust JB. Complications of needle catheter jejunostomy in 2002 consecutive applications. Am J Surg 1995; 170:547–551. 53. Holmes JH, Brundage SI, Hall RA, Yuen P, Maier RV, Jurkovich GJ. Complications of surgical jejunostomy in trauma patients. J Trauma 1999; 47:1009–1012. 54. Munshi I, Steingrub JS, Wolpert L. Small bowel necrosis associated with early post operative tube feeding in a trauma patient. J Trauma 2000; 49(1):163–165. 55. Marvin RG, McKinley BA, McQuiggan M, Cocanour CS, Moore FA. Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition manifests no reliable signs for early detection. Am J Surg 2000; 179:7–12. 56. McQuiggan MM, Marvin RG, McKinley BA, Moore FA. Enteral feeding following major torso trauma: from theory to practice. New Horizons 1999; 7:131–140. 57. Kozar RA, McQuiggan MM, Moore EE, Kudsk KA, Jurkovich GJ, Moore FA. Postinjury enteral tolerance is reliably achieved by a standardized protocol. J Surg Res 2002; 104:70–75. 58. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999; 27(8):1409–1420. 59. American Society of Parenteral and Enteral Nutrition: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002; 17(suppl): 61SA–65SA. 60. Kudsk KA, Tolley EA, DeWitt RC, et al. Preoperative albumin and surgical site identify surgical risk for major postoperative complications. J Parenter Enteral Nutr 2003; 27:1–9. 61. Souba WW. Drug therapy: nutritional support. N Engl J Med 1997; 336:41–48. 62. Muller JM, Brenner U, Dienst C, Pichlmaier H. Preoperative parenteral feeding in patients with gastrointestinal cancer. Lancet 1982; 1:68–71. 63. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991; 325:525–532. 64. Bellantone R, Doglietto GB, Bossola M, et al. Preoperative parenteral nutrition in the high risk surgical patient. J Parenter Enteral Nutr 1988; 12:195–197. 65. Detsky AS, Baker JP, O’Rourke K, Goel V. Perioperative parenteral nutrition: a meta-analysis. Ann Intern Med 1987; 107: 195–203. 66. Sandstrom R, Drott C, Hyltander A, et al. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg 1993; 217:185–195. 67. McGee DC, Gould MK. Preventing complications of central venous catheterization. N Engl J Med 2003; 348:1123– 1233. 68. O’Grady NP, Alexander M, Pellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 2002; 35:1281–1307. 69. Ma TY, Yoshinaka R, Banaag A, Jphnson B, Davis S, Berman SM. Total parenteral nutrition via multilumen catheters does not increase the risk of catheter-related sepsis: a randomized, prospective study. Clin Infect Dis 1998; 27:500–503.

63

70. Raad I, Darouiche R, Dupuis J, et al. Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections: a randomized trial. Ann Intern Med 1997; 127:257–266. 71. Cook D, Randolph A, Kernerman P, et al. Central venous catheter replacement strategies: a systematic review of the literature. Crit Care Med 1997; 25:1417–1424. 72. Rombeau JL, Rolandelli RH, Wilmore DW, Daly JM. Nutritional support. In: Wilmore DW, Cheung LY, Harken AH, Holcroft JW, Meakins JL, eds. Care of the Surgical Patient. New York: Scientific American Surgery, 2001:15. 73. Van der Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–1367. 74. Van den Berghe G, Wouters PJ, Boullion R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003; 31:359–366. 75. Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutrition 2001; 17:632–637. 76. Cerran FB, Mazuski JE, Chute E, et al. Branched chain metabolic support. A prospective, randomized, double-blind trial in surgical stress. Ann Surg 1984; 199:286–291. 77. Garcia-de-Lorenzio A, Ortiz-Leyba C, Planas M, et al. Parenteral administration of different amounts of branch-chain amino acids in septic patients: clinical and metabolic support. Crit Care Med 1997; 25:418–429. 78. Daly JM, Weintraub FN, Shou J, Rosato EF, Luci M. Enteral therapy in upper gastrointestinal cancer patients. Ann Surg 1995; 221:337–338. 79. Gianotti L, Braga M, Vignali A, et al. Effect of route of delivery and formulation of postoperative nutrition support in patients undergoing major operations for malignant neoplasms. Arch Surg 1997; 132:1222–1229. 80. Copeland EM. Historical perspective on nutritional support of cancer patients. CA Cancer J Clin 1998; 48:67–68. 81. Rivadeneira DE, Evoy D, Fahey TJ, Lieberman MD, Daly JM. Nutritional support of the cancer patient. CA Cancer J Clin 1998; 48:69–80. 82. Rombeau JL, Rolandelli RH. Enteral and parenteral nutrition in patients with enteric fistulas and short bowel syndrome. Surg Clin N Am 1987; 67:551–571. 83. Dudrick SJ, Latifi R, Fosnocht DE. Management of the short bowel syndrome. Surg Clin N Am 1997; 71(3):625–643. 84. Shanbhogue LKR, Molenar JC. Short bowel syndrome: metabolic and surgical management. Br J Surg 1994; 81:486–499. 85. Li JS. Short bowel syndrome. In: Shao JZ, Gu JF, Zhang SY, eds. Enteral Nutrition. Bejing: Military Medical Science Press, 1999:205–206. 86. Allard JP, Jeejeebhoy KN. Nutritional support and therapy in the short bowel syndrome. Gastroenterol Clin N Am 1989; 589–601. 87. Al-Jurf AS, Younasazi MK, Chapman-Furr F. Effect of nutritional method on adaptation of the intestinal remnant after massive small bowel resection. J Pediatr Gastroenterol Nutr 1985; 4:245–252. 88. Vanderhoof JA, Langnas AN. Short-bowel syndrome in children and adults. Gastroenterology 1997; 113:1767–1778. 89. Vanderhoof JA, Young RJ. The role of probiotics in the treatment of intestinal infections and inflammation. Curr Opin Gastroenterol 2001; 17:58–62. 90. Byrne TA, Persinger RL, Young LS, Ziegler TR, Wilmore DW. A new treatment for patients with short bowel syndrome. Ann Surg 1995; 222:243–255. 91. Pipkin WL, Gadacz TR. Nutritional considerations for dealing with intestinal diseases in the ICU. In: Shikora SA, Martindale RG, Schwaitzberg SD, eds. Nutritional Considerations in the ICU. Iowa: Kendall Hunt Publishing, 2002:279–285. 92. Olah A, Pardavi G, Belagyi T, Nagy A, Issekutz A, Mohamed GE. Early nasojejunal feeding in acute pancreatitis is associated with a lower complication rate. Nutrition 2002; 18:259–262. 93. Abu-Assi S, Craid K, O’Keefe SJ. Hypocaloric jejunal feeding is better than TPN in acute pancreatitis: results of a

medwedi.ru

64

Part One: General Considerations

randomized comparative study. Am J Gastroenterol 2002; 97: 2255–2262. 94. Kalfarentzos F, Kehagias J, Mead N, Kokkinis K, Gogos CA. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial. Br J Surg 1997; 84:1665–1669. 95. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr 2001; 74:534–542.

96. Duerksen DR, Bector S, Parry D, Yaffe C, Vajcner A, Lipschitz J. A comparison of the effect of elemental and immune-enhancing polymeric jejunal feeding on exocrine pancreatic function. J Parenter Enteral Nutr 2002; 26(3): 205–208. 97. Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998; 42:431–435.

4 The Immune System and the Immunocompromised Patient Kathryn M. Verbanac, Lorita Rebellato, and Carl E. Haisch

INTRODUCTION The immune system functions to protect the body’s internal environment from a variety of potential insults such as foreign proteins, potentially adverse cells, microorganisms, and other noxious substances. Since immune competence plays such an important role in the insurance of good health and the response of a patient to surgical intervention, alterations in the immune system can greatly affect the outcome of an operation both in terms of morbidity and mortality. Immune competence reflects the highly integrated, carefully orchestrated homeostatic interplay of a number of physiologic processes whose primary function is to discriminate between substances that are part of the body’s own makeup (‘‘self’’) and those that are foreign to it (‘‘noself’’). The purpose of this chapter is to review the components of this immune system, how they interrelate, how this recognition of self and nonself occurs, and the impact that alterations in these processes can have on the surgical patient.

AN OVERVIEW OF THE IMMUNE SYSTEM In this section, we introduce the cellular components of the immune system, describe the initiation and effector stages of the humoral and cellular immune response, and discuss clinical assessment of immune function. This is to serve as a general introduction and review and to provide a basis for the clinical considerations that follow. There are several excellent textbooks on immunology, which should be referred to for a more comprehensive description of the immune system (1–5). In addition, we have cited key articles within each section that provide current reviews and references of the primary literature.

Cellular Components Leukocytes, the white blood cells that participate in the immune response, are derived from a common pluripotent stem cell in the bone marrow (Fig. 1). The mature cellular components of the immune system are distinguished on the basis of function and phenotype. Lymphocytes are distinguished from the other cells of the immune system because only lymphocytes exhibit diversity, specificity, memory, and self-/non–self-recognition. The cellular phenotype is principally defined by cell surface markers, the majority of which are designated cluster of differentiation (CD) antigens and are identified by monoclonal antibodies. Monoclonal antibodies serve as important immunological reagents for both the identification and quantitation of leukocyte and lymphocyte subpopulations that express these markers. There are currently 247 CD antigens that have been designated by the

International Workshops on Leukocyte Differentiation Antigens (6). Because the expression of cell surface antigens will vary qualitatively and quantitatively with both the maturation stage and activation state of the cell, monoclonal antibodies are also valuable for monitoring the phenotype of a specific leukocyte subpopulation (Table 1). Many of the cell surface antigens serve as specific receptors for ligands, thus ligand binding and receptor engagement have important immunological consequences. These ligands include immunoglobulins (Igs), complement, cytokines, viruses, and bacterial products.

B-Lymphocytes A schematic diagram of an Ig is presented in Figure 2. The development of the B-lymphocyte occurs predominantly in the bone marrow of mammals and is centered around the expression of membrane-bound Ig. Because the antigenbinding variable region of the membrane Ig is extracellular, it readily binds to soluble antigen. The expression of surface Ig will imbue the B-lymphocyte with both antigen specificity and memory. After antigen binding, signal transduction is mediated by another component of the B-cell receptor, a disulfide-bonded heterodimer that is noncovalently complexed with surface Ig and is designated as Ig-a/Ig-b or CD79a/CD79b (7). The DNA encoding antibody heavy chains, k light chains, and l light chains are located on different chromosomes. Within each chromosome, Ig sequences are present in germ line DNA as multigene families that contain numerous gene segments (Fig. 3). In progenitor and precursor B-cells, the variable region–D region–joining region (V-D-J) gene segments that comprise the variable region of the heavy chain undergo random gene rearrangement to form a functional Ig heavy chain (8). This is followed by light chain gene rearrangements that result in the expression of membrane-bound IgM. These rearrangements are regulated so that only one of the allelic forms of the Ig is expressed, that is, DNA from only one of the parental chromosomes is rearranged. This is referred to as allelic exclusion and insures that Ig with a single antigenic specificity is expressed by a given B-cell. B-cells at this developmental stage are released from the bone marrow into the blood. Most B-cells encounter antigen in regional lymph nodes or in the spleen, where they undergo antigen-dependent stages of differentiation. In the absence of antigen activation, peripheral B-cells will die within several days. If the membrane-bound antibody present on the surface of the B-cell encounters specific antigen, these cells undergo class switching by additional gene rearrangements of the constant region of the heavy chain and by changes in RNA processing. These classswitching events lead to different clones of B-cells that

medwedi.ru 65

66

Part One: General Considerations

Pluripotent Stem Cell

Myeloid Progenitor

Lymphoid Progenitor THYMUS

B Lymphocyte

Erythroid Megakaryocyte Basophil Precursor Precursor

T Lymphocyte

Platelets

Basophils

Lymphoid/ Plasmacytoid Dendritic Cell DC2

Granulocyte-Monocyte Precursor

Eosinophil Precursor

Neutrophils

Erythrocytes

Natural Killer Cell

Monocytes

Eosinophils Macrophage

express different isotypes or classes of antibody with the same antigenic specificity. Different antibody isotypes have different effector functions, thus the range and type of immune response is broadened (Table 2). At this stage, some B-cells will clonally expand and differentiate into plasma cells that secrete various isotypes. Other B-cells will differentiate into memory B-cells that have a longer life span and express membrane-bound Ig of different isotypes. Memory B-cells are able to undergo somatic mutation to generate higher affinity antibodies, that is, antibodies with a greater binding strength or association constant, but of the same specificity. This process is termed affinity maturation. All of these mechanisms contribute to the generation of a high degree of antibody diversity; it is estimated that humans can produce antibodies that have 108 to 1011 different specificities.

T-Lymphocytes T-lymphocytes are termed ‘‘thymus dependent’’ because the lymphoid stem cell migrates from the bone marrow

Myeloid Dendritic Cell DC1

Figure 1 Maturation of blood cells from the pluripotent stem cell in bone marrow.

to the thymus, where it differentiates and matures during normal fetal development. It is in the thymus that T-cell receptor (TCR) rearrangement occurs to generate the diverse repertoire of antigen specificities exhibited by T-cell clones in the periphery. During thymic education, negative and positive selection processes result in the death of most high-affinity self-reactive T-cells (9). A large number of major histocompatibility complex (MHC)restricted T-lymphocyte clones survive that are tolerant to self-antigens and bear different antigen receptors, thus enabling adaptive immune responses to a large variety of pathogens. The TCR is the antigen-binding receptor on the surface of T-cells. It is expressed either as an a/b or a g/d heterodimer and is associated on the membrane with the multiple components of CD3 (Fig. 4). The invariant CD3 components (g, d, e, and z) are critical for the signal transduction events that occur after antigen binding (10). Interaction between an appropriate TCR and a peptide–MHC complex on antigen-presenting cells (APCs) or target cells induces

Table 1 Characteristic Leukocyte Cell Surface Markersa B-cell T-cell Th T cytotoxic NK cell Monocyte/macrophage Granulocytes a

CD19, CD20, CD21, CD22, slg, CD45RB, CD40, CD80/CD86 (B7-1/B7-2) CD2, CD3, CD5, TCR, CD28 CD4 CD8 CD2, CD16 (FcgRIII), CD56, CD11b (iC3bR), CD11c CD11b, CD11c, CD14, CD16, CD32 (FcgRII), CD64 (FcgRI), CD91 CD10 (CALLA), CD11b, CD11c, CD14, CD15 (Lewisx), CD16, CD32

This list is not comprehensive. The cell surface antigens unique to the cell type are in italics. The combination of coexpressed antigens is often most characteristic of a cell type. Abbreviations: CD, cluster of differentiation; Th, T helper; TCR, T-cell receptor.

Chapter 4: The Immune System and the Immunocompromised Patient

Figure 2 Schematic diagram of an immunoglobulin molecule. Each heavy (H) and light (L) chain contains an amino-terminal variable (V) region that is unique to each B-cell clone and which together form the antigen-binding site. The constant (C) domains exhibit limited variation and define the immunoglobulin isotype and effector functions. Intrachain and interchain disulfide bonds play a major role in the folding of the protein domains and in the formation of the polypeptide chain tetramer. The g, d, and a heavy chains contain a hinge region and the m and E heavy chains contain a fourth central CH domain.

the redistribution and/or catalytic activation of intracellular protein tyrosine kinases. These kinases then phosphorylate immunoreceptor tyrosine-based activation motifs (ITAM) within the cytoplasmic domains of the invariant chains of the CD3 subunits. This initial phosphorylation is followed

67

by a cascade of diverse intracellular signals, whose key outcome is to affect the expression of cytokine genes. Although the TCR is the unique distinguishing marker for the T-cells today, T-cells were historically distinguished from B-cells on the basis of the so-called E rosette receptor, now designated CD2. T-cells have been subdivided into two subtypes: those with helper function (primarily CD4þ) and those with cytotoxic function (primarily CD8þ). In the thymus, CD4CD8 bone marrow progenitors go through sequential developmental changes before the so-called single positive T-cells, expressing either CD4 or CD8, and the abTCR are produced. Although these latter cells comprise the vast majority of peripheral T-cells, it has recently been discovered that a small number of T-cells expressing the gdTCR are present in adult epithelial tissues and they can also be found in lymphoid organs. The majority of the abTCRþ T-cells in the periphery are naive or precursor T-cells that have not yet encountered antigen and are in the G0 stage of the cell cycle. Once antigen activated (as discussed below), these cells become effectors that perform helper, cytotoxic, or delayed-type hypersensitivity (DTH) functions. Memory T-cells are also generated during a primary response to antigen and recirculate in the blood and lymph as extremely long-lived resting cells with less stringent requirements for activation. Antigen-stimulated T helper (Th) cells have been classified into Th1 and Th2 cells on the basis of the distinct cytokines they secrete and on the functional effects of these cytokines. Originally discovered in mice, Th1 and Th2 patterns of cytokine exist in humans as well, but the cytokine patterns are less exclusive. In humans, interferon (IFN)-g is most consistently expressed by Th1 cells, and interleukin (IL)-4, IL-5, and IL-9 are most consistently produced by Th2 cells. IL-2 and tumor necrosis factor (TNF)-b (predominantly Th1 cytokines) and IL-6, IL-10, and IL-13 (predominantly Th2

Germ-line H-chain DNA (Chromosome 14) L VH1−L VH100

DH1−DH30 JH1−JH6

Cµ1 Cµ2

Cµ3

Cµ4

Cδ−Cγ−Cε−Cα

5'

3'

L Vκ1−L Vκ100 Germ-line κ-chain DNA (Chromosome 2)

Jκ1−Jκ100 Cκ

5'

3'

Germ-line λ-chain DNA (Chromosome 22) L Vλ1−L Vλ100

Jλ1 Cλ1

Jλ2 Cλ2 Jλ3 Cλ3 Jλ4 Cλ4 Jλ5 Cλ5 Jλ6 Cλ6

5'

3'

GENE REARRANGEMENT - DJ Joining, VDJ Joining, VJ Joining GENE TRANSCRIPTION - Polyadenylation and Splicing RNA TRANSLATION

Nascent Polypeptides VDJ Cµ1 Cµ2 Cµ3 Cµ4

VJ Cκ +

VHCµ

= VκCκ

Membrane lgM

medwedi.ru

Figure 3 Immunoglobulin gene rearrangement for surface IgM expression in B-cells. Abbreviation: IgM, immunoglobulin M.

68

Part One: General Considerations

Table 2 Properties and Biological Activitiesa of Serum Igs Property/activity c

Molecular weight (kDa) Heavy-chain component Normal serum level (mg/mL) In vivo serum half-life (days) Activates classical complement pathway Crosses placenta Present on membranes of mature B-cells Binds to phagocyte Fc receptors Mucosal transport Induces mast-cell degranulation

IgG1

IgG2

IgG3

IgG4

IgA1

IgA2

IgMb

IgE

IgD

150 1 9 23 þ

150 2 3 23 þ/

150 3 1 8 þþ

150 4 0.5 23 –

150–600 1 3 6 –

150–600 2 0.5 6 –

900 m 1.5 5 þþþ

190 E 0.0003 2.5 –

150 d 0.03 3 –

þ –

þ/ –

þ –

þ –

– –

– –

– þ

– –

– þ

þþ

þ/

þþ

þ

–

–

?

–

–

– –

– –

– –

– –

þþ –

þþ –

þ –

– þ

– –

a

Activity levels indicated as follows þþ, high; þ, moderate; þ/, minimal; ?, questionable; and , none. þ IgM is the first isotype produced by the neonate and during a primary immune response. c þ IgG, IgE, and IgD always exist as monomers; IgA can exist as a monomer, dimer, trimer, or tetramer. Membrane-bound IgM is a monomer, but secreted IgM in serum is a pentamer. Abbreviation: Ig, Immunoglobulins. Source: From Ref. 5. b

cytokines) tend to segregate less clearly among human subsets than in the mouse. Cytokines produced by APCs are the dominant factors guiding the development of Th1 and Th2 cells. Furthermore, specific transcription factors are required to be activated for each pathway: T-bet and signal transducer and activator of transcription (STAT)-4 for Th1 cells and GATA-3 and STAT-6 for Th2 cells (11,12). Reciprocal regulation occurs between the Th1 and Th2 subsets, mediated by Th cytokine effects on differentiation and on effector functions.

Figure 4 Schematic diagram of the TCR-CD3 complex. The polypeptide chains of CD3 noncovalently associate with the TCR a/b chains and with each other as heterodimers as well as ZZ homodimers. The solid rectangle represents an ITAM. Abbreviations: TCR, T-cell receptor; ITAM, immunoreceptors tyrosme-based activation motifs.

Antigens derived from pathogens stimulate the clonal proliferation of T-lymphocyte precursors that carry receptors specific for that antigen. Thus, in response to different pathogen-derived antigens, CD4 T-cells become either Th1 or Th2 cells. Th1 cells produce the cytokine IFN-g and are effective against intracellular bacteria, viruses, and protozoa, whereas Th2 cells produce IL-4, IL-5, and IL-13 and eliminate extracellular parasites. Like Th1 cells, CD8 T-cells are activated in response to intracellular pathogens and share some of the same effector mechanisms, particularly production of IFN-g. Upon antigenic stimulation, Th1 cells secrete IL-2, IFN-g, and TNF-b, which serve to channel the immune system toward cell-mediated immunity (CMI), including macrophage activation and DTH responses. Th1 cells are thus effective in the defense against intracellular pathogens (e.g., Leishmania) and are thought to be involved in the pathogenesis of acute allograft rejection, organ-specific autoimmune disorders, contact dermatitis, and certain chronic inflammatory diseases. In contrast, Th2 cells secrete IL-4, IL-5, IL-6, and IL-10, induce humoral and allergic responses, and are most effective against extracellular microorganisms and soluble toxins. Studies of Th2 cells have concentrated on IgE responses to helminth antigens and allergens. Th2 cytokines generally exert anti-inflammatory, immunosuppressive effects, and Th2 responses have been associated with transplantation tolerance, the immunopathology of chronic graft-versus-host disease, and systemic autoimmune disease. It is clear that reciprocal regulation occurs between the Th1 and Th2 subsets, mediated by specific cytokine effects on differentiation and on effector functions. Over the past five years, a great deal of interest has focused on regulatory T-cells (Treg) that appear to control the development of autoimmune disease and transplant rejection, and that might also play a critical role in controlling the expression of asthma and allergy. The term ‘‘regulatory T-cell’’ refers to cells that actively control or suppress the function of other cells, generally in an inhibitory fashion. CD4þCD25þ Treg cells have emerged as a unique population of suppressor T-cells that maintain peripheral immune

Chapter 4: The Immune System and the Immunocompromised Patient

tolerance (12,13). Transforming growth factor (TGF)-b has been implicated in the conversion of na€ve CD4þCD25 T-cells into CD4þCD25þ anergic/suppressor T-cells (14). The Treg subset has been isolated in humans, but it is still unclear if these regulatory cells can be used to inhibit ongoing T-cell responses in vivo or to reverse established pathology. There have not been similar functional divisions of CD8þ T-cell subpopulations. Although CD8 originally characterized suppressor and cytotoxic cells, a definitive CD8 suppressor cell has been elusive and has not been isolated or cloned. Therefore, most contemporary immunologists view the suppressor cell as a functional designation rather than the definition of a separate subpopulation. The classical CD8þ T-lymphocyte is the cytotoxic T-lymphocyte (CTL). CTL are MHC class I–restricted cells, which recognize and eliminate ‘‘altered self’’ target cells. Target cells include virally infected cells, malignant cells, and allogeneic cells. The primary mechanism of CTL-mediated killing, at least in vitro, involves granule exocytosis and release of a poreforming protein (perforin) and a battery of serine proteases (granzymes) that rapidly induce target cell lysis (15). CTL can also use the Fas (CD95) pathway to induce apoptosis, or programmed cell death, of target cells (16).

NK Cells Although their developmental pathway is not fully understood, natural killer (NK) cells, like T- and B-lymphocytes, arise from CD34þ lymphoid stem cells in the bone marrow. NK cells make up 5% to 10% of human peripheral blood mononuclear cells (PBMC). NK cells are termed null cells, because they do not express the distinct cell membrane markers that would characterize them as T- or B-cells, including the T-cell and B-cell antigen-binding receptors. NK cells and T-cells are both CD2þ and are thought to share a common thymic developmental precursor. Unlike CTL, NK cells typically express the phenotype CD16 and CD56 and do not typically express CD3 or CD8. Distinct subpopulations of NK cells with atypical phenotypes have been observed at very low levels in normal individuals, and at significant levels in recovering bone marrow–transplant recipients. NK cells were originally referred to as large granular lymphocytes, and discovered on the basis of their tumoricidal activity. The granules contain cytotoxic agents, including perforin and granzymes. The adjective ‘‘natural’’ refers to the important fact that NK cell–effector activity does not require antigen activation or sensitization and thus provides ‘‘natural immunity’’ or ‘‘innate’’ antiviral and antitumor protection. This immunity is critical in the early days of exposure, before CTL precursor cells can become activated and proliferate and differentiate into mature CTLs. Unlike CTLs, most NK cells do not express antigen receptors, hence they do not exhibit immunological specificity or memory. NK cells uniquely express inhibitory NK-cell receptors (NKR) that recognize polymorphic epitopes common to groups of human leukocyte antigen (HLA) alleles and transduce inhibitory signals, which suppress the NK-mediated cytolysis (17). NK cells thus recognize ‘‘absence of self,’’ and healthy cells avoid being killed via their expression of self-HLA. If HLA class I expression is downregulated by a viral infection or tumor transformation, no inhibitory signal is generated and the NK cells release their lytic mediators to kill these abnormal cells. In addition to inhibitory NKR, NK cells may also express activating NKR that are specific to MHC class I–related molecules expressed during infection, tumor transformation, or stress. The ligation of activating

69

NKR will further enhance the NK-cell lytic activity. Each NK cell of an individual can express a unique receptor repertoire, with a spectrum of different numbers (1–19) and combinations (inhibitory and activating types) of killer immunoglobulin-like receptors (KIR) and NKG2 receptors with multiple class I specificities. NK cells also identify target cells and mediate antibody-dependent cell-mediated cytotoxicity (ADCC), which is described in detail later in this chapter. In short, NK cells express CD16 (the Fc gamma receptor IIIA) and can thus bind IgG that is bound to target cell membranes. CD16 engagement activates the NK cell, inducing the lytic mechanism and cytokine production. NK cells appear to kill target tumor cells and virally infected cells by mechanisms similar to those described for CTL, namely the release of lytic granules. NK cells have also been recently shown to induce apoptosis via direct target cell killing or in ADCC. These two mechanisms are probably not mutually exclusive and some studies suggest that perforin and granzymes may synergistically trigger apoptosis.

Monocytes/Macrophages The remaining cellular components to be described also develop from the pluripotent hematopoietic stem cell in the bone marrow, but from the myeloid lineage, rather than the lymphoid lineage. These cells differ from lymphocytes in several significant properties; they lack antigen specificity and they lack memory. The monocyte is a phagocytic mononuclear myeloid cell that circulates briefly before migrating into tissue where it differentiates into a macrophage. The macrophage can take up permanent residence in particular tissues or remain motile. The primary function of the monocyte/macrophage is to phagocytose and eliminate antigen (18). Their digestive granules contain lytic enzymes, reactive oxygen and nitrogen intermediates, and TNF. Macrophages can ingest and digest whole microorganisms as well as injured and dead cells, cellular debris, and activated clotting factors. The macrophage also digests internalized proteins and presents peptides in association with MHC class II on its surface. It plays a critical role in Th cell activation, both as an APC and as a source of IL-1. The Th cell, in turn, promotes macrophage activation by secretion of IFN-g. Activated macrophages have increased phagocytic and microbicidal activity and secrete many factors that promote the inflammatory response. Finally, monocytes and macrophages express all three forms of the FcgR (CD16, CD32, and CD64), and thus can participate in ADCC, which is discussed later.

Dendritic Cells The dendritic cell (DC) has achieved recent prominence as the most highly specialized APC due to its superior ability to activate na€ve T-cells to initiate immune responses (19). DCs appear to originate from bone marrow precursors of two different hematopoietic lineages. CD11cþ Type 1 DC (DC1) is myeloid derived, either directly from myeloid progenitors or from monocytes (20). CD11c Type 2 DC (DC2) appear to be lymphoid derived, and DC2 CD4þ precursors have been referred to as plasmacytoid T-cells, plasmacytoid monocytes, type 1 IFN-producing cells, and plasmacytoid DC (21). Although DC1 and DC2 were initially thought to secrete cytokines to induce respective Th1 and Th2 responses, it now appears that this functional correlation is not rigid. DCs are located throughout the body in different maturation states and they mature into potent APCs during

medwedi.ru

70

Part One: General Considerations

conditions of infection or inflammation. DCs are characterized by branch-like membrane projections, motility in response to chemokine gradients, and surface expression of MHC class I and II and of the costimulatory molecules CD40, CD80, and CD86. These properties are responsible for their superior ability to capture and present antigen, to travel from the sites of infection to lymphoid organs where they activate na€ve T–cells, and initiate immune responses.

Granulocytes Granulocyte is a general term for a motile cell that contains cytoplasmic granules. These cells are categorized into basophils, eosinophils, and neutrophils on the basis of cell morphology and cytoplasmic staining properties. Granulocytes characteristically play a major role in the inflammatory response, which can be beneficial in host defenses and detrimental in inflammatory diseases. Neutrophils are also referred to as polymorphonuclear leukocytes (PMNs), and constitute 50% to 70% of the circulating white blood cells in humans. Neutrophils are active phagocytic scavengers of the immune system and are usually the first cells to arrive at an inflammatory site. Their granules contain lytic enzymes, bactericidal defensin peptides, and reactive oxygen and nitrogen intermediates; however, unlike macrophages, they do not contain TNF. The neutrophil is a critical effector cell in humoral and innate immunity and plays a key role in bacterial killing (22). Eosinophils are also phagocytic and function primarily against parasites via ADCC. They are the principal effector cell for the pathogenesis of allergic inflammation, caused by granular proteins that include eosinophil cationic protein, major basic protein, and eosinophil protein X (23). The nonphagocytic basophils play a major role in allergic responses when they release their granules of pharmacologic agents, including histamine.

The Innate Immune Response The innate immune response refers to the rapid response to microbial infection that relies on preexisting mechanisms (24). The innate immune system includes epithelial barriers, phagocytic cells, NK cells, the complement system, and cytokines. The innate immune response lacks both specificity and memory and is activated by a large variety of conserved molecular structures that are unique to microorganisms. These are primarily microbial metabolites that are referred to as pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), peptidoglycan, b-glucans and mannans, and double-stranded RNA. Families of Toll-like receptors (TLRs) on macrophages and DCs that recognize distinct PAMPs are now known to be the primary sensors of microbial infection. In addition to contributing to the signal transduction induced by many PAMPs, TLRs may also contribute to endogenous damage signals at inflammatory sites (25).

The Acquired Immune Response The interaction of a Th cell with an APC is the central event that initiates virtually all acquired immune responses, for generation of both CMI and antibody-mediated immunity (humoral). The T-cell and APC interact primarily in the secondary lymphoid organs—the lymph nodes and the spleen. Antigen can be transported to these organs as soluble antigen, as antigen-antibody complexes, or via mobile APC (including certain DCs and macrophages). After recognition of a peptide–MHC class II complex on an APC, Th cells are

activated and proliferate extensively. The Th cell progeny secrete cytokine ‘‘help’’ and play a central role in the activation of B-cells, T cytotoxic cells, and macrophages.

T-Cell–APC Interactions This association is based upon specific antigen recognition and is mediated by the requisite binding of two cell surface molecules, the TCR of the Th cell with the MHC–peptide complex of the APC. MHC molecules (termed ‘‘HLA’’ in humans) are cell surface molecules encoded by the MHC gene complex, which control the ability of an animal to respond immunologically to a given antigen. The multiple alleles (estimated at greater than 300) within a given HLA locus encode highly polymorphic gene products that vary in their individual ability to bind a specific peptide. The inherited HLA polymorphisms provide a large repertoire of specificities for antigen-derived peptides and thus provide the host with the ability to respond immunologically to a large range of different antigens. T-cells can also recognize microbial lipid and glycolipid antigens presented by CD1 proteins. CD1 belongs to MHC class I molecules that map outside of the MHC, have limited tissue distribution, and include H2M3 and MICA as members. CD1 proteins (CD1a, -b, and -c) can present foreign microbial lipid antigens, including several mycobacterial antigens. CD1d-restricted natural killer T-cells (NKT) play a role in immunity to bacteria, parasites, yeasts, and viruses (26). In particular, CD1d-restricted NKT-cells can activate innate and adaptive immune responses and appear to modulate immunity to infectious agents (27). Although difficult to characterize in humans, NKT-cells express a/b TCR and NKR1.1, a C-type lectin receptor. Many cell types can present antigen to T-cells, that is, they can degrade and present antigen-derived peptides via their MHC class I and class II molecules. The so-called ‘‘professional antigen presenting cells (APC)’’ are those cells that constitutively express MHC class II antigens, and, in humans, include DCs, macrophages, B-cells, and vascular endothelial cells. These cell types can vary in the effectiveness with which they present antigen and stimulate an immune response in vitro. The DC appears to be one of the most potent APC in vitro, expressing high levels of MHC class II and possessing long dendrite-like membrane processes that provide a large surface area for cell–cell interactions. The concentration of antigen, as well as other variables, may determine which cell type is the operative APC in vivo. Because a B-cell recognizes an antigen specifically via its surface Ig, it can present antigen effectively even at very low antigen concentrations. After intracellular degradation of foreign proteins, the MHC class I and class II molecules of the APC bind certain processed peptides within a groove formed by the polymorphic residues of the MHC. The TCR thus recognizes the specific amino acid sequence of a peptide (processed antigen) in association with self-MHC. This interaction is termed self-MHC restriction or associative recognition. APC generally ‘‘present’’ processed foreign antigen that are in association with MHC class II to CD4 T-cells and in association with MHC class I to CD8 T-cells (Fig. 5). CD4 and CD8 specifically recognize residues within the monomorphic conserved domains of MHC class II and class I antigens, respectively; thus CD4 and CD8 cells are termed MHC class II– and MHC class I–restricted, respectively. There are additional accessory cell surface proteins that play important roles in the T-cell–APC interaction. Some act as adhesion molecules to stabilize or increase the strength of T-cell–APC interactions and redistribute within the membrane to contribute to the formation of the immunological synapse

Chapter 4: The Immune System and the Immunocompromised Patient

Figure 5 Antigen presentation and recognition.

between the two cell types. Examples of such T-cell–APC ligand pairs include CD2–leukocyte function antigen (LFA)-3; LFA-1– ICAM-1 or ICAM-2; CD4–MHC class II; and CD8– MHC class I. Some ligand pair interactions provide signals to enhance T-cell activation—many ligands have cytoplasmic domains possessing enzymatic activity, usually kinase activity (phosphorylating enzymes). Such ligands are often called signal transducers because they send a signal from outside the cell to the inside. CD4 and CD8 molecules are associated with intracellular T-cell protein tyrosine kinases that appear to be activated by binding to the monomorphic domains of MHC molecules. There is compelling evidence that certain ligand pair interactions provide critical ‘‘second signals’’ required for T-cell activation after the antigenic ‘‘signal 1’’ is delivered via TCR ligation to the MHC peptide. In addition to the TCR, T-cells have multiple so-called ‘‘coreceptors’’ with both shared and unique properties that regulate the T-cell response. The most significant activating ligand pairs that have been identified on T-cells and APC, respectively, are CD40L–CD40 and CD28–CD80 (28,29). In the current working model of Th cell activation (Fig. 6), CD40L expression is upregulated by T-cells that have received signal 1 (ligation

Figure 6 T-cell activation.

71

of the TCR with MHC antigen). CD40L can then engage CD40, its cognate ligand on the APC, which in turn triggers the APC to upregulate the expression of CD80 and CD86 (originally named B7.1 and B7.2). CD80 binding to CD28, which is constitutively expressed on T-cells, results in full T-cell activation. Inducible costimulatory molecule is a coreceptor that is induced in na€ve and memory T-cells, binds to B7H on APC, and apparently provides signals that can substitute for CD28. Finally, CTL antigen-4 is a T-cell coreceptor that is homologous to CD28, and is a negative regulator of T-cell responses by inhibiting proliferation. It is important to note that APC activation is usually a corollary to these interactions and is also dependent on CD40–CD40L engagement. Activated B-cells, macrophages, and DCs are key players in the effector phase of an immune response. Soluble cytokines are also involved in mediating this ‘‘cross-talk,’’ and include T-cell–derived IL-4 as well as IL-1, IL-6, and IL12, which are secreted by specific APC cell types. Once the Th cell is activated by productive engagement of the appropriate receptor ligand pairs, and after receipt of the appropriate signals, it produces IL-2 ‘‘help,’’ which functions in an autocrine manner to induce proliferation and clonal expansion. These Th progeny can now produce cytokines that ‘‘help’’ B-cells, macrophages, and CTLs differentiate and perform their full effector functions. The central role of the Th cell in the effector mechanisms of the immune response is presented in Figure 7.

The Humoral Immune Response It is clear that B-cells, T–cells, and APC are required for the generation of most humoral immune responses. As described above, the B-cell antigen receptor is a multicomponent receptor consisting of surface Ig noncovalently associated with two other distinct transmembrane proteins. The surface antibody mediates the internalization of specific antigen via receptor-mediated endocytosis. In the B-cell endosome, newly synthesized MHC class II antigens encounter peptides derived from antigen proteolysis and present certain peptides on the surface of the B-cell. These ‘‘antigen primed’’ B-cells act as APC to interact with activated Th cells (which are antigen specific on the basis of their TCR) and form specific B–Th cell conjugates. Antigen-specific conjugate formation appears to actually cause redistribution of the TCR, LFA-1, and CD4 molecules within the T-cell at the interface of the cell-to-cell contact. Conjugate formation induces T-cell expression of CD40L, which then engages CD40 on the B-cell surface, as described above. The B-cell receptor itself is associated with cytoplasmic src-family tyrosine protein kinases that are activated upon antigen binding and initiate an intracellular signaling cascade that leads to many cellular responses, including cytokine production. B-cell activation ensues, triggered by a combination of membrane events and cytokine signaling. The Th cytokines IL-1 and IL-4 play predominant roles as the costimulatory signals in B-cell activation. The activated B-cell is driven into the S (or DNA synthesis) phase of the cell cycle by IL-2, IL-4, and IL-5. As discussed earlier, IgM is the first isotype expressed by plasma cells during a primary immune response. Numerous Th1 and/ or Th2 cytokines (including IL-2, IL-4, IL-5, IFN-g, and TGF-b) induce differentiation into plasma cells, producing different Ig isotypes. The changes in the activation and maturation stage of the cells are caused as well as marked by changes in gene expression.

medwedi.ru

72

Part One: General Considerations

APC

T helper cell

IL-2, IL-4, IL-5, IL-6 IL-2

TDTH

Activated macrophage

IL-2

+

+

CD8 TC

CD4 TC

B cell

IFN-γ TNF-β

Cytotoxicity MHC expression

CD8+ CTL

Lytic enzymes Class I MHC alloantigen

Membrane damage Class II MHC alloantigen

CD4+ CTL

NK cell or macrophage C

Lysis

Target tissue

It must be noted that ‘‘T-independent’’ antigens exist that can directly stimulate B-cells and elicit antibody responses without the assistance of Th cells (30). This type of antigen, usually carbohydrate in nature and comprised of repeating epitopes, is best exemplified by bacterial polysaccharides. Complement-Mediated Cytolysis It is the major effector of the humoral immune response. Complement refers to a group of at least 20 distinct serum proteins that participate in a highly regulated enzymatic cascade (31,32). There are two pathways of complement activation, the classical and the alternative pathways. Both pathways generate a membrane attack complex that forms pores in cell membranes and causes cell lysis. A conformational change occurs when an antibody binds to its antigen on a cell surface, such that a binding site on the Fc portion of the molecule is exposed. Binding of the C1 component of the complement system to the Fc sites exposed on two adjacent antibody molecules activates the classical pathway. In humans, IgM and certain subclasses of IgG (IgG-1, -2, and -3) are capable of ‘‘fixing’’ complement in this manner. The alternative pathway is usually initiated by bacteria, yeast, and certain viruses in an antibody-independent fashion. Complement reaction products cause vasodilation and chemotaxis to promote a localized inflammatory response and also act as opsonins to promote phagocytosis of antigen. Anaphylaxis It is an immediate hypersensitivity reaction that is triggered by IgE-mediated mast cell or basophil degranulation and

ADCC

Fc receptor

Figure 7 Schematic of the central role of the Th cell in the effector mechanisms of the immune response. Abbreviations: C, complement; ADCC, antibody-dependent cell-mediated cytotoxicity; Th cell, T helper cell. Source: From Ref. 5.

is initiated within 2 to 30 minutes of antigen exposure. Anaphylaxis can be localized to a specific target tissue or can occur throughout the organism, inducing systemic effects that can be fatal. Upon primary exposure to parasitic antigens or allergens, B-cells are activated to become IgEsecreting plasma cells. IgE binds to the cell surface of mast cells and basophils via the high-affinity FceRI, thus increasing the half-life of IgE from days to weeks. Mast cells are bone marrow–derived cells that differentiate in connective tissues where they reside. Upon secondary exposure to antigen, the IgE on these sensitized cells is cross-linked, which triggers degranulation and the release of pharmacologically active mediators. These mediators include histamine and serotonin, which cause increased vascular permeability and smooth muscle contraction, as well as granulocyte chemotactic factors and proteases that mediate tissue destruction. Additional secondary mediators such as leukotrienes are generated by the breakdown of the mast cell membrane phospholipids after degranulation. Eosinophils are also attracted to the site and can bind directly to antibody-coated antigen. They in turn are activated, degranulate, and release inflammatory mediators. Opsonization It refers to the deposition of molecules on an antigen (including a microorganism) that promotes contact with an appropriate phagocytic cell. Such molecules, or opsonins, are usually antibodies or components of complement. Because macrophages and granulocytes express receptors for both antibody and complement on their cell surfaces, opsonization increases antigen binding by these phagocytes.

Chapter 4: The Immune System and the Immunocompromised Patient

Opsonins thus serve as a bridge between antigens and effector cells. The enhanced antigen binding results in a significant increase in the rate of phagocytosis.

Antibody-Dependent Cell-Mediated Cytotoxicity Antibodies can also affect cell-mediated responses to foreign cells in a complement-independent process termed ADCC (22). In this scenario, antibody serves as a bridge connecting a foreign target cell to an immune effector cell, and thus provides antigen specificity to a nonspecific cytotoxic cell. NK cells, neutrophils, macrophages, and eosinophils express Fc receptors on their cell surfaces. These receptors can thus recognize the carboxy terminal region of an Ig molecule that is bound to foreign cells via its amino-terminal antigen-binding hypervariable domains. This binding stimulates the cytotoxic cell to increase the lytic components in their cytoplasmic granules (including enzymes, TNF, and perforin) and then to release the granule contents, culminating in destruction of the target cell.

CTL-Mediated Cytotoxicity The CTL-mediated immune response is initiated by the activation and differentiation of precursor CTL (CTLp) into functional effectors. The interaction of the TCR of a resting CTLp with the MHC class I–peptide complex of its target cell induces the expression of T-cell IL-2 receptors. As described earlier, IL-2 ‘‘help’’ is produced as a result of a similar interaction between CD4þTh and MHC class IIþ APC. This IL-2 provides the principal ‘‘second signal’’ required by CTLp for activation, triggering its clonal proliferation and differentiation into a mature CTL effector. As discussed above, other ligand interactions also appear to supply strong costimulatory signals. The B7/CD28 interaction has been reported to induce CTLp to express IL-2 by themselves, bypassing the requirement for Th cells. The CTL progeny, mature effectors, are now able to form conjugates with target cells that bear the appropriate MHC class I–peptide complexes. Exocytosis of cytoplasmic granules at the interface of cell–cell contact releases lytic molecules that damage the membrane of the target cell and cause death, as described above. Secondary to antigen recognition, the LFA-1/ICAM interaction between the T-cell and target cell appears to be critical for both conjugate formation and subsequent dissociation of the CTL from the target cell.

DTH Reactions DTH responses refer to an increased reactivity to a specific antigen, which is T-cell–mediated. The increased reactivity is a function of previous antigen sensitization (via APC–T-cell interactions described above) that has induced T-cells to proliferate and differentiate into a subset of T-cells (usually CD4þ Th1), designated TDTH cells. Following the second exposure to an antigen, TDTH cells secrete a myriad of cytokines, which induce a localized inflammatory reaction (DTH). Macrophages are attracted by these cytokines and activated. The DTH response usually peaks 48 to 72 hours after secondary contact. This response is important and generally very effective in the defense against intracellular pathogens and contact antigens.

Mediators of Immune Function As previously discussed, cytokines play a major role in immune function and regulation (33). Cytokines are regulatory proteins that have pleiotropic effects on cells that participate

73

in host defense and repair processes via control of cell differentiation, activation, and proliferation. Originally termed ‘‘lymphokines,’’ the cytokine terminology evolved to indicate that these factors can be non–lymphocyte derived and can also have nonlymphoid targets. The current ‘‘interleukin’’ terminology was born at the 1978 Second International Lymphocyte Workshop, and incorporates the concept of bidirectional, intercellular signaling between somatic, myeloid, and lymphoid cells. At this writing, IL-30, a member of the IL-2 subfamily, is the most recent cytokine named by the IUIS/WHO Standing Committee on Interleukin Designation (34). Cytokines typically are very potent—they act at picogram-nanogram levels and exert paracrine and autocrine effects. The expression of cytokines is inducible, triggered by diverse stimuli from diverse cellular sources. Cytokines operate in a network that can be overlapping, redundant, synergistic, additive, and/or antagonistic. Cytokines are grouped into families based on structural homologies and are also classified by function (see Table 3 for representative examples). Finally, they act by binding to high-affinity receptors that are transmembrane proteins, many possessing kinase activity or enzymatic activities, which activate the kinases that effect signal transduction. Further comprehensive descriptions of the cytokines are beyond the scope of this chapter and can be found elsewhere (35,36).

Clinical Assessment of Immune Function Clinical assessment of human immune function can help define defects in local and systemic defense mechanisms. This is true for both patients with primary hereditary immunodeficiencies and for those with acquired immunodeficiencies. Although some of the tests described below are not routinely conducted clinically, they are available at most tertiary care centers and can be valuable for the identification of the immunocompromised patient at increased risk for local and systemic infections. A summary of laboratory tests used to detect immunodeficiencies is found in Figure 8. An obvious key to the successful treatment of infection in the immunocompromised host is early diagnosis of infection. Discussion of these detection techniques is beyond the scope of this review; however, it should be noted that advances in molecular biology have brought innovations to these analyses. Molecular techniques include the use of chemiluminescent-labeled DNA probes that hybridize to DNA of specific bacteria and viruses as well as virus- and bacteria-specific DNA primers that have been developed for DNA amplification in the polymerase chain reaction. In this section, we will briefly discuss some of the clinical predictors and laboratory tests that are available.

Leukocyte Enumeration and Subsets Quantitative determinations of circulating leukocytes are routinely determined by critical blood count (CBC), including platelet size and number and differential analysis (Table 4). This test will detect gross changes in cells that might occur in conditions such as leukemia or in certain immunodeficiency diseases. CBC is the first step to evaluating all suspected immune defects and the absolute counts must be compared to age-appropriate normative values. Small-sized platelets are a characteristic finding in Wiskott– Aldrich syndrome. The absolute neutrophil count is very important in cancer patients; less than 1000 cells/mL strongly correlates with an increased incidence of sepsis and less than

medwedi.ru

74

Part One: General Considerations

Table 3 Cytokine Classification by General Function Hematopoietic B-cell Growth T-Cell Growth Antiviral Inflammatory Chemotactic Antimitotic Immunosuppressive

IL-3, IL-11, IL-17, colony-stimulating factors, stem cell factor, erythropoeitin IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-14, IL-15, IL-21, TGF-b IL-2, IL-4, IL-7, IL-9, IL-12, IL-15, IL-16, IL-18, IL-21, IL-23, IL-27 Interferon family (a/b/c/x, s), IL-28, IL-29 TNF family (TNFa/b, Lymphotoxin), IL-1 family (IL-1a/b, IL-1RA), MIF, IL-6, IL-8, IL-17 IL-8, MCP-1-MCP-5, MIP-1, MGSA/GRO, RANTES, IL-16 TNF family IL-4, IL-10, IL-13, TGF-b

Abbreviations: IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor; IL-1 RA, IL-1 receptor antagonist; MCP, macrophage chemotactic protein; MIF, migration inhibitory factor; MGSA, melanocyte growth stimulatory activity; GRO, growth-related oncogenes.

500 cells/mL, if not corrected, is associated with an increased incidence of death. The CBC may be normal, however, in the most common immune deficiency, asymptomatic selective IgA (SIGA) deficiency. If lymphopenia is observed, screening for T- and B-cell disorders should be initiated. Enumeration of lymphocyte subsets can be performed by flow cytometric analysis, and characteristic markers have been described in the previous sections. Flow cytometry has become an important part of the workup of patients suspected of having primary immunodeficiency diseases (38). For example, there is a marked reduction of both T- and B-cell counts in severe combined immunodeficiency disease (SCID). Although lymphocytes comprise about 25% of the mononuclear cells in the human circulation, the blood actually contains a small proportion (about 2%) of the body’s total T- and B-lymphocyte pool (39). Lymphocyte trafficking is regulated largely by differential expression of adhesion molecules and chemokine receptors on T-cells (40). The

majority of the lymphocytes are concentrated in the lymph nodes and the spleen, however, it is estimated that about 500 109 lymphocytes travel through the blood compartment each day. The CD4:CD8 ratio in peripheral blood cells is approximately 2:1 in healthy individuals, and deviations from this ratio can be prognostic indicators of immune dysfunction, especially of immunodeficiency and autoimmune diseases. This ratio is monitored closely clinically in conditions such as AIDS. However, the blood does not always mirror lymphocyte alterations in other tissues, and inferences about pathological changes in other organs must be made judiciously. As a further caution, CD4 and CD8 are not absolute indicators of cell function. Bone marrow and lymph nodes may also be examined in addition to blood, to determine if the immune cell distributions are normal. Flow cytometry can also analyze cell surface antigens that are unique to cells at different stages of differentiation,

Figure 8 A diagnostic testing algorithm for primary immunodeficiency diseases. Source: From Ref. 37.

Chapter 4: The Immune System and the Immunocompromised Patient

Table 4 Normal Adult Circulating White Blood Cell Populations Cell type White blood cells Lymphocytes T-cells B-cells NK cells Monocytes Granulocytes Neutrophils Eosinophils Basophils

Absolute counta 4.5–11.0 1–4.8

0–0.8 1.8–8.4 1.8–7.7 0–0.5 0–0.2

Percentage 25–30% of white blood cells ~70% of lymphocytes 15–25% of lymphocytes 5–15% of lymphocytes

50–70% of white blood cells

(103 cells mm3) Abbreviation: NK, natural killer. a

as described earlier for surface Ig isotypes in B-cell development. Flow cytometry has basically replaced previous tests such as E-rosette formation for T-cell detection and fluorescent microscopy detection of surface Igs for B-cells. Flow cytometry can be used to enumerate a specific cell type, evaluate function, or detect a specific gene product. Most major immunodeficiency diseases can be diagnosed by flow cytometry, with the exception of Che´diak–Higashi syndrome, ataxia telangiectasia, and complement deficiencies (38). The enzyme-linked immunospot (ELISPOT) was developed to detect and quantitate plasma (antibody-secreting) cells and provided a rapid and versatile alternative to conventional plaque-forming assays. The ELISPOT is very sensitive and detects the high concentration of antibody that surrounds each plasma cell. The ELISPOT has more recently been used to enumerate antigen-specific T-cells via detection of cell-associated cytokine production in patients with viral infections, cancer patients, and transplant recipients. Peripheral blood cells can be measured directly or after ex vivo stimulation with antigen. The frequency of antigen-specific CTL, Th cells, and their precursors can be measured in peripheral blood by in vitro limiting dilution analysis (LDA) of PBMC. LDA is not routinely available in clinical laboratories. Although LDA is a standard immunological method in many research laboratories, it is cumbersome, labor intensive, and operator dependent.

Serum Components Serum Ig levels can be determined electrophoretically and by enzyme-linked immunoabsorbent assay (ELISA). In humoral immunodeficiency diseases, serum Igs may be totally absent, as occurs in X-linked agammaglobulinemia, or decreased, as occurs in common variable hypergammaglobulinema. There may also be selective increases or decreases in certain classes of Igs in the immunocompromised patient. Complement components can also be accurately measured in serum (41), most typically by the CH50 test, which simply measures the amount of serum required to lyse 50% of antibody-coated sheep red cells. If abnormal, this test is followed by analysis of individual complement components, usually C3 and C4. Although not commonly occurring in the homozygous state in humans, genetic deficiencies have been identified in each of the complement components and are associated with increased susceptibility to bacterial infections and/or immune complex diseases, including systemic lupus erythematosus and glomerulonephritis (31). Interestingly, an inherited deficiency in C1 inhibitor, a complement regula-

75

tory protein, occurs more frequently and results in hereditary angioedema. The functional activity of lymphoid cells can be evaluated on the basis of the cytokines they secrete. As described above, the different populations and subpopulations of leukocytes secrete distinct cytokines and all of the major human cytokines can be measured by ELISA or bioassay and more recently by flow cytometry. However, accurate methods are still lacking for the standard quantitation of many immune mediators in biological fluids and cells (42). For many cytokines, serum levels have not proven to be consistent indicators of immune status. This is partly due to their short half-lives and the fact that many cytokines are associated with protein carriers in the serum or are predominantly present in latent, inactive forms. In addition, cytokines typically act locally in an autocrine or paracrine manner and are not usually systemic effectors. Cytokine production is thus often measured after the isolation of leukocytes from an individual and subsequent in vitro culture with antigen. In bacterial septic shock, high levels of both pro- and anti-inflammatory cytokines are detectable within the bloodstream (43). In this condition, bacterial cell wall endotoxins stimulate macrophages to overproduce IL-1 and TNF-a, and high blood levels of these cytokines have been associated with poor survival. These and other proinflammatory cytokines mediate drastic systemic effects that can be fatal, including a drop in blood pressure, fever, diarrhea, and extensive blood clotting. However, therapies targeting these cytokines have been clinically ineffective (44). Although not routinely analyzed clinically, other regulatory molecules circulate in the serum in soluble form and may modulate the immune response. Many of these are cell surface antigens that can be synthesized in a soluble form by alternative mRNA splicing or can be ‘‘shed’’ or generated via proteolytic cleavage from the cell surface. Soluble forms of certain antigens are frequently produced by activated cells, thus elevations may indicate an ongoing immune response. For example, many cytokine receptors exist as secreted/soluble proteins (45) and are involved in the endogenous regulation of cytokine activity. Certain soluble cytokine receptors appear to serve as markers of immune suppression (IL-2R) and sepsis (TNFR). There is substantial interest in the potential application of soluble cytokine receptors in biological therapy (46). Serum components can also be assayed indirectly by measuring their mRNA levels. Quantitative molecular methods are being implemented, such as real time reverse transcriptase–polymerase chain reaction, and offer the advantages of speed and specificity.

Leukocyte Function Analyses can also be conducted to determine if the leukocytes that are present in a patient exhibit normal functional activities. PBMC are generally isolated by density gradient centrifugation on Ficoll-Hypaque, prior to analysis in one of the following tests. Mitogenic Proliferation Mitogens are substances that induce DNA synthesis and cell division. Mitogens are often termed polyclonal activators, because they activate cells without regard to their clonal antigenic specificities. Many mitogens are plant proteins termed ‘‘lectins,’’ which have affinities for specific carbohydrate moieties on cell surface glycoproteins and glycolipids. Some

medwedi.ru

76

Part One: General Considerations

mitogens are T-cell specific [such as concanavalin A (ConA) and phytohemagglutinin (PHA)], some are B-cell specific (such as the LPS of gram-negative bacteria), and some mitogens activate both T- and B-cells (such as pokeweed mitogen). Proliferation is generally measured in the laboratory by incorporation of 3H-thymidine into DNA. Finally, many superantigens are potent activators of T-cells (e.g., staphylococcal enterotoxin A) and B-cells (e.g., staphylococcal protein A). Mixed Lymphocyte Reaction The mixed lymphocyte reaction (MLR) is an assay in which lymphocytes from different individuals are cultured together, and proliferate in response to allogeneic antigens. In the typical one-way MLR, cells from the individual to be tested (the responder cells) are mixed with different allogeneic stimulator cells that have been irradiated to prevent proliferation. This assay can also be used to test the ability of the stimulator lymphocytes (the APC) to present antigen. The amount of 3H-thymidine incorporated into DNA is determined after four days of culture and is proportional to the proliferative response. The MLR primarily measures the proliferation of Th cells and thus is a strong indicator of differences in the MHC class II antigens of responder and stimulator cells. However, MHC class I antigens as well as minor transplantation antigens have also been reported to contribute to this response. Nowadays, this assay is no longer used to measure compatibility at the MHC class II region. Molecular methods using polymerase chain reaction–based methods are being used to determine MHC alleles. Cell-Mediated Lympholysis It is an analogous assay to the MLR, but analyzes the activity of CD8þ CTL instead of CD4þ Th cells. This assay can evaluate in vivo–generated CTL (isolated from the circulation) or CTL that are induced in vitro by MLR. In either case, effector function is measured by the ability of these cells to lyse target cells. Target cells are generally allogeneic or virally infected syngeneic cells. Target cells are genetically identical to the cells injected or transplanted in vivo or identical to the stimulator cells for in vitro MLR-induced cell-mediated lympholysis (CML) assays. Target cells are prelabeled intracellularly with 51chromium or a dye that, upon lysis, is released from the cell into solution at a level proportional to the level of cell-mediated cytotoxicity. When conducted as an MLR-induced CML, this assay can also be used to evaluate the functional ability of Th cells to induce CTL effectors.

In Vivo Tests DTH is the most common in vivo assay of cell-mediated immune status in humans. The presence of a DTH reaction can be measured in vivo by injecting the antigen intradermally. A characteristic skin lesion caused by erythema at the injection site indicates a positive reaction and is evident 48 to 72 hours after antigen application. DTH can be used to assess cellular immune function by evaluating the response of an individual to recall antigens—antigens to which the patient presumably had been previously exposed. The CMI multitest includes eight recall antigens. Dinitrochlorobenzene (DNCB) has also been used as an antigen to test for cellular immune function, and patient response to de novo antigen challenge is measured two weeks after the initial DNCB skin contact. DTH has been used in a variety of clinical settings, including patients in intensive care units, surgical populations,

and transplant and HIV patients. This assay has been used to predict prognosis, overall survival, and response to therapies. The prototype of this test in humans is the administration of the purified protein derivative (PPD) extracted from the cell wall of Mycobacterium tuberculosis; however, other test antigens from the organisms causing histoplasmosis, candidiasis, and nocardiosis are also used. This test is usually given to determine if an individual has been previously exposed to the bacteria (either through infection or prior immunization). A more sensitive ELISPOT has been developed to detect T-cells specific for M. tuberculosis using antigens that are absent from Mycobacterium vaccines and most environmental mycobacteria (47). The status of humoral immune function can be tested in vivo by testing antibody titers to recall antigens such as diptheria and tetanus toxins. If titers are low, antibody responses to these antigens can also be tested two weeks after antigen boost or after active vaccination. Pneumococcal vaccine has been used in this manner to test human antibody responses to carbohydrate antigens. B-cell function can also be tested by analyzing serum for appropriate isohemagglutinin titers (antibodies against the A or B blood group antigens). In addition, if the patient has experienced a documented infection, the current antibody titer against the specific organism can be informative. Finally, the function of circulating neutrophils and monocytes can be evaluated by the nitroblue tetrazolium (NBT) test. NBT is reduced during the normal respiratory oxidative burst and can provide both qualitative and quantitative data on freshly isolated cells.

THE IMMUNOCOMPROMISED SURGICAL PATIENT Immunodeficiency Clinical States Primary Immunodeficiency There are more than 95 primary immunodeficiency diseases (Table 5). Some are manifest from birth while others are not identified until much later in life. The World Health Organization has categorized primary immunodeficiencies into five basic groups: (i) combined deficiencies, (ii) predominantly antibody deficiencies, (iii) cellular deficiencies, (iv) complement deficiencies, and (v) defects of phagocytic function (49). The major complication of primary immunodeficiencies is an increased susceptibility to viral or bacterial infection, although there are increases in certain types of cancer. Patients with severe T- or B-cell immune defects have an increased incidence of cancer and autoimmune diseases. The type of immunodeficiency can determine the type of cancer that develops. In those patients with combined immunodeficiencies, non-Hodgkin’s lymphomas represent the major type of tumor reported. This was the case even though almost half of the patients had received some therapy aimed at immunoreconstitution (50). In patients with SCID, the major cause of death is infection. Those patients with primary antibody deficiencies have an increased propensity to recurrent and chronic pyogenic infections, usually involving the respiratory tract. The usual tumor is a lymphoma, with gastrointestinal carcinomas following. Compared to other immunodeficiency states, central nervous system lymphomas are less common. The incidence of gastric carcinoma may be related to the gastric atrophy, achlorhydria, and decreased acid secretions. Many of these patients have low IgA levels and may be at increased risk of Helicobacter or related infections (51).

Chapter 4: The Immune System and the Immunocompromised Patient

77

Table 5 Examples of Primary Immunodeficiency Diseases Designation

Gene

Description/pathogenesis

Antibody deficiencies XLA

BTK

Mutations in the gene encoding BTK, a regulator of B-cell development; absence of mature circulating B-cells and undetectable or substantially low serum Ig levels lead to recurrent bacterial infections during the first year of life. Absent or marked reduction of serum IgA; majority of patients are asymptomatic; others have recurring respiratory infections, chronic diarrhea, allergies, or autoimmune disease. Defect in the AICDA required for Ig isotope switching and somatic hypermutation in Bcells; low IgG and IgA, normal or increased IgM. Low IgG, IgA; normal or increased IgM; bacterial and opportunistic infections.

IgA deficiency

Hyper-IgM syndrome type 2 (AID deficiency) Hyper-IgM syndrome type 3

IGAD1

AID (AICDA) CD40

Combined B- and T-cell deficiencies X-linked SCID

IL2RG

Jak3 deficiency

JAK3

RAG1 deficiency RAG2 deficiency ADA deficiency

RAG1 RAG2 ADA

X-linked hyper-IgM syndrome

CD40L

WAS

WASP

Ataxia-telangiectasia X-linked lymphoproliferative syndrome

ATM SH2D1A (SAP)

Phagocytic defects LAD1

ITGB2

LAD2

FUCT1

Most common form of SCID; caused by a mutation in the IL-2 receptor gene on the X chromosome needed for the normal growth and function of T-cells and B-cells; lymphopenia occurs primarily from the absence or near absence of T-cells and natural killer cells; B-cells are immature and defective. Mutation in the gene that encodes JAK3 needed for differentiation of hematopoietic cells; lymphopenia occurs primarily from the absence or near absence of T-cells and natural killer cells; B-cells are present but defective. Mutations in RAG1 lead absence of mature B- and T-cells. Mutations in RAG2 lead absence of mature B- and T-cells. Mutation in a gene encoding the enzyme ADA; lymphopenia occurs from the death of B-cells because of accumulation of toxic metabolite and functional antibodies are decreased or absent. Mutations in the CD40 ligand gene lead to impairment of T-cell/B-cell interaction, lack of Ig isotope switching; recurrent and opportunistic infections. Defect in cytoskeletal WASP, affecting platelets and T-cells, leads to thrombocytopenia, small defective platelets, eczema, lymphomas, autoimmune disease, and infections. Progressive multisystem disorder characterized by neurologic impairment with ataxia, telangiectasia of the conjunctiva and skin, malignancy, and radiation sensitivity. Uncontrolled lymphoproliferation induced by severe EBV infections, B-cell lymphoma.

Disorder of neutrophil adhesion caused by lack of CD18 characterized by recurrent or progressive necrotic soft-tissue infection, periodontitis, poor wound healing, leukocytosis, and delayed umbilical cord detachment. Defect in GDP fucose transporter 1; associated with mental retardation, soft-tissue infection, and delayed healing.

Complement deficiencies Deficiency of individual complement CIQA, C1QB, C1QG, Absence of complement components; results in increased infections and lupus-like components C1q, C1r, C1s, C2, C3, C4, C5, C1R, C15, C2, C3, diseases; C1, C2, C3, and C4 associated with autoimmunity and pyogenic C6, C7, C8, C9 C4A, C4B, C5, C6, C7, infections. C8A, C8B, C8G, C9 Factor B, Factor H1 BF, HF1 C5–C9 and properdin deficiencies associated with neisserial infections. Abbreviations: Ig, immunoglobulin; SCID, severe combined immunodeficiency disease; WAS, Wiskott–Aldrich syndrome; BTK, Bruton’s tyrosine kinase; AICDA, activation-induced cytidine deaminase; XLA, X-linked agammaglobulinemia; JAK3, Janus-associated kinase 3; RAG, recombinase activity gene; ADA, adenosine deaminae; WASP, WAS protein; EBV, Epstein–Barr virus; GDP, guanosine diphosphate. Source: From Ref. 48.

Those patients with well-characterized immunodeficiencies such as Wiskott–Aldrich syndrome also have an increased risk of developing malignant tumors. This risk is almost 100% by the age of 30 in patients with Wiskott–Aldrich syndrome, with the most common site of involvement being the brain (52). Respiratory infections are common in ataxia telangiectasia. Non-Hodgkin’s lymphomas account for almost half of the malignancies in this group of patients, however, almost a quarter of the patients develop leukemia. Bone marrow transplantation has been used successfully in the treatment of patients with immunodeficiencies. Gene therapy has also been used but with limited success. The patients who have a primary immunodeficiency and those who develop a secondary immunodeficiency develop a high proportion of lymphoproliferative disorders.

The incidence of cancer in patients with primary immunodeficiencies is approximately 1% to 4% (47). It must be remembered that this apparently low figure is for all patients with immunodeficiencies and that there are specific immunodeficiencies that have a very high incidence of cancer. This incidence is comparable to the incidence of cancer in organ transplant patients, which is approximately 1% to 5% (53). In cardiac transplant patients, the risk of posttransplant B-cell lymphoproliferative disease is 5% to 6% of patients. This is believed to be due to the very high immunosuppressive drug doses that cardiac recipients receive (54). The increased use of powerful immunosuppressants as induction agents for many solid organ transplants has increased the incidence of post-transplant lymphoproliferative disease. This has been shown to be associated with the

medwedi.ru

78

Part One: General Considerations

use of OKT3 or antithymocyte globulin, but not with antiCD25 antibody (55). Together, these data would lead to the conclusion that there may be a common mechanism to explain the incidence of cancer in patients who have been immunosuppressed to maintain an organ transplant and in patients suffering from primary immunodeficiencies.

Transplant Recipients as Secondary Immunodeficiency Patients Transplant recipients can be viewed as secondary immunodeficiency patients due to the chronic use of immunosuppressive agents (Table 6). The interval between transplantation and the onset of a cancer after transplant (approximately 32 months) is much shorter than that in the general population that has been exposed to a carcinogen (5–20 years) (56). The time of appearance of the cancer after transplant is dependent on the type of cancer that occurs. Kaposi’s sarcoma appears an average of 21 months after transplant compared with anogenital carcinomas, which occur an average of 115 months after transplant. The incidence of most common cancers such as lung, breast, prostate, colon, and invasive uterine cancer observed in the general population is not changed in transplant recipients. However, squamous cell carcinomas of the skin are markedly increased. A variety of tumors in the transplant recipients compared to the general population are as follows: lymphomas, 23% versus 5%; lip cancers, 7% versus 0.3%; Kaposi’s sarcoma, 6% versus minimal; carcinoma of the kidney, 5% versus 2%; and sarcomas, 1.7% versus 0.5%, respectively (57). A population-based study from Sweden shows the same patterns: an excess of nonmelanomatous skin cancers with a standardized incidence ratio (SIR) of 56, lip cancer (SIR 53), and non-Hodgkin’s lymphoma (SIR 6). There was also a 10-fold increased incidence of anal cancer and a 20-fold increase in vulvar and vaginal cancer compared to the general population. Those patients with a nonrenal transplant had a higher risk of cancer compared to those with a renal transplant (58). Thus in certain tumors the incidence is markedly different from the general population. Viral infections have been postulated to play a role in the etiology of cancer development in these immuno-incompetent patients. Epstein–Barr virus (EBV) has been associated with Burkitt’s lymphoma and Hodgkin’s disease in the general population. Approximately 30% to 60% of patients with primary disorders are EBV positive. The postulated mechanism is that the virus infects B-cells and stimulates a polyclonal B-cell proliferation (59). B-cell proliferation is abated in normal patients by cytotoxic T-lymphocytes, but in immunocompromised individuals the proliferation continues

unchecked. This proliferation of multiple B-cells is occasionally interrupted by an unknown event, which results in the emergence of a monoclonal tumor, thus explaining the incidence of EBV-DNA–specific sequences in tumor specimens of patients who have received a transplant, who are congenitally immunodeficient, or who have AIDS (60,61). The reasons why patients with primary immunodeficiency or transplants develop disturbances in immunity that result in cancer are not clear. There are several theories that are open to discussion. The first theory is that the patients have a defective surveillance system. If this were the case, then one would expect a higher percentage of cancers of all types and not an increase in certain cancers that have been described. Indeed in those patients who develop a non-Hodgkin’s lymphoma or a Kaposi’s sarcoma, when immunosuppression is withdrawn, the patients will frequently have a regression of their tumor. Thus the innate immune response can be effective. Another popular theory is that patients have chronic antigenic stimulation. Animal models have shown that continuous stimulation with a foreign antigen can give a high yield of lymphomas (57). AIDS patients have chronic infections, which could result in continued immunologic stimulation. Transplant patients have a chronic source of antigenic stimulation from the transplant, which could thereby result in the development of lymphomas. Transplant patients may also develop cancer because of the carcinogenic effects of the immunosuppressive agents. Azathioprine, cyclophosphamide, and cyclosporin may directly damage DNA and cause malignant changes (57). However, most animal models require these drugs in combination with another chemical or physical agent to develop cancer. There is also an established increased incidence of skin cancer in patients who reside in climates with sun exposure, such as the Southwestern United States or Australia. The most fascinating question regarding cancer development in immunocompromised patients is why such a small percentage of these patients develop cancer. There may be a genetic predisposition in a small number of patients for an increased susceptibility to viral infections or malignancies. There are several studies that link HLA types to susceptibility or resistance to Kaposi’s sarcoma.

Malnutrition General Malnutrition is an important problem in surgical patients. In fact it is the most common cause of acquired immunodeficiency in the world. Surgical patients who present with cancer, fistulas, burns, and trauma are predisposed to the

Table 6 Effects of Major Immunosuppressive Agents

Myelosuppression Cell specificity Delayed wound healing Impaired microbial defense Organotoxicity Tumorigenesis Diabetogenicity Therapeutic monitoring possible a

Calcineurin inhibitors

Sirolimus (Rapamycin)

Mycophenolate mofetil

– – þ þa Yes

þ þ þ – – Yes

þ þ – – – Yes

Significant for Tacrolimus (FK506), not cyclosporin. Abbreviations: , No effect; þ, small, variable effect; , significant effect.

Corticosteroids

Anti-CD3 monoclonal antibody

Anti-CD25 monoclonal antibody

Polyclonal antilymphocyte antibody

– – – – þ No

– – þ – – No

– – – – – – No

þ – – – – No

Chapter 4: The Immune System and the Immunocompromised Patient

development of sepsis and infection. The relationship between host nutrition and wound healing has been recently reviewed (62). A consistent finding in malnutrition is the lack of maturation of T-lymphocytes in the thymic environment. This is caused by decreased amounts of thymic hormones and a defect in the thymic epithelium, and results in the release of immature cells to the periphery (63). The decrease in mature T-lymphocytes is manifested by in vivo abnormalities such as lack of impaired DTH responses. In vitro, this is detected as a decrease in mitogen and antigen lymphocyte proliferative responses to mitogens and antigens (64). Malnourished patients exhibit many abnormal T-cell responses that lead to additional host abnormalities in those processes that are dependent on the T-cell response. These include macrophage activation, T-cell–dependent antibody production, and T-cell–mediated cytotoxic responses to viruses. The patient who is malnourished as well as vitamin A deficient has depressed CMI. These individuals also exhibit decreases in antibody response, and there can be defects in B-cell clonal expansion. One can show that Ig levels are normal or even high in these malnourished patients (65). Even with the above changes, the use of live vaccines in malnourished children is generally safe. The complement cascade is very important in the defense against infection. Malnutrition results in decreased serum levels of most complement components, particularly C3. In addition, the normal increase in complement levels seen in stress situations is blunted. In malnourished children, complement activation by both pathways appears to be intact but diminished (particularly the alternative pathway). This may be a major predisposing factor to the increased susceptibility of malnourished patients to gramnegative sepsis (66). Clinically malnourished patients tend to fare poorly and are found to have prolonged infections or infections of greater severity than patients with normal nutritional levels. Malnutrition and infection can become part of a vicious cycle, with infection causing increased malnutrition, which in turn causes prolonged or exacerbated infection. Malnutrition is a major predisposing factor for complications in postoperative patients. It is associated with decreased wound healing, an increased complication rate, and an increased death rate (67). The route of nutritional support has also been determined to be of importance in the posttraumatic care of patients. Moore et al., have shown that among patients with abdominal trauma, those who received early enteral feedings had significantly fewer intra-abdominal abscesses and lower rates of pneumonia, compared to patients who received delayed total parenteral nutrition (TPN) (68). These findings were confirmed by Kudsk et al., who found a decreased incidence of intra-abdominal abscesses, pneumonia, and number of infections in patients who received enteral feeding (69). Interestingly, these findings are opposite to those found by authors who reviewed enteral and parenteral nutrition in patients with severe head injuries, who show that parenteral feedings were more favorable (70). Thus one must evaluate a patient carefully and make sure that there are no contraindications for a particular form of nutrition. A recent review of data published in 2001 and 2002 confirmed the benefits of preoperative administration of immunonutrition in surgical patients (71). Decreased infectious complications were observed in critically ill patients receiving immune-enhancing diets. However, postoperative

79

administration offered no advantages to surgical, critically injured, or critically ill patients in this data review.

Nutritional Supplements The number of nutritional supplements that have been identified in nutritional support has continued to increase. There are some agents that have been shown to have clinical utility and others that are still experimental. These agents include vitamins, prostaglandins, lipids, and amino acids. Vitamins that have been studied include A, D, E, and K. Vitamin A deficiency has been shown to have a markedly favorable influence on the survival of children who have measles and in patients with bacterial, protozoal, and viral infections. Vitamin A levels are markedly decreased in postoperative patients or in those who have suffered a major burn. In these groups of patients, vitamin A supplementation is crucial and can reverse the postinjury immunosuppression (72). Other fat-soluble vitamins such as D, E, and K are important in immune function. Vitamin E has a major influence on immune function and its deficiency results in a decrease in T-cell–mediated antibody response. Fatty acids also have an influence on immune function. Linoleic acid can prolong graft survival in mice, whereas a deficiency in the same fatty acid decreases allograft survival in the same model. These results indicate the importance of linoleic acid in immunomodulation (73). Diets high in soybean, corn, sunflower, and safflower oil suppress the response of splenocytes and T-cells to mitogens, in mice and guinea pigs. These same sources of fatty acids also result in decreased immune competence. Large amounts of prostaglandin E2 (PGE2) are produced by suppressor cells in chronic inflammatory conditions such as multiple sclerosis, rheumatoid arthritis, and infections (74). PGE2 is produced by monocytes and macrophages and can modulate the responses of immune cells. The importance of PGE2 has been studied in patients with chronic infections, who have abnormally high circulating levels of PGE2. Postoperative patients who experience a suppressed immune function have a marked increase in PGE2 synthesis (75). Tumor cells can also stimulate large amounts of PGE2 to be released by macrophages. These macrophages seem to produce PGE2 in an uncontrolled fashion and are not subject to the normal feedback mechanism. PGE2 can suppress NK cells, T-cell proliferation, and cytotoxic T-cells and cause an overall decrease in immune surveillance, and may be one mechanism by which tumor cells escape normal immune surveillance (76). Patients with Hodgkin’s disease produce four times the normal amount of PGE2. This suppresses the immune response by inhibiting the production of lymphokines necessary for lymphocyte function. Prostaglandin synthetase inhibitors have been shown in some models to improve immune function and inhibit tumor growth. An amino acid that has been shown to be of major importance in stress situations is arginine. L-Arginine is the substrate for the synthesis of nitric oxide as well as other biologically active molecules. It is now viewed as an essential amino acid for young mammals (including parentally fed human infants), and as a conditionally essential amino acid for adults under conditions such as trauma and burn injury (77). Arginine has also been shown to be of importance in wound healing (62). Through both nitric oxide– dependent and nitric oxide–independent effects, it has been shown to reverse endothelial dysfunction and improve many common cardiovascular disorders (78).

medwedi.ru

80

Part One: General Considerations

Finally, arginine has documented effects on immune functions. However, both animal and human studies have shown that enteral arginine supplementation as a single variable does not show clear immunologic benefit (79). Inconsistent results to date may be due to differences in the amount and timing of arginine administration, the animal species, and model. A recent study suggests that expression of the arginine-metabolizing enzyme arginase may be essential in regulating the cellular immune response and the inflammatory process during a critical illness (80). In human studies, oral arginine significantly increases peripheral blood lymphocyte blastogenesis in response to ConA and PHA. This change begins within three days of supplementation. Supplementation has also been studied in the clinical setting of patients receiving TPN with and without arginine. Those patients who received arginine showed an increased response of both PHA and ConA stimulation at days 3 and 7 after surgery, compared to those patients who did not receive arginine (81). The same author completed a study of HIV patients with a CD4/CD8 ratio of 0.8 or less (normal ¼ 2.0). These patients were supplemented with 20 g of arginine daily for at least two weeks. There were no changes in the CD4/CD8 ratio but there was a significant increase in the mitogenic responses to ConA and PHA in the patients tested. Arginine has also been used in postoperative surgical patients and has been shown to give an increased T-cell response to ConA and PHA as well as increased Th cell numbers. There was no change in other T-cell subsets (82). As a note of caution, Sucher et al. indicate that arginine in larger amounts may increase systemic inflammation and result in poorer clinical outcomes (83). Glutamine, a nonessential amino acid that has large body stores, is depleted following major insults such as infection and injury. Supplementation with additional glutamine in adult trauma patients resulted in a decrease in soluble tumor necrosis receptors and a lower incidence of sepsis and pneumonia (84). Similar improved outcomes were shown in severely burned patients (total body surface area greater than 25%). Intravenous glutamine was given to isonitrogenous controls or treatment patients. C-reactive protein levels and the incidence of gram-negative bacteremia were significantly decreased in treated patients. Nutritional parameters such as transferrin and prealbumin were improved compared to controls at 14 days. These studies suggest the benefits of glutamine, but the mechanisms and eventual place in surgical therapy remain to be defined (85). Cerra et al. reported the use of arginine, RNA precursor purines and pyrimidines, and n-3 polyunsaturated fatty acids, a major component of the cell membrane, in a group of intensive care unit (ICU) patients (86). These three agents in combination were associated with an improvement in the in vitro responses to ConA, PHA, and tetanus antigen. This study showed that nutritional supplementation must not only supply calories but must also supply elements that are essential to the improvement of immune parameters.

Trauma, Burns, and Surgery Trauma and Surgery The importance of immune changes during trauma, burns, or surgery is becoming better understood. Much of the data that have been discovered are now being used as a basis for intervention and treatment to prevent further morbidity after the traumatic event. These immune changes may occur secondary to blood transfusions, tissue injury, or the neuroendocrine changes that have occurred (Table 7).

Even in the individual who has undergone uncomplicated surgery there are postoperative changes in the immune system, which include a depression of both T- and B-lymphocytes. There is also a decrease in the response to a number of agents that cause a blastogenic response, including PPD, Staphylococcus aureus, and Escherichia coli, pokeweed mitogen, and phytohemagglutinin. Even with uncomplicated surgery there can be major depression in these blastogenic responses. The major change occurs on day 3 and normality is restored by day 9 (88). In patients who were judged to have moderate to severe injuries, creatine phosphokinase (CPK), cortisol, and white blood cell and T- and B-cell counts were performed. There were depressions in the total number of T- and B-lymphocytes as well as in the WBC by injury day 1, which returned to normal within approximately five days. During these changes in lymphocyte levels, the serum cortisol and CPK levels also increased markedly and returned to normal within five to seven days (89). The realization that major trauma caused a change in immune status provided impetus to examine other measures of immune reactivity. Keane et al. studied 31 injured patients and their lymphocyte responsiveness for up to 20 days after injury, comparing patients who became septic with those who did not. When compared to normals, the immune responses in trauma patients were depressed for over 20 days. In addition, the immune responses studied were significantly lower in the septic compared to the nonseptic patients. Afterinjury responses to streptokinase, streptodornase, mumps antigen, ConA, and PHA were all depressed and did not return to normal levels even after 20 days. In addition, the mixed lymphocyte culture was also abnormally depressed. Those patients were severely injured as indicated by the number of units of blood required and by the number of organ systems injured. Blood transfusions may also have contributed to the observed immune depression (90). Another study reviewed cellular immune depression after multiple trauma in patients who did not become septic during their hospital course. Significant suppression of lymphocyte responses to mitogens was noted, and there was a reversal of the Th–suppressor ratio (normal 2.0:1 vs. patients 0.96:1) suppressor cell functional activity was also detected early after trauma. This suppressor cell activity decreased, but persisted in three patients who developed sepsis (one of whom died). These data indicate that lymphocyte abnormalities exist after major trauma and some of these depressions can be associated with ultimate sepsis (91). This depression in cellular immunity is also reflected in antibody production in surgical patients. Nohr et al. have shown that abnormalities of both in vivo and in vitro antibody production are decreased in all surgical patients and antibody production is most depressed in those patients who have demonstrated reduced DTH responses (92). The studies outlined above have basically examined lymphocyte function. There are also abnormalities in the PMN in these seriously injured patients. Defects in the adherence and killing ability of PMNs have been reported along with migration abnormalities (93). These latter patients showed marked depression of both serum and cell-mediated migration that was proportional to the degree of trauma suffered. The macrophage is a pivotal cell in the immune response exerting both helper and suppressive effects, and may play a major role in the immunosuppressive effects of trauma. In one study, macrophage function was measured in a group of traumatized patients with a mean injury

81

Chapter 4: The Immune System and the Immunocompromised Patient

Table 7 Effect of Illness, Injury, or Treatment on Host Defense Mechanisms Condition Primary immunodeficiencies Secondary (acquired) immunodeficiencies Age Malnutrition Malignancy Burns Infection Trauma or surgery Anesthesia Blood transfusion Diabetes mellitus Renal failure Liver disease Splenectomy Radiation Protein-losing diseases Foreign bodies Drugs

Local immunity

T-cell function

B-cell function

Phagocytic function

Complement

#

#

#

#

#

NC NC NC # # # NC NC # NC NC NC # NC # NC

# # # # # # # # # # # NC ? # NC #

# " or # # # ? ? ? ? ? NC or # # # ? # NC " or #

NC # NC # # # # ? # # ? # ? NC NC #

NC # NC # ? ? ? ? ? ? ? ? ? ? ? ?

Abbreviations: NC, no change; ", increased; #, decreased; ?, unknown. Source: From Ref. 87.

severity score (ISS) of 38 (ISS of 25–40 gives approximately 50% mortality). The number of macrophages increased almost threefold from day 3 to 14 and the number of Th cells markedly decreased. During this same period, the level of PGE2 synthesis in vitro of isolated monocytes was also found to be highly elevated and, in fact, correlated with the level of injury reflected by the ISS. The level of IL-2 generated in an in vitro assay was also decreased, which would lead to decreased clonal expansion of T-cells (94). Changes in the surface expression of MHC antigens on monocytes and T-cells can be detected in postoperative patients. Because these molecules are critical for antigen presentation, their expression is central to the specific immune response that an individual can mount to a unique antigen. Wakefield et al. detected changes in MHC class II expression in a group of patients after surgery. HLA-DR expression on monocytes declined in all postoperative patients, with a more marked decline in those who developed sepsis. All postoperative patients had a marked increase in the number of T-cells that expressed HLA-DR, with a larger increase in those patients who did not develop sepsis (95). The exact mechanism of these changes is not known, but it appears that the patients who developed sepsis were unable to mount an appropriate immune response and had major defects in antigen presentation and T-cell activation. IFN-g production has been reported to be decreased after trauma, and it has been suggested that exogenous administration of IFN-g may be effective in reducing infection in trauma patients. This effect may be related to effects on HLA-DR expression (96). Polk et al. have tested the hypothesis that increased HLA class II expression may make a difference in the survival of patients after use of recombinant IFN-g. In a randomized, prospective trial, the authors were able to show that those trauma patients who received IFN-g for 10 days had an increased level of HLA-DR expression on their monocytes, compared to those patients who received placebo only. Although there was a trend for a decreased death rate among IFN-g–treated patients, the changes were not statistically significant. There were also fewer severe infections in the treatment group that required reoperation or computerized axial tomography (CAT) scan– guided drainage. The authors believed that a larger trial or a

longer treatment period would be useful to determine the utility of IFN-g in these patients (97). Other cytokines also appear to act in part by this mechanism; granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to increase the HLA-DR expression of monocytes and thus their antigen presenting capacity (98). It may be possible to predict the potential for infection in patients based on postoperative levels of HLA-DR expression on monocytes or T-cells. Peripheral blood monocytes have also been examined for the expression of CD4, CD14, and CD16. Kampalath et al. have shown a pattern in trauma patients, which is similar to that of cord blood from immunologically naive newborns. Thus monocytes may be central to both antigen presentation as well as to the clearance of bacteria in the trauma patients (99). IL-4 and IL-10, two cytokines associated with the Th2 lymphocyte subset, have also been implicated in the occurrence of sepsis after surgery. These cytokines are generally considered immunosuppressive. In a posthemorrhage mouse model, splenocytes and T-cells showed increased levels of IL-10 release compared to macrophages. PGE2 was shown to stimulate the release of IL-10, suggesting that IL-10 may be the ultimate effector of posttrauma PGE2 (100). Mack et al. have used a mouse model in which the animals received a femur fracture and hemorrhage to show that the cytokine pattern in splenocytes after injury was consistent with Th2. This pattern may explain some of the changes in the cellular immune response after injury (101). IL-4 activity has been studied in a group of trauma patients with an ISS > 25. Plasma IL-4 was found to be higher in those with greater severity of injury, lower patient age (age 30 years or younger), and hypotension, when admitted to the hospital. Those patients who had high levels of IL-4 on admission had a lower incidence of nosocomial infection compared to those patients with a lower IL-4 level. However, if the IL-4 increased during the ICU stay, the patients had a greater incidence of sepsis, pneumonia, or renal dysfunction even if they had shown low IL-4 levels on admission (102). IL-6 in septic patients who died was elevated compared to nonseptic patients. Those patients who had a poor cytokine response to a septic challenge had a poor clinical outcome (103).

medwedi.ru

82

Part One: General Considerations

In studying the interrelationship between Th1 and Th2 cells in trauma and burns, Goebel et al. studied the occurrence of IL-2 and IFN-g (Th1 cytokines) and IL-4 (Th2 cytokine). Following trauma (ISS > 25) in human subjects, the authors showed a markedly decreased level of IL-2 when compared to normal controls. However, the production of IL-4 was markedly increased. The same pattern was observed in a murine burn model. IL-12 was found to be significantly decreased in injured humans. In the concurrent murine model in the study, when IL-12 was given to the animals after cecal puncture and ligation, a significant decrease in death from sepsis resulted. This study suggests that there may be a shift away from Th1 cells toward Th2 cells, and this may result in an increased susceptibility to sepsis after trauma but replacement may improve survival (104). The cause of the shift from Th1 to Th2 cytokine pattern is still being investigated. The change may be due to increased levels of glucocorticoids and epinephrine, both of which inhibit Th1 but not Th2 cytokine production. The changes in cytokine levels in the traumatized and septic patient have yielded information that may be helpful in treating the patient. However, understanding of the recruitment of active cells to the site of injury has been shown to be an important aspect of medicine. Chemokines, a class of chemoattractant cytokines, are being studied in trauma, transplantation, atherosclerosis, and infectious disease. There are four main families of chemokines, represented as CC, CXC, C, and CX3C based on the cysteine motif at the amino terminal of the protein. These families are specific chemoattractants for different leukocyte subgroups. CC chemokines attract macrophages and lymphocytes, whereas CXC attract leukocytes. These proteins are major players in augmenting the ability of leukocytes to adhere to endothelial cells and then to move through the vessel wall into tissues. Chemokines have been identified in patients after trauma. Adams et al. found growth-related oncogenes (GRO)-alpha (a chemokine with a new designation CXCL1) in laparotomy pads of patients who had undergone a laparotomy and had damage control laparotomy performed (105). A subsequent study by the same authors showed the presence of IL-8, a proinflammatory chemokine, in the plasma of patients who had undergone exploration of the abdomen after damage-control laparotomy (106). Thus the homing of leukocyte subclasses is dependent on chemokines. Understanding of the role of these proteins in the surgical patient may allow manipulation to improve patient outcomes by increasing the number of cells at the damaged site.

Burns Those patients who have undergone a severe burn injury also have major changes in immune status. In addition to nonspecific loss of the skin barrier, they have other immune defects. The total number of lymphocytes is reduced, as in severe nonburn trauma, and there is a decrease in the number of Th cells as well as T suppressor cells. Lymphocytes from severely burned patients exhibit decreased expression of HLA-DR and IL-2 receptor, both markers of T-cell activation. Serum from burned mice has been shown to inhibit lymphocyte proliferation and surface antigen expression in vitro. This may be due to PGE2 effects. Patients who have experienced large burns exhibited a 5- to 10-fold increase in PGE2, which results in a concomitant suppression of the T-lymphocyte response. The lymphocyte response can be restored when PGE2 synthesis is blocked (107). Burn patients have a decreased level of IL-2, which may also contribute to the immunosuppression evident

in them. IL-2 plays a central role in immunoregulation— supporting lymphocyte proliferation, increasing Th cell proliferation, and causing CTL precursors to differentiate into cytotoxic T-cells (108). Surgery and other trauma can result in marked changes in the immune system. These changes are being studied and defined and various measures are being designed for intervention. It is hoped that these interventions will result in decreased morbidity and mortality.

Aging Surgery in the aged patient is fraught with many physiological concerns such as cardiac and pulmonary disease. The mortality rate increases with age after major surgery and after major trauma. In the aged patient, the natural barriers against infection are impaired. The skin becomes thinner and there is a loss of Langerhans cells. There is also a decrease in blood supply to the skin. There is loss of bacteriostatic effects of urine and decline of renal function leading to less acidification of the urine, and a propensity for urinary tract infection. The pulmonary tree is also compromised by decreased ventilation and decreased saliva. There are also immunological changes that occur with aging, which influence the susceptibility to infection in these patients. A study by Charpentier et al. found that there were no significant differences in T-cell function between young patients and those over 70 years of age, when T-cell levels, PHA stimulation, and allogeneic responses were compared. However, if low levels of mitogens were used, lower levels of stimulation were observed in the older patients (109). Age-related changes have also been detected in B-cell function. A Japanese group showed that there was a decrease in IgG antibody synthesis after administration of tetanus toxoid in aged patients (110). Most T- and B-cells decrease in numbers with age, however, the changes in NK cells are less straightforward. NK cells with high activity actually increase with age in humans, which is in contrast to NK cells with low activity, which may be a compensatory mechanism to cope with a decreased T-cell number (111). The activity of NK cells in different compartments of the body may provide insights into the reason for increased occurrence of neoplasms in elderly. NK cells isolated from murine spleen and lymph nodes exhibited markedly decreased NK activity. This is in contrast to those NK cells isolated from human peripheral blood cells that showed normal activity. Thus, in solid organs, cells that could prevent neoplasm may be lacking effective activity. Specific cytokines and lipid mediators are also decreased during aging. As mentioned above, there is an in vivo decrease of delayed hypersensitivity to common antigen skin tests. This decrease may also be due to decreased production of IL-2 by stimulated cells, and therefore a decrease in the number of Th cells and T suppressor cells. This decrease may be due to a decrease in the level of thymic hormones. During the aging process, there are markedly decreased levels of natural antibodies and a decrease in the primary immune response to an antigen. It has been postulated that the immunosuppression of old age is due to the development of a greater sensitivity to PGE2, which would cause increased activation of suppressor T-cells by PGE2. Newer evidence indicates an increase in IL-10 production, indicating a shift toward the anti-inflammatory Th2 cytokine response (112). These changes in delayed cellular immunity increase the susceptibility to all infectious agents. This can result in an increase in colonization and frank infection and increase the incidence of bacteremia, septicemia, and infections that

Chapter 4: The Immune System and the Immunocompromised Patient

are spread via the hematogenous route. Because of these changes, care must be taken to make certain the aged patient is as well physiologically as possible prior to elective surgery. Adequate nutrition is required. Underlying diseases must be controlled prior to any invasive procedures. Vaccinations also decrease morbidity and mortality in these patients.

Splenectomy and Blood Transfusion Splenectomy The incidence of overwhelming sepsis after splenectomy is increased compared to patients with an intact spleen. The important phagocytic and antibody production capabilities of the spleen are lost after splenectomy. The greatest risk for sepsis is from encapsulated organisms and appears to be the greatest within the early postsplenectomy period, however, this risk remains lifelong. In a study in adult patients who had either underlying malignancy or trauma as the reason for splenectomy, lethal sepsis occurred in 2.7% of adult patients approximately two years after splenectomy (113). The highest risk was in those patients who had an underlying malignancy. In this study, the most common organism involved was Streptococcus pneumoniae. Splenectomy is known to be associated with gram-negative rods, Neisseria menigitidis, E. coli, and H. influenza. Less common problems include babesiosis, histoplasmosis, and malaria. Splenectomy decreases a major protective mechanism in the body. Splenectomy in animals has been shown to decrease the removal of bacteria from the bloodstream. The liver can remove organisms that are well opsonized, but the spleen can remove those organisms that are not well opsonized. The spleen is a major site of antigen presentation to B-cells; splenic removal of an organism not only removes the organism but also promotes an antibody response in which the spleen plays a pivotal role. The spleen is the first site in which antibody to an organism is detected after exposure to the offending agent. Consistent with this observation, splenectomy also causes IgM antibody levels to decrease. Strategies for prophylaxis include prophylactic antibiotics or starting prescribed antibiotics at the first sign of infection. Pneumococcal vaccine is ideally given to patients after splenectomy. Those patients who have had splenectomy for malignancy show a poor antibody response to the vaccine. Those who have received it for trauma apparently have a better response, but this is less than in normal controls in terms of absolute titer, relative rise, and rate of rise. Those patients who receive meningococcal and H. influenza vaccine show similar titers to those obtained with pneumococcal vaccine. Clearly patients must be educated about the risks, have a supply of antibiotics, and be given the vaccines. Some physicians recommend repeating pneumococcal vaccination at 5- to 10-year intervals or in the face of a falling titer.

Hemorrhage and Blood Transfusion Hemorrhage itself can have an effect on the immune response. Experimentally, there are many changes that are documented in animal models. In a rat model, there is a marked decline in the mitogen-induced response of lymphocytes and a decrease in the production of IL-2. However, this response did return to normal within 48 hours after hemorrhage without resuscitation (114). The serum from these animals will also depress the mitogen response of lymphocytes from normal animals. The above results were confirmed using a mouse model. In addition, although there was no change in the

83

relative numbers of T- and B-cells, there was still the depression of splenocyte mitogenic responses. An additional murine study added resuscitation after the hemorrhage and showed the same impairment in mitogen responses, which were evident up to day 10 when they returned to normal. The production of IL-2 was also depressed during this time course (115). Additional studies confirmed the finding that murine splenocyte IL-2 levels were depressed after hemorrhage, but also showed that IL-3, IL-6, and IFN-g were also depressed. The depression of IFN-g might result in the marked decline of macrophage function, depression of NK cell function, and decreased activation of cytotoxic T-cells. The lack of IL-6 production may result in the depressed humoral function because this cytokine is heavily involved in B-cell activation (116). Humoral immunity can also be shown to be depressed after hemorrhage in a murine model. The cause of nonspecific immune dysfunction after hemorrhage is unknown. There is data to indicate that this depression may be due to macrophage dysfunction. The macrophage is also key to antigen presentation in a shock state. In a murine model, Stephan et al. demonstrated that antigen presentation was markedly depressed after hemorrhage and resuscitation one hour later (117). The length of this depression is at least 120 hours, with an onset of as early as 15 minutes with a blood pressure of 35 mmHg. Thus this change in antigen presentation in a murine model can be early and prolonged even in the face of adequate resuscitation. Additional studies using Kupffer cells have shown similar findings. The cause of the changes in immune function after hemorrhage is yet to be clearly elucidated. The agent that is most widely implicated is endotoxin, believed to come from the gastrointestinal tract. The poor O2 and nutrient delivery during severe hemorrhage may also cause immune suppression. Hemorrhage is also a major stimulator of catecholamine release. Epinephrine has been shown in humans to result in altered mitogen-induced proliferation of lymphocytes and changes in the ratios of different subsets of lymphocytes. Catecholamines can also suppress phagocyte function and B-cell function. These changes may be addressed by various specific pharmacologic interventions. Hemorrhage plus injury has an additive detrimental effect on immune function. Wichmann et al. have shown in a murine model that hemorrhage caused a depression in splenic and macrophage function; however, the addition of a femur fracture caused an even deeper depression in these parameters (118). Thus trauma patients may be experiencing an immune depression secondary to the blood loss and shock as well as the injury. Blood transfusions are given with little thought to the potential immunological consequences. Blood transfusions are believed to have some deleterious effects on the immune system in those patients who have cancer. These changes have been studied in a number of types of cancers. In those patients with colorectal cancer, cancer recurrence was increased in patients who received blood. The results of this retrospective study took into account the complexity of the surgery. Foster et al. confirmed these findings showing that those patients who did not receive any blood during their hospitalization did significantly better than those who received blood transfusions (119). In evaluating those patients who underwent surgery for lung cancer, similar findings have been discovered. Hyman et al. reported that a group of patients who underwent resection for non–small cell carcinoma of the lung and

medwedi.ru

84

Part One: General Considerations

were transfused showed a significantly worse five-year survival rate than those patients who had not been transfused (120). The same sort of association between blood transfusion and long-term survival has been identified in patients suffering from soft tissue sarcomas. Those patients who received blood transfusions had a 20% decrease in five-year survival. The three major cancer groups examined above are in contrast to breast cancer, renal cell carcinoma, and head and neck cancers. Breast cancer patients who had invasive breast cancer and had either a complete or partial mastectomy showed no effect of blood transfusion on long-term survival (121). Likewise, no effects of blood transfusion can be found in those patients with renal cell carcinoma and those with head and neck cancer in long-term survival. It is unclear why transfusion effects in cancer patients appear to be tissue specific. This immunosuppressive effect is clearly seen in those patients who have received a renal transplant. Early in the history of transplantation, blood transfusions to the recipient were largely avoided; however, in 1973, Opelz et al. reported a beneficial effect of transfusions on graft survival. The major reason for this effect was believed to be the immunosuppressive action of blood (122). This finding could not be replicated in those patients who received frozen packed red cells. Fischer et al. showed that transfusion with one to three units of blood caused suppression of cellular immunity, defined by a mixed lymphocyte response. When he compared the effects to autologous units, there was no depression in cellular immunity (123). Matsumoto et al. studied MLR in patients who had undergone donor-specific transfusions while being readied for transplant. He found both suppressor cells and antibodies, which he thought were anti-idiotypic antibodies. This latter finding was confirmed by Singal who showed that sera from transfused patients resulted in depression of MLR, while sera from nontransfused patients did not give the same depression (124,125). Animal studies suggested that prostaglandin E may be a mediator of these changes. There is no doubt that blood transfusion has a major influence on the immune system. Some of these immunosuppressive effects maybe desirable, as in the case of a transplant in which transfusion improves graft survival. Transfusion effects are also undesirable in the case of patients with certain types of cancer. The use of transfusions is always worth careful evaluation for the individual patient.

Renal Failure Infections are common in patients with renal failure and are a major cause of death in patients with end-stage renal disease. One would expect major changes in the immune system of these patients and, in fact, they show defects in specific as well as nonspecific immunity. Abnormal cellular immunity has been confirmed clinically in various ways. These patients also have a markedly decreased response to cutaneous injection of various antigens (126). Hepatitis B vaccination in chronic renal failure patients on dialysis resulted in a very low rate of seroconversion after vaccination compared to the general population (127). This was in the face of the normal levels of Ig in the dialysis patients. Lymphocyte counts have also been shown to be decreased in these patients; however, the CD4/CD8 ratios are reported to be normal (128). In vitro studies have shown that uremic patients have impaired responses to mitogens and allogeneic lymphocytes. Because these findings are marked in the presence

of uremic serum, there may be a soluble factor that causes this depression (129). Because these changes were seen in patients who are being dialyzed, the substance is not dialyzable. There were indications that the TCR/CD3 antigen complex in the uremic patient may be downregulated. This finding may be due to a combination of uremia, hyperparathyroidism, and dialysis itself (130). Other cells that are affected in uremia are B-cells and NK cells. Uremic patients show normal to supranormal levels of IgG and IgM, although the actual mechanism for this finding is not well delineated. There is recent evidence that monocytes may be defective in uremic patients (131). This defect also influences how the monocytes present antigens. Thus, the defects that are seen may be a combination of both T-cell and APC deficiencies. The disturbances outlined above undoubtedly have an influence on the decreased ability of these patients to handle both bacterial and viral infectious challenges. Vigilance for infection is necessary in these patients. This concern is heightened for the large number of dialysis patients who are diabetic. Patients who are diabetic and on dialysis appear to be at an especially high risk of developing infections.

Diabetes Mellitus Most of the deaths in these patients can be attributed to cardiovascular disease; however, infection is a major cause of morbidity in these patients. Early studies indicated that diabetics had a greater number of infections than did control subjects. For example, one early study reported a 2.4% incidence of limb infection in diabetic patients compared to 0.5% in nondiabetic subjects (132). In addition, those patients with diabetes for longer than 20 years were found to have a prevalence of bacteriuria (19% compared to controls with a prevalence of 8%) (133). Most clinicians agree that diabetics will have more severe infections and a more protracted clinical course than nondiabetics. The World Health Organization classifies diabetes as a secondary immunodeficiency disease. The ability of patients to fight infection is altered in diabetics. PMN granulocytes have several functional abnormalities, with decreased migration characteristics, especially in those patients with poorly controlled serum glucose levels (134). Phagocytosis is defective in diabetics, especially when the glucose level is elevated (135). However, following normalization of glucose levels, these abnormalities disappear. Lymphocyte subsets can be altered in diabetics. A study of type 1 diabetics reported a decrease in circulating CD4 cells, which results in a decrease of the CD4/CD8 ratio (136). This change may be due to decreased levels of insulin or decreased insulin activity. As was found with neutrophil function, normalization of insulin levels results in normal lymphocyte transformation upon stimulation, as well as normalization of lymphocyte levels (137). However, the report that approximately 50% of the diabetic patients who received hepatitis B vaccine responded poorly indicates that there may be additional immunosuppressive factors operative in these patients. Patients who have a well-controlled glucose level do not have a higher susceptibility to Staphyloccus infections. However, in older patients, the risk of bacteremia is higher. Specific infections can be more fatal in diabetics compared to normal patients, and those patients who are diabetic and develop bacteremia have a higher mortality rate than those without diabetes (138). Candida infections are more prevalent

Chapter 4: The Immune System and the Immunocompromised Patient

in diabetics compared to the normal population and are particularly more common in those patients whose glucose levels are poorly controlled. However, this was not the case with other fungal infections. The treatment of fungal and bacterial infections requires the initiation of good glucose control and appropriate antibiotic or antifungal therapy. Major factors that lead to increased infections in diabetics in addition to poor glucose control include underlying vascular disease and nerve damage. Poor blood supply results in inadequate oxygenation, which leads to anaerobic infection and also limits host-defense mechanisms. If a patient has a peripheral neuropathy, the result can be an ulcer, which can become secondarily infected. The key to prevention of infection in the diabetic includes control of hyperglycemia; if one reduces the glucose to normal levels the incidence of infections decreases. Complications that lead to increased levels of insulin must be avoided. One must also aggressively look for infection and treat those conditions that can result in the infection becoming widespread or locally uncontrollable.

Prevention and Therapy Clinical Guidelines Prevention of infection in the immunocompromised patient calls for an awareness of the possible infections these patients can develop and an approach to deal with the problem. One must also be aware that patients with certain immune defects can develop cancer. When these patients are examined, one must check for the presence of palpable lymph nodes and also carefully examine the skin to look for suspicious lesions. The risk of infection in these patients is dependent on both the immunosuppressive status of the patient and environmental factors. The amount of immunosuppression is dependent on the level of nutrition, the state of the various portions of the immune system, defects in the skin or mucus membranes, and any invasive lines or procedures that have been undertaken. The importance of environmental factors is illustrated by the realization that even a normal healthy individual can be infected if in contact with a large enough inoculum of an infectious agent. Thus a patient who is immunosuppressed can become infected on exposure to a proportionately smaller number of infectious agents, depending upon his overall immune status. In caring for these patients, one must apply the principles outlined in Table 8. Hand washing is particularly critical in these patients to prevent patient-to-patient transmission of infection. Deep lines such as subclavian and internal jugular lines, and Swan–Ganz catheters must be watched particularly carefully. In immunosuppressed patients, there will be no evidence of infection, and therefore changing the lines or making sure they are absolutely necessary is imperative. Nutritional support will bolster the immune system and prevent a catabolic state in the immunocompromised patient. One must also be certain that the integument is intact and that the skin does not become a site for entrance of bacteria. The Guidelines for Prevention of Surgical Site Infection from the Centers for Disease Control should be rigorously followed in this group of patients. Immunocompromised patients can develop infections in a number of places. These infections can include skin, respiratory, gastrointestinal or central nervous systems. Suspicious skin lesions should be biopsied, aspirated, or cultured. The neutropenic patient who develops a fever requires careful evaluation. Approximately 40% of patients who are

85

neutropenic and develop a fever will have a documented infection (140). Only 20% of fevers in these patients are due to the underlying disease or to other noninfectious causes. The remaining 40% are due to possible but nonproven infections. The classical signs of infection in these patients frequently are missing. They will not exhibit fluctuance, calor, rubor, or lymphadenopathy as commonly as patients with a normal neutrophil count do. The physical examination should focus on skin, mucosa, and perianal areas. The therapy early on should include broad-spectrum antibiotics after adequate cultures have been obtained. The optimal drug choice is still debated. Antibiotics are useful in these patients but other methods of stimulating the immune response are being sought.

Biologic Response Modifiers Biologic response modifiers (BRM) are being explored in hopes of increasing the activity of specific groups of cells in the body. Commonly used biological response modifiers include cytokines, colony-stimulating factors, IFNs, and TNFs, but can include microorganisms, polysaccharides, polypeptides, thymic factors, synthetic compounds, polyribonucleotides, and vaccines. Most were named based upon a primary property, but these agents have a large amount of overlap in their individual effects and have many diverse effects. IL-1 is a product of monocytes and has a myriad of effects. These include activation of T, B, and NK cells and activation of vascular endothelium, fibroblast proliferation, and activity against human tumors. It has also been shown to prevent infection and protect against IL-2 toxicity. It has been shown to protect against bacterial infections in mice (141). IL-1 has also been used in patients with cancers and has been shown to increase the white blood cell count, increase the cellularity in bone marrow, and give rise to major hypotension after use (142). IL-2 is produced primarily by Th1 cells. Treatment of NK cells with IL-2 results in their differentiation into lymphokineactivated killer cells, which appear to home to the site of viral infection. Because of these promising results it was the first BRM used in clinical trials. The cytokine has been shown to be effective in a number of animal models, yet its use in clinical trials has been disappointing. Surprisingly, when used in AIDS patients, it was shown to decrease some immune functions such as that of NK cells. Because of its general effectiveness in increasing the activity of NK cells, it is still used in cancer patients. The precise dose and combination of additional chemotherapeutic agents are being evaluated in metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma. It is used at the maximal tolerated dose with the major side effects being cardiovascular. Colony-stimulating factors are commonly used in cancer chemotherapy. The major interest in these agents is because they can reverse the severe neutropenia after chemotherapy, which can lead to severe bacterial infections. Granulocyte colony-stimulating factor (G-CSF) is produced by a number of cells in the body including endothelial cells, fibroblasts, and macrophages. The agent has been used in cancer chemotherapy to prevent the periods of severe neutropenia and the use of broad-spectrum antibiotics (143). G-CSF has minimal toxicities, which include mild bone pain and cellulitis at the injection site. G-CSF is not useful in patients who have an established infection, but is only useful in preventing the neutropenia associated with cancer chemotherapy (144).

medwedi.ru

86

Part One: General Considerations

Table 8 Principles of Infection Prevention in the Compromised Host Reduce acquisition of ambient organisms from hospital environment Avoid hospitalization Segregate patients with potentially communicable diseases Avoid overcrowding in wards and ICU Enforce strict hygiene, particularly hand washing, among physicians, nurses, and aides Avoid invasive procedures whenever possible Employ indwelling intravenous and urinary catheters only if absolutely necessary Change scalp vein needles, tubing, and intravenous bottles daily Use respiratory assistance devices, particularly those requiring intubation, with great care and with close monitoring to ensure that they are adequately decontaminated Reduce number of colonizing organisms Remove or reduce sites of prior infection Consider the use of isoniazid prophylaxis in patients with histories, positive skin tests, or chest X-ray findings of old tuberculosis Closely monitor serologic tests and clinical course in patients with evidence of old coccidioidomycosis or histoplasmosis who have now become immunosuppressed Bolster host defense mechanisms Successfully treat the underlying disease Prescribe adequate nutrition and exercise Improve respiratory toilet Control diabetes mellitus, congestive heart failure, or respiratory insufficiency Reduce local obstruction caused by tumor Protect the integrity of oral and anorectal mucosae When appropriate, prescribe immunotherapy with vaccines and/or immunoglobulin preparation Abbreviation: ICU, intensive care unit. Source: From Ref. 139.

GM-CSF factor has an effect on both stem cells and megakaryocytes and stimulates the production and antibacterial function of neutrophils and monocytes. Like G-CSF, it is produced by endothelial cells, fibroblasts, and T-lymphocytes. GM-CSF has been used in patients with aplastic anemia and those who have undergone bone marrow transplantation. It has also found clinical applications in patients with acute and chronic leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, treatment-related cytopenias from chemotherapy in solid tumors (145,146), and AIDSrelated neutropenia (147). The functional capabilities of the induced cells are normal. The therapy results in increased numbers of leukocytes in peripheral blood. The toxicity is mild when used in small doses; however, there is marked toxicity in large doses, including fever, capillary leak syndrome, and pericarditis. Data from animal experiments and ex vivo human experiments suggested that administration of GM-CSF might provide clinical benefit in the treatment or prevention of neonatal infections. Although a significant number of clinical studies have administered GM-CSF to neonates, there is insufficient evidence of clear efficacy or benefit to support their routine use. Several recent clinical reviews agree that further adequately powered, randomized, placebo-controlled clinical trials of this promising immunotherapy are warranted (148). The IFNs were among the first BRM discovered to have clinical application. IFN-a has shown clinical use in hairy cell leukemia, condyloma acuminatum, AIDSassociated Kaposi’s sarcoma, melanoma, lymphoma, and chronic myelogenous leukemia (149–151). The side effects are primarily a flu-like syndrome including, fever, headache, nausea, vomiting, anorexia, and occasionally impaired cognitive function. In most patients, these symptoms abate and therapy is not limited. IFN-g is important in macrophage activation and in B- and T-cell responses (152,153). IFN-a has been used to treat hepatitis B. It has been shown to give a serocoversion rate of approximately 25% to 40%

(154). Hepatitis C has been especially prominent in the dialysis population and is associated with a chronic carrier state. Treatment with IFN-a for approximately six months has been shown to give a response rate of approximately 50%, but about half of those who respond will relapse (155). The response rate has been shown to increase with the addition of ribavirin to the IFN-a. The last group of BRM to be discussed is TNFs. This group of agents was discovered when it was shown that certain bacterial products could reduce the size of tumors (156). TNF-a is released by macrophages. It has many biological effects including: proliferation of T-cells and NK cells; adherence of neutrophils to endothelium; increased cytolytic activity of T- and NK cells; and stimulation of other BRM such as IL-1 and IL-6. It has been proved useful in hairy cell leukemia and in patients with Kaposi’s sarcoma (149,157). During clinical use the side effects of TNF-a are quite mild, including fever, headache, nausea, and vomiting. TNF-b carries some similarity to TNF-a and is produced by T-, B-, and NK-cells. It mediates the biological response to microbial infections. The agent has been used in an attempt to improve outcomes in infection in an animal model (158). Antibodies to TNF have been used in septic patients, however, there was no survival benefit noted in this group of patients (159). The use of these agents in the treatment of human disease is still being explored. The importance of BRM is now being realized, as is the complexity of their interactions. Much additional work will need to be completed before their potential for therapy can be realized.

SUMMARY The causes of immunosuppression in surgical patients have been outlined. These include malnutrition, trauma, blood transfusions, sepsis, diabetes mellitus, and cancer. Each of these causes can be evaluated and the individual problem

Chapter 4: The Immune System and the Immunocompromised Patient

corrected if possible. The individual patient with severe neutropenia must be evaluated very carefully and steps taken to prevent infection. The place of BRMs has been defined in neutropenia in certain disease states but additional uses still are to be defined.

ACKNOWLEDGMENTS The authors wish to thank Mrs. Valerie Brookins and Mr. Dorian Araneda for their assistance in the preparation of Figures and Tables.

REFERENCES 1. Paul WE, ed. Fundamental immunology. 5th ed. Philadelphia: Lippincott, Williams & Wilkins, 2003:1701. 2. Rich RR, Fleisher TA, Shearer WT, Kotzin BL, Schroeder Jr HW, eds. Clinical Immunology. 2nd ed. London: Mosby, 2001:664. 3. Janeway CA Jr, Travers P, Walport M, Capra JD. Immunobiology: The Immune System in Health and Disease. 4th ed. Garland, London: Current Biology, 1999:635. 4. Abbas AK, Lichtman AH, Pober JS. Cellular and Molecular Immunology. 4th ed. Philadelphia: Saunders, 2000. 5. Kuby J, ed. Immunology. 4th ed. New York: W.H. Freeman, 2000. 6. Zola H, Swart B, Boumsell L, Mason Dy. Human leucocyte differentiation antigen nomenclature: update on CD nomenclature. J Immunol Meth 2003; 275:1–8. 7. Matsuuchi L, Gold MR. New views of BCR structure and organization. Curr Opin Immunol 2001; 13:270–277. 8. Jung D, Alt FW. Unraveling V(D)J recombination: insights into gene regulation. Cell 2004; 116:299–311. 9. Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T-cells. Ann Rev Immunol 2003; 21:139–176. 10. Pitcher LA, van Oers NSC. T-cell receptor signal transmission: who gives an ITAM? Trends Immunol 2003; 24:554–560. 11. Pearce EL, Mullen AC, Martins GA, et al. Control of effector CD8þ T-cell function by transcription factor Eomesordemin. Science 2003; 302:1041–1043. 12. Sakaguchi S. Regulatory T-cells: key controllers of immunologic self-tolerance. Cell 2000; 101:455–458. 13. Shevach EM. CD4þCD25þ suppressor T-cells: more questions than answers. Nat Rev Immunol 2002; 2:389–400. 14. Chen WJ, Jin W, Hardegen N, et al. Conversion of peripheral CD4þCD25– na€ve T-cells to CD4þCD25þ regulatory T-cells by TGF-b induction of transcription factor Foxp3. J Exp Med 2003; 198:1875–1886. 15. Trapani JA, Smyth JA. Functional significance of the perforin/ granzyme cell death pathway. Nat Rev Immunol 2002; 2: 735–747. 16. Russell JH, Ley TL. Lymphocyte-mediated cytotoxicity. Ann Rev Immunol 2002; 20:323–370. 17. Parham P. Immunogenetics of killer-cell immunoglobulin-like receptors. Tissue Antigens 2003; 62:194–200. 18. van Rooijen N, Wijburg OL, van den Dobbelsteen GP, Sanders A. Macrophages in host defense mechanisms. Curr Top Microbiol Immunol 1996; 210:159–165. 19. Lotz MT, Thompson AW, eds. Dendritic Cells: Biology and Clinical Applications. London: Academic Press, 2001. 20. Liu Y-J. Uncover the mystery of plasmacytoid dendritic cell precursors or type 1 interferon producing cells by serendipity. Hum Immunol 2002; 63:1067–1071. 21. Blom B, Ligthart SJWC, Schotte R, Spits H. Developmental origin of pre-DC2. Hum Immunol 2002; 63:1072–1080. 22. Burg ND, Pillinger MH. The neutrophil: function and regulation in innate and humoral immunity. Clin Immunol 2001; 99:7–17. 23. Robinson DS, Kay AB, Wardlaw AJ. Eosinophils. Clin Allergy Immunol 2002; 16:43–75.

87

24. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med 2000; 343(5):338–344. 25. Sabroe, I, Read RC, Whyte MKB, Dockrell DH, Vogel SN, Dower SK. Toll-like receptors in health and disease: complex questions remain. J Immunol 2003; 171:1630–1635. 26. Porcelli SA. The CD1 family: a third lineage of antigen presenting molecules. Adv Immunol 1995; 59:1–98. 27. Skold M, Behar SM. Role of CD1d-restricted NKT-cells in microbial immunity. Infect Immun 2003; 71:5447–5455. 28. van Kooten CS, Banchereau J. CD40–CD40 ligand. J Leukocyte Biol 2000; 67:2017. 29. Rudd CE, Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signaling. Nat Rev Immunol 2003; 3: 544–556. 30. Mond JJ, Lees A, Snapper CM. T cell-independent antigens type 2. Ann Rev Immunol 1995; 13:655–692. 31. Walport MJ. Complement. N Engl J Med 2001; 344(14): 1058–1066. 32. Walport MJ. Complement. N Engl J Med 2001; 344(15): 1140–1144. 33. Raeburn CD, Sheppard F, Barsness KA, Arya J, Harken AH. Cytokines for surgeons. Am J Surg 2002; 183(3):268–273. 34. Schrader JW. Interleukin is as interleukin does. J Immunol Meth 2003; 276:1–3. 35. Thompson AW, Lotze MT, ed. The Cytokine Handbook. 4th ed. San Diego, CA: Academic Press Inc., 2003:1800. 36. Oppenheim JJ, Feldmann M, eds. Cytokine Reference. San Diego: Academic Press, 2001. 37. CDC. Morbidity and Mortality Weekly Report. Applying public health strategies to primary immunodeficiency diseases; a potential approach to genetic disorders. MMWR Recomm Rep. 16:53(RR-1):38. Available at http://www.cdc.gov/ mmwr/preview/mmwrhtml/rr5301a1.html. 38. Illoh OC. Current applications of flow cytometry in the diagnosis of primary immunodeficiency diseases. Arch Pathol Lab Med 2004; 128:23. 39. Westermann J, Pabst R. Distribution of lymphocyte subsets and natural killer cells in the human body. Clin Invest 1992; 70:539–544. 40. Westermann J, Engelhardt B, Hoffmann JC. Migration of T-cells in vivo: molecular mechanisms and clinical implications. Ann Intern Med 2001; 135:279–295. 41. Ahmed AE, Peter JB. Clinical utility of complement assessment. Clin Diag Lab Immunol 1995; 2:509–517. 42. Patarca R, Sandler D, Walling J, Lunn BC, Fletcher MA. Assessment of immune mediator expression levels in biological fluids and cells: a critical appraisal. Crit Rev Oncog 1995; 6:117–149. 43. Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen D. Cytokine cascade in sepsis. Scand J Infect Dis 2003; 35(9): 535–544. 44. Remick DG. Cytokine therapeutics for the treatment of sepsis: why has nothing worked? Curr Pharm Des 2003; 9(1):75–82. 45. Heaney ML, Golde DW. Soluble cytokine receptors. Blood 1996; 87:847–857. 46. Fernandez-Botran R, Crespo FA, Sun X. Soluble cytokine receptors in biological therapy. Expert Opin Biol Ther 2002; 2(6):585–605. 47. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003; 361:1168–1173. 48. Fasth A. Primary immunodeficiency disorders in Sweden: cases among children 1974–1979. J Clin Immunol 1982; 2:86–92. 49. Bonilla FA, Geha RS. Primary immunodeficiency diseases. J Allergy Clin Immunol 2003; 111:S571–S581. 50. Kersey JH, Filipovich AH, Spector BD, Frizzera, G. Lymphoma after thymus transplantation [Letter to the editor]. N Engl J Med 1980; 302:301. 51. Den Gartog G, Van Der Meer JWM, Jansen J, Van Furth R, Lamers CBHW. Decreased gastrin secretion in patients with late onset hypogammaglobulinemia. N Engl J Med 1988; 318:1563–156.

medwedi.ru

88

Part One: General Considerations

52. Perry GS III, Spector BD, Schuman LM, et al. The WiskottAldrich syndrome in the United States and Canada (1892– 1979). J Pediatr 1980; 97:72–78. 53. Hoover R, Fraumeni JF Jr. Risk of cancer in renal transplant recipients. Lancet 1973; 3:55–57. 54. Brumbaugh J, Baldwin JC, Stinson EB. Quantitative analysis of immunosuppression in cyclosporin-treated heart transplant patients with lymphoma. J Heart Transplant 1985; 4:307–311. 55. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2003; 4:222–230. 56. Penn I. The changing patterns of posttransplant malignancies. Transplant Proc 1993; 23:1101–1103. 57. Penn I. Why do immunosuppressed patients develop cancer? Crti Rev Oncognesis 1989; 1:27–52. 58. Adami J, Gabel H, Lindelof B, et al. Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer 2003; 89:1221–1227. 59. Nalasnik MA, Makowka L, Starzl TE. The diagnosis and treatment of post-transplant lymphoproliferative disorders. Curr Probl Surg 1988; 25:371–472. 60. Penn I. Depressed immunity and the development of cancer. Cancer Detect Prevent 1994; 18:241–252. 61. Filipovich AH, Zerbe D, Spector BD, Kersey JH. Lymphomas in persons with naturally occurring immunodeficiency disorders. In: McGrath IT, O’Conor GR, Ramot B, eds. Pathogenesis of Leukemias and Lymphomas: Environmental Influences. New York: Raven Press, 1984:225–234. 62. Williams JZ, Barbul A. Nutrition and wound healing. Surg Clin North Am 2003; 83:571–596. 63. Gershwin ME, Beach RS, Hurley LS. Nutrition and Immunity. New York: Academic Press, 1985. 64. Nohr CW, Tchervenkov JI, Meakins JL, Christou NV. Malnutrition and humoral immunity: short-term acute nutritional deprivation. Surgery 1985; 98:769–776. 65. West KP Jr, Howard GR, Sommer A. Vitamin A and infection: public health implications. Annu Rev Nutr 1989; 9:63–86. 66. Keusch GT, Torun B, Johnston RB Jr, Urrutia JJ. Impairment of hemolytic complement activation by both classical and alternative pathways in serum from patients with kwashiorkor. J Pediat 1984; 105:434–436. 67. Keusch GT. Nutrition and infection. Curr Clin Top Infect Dis 1984; 5:106–123. 68. Moore FA, Moore EE, Jones TN, McCroskey BL, Peterson VM. TEN vs TPN following major abdominal trauma: reduced septic morbidity. J Trauma 1989; 29:916–923. 69. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding: effects on septic morbidity following blunt and penetrating abdominal trauma. Ann Surg 1992; 215: 503–513. 70. Rapp RP, Young B, Twyman D, et al. The favorable effect of early parenteral feeding on survival in head-injured patients. J Neurosurg 1983; 58:906–912. 71. Sacks GS, Genton L, Kudsk KA. Controversy of immunonutrition for surgical critical-illness patients. Curr Opin Crit Care 2003; 9:300–305. 72. Cohen BE, Gill G, Cullen PR, Morris PJ. Reversal of postoperative immunosuppression in man by vitamin A. Surg Gynecol Obstet 1979; 149:658–662. 73. Mead CJ, Mertin J. Fatty acid and immunity. Adv Lipid Res 1988; 16:127–165. 74. Lands WEM. Essential fatty acids revisited. Nutr Rev 1986; 44:189–195. 75. Goodwin JS. Prostaglandins and Immunity. Boston, MA: Martinus Nijhoff Publishing, 1985. 76. Seifter E, Rettura G, Barbul A, Levenson SM. Arginine: an essential amino acid for injured rats. Surgery 1978; 84:224–230. 77. Flynn NE, Meininger CJ, Haynes TE, Wu G. The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother 2002; 56:42738. 78. Wu G, Meninger CJ. Arginine nutrition and cardiovascular function. J Nutr 2000; 130:2626–2629.

79. Nieves C Jr, Langkamp-Henken B. Arginine and immunity: a unique perspective. Biomed Pharmacother 2002; 56:471–482. 80. Bansal V, Ochoa JB. Arginine availability, arginase, and the immune response. Curr Opin Clin Nutr Metab Care 2003; 6: 223–228. 81. Barbul A. Arginine and immune function. Nutrition 1990; 6: 53–62. 82. Daly JM, Reynolds H, Sigal RK, Shou J, Liberman MD. Effect of dietary protein and amino acids on immune function. Crit Care Med 1990; 18:S86–S93. 83. Sucher U, Heland DK, Peter K. Immune-modulatory actions of arginine in the critically ill. Br J Nut 2002; 87(suppl 1): S121–S132. 84. Houdijk APT, Rijnsburger ER, Jansen J, et al. Randomized trial of glutamine-enriched nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998; 352:772–776. 85. Wischmeyer PE, Lynch J, Liedel J. Glutamine administration reduces Gram negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med 2001; 29:2075–2080. 86. Cerra FB, Lehman S, Konstantinides N, Konstantinides F, Shronts EP, Holman R. Effect of enteral nutrient on in vitro tests of immune function in ICU patients: a preliminary report. Nutrition 1990; 6:84–98. 87. Nohr C. Host defenses. In: Meakins JL, ed. Surgical Infections: Diagnosis and Treatment. New York: Scientific American, 1994:25. 88. Kehlet H, Thomsen M, Kjer M, Platz P. Postoperative depression of lymphocyte transformation response to microbial antigens. Br J Surg 1977; 64:890–893. 89. Bauer AR, McNeil C, Trentelman E, Swift SA, Mason JD. The depression of T lymphocytes after trauma. Am J Surg 1978; 136:674–680. 90. Keane RM, Birmingham W, Shatney CM, Wichurch RA, Munster AM. Prediction of sepsis in the multitraumatic patient by assays of lymphocyte responsiveness. SG&O 1983; 156: 163–167. 91. O’Mahony JB, Palder SB, Wood JJ, et al. Depression of cellular immunity after multiple trauma in the absence of sepsis. J Trauma 1984; 24:869–875. 92. Nohr CW, Christou NV, Rode H, Gordon J, Meakins JL. In vivo and in vitro humoral immunity in surgical patients. Ann Surg 1984; 200:373–380. 93. Maderazo EG, Albano SD, Woronick CL, Drezner AD, Quercia R. Polymorphonuclear leukocyte migration abnormalities and their significance in seriously traumatized patients. Ann Surg 1983; 198:736–742. 94. Faist E, Mewes A, Strasser T, et al. Alteration of monocyte function following major injury. Arch Surg 1988; 123: 287–292. 95. Wakefield CH, Carey PD, Foulds S, Monson JRT, Guillou PF. Changes in major histocompatibility complex class II expression in monocytes and T-cells of patients developing infection after surgery. Br J Surg 1993; 80:205–209. 96. Hershman MJ, Apell SH, Wellhausen SR, Sonnenfield G, Polk HC Jr. Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients. Clin Exp Immunol 1989; 77:67–70. 97. Polk HC Jr, Cheadle WG, Livinston DH, et al. A randomized prospective clinical trail to determine the efficacy of interferon-gamma in severely injured patients. Am J Surg 1992; 163:191–196. 98. Morrissey PH, Bressler L, Park LS, Alpert A, Gillis S. Granulocyte-macrophage colony-stimulating factor augments the primary antibody response by enhancing the function of antigen-presenting cells. J Immunol 1987; 137:1113–1119. 99. Kampalath B, Cleveland RP, Chang C, Kass L. Monocytes with altered pheonotypes in posttrauma patients. Arch Path Lab Med 2003; 127:1580–1585. 100. Ayala A, Lehman DL, Herdon CD, Chaudry IH. Mechanism of enhanced susceptibility to sepsis following hemorrhage: interleukin-10 suppression of T-cell response is mediated by

Chapter 4: The Immune System and the Immunocompromised Patient

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113. 114.

115.

116.

117.

118.

119.

120.

eicosanoid-inducted interleukin-4 release. Arch Surg 1994; 129:1172–1178. Mack VE, McCarter MD, Naama HA, Calvano SE, Daly JM. Dominance of T-helper 2-type cytokines after severe injury. Arch Surg 1996; 131:1303–1309. DiPiro JT, Howdieshell TR, Goddard JK, Callaway DB, Hamilton RG, Mansberger AR. Association of interleukin-4 plasma levels with traumatic injury and clinical course. Arch Surg 1995; 130:1159–1163. Cabiogla N, Bilgic S, Deniz G, et al. Decreased cytokine expression in peripheral blood leukocytes in severe sepsis. Arch Surg 2002; 137:1037–1043. Goebel A, Kavanagh E, et al. Injury induces deficient interleukin-12 production, but interleukin-12 therapy after injury restores resistance to infection. Ann Surg 2000; 231:253–261. Adams JM, Hauser CJ, Livingston DH, et al. The immunomodulatory effects of damage control abdominal packing on local and systemic neutrophil activity. J Trauma 2001; 50: 792–800. Tarlowe MH, Kannan KB, Itagaki K, et al. Inflammatory chemoreceptor cross-talk suppresses leukotriene B4 receptor 1-mediated neutrophil calcium mobilization and chemotaxis after trauma. J Immunol 2003; 171:2066–2073. Freeman TR, Shelby J. Effects of anti-PGE antibody on cell mediated immune response in thermally injured mice. J Trauma 1988; 28:190–194. Horgan AF, Mendez MD, O’Riordain DS, Holzheimer RG, Mannick JA, Rodrick ML. Altered gene transcription after burn injury results in depressed T-lymphocyte activation. Ann Surg 1994; 220:342–352. Charpentier B, Fournier C, Fries D, Mathieu D, Noury J, Bach JF. Immunological studies in human ageing I. In vitro functions of T-cells and polymorphs. J Clin Lab Immunol 1981; 5: 87–93. Kishimoto S, Tomino S, Mitsuya H, Fujiwara H, Tsuda H. Age-related decline in the in vitro and in vivo synthesis of anti-tetanus toxoid antibody in humans. J Immunol 1980; 125:2347–2357. Franceschi C, Monit D, Sansoni P, Cossarizza A. The immunology of exceptional individuals: the lesson of centenarians. Immunol Today 1995; 16:12–16. Castle S, Uyemura K, Crawford W, et al. Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12. Exp Gerontol 1999; 34:243–252. O’Neal BJ, McDonald JC. The risk of sepsis in the asplenic adult. Ann Surg 1981; 194:775–778. Abraham E, Chang YH. Cellular and humoral bases of hemorrhage-induced depression of lymphocyte function. Crit Care Med 1986; 14:81–86. Stephan RN, Kupper TS, Geha AS, Baue AE, Chaudry IH. Hemorrhage without tissue trauma produces immunosuppression and enhances susceptibility to sepsis. Arch Surg 1987; 122:62–68. Meldrumn DR, Ayala A, Perrin MM, Ertel W, Chaudry IH. Diltiazem restores IL-2, IL-d, IL-6, and IFN gamma synthesis and decreases host susceptibility to sepsis following hemorrhage. J Surg Res 1991; 51:158–164. Stephan RN, Ayala A, Harkema JM, Dean RE, Border JR, Chaudry IH. Mechanism of immunosuppression following hemorrhage: defective antigen presentation by macrophages. J Surg Res 1989; 46:553–556. Wichmann MW, Zellweger R, DeMaso CM, Ayala A, Williams C, Chaudry IH. Immune function is more compromised after closed bone fracture and hemorrhage shock than hemorrhage alone. Arch Surg 1996; 131:995–1000. Foster RS Jr, Constanza MC, Foster JC, Warner MC, Foster CB. Adverse relationship between blood transfusions and survival after colectomy for colon cancer. Cancer 1985; 55:1195–1201. Hyman NH, Foster RS, DeMeules JE, Costanza ME. Blood transfusions and survival after lung cancer resection. Am J Surg 1985; 149:502–507.

89

121. Foster RS Jr, Foster JC, Costanza MC. Blood transfusions and survival after surgery for breast cancer. Arch Surg 1984; 119:1138–1140. 122. Opelz G, Sengar DPS, Mickey MR, Terasaki P. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc 1973; 5:253–257. 123. Fischer E, Lenhard V, Seifer P, Kluge A, Johannsen R. Blood transfusion induced suppression of cellular immunity in man. Hum Immunol 1980; 1:187–194. 124. Matsumoto T, Sakagami K, Orita K. Role of donor specific blood transfusions in prolongation of kidney graft survival. Transplant Proc 1983; 19:2264–2267. 125. Singal DP, Fagnilli L, Joseph S. Blood transfusions induce antiidiotypic antibodies in renal transplant patients. Transplant Proc 1983; 15:1005–1008. 126. Boulton-Jones JM, Vick R, Cameron JS, Black PJ. Immune responses in uremia. Clin Nephrol 1973; 1:351–360. 127. Stevens CE, Alter HJ, Taylor PE, Zang EA, Harley EJ, Szmuness W. Hepatitis B vaccine in patients receiving hemodialysis: immunogenicity and efficacy. N Engl J Med 1984; 311:496–501. 128. Donati D, Degiannis D, Homer L, Gastaldi L, Raskovaj J, Roskak JR. Immune deficiency in uremia: interleukin-2 production and responsiveness and interleukin-2 receptor expression and release. Nephron 1991; 58:268–295. 129. Chatenaud L, Heberlin A, Beaurain G, Descamps-Latscha B. Immune deficiency of the uremic patient. Adv Nephrol 1990; 19:259–274. 130. Touraine JL, Touraine F, Reveillard JP, Brochier J, Traegor J. T-lymphocytes and serum inhibitors of cell mediated immunity in renal insufficiency. Nephron 1975; 14:195–208. 131. Gibbons RAS, Marinex OM, Garovoy MR. Altered monocyte function in uremia. Clin Immunol Immunopathol 1990; 56: 66–80. 132. Robbins SL, Rucker AW Jr. The causes of death in diabetics. A report of 307 autopsied cases. N Engl J Med 1944; 231:865–869. 133. Vejilsgaard R. Studies on urinary infection in diabetes. Bacteria in patients with diabetes mellitus and in control subjects. Acta Med Scand 1966; 179:173–178. 134. Moutschen MP, Scheen AJ, Lefebvre PF. Impaired immune responses in diabetes mellitus: analysis of the factors involved. Relevance to the increase susceptibility of diabetic patients to specific infections. Diabetes Met 1992; 18: 187–201. 135. Wilson RM, Reeves WG. Neutrophil function in diabetes. In: Nattrass M, ed. Recent Advances in Type 2 Diabetes. London: Churchill Livingston, 1986:127–138. 136. Rodier M, Andary M, Ricahr JL, Mirouse J, Clot J. Peripheral blood T cell subsets studies by monoclonal antibodies in type 1 (insulin-dependent) diabetes: effect of blood glucose control. Diabetologia 1984; 27:136–138. 137. Visalli N, Signore A, Pozzilli P. Immunodeficiency in longstanding diabetes: evidence and approaches to prevention. In: Andreani D, Kolb H, Pozzilli P, eds. Immunotherapy of Type 1 Diabetes. Chichester: Wiley, 1989:185–192. 138. Cluff LE, Reynolds RC, Page DL. Staphyloccal bacteremia: demographic, clinical and microbiological features of 185 cases. Trans Am Clin Climat Ass 1968; 79:905–915. 139. Rubin RH, Cosimi AB. Infections in the immuno-compromised host. In: Howard RJ, Simmons RL, eds. Surgical Infectious Diseases. Norwalk, CN: Appleton & Lange, 1995:1311. 140. The International Antimicrobial Therapy Project Group of the European Organization for Research and Treatment of Cancer: Combination of amikacin and carbenicillin with or without cefazolin as empirical treatment of febrile neutropenic patients. J Clin Oncol 1983; 1:597–603. 141. Ozaki Y, Ohashi T, Minami A, Nakamura S. Enhanced resistance of mice to bacterial infection induced by recombinant human interleukin-1 alpha. Infect Immunol 1987; 55: 1436–1440. 142. Smith JW, Urba WJ, Curti BD, et al. The toxic and hematologic effects of interleukin-1 alpha administration in phase I trial to

medwedi.ru

90

143.

144.

145.

146.

147.

148.

149.

150.

Part One: General Considerations patients with advanced malignancies. J Clin Oncol 1992; 10:1141–1152. Sarosy G, Kohn E, Stone DA, et al. Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer. J Clin Oncol 1992; 10:1165–1170. Linch DC, Scarfee H, Proctor S, et al. Randomized vehiclecontrolled dose-finding study of glycosylated recombinant human granulocyte colony-stimulating factor after bone marrow transplantation. Bone Marrow Transplant 1993; 11:307–311. Fan D, O’Brian CA, Ioannides CG, Clyne RK. Granulocytemacrophage colony-stimulating factor (GM-CSF) in the management of cancer. In Vivo 1991; 5:571–577. Peters WP, Rosner G, Ross M, et al. Comparative effects of granulocytes-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy. Blood 1993; 81:1709–1719. Baldwin GC, Gason JC, Quan SG, et al. Granulocytemacrophage colony-stimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proc Natl Acad Sci USA 1988; 85:2763–2766. Carr R, Modi N, Dore C. G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Syst Rev 2003; 3:CD003066. Quesada JR, Reuben J, Manning JT, Hersh EM, Gutherman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med 1984; 310:15–18. Tyring SK. Treatment of condyloma acuminata with interferon. Semin Oncol 1988; 15(suppl 5):35–40.

151. Groopman JE, Scadden DT. Interferon therapy for Kaposi’s sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989; 110:335–337. 152. Rothermel CD, Rubin BY, Murry H. Gamma interferon is the factor in lymphokine that activates human macrophages to inhibit intracellular Chlamydia psittaci replication. J Immunol 1983; 131:2542–2544. 153. Siegel JP. Effects of human interferon-gamma on the activation of human T lymphocytes. Cell Immunol 1988; 111:461–472. 154. Wong DKH, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. Ann Intern Med 1993; 119:312–323. 155. Kleter GEM, Brouwer JT, Heijtink RA, Schalm SW, Quint WF. Detection of hepatitis C virus RNA in patients with chronic hepatitis C virus infections during and after therapy with alpha interferon. Antimicrob Agents Chemother 1993; 37:595–597. 156. Carswell EA, Old LJ, Kassel RL, Green S, Fiove N, Williamson B. An endotoxin induced serum factor which causes necrosis of tumors. Proc Natl Acad Sci USA 1975; 72:3666–3670. 157. Lane HC, Kovacs JA, Feinberg J, et al. Anti-retroviral effects of interferon-alpha in AIDS-associated Kaposi’s sarcoma. Lancet 1988; 2:1218–1222. 158. Sheppard BC, Fraker DL, Norton JA. Prevention and treatment of endotoxin and sepsis lethality with recombinant human tumor necrosis factor. Surgery 1989; 106:156–161. 159. Fisher CJ, Opal SM, Dhainaut JF, et al. Influence of an antitumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Crit Care Med. 1993; 21:318–327.

5 Physiologic Basis of Transplantation Yuan Zhai and Rafik M. Ghobrial

INTRODUCTION Successful clinical transplantation is limited not by technical pitfalls but rather by the immune process that mediates rejection of the transplanted tissue or organ (1). Thus, the physiologic basis of transplantation rests on understanding the immunologic rejection process. The goal of the transplant surgeon is to manipulate either the host (i.e., the recipient of the transplanted organ or tissue) or the allograft (i.e., the organ or tissue being transplanted from a donor, within the same species) to avert, minimize, or reduce this physiologic process. Immunologic events leading to allograft rejection can be divided into afferent, central, and efferent limbs. The afferent limb is the initiation of immune responses, which includes presentation of foreign histocompatibility antigens to T-lymphocytes by antigen-presenting cell (APC). The activation of antigen-nonspecific innate immunity is critical for this process, which by itself is also able to directly cause damage to allografts. The central limb is the activation of alloantigen-specific T- and B-lymphocytes, including their proliferation and differentiation. The efferent limb is execution of effector functions of activated lymphocytes, including both cellular and soluble cytotoxicities to destroy grafts. In the following discussion, we will use alloreactive T-cells as an example, and provide a mechanistic overview of various components of alloimmune responses and how alloimmune responses proceed.

ALLOGRAFT REJECTION Afferent Limb This section aims to delineate the molecular and cellular components of the immune system, which provide the structural basis of T-cell recognition of allogeneic antigens. As we know now, organ transplantation presents both physical and biological stresses to the host immune system. The first response to these stresses is inflammation, which is mediated by the host innate immune system and provides the initial milieu for subsequent activation of the host’s antigen-specific adaptive immune system.

Innate Immunity The innate immune system consists of both cellular and soluble components. Dendritic cells, macrophages, neutrophils, eosinophils, mast cells, natural killer (NK) cells, as well as intraepithelial lymphocytes at the mucosal surface, form the first line of cellular defence against infectious agents in mammalian tissues. Soluble components include complements, C-reactive protein, mannan-binding lectin, cytokines, and chemokines. Activation of the innate immune system is mediated by receptor–ligand interactions. Infectious agents

carry distinctive pathogen-associated molecular patterns, which are often lipid and carbohydrate moieties, constituents of microbial cell walls (2). They can be recognized by various cell–surface pattern recognition receptors, including toll-like receptors (TLRs), scavenger receptors (sialic acid), macrophage mannose receptor, b-glycan receptor, and galactose-specific lectin. Phagocytosis is one of the classical outcomes of the innate immune reaction. Recently, it has been recognized that the activation of innate immunity is in fact a prerequirement for effective adaptive immunity involving antigen-specific T- and B-cell responses. Despite its sentinel role in host immune responses, innate immunity has long been ignored in allograft rejection because of a common but misleading observation, in animal models, that allografts survive long term in T- and B-cell–deficient recipients. In fact, the first wave of graft-infiltrating lymphocytes are macrophages and neutrophils, but not T- or B-cells, in both allo- and xenograft transplantation (3). While it is true that innate immune responses alone may not be sufficient to acutely reject allografts, it was recently demonstrated that inhibition of innate responses could disrupt the development of alloantigen-specific T-cell responses and prolong allograft survival. An elegant example is the observation that the absence of local synthesis of the complement component C3 can promote major histocompatibility complex (MHC)–fully mismatched renal allograft survival in a murine model (4). On the other hand, with the effective control of acute allograft rejection by current immunosuppressive agents, innate immune responses, possibly spared from T-cell or B-cell targeted therapies, may show critical impact on chronic allograft rejection. In the solid organ transplantation setting, the surgical procedure and ischemia–reperfusion injury are two major antigen-independent stimulants that trigger innate immune responses in the early post-transplantation phase. Cell death is a key event in initiating the inflammation cascade, which is enhanced during reperfusion by reactive oxygen species, cellular adenosine triphosphate depletion, expression of death ligands [tumor necrosis factor (TNF)-a, FasL], and complement activation. Although, the molecular mechanism activating the innate immune system in transplantation has not been determined, the finding of endogenous ligand for TLR implied the potential role for this particular innate receptor system (5). TLRs were initially identified as homologues of the Drosophila Toll proteins, and developed in mammalians to a highly conserved receptor system that recognizes functionally essential molecules shared by microbial pathogens (6). TLRs are expressed on different cell types, particularly APCs, such as macrophages and dendritic cells (DCs). TLR engagement by microbial products initiates the process of DC maturation, resulting in the upregulation of surface expression of MHC and costimulatory

medwedi.ru 91

92

Part One: General Considerations

molecules, and the production of immunostimulatory cytokines. These matured DCs are the key leading to T-cell activation and the development of adaptive immunity. Molecules generated during tissue damage and inflammation including heat shock proteins (HSPs), hyaluronan, heparin sulfate, and fibronectin have been shown to act as endogenous TLR ligands and effectively stimulate DCs via TLR system (5). Upregulation of chemokine and cytokine production as a result of intragraft DC and endothelial activation leads to the recruitment and activation of infiltrating lymphocytes, including macrophages, NK cells, and T-cells. Clearly, there are bidirectional interactions between innate and adaptive immune responses during this progressive graft rejection process: the initial innate immune activation probably starts the cellular cascade in an antigen-nonspecific fashion to trigger T-cells, whose activation then not only elicits antigen-specific adaptive immune responses, but also feeds back and amplifies the innate immune responses. Chemokines and Their Receptors As one of the major products from innate immune system activation, chemokines play critical roles in intragraft recruitment and activation of not only antigen-nonspecific leukocytes of innate immunity, but also T- and B-cells of adaptive immunity. Chemokines are a large family of low-molecular-weight (8–11 kDa), heparin-binding proteins initially recognized with chemoattractant activity for leukocytes and later with other important developmental functions, e.g., hematopoiesis and organogenesis (7). Currently, there are approximately 60 chemokines divided into four subfamilies, based on cysteine motifs near the amino-terminal end of the molecules: C, CC, CXC, and Cx3C. Functionally, however, chemokines within the same subfamily vary significantly in their biological targets and effects. Two major functional groups of chemokines involve either inflammation or homeostasis, which also differ in their expression regulation (inducible by proinflammatory or constitutive stimuli, respectively). Chemokine receptors are members of the serpentine, heterotrimeric G-protein–coupled, seven-transmembrane– spanning receptor superfamily. Eighteen chemokine receptors have been identified so far, with each binding a distinct set (more than one) of chemokines (7). The complexity and specificity of the chemokine system stem from not only the multitude of receptor–ligand pairing but also the regulated expression of ligands and receptors, which differ according to cell subsets and state of cell activation. The array of chemokine receptors displayed on a leukocyte surface regulate its homing and chemotactic potentials. Thus, each chemokine recruits only specific cell types at a particular activation or differentiation state. Table 1 lists some of the common chemokines and their receptors that have been implicated in transplant immune responses (8,9).

Alloantigen Presentation and Recognition Alloantigen-specific immune responses involve three types of lymphocytes: T-cells, B-cells, and APCs (particularly DCs). As in the innate immune response, the ‘‘adaptive immune response’’ is also mediated by receptor–ligand interactions, but in a much more complicated fashion. Multiple pairs of receptor–ligand interactions are required for effective T (or B) -cell activation. In this section, we will review the molecular structure of such receptors or ligands, including the MHC, minor histocompatibility antigens, T- or B-cell receptors, and costimulation molecules.

Table 1 Chemokine Cascades Following Organ Transplantation Chemokine cascade

Receptor

Early (3–72 hr) Gro-a/MIP-2

CXCR2

Neutrophils

IL-8 MCP-1/JE

CXCR1/2 CCR2

Neutrophils Macrophages, T

MIP-1a

CCR1/5

MIP-1b

CCR1/5

IP-10

CXCR3

Fractalkine

CX3CR1

Late (48–72þ hr) RANTES

CCR1/3/5

Target lymphocyte

Murine cardiac allograft outcome after treatment Delayed rejection (<20 days) by anti-Gro-a

Delayed rejection in CCR2 KO Macrophages, NK, No effect in MIPT 1aKO; delay rejection in CCR5 KO Macrophages, NK, T Activated T Prolonged survival ( < 20 days) in IP-10 donor KO, CXCR3 KO, or anti-CXCR3; delayed rejection by anti-IP-10 T, NK No effect in CX3CR1KO, prolong survival by anti-CX3CR1

MIG

CXCR3

T, NK, macrophages Activated T

IP-10 I-TAC

CXCR3 CXCR3

Activated T Activated T

No effect in RANTES KO Delayed rejection by anti-MIG

Abbreviations: IL, interleukin; MCP, monocyte chemotactic protein; NK, natural killer.

Major Histocompatibility Antigens Major Histocompatibility Complex. The antigen (Ag) disparity between the host and the graft initiates the immune response and ultimately the rejection process. Early experiments in clinical transplantation revealed the presence of a single, strong, antigenic system controlling the outcome of transplantation in every species. The human MHC encodes the human leukocyte antigens (HLA), including class I, class II, and class III, and many other genes that encode proteins of unknown function. The MHC spans 3.5 million DNA base pairs, approximately 2% of the genetic material in autosomal chromosome 6 (Fig. 1). The class II genes are located closest to the centromere in the order DP, DQ, and DR. The class III region encodes components of the complement system (C2, C4A, C4B, and Factor B) as well as the enzyme steroid 21-hydroxylase. The genes for HSP, TNF, lymphotoxin (LT)-a, and LT-b lie between the complement and class I genes. The most telomeric portion of the MHC contains the class I-ab chain genes in the sequence B, C, and A. Nonpolymorphic class I–like genes and pseudogenes, located in the large space between the C and A genes and telomeric to HLA-A, occupy 11 centimorgans. The function of the class I–like genes remains largely unknown. However, these genes may serve as a repository for alternative nucleic acid sequences used for generating polymorphism in the true class I molecules by the process

Chapter 5:

Figure 1 Chromosomal map of the human major histocompatibility complex (MHC). The MHC locus encodes HLA class I (A, B, and C), class II (DP, DQ, and DR), and class III, including the complement (C0 ) locus. Proteasome and transporter (TAP-1 and TAP-2) genes are located in the class II region. Genes encoding HSP and TNF/LT family of cytokines (LT-b, LT, and TNF) sit in a telomeric position to class III loci. Class I–like genes and multiple pseudogenes are located between the C and A loci. Abbreviations: HSP, heat shock proteins; HLA, human leukocyte antigen; LT, lymphotoxin; TAP, transporter in antigen processing; TNF, tumor necrosis factor.

of gene conversion (incorporation of variant sequences in the class I or class II genes without reciprocal crossing over). Located within the class II region are the genes encoding multiple subunits of a cytosolic protease termed proteasome, which is involved in the generation of peptide fragments from intracellular endogenous cytosolic proteins. The transporter in antigen processing (TAP) 1 and 2 genes are located next to the proteasome complex in the class II region. Such TAP genes encode subunits of a heterodimeric pump protein that transports the endogenous peptide fragments into the endoplasmic reticulum (ER) where such peptides bind to class I, but not to class II, molecules. Class I and class II glycoproteins serve as scaffolds for the presentation of processed antigenic peptides to T-cells: Class I molecules present peptides from endogenous proteins to CD8þ T-cells, while class II molecules present peptides from exogenous antigens to CD4þ T-cells. The polymorphism, and therefore antigenicity, of the MHC class I and class II transplantation antigens is the result of amino acid (a.a.) sequence differences between donor and recipient MHC molecules. Characteristics of Class I MHC Antigens Structure. The class I MHC antigens are expressed as complexes of a membrane-bound glycoprotein, heavy-chain polypeptide (45 kDa) that is noncovalently associated with a non-MHC encoded b2-microglobulin (b2m; 12 kDa) light chain (Fig. 2A). Crystallographic analysis of human HLA-A2, HLA-B27, and HLA-Aw68, and mouse H-2Db class I molecules revealed similar molecular configurations. The membrane-distal polymorphic a1 (90 a.a.) and a2 (92 a.a.) domains bear eight antiparallel b-pleated strands bordered by two a-helical regions (the first from the a1 and the second from the a2 domain), which jointly form the peptide-binding cleft (Fig. 2B). The a domain is attached to a less-polymorphic, immunoglobulin (Ig)-like, membrane-proximal (92 a.a.) domain, which is followed by conserved transmembrane (25 a.a.), and intracytoplasmic (30 a.a.) segments. The a3 domain contains the binding sites for the CD8 molecule. The b2m forms an Ig-like domain, which is noncovalently associated with the extracellular

Physiologic Basis of Transplantation

93

Figure 2 Major histocompatibility complex class I antigen. (A) Schematic illustration of the heavy chain including a1, a2, and a3, transmembrane and intracytoplasmic domains noncovalently associated with the light chain (b2m). (B) Schematic illustration of the peptide-binding cleft formed by the a1 and the a2 domains, each contributing an a-helix and four b-strands. Both domains are in continuity with one another (180 a.a.) to provide a peptide-binding groove with closed ends. A–F denote peptide-binding pockets formed by polymorphic a.a. residues in the cleft. NH2 and COOH are the amino and carboxy-terminal ends of the protein.

portion of the heavy chain and appears to be critical in maintaining the native confirmation of class I molecules. Antigen Presentation. Class I molecules present peptides derived from proteins in the cytosol to CD8þ-bearing T-cells. T-cells recognize both the MHC molecule and the associated peptide presented in the peptide-binding groove. The six pockets (A, B, C, D, E, and F) present within the groove (Fig. 2B) provide specificity for interactions with the peptide side chains. The closed ends of the groove result in a strong bias for the stable binding of short peptides in the range of 8 to 10 residues (10). A broad peptide-binding capacity arises from hydrogen bonding between the NH2 and COOH groups of the peptide and the residues at the end of the groove (A and F pockets). A second, more specific bonding links the polymorphic residues in the pockets B to E to specific peptide side chains (anchor residues). Such anchor peptide residues that fit optimally into the pockets of the peptide-binding groove stipulate the repertoire of peptides that associate with a particular class I molecule. For example, HLA-A0201 binds peptides exhibiting leucine at position 2 and valine at position 9. Such peptide motifs have been defined for HLA-A0205 and HLA-B27 as well as many mouse class I molecules. Thus each class I allelic product selects its bound peptides according to ‘‘specific motifs’’ characterized by an allele-specific length and positions of anchor peptide residues. Assembly and Expression. Short nanomeric peptides loaded onto MHC class I molecules are generated in the cytosol by proteasome degradation of newly synthesized proteins. Targeting of proteins for proteasomal degradation requires their ubiquitination. The peptides are transferred to ER by specialized peptide transporters, TAP, and loaded on new MHC class I molecules (consisting of class I heavy chain and b2m) under the control of a loading complex composed of several ER resident chaperons (including tapasin,

medwedi.ru

94

Part One: General Considerations

calnexin, and calreticulin), which retard the intracellular transport of peptide-free class I molecules (11). Once associated to peptides, the trimolecular complexes are rapidly transferred through the golgi apparatus to the plasma membrane via the constitutive secretory pathway, and expressed as membrane-bound glycoproteins (Fig. 3). Class I antigens are expressed on almost all cells of the body, although levels of expression may vary and are typically highest on hematopoietic elements. Recent studies have confirmed the existence of ‘‘cross presentation’’ by MHC class I molecules, in which internalized exogenous antigens are loaded onto MHC class I molecules (12). Macropinocytosis allows receptor-independent cross presentation of soluble antigens by DCs. Physiologically, phagocytosis is the major route for antigen uptake and cross presentation. Phagocytosis of bacteria and apoptotic cells, Fc receptor (FcR)–mediated uptake of immune complex, opsonized liposomes, or dead cells all result in efficient cross presentation. Peptide bound to HSPs, which are internalized through receptors, such as CD91, also induce cross presentation. Two main intracellular pathways for cross presentation have been identified. TAP-independent endocytic cross presentation utilizes recycling MHC class I molecules in endosomes and lysosomes, where exogenous peptides exchange with endogenous peptides at low pH. TAP-dependent cross presentation utilizes a membrane transport pathway linking the lumen

of endocytic compartment and the cytosol, which allows selective delivery of internalized antigens to the cytosol, leading to ER loading of the exogenous antigens. In vivo cross presentation was mostly dependent on TAP, which may play an important role in peripheral tolerance of cytotoxic T-lymphocytes (CTLs) to tissue-specific antigens. Characteristics of Class II MHC Antigens Structure and Antigen Presentation. Class II MHC antigens are composed of a heterodimer of two transmembrane a (33 kDa) and b (29 kDa) molecular chains, each bearing one peptide-binding domain (a1 or b1) and one Ig domain (a2 or b2; Fig. 4A). Crystallographic analysis of the class II HLA-DR1 revealed a three-dimensional structure similar to that of class I molecules (13). Similar to class I molecules, class II polymorphic residues are concentrated in the a-helical sides or the b-strands of the peptide-binding cleft, which bear allele-specific motifs that interact with the peptide anchor residues at five binding pockets. In contrast to class I molecules, the peptide-binding site of class II molecules includes two noncovalently associated halves (a1 or b1), with one a-helix and four bb-strands (90 a.a.) contributed by each chain (Fig. 4B) to form an open peptide-binding groove (Fig. 5). In addition, class II molecules form conserved bonds with the main chain atoms of the peptide, not the terminal groups, thus allowing the ends of the peptides to extend out of the binding groove. Thus, class II–associated peptides exhibit a broader range of lengths, typically 12 to 24 residues (Fig. 5). Class II molecules may even bind whole proteins. Assembly and Expression. Whereas class I molecules present peptides derived primarily from endogenous proteins synthesized within the cell, class II molecules bind to foreign peptides introduced into the cell through the endocytic pathway (exogenous antigen). These differences result from distinct intracellular trafficking and assembly pathways of class I and class II molecules. In contradistinction to the endogenous pathway utilized by class I molecules,

Figure 3 Schematic illustration of antigen processing and presentation by class I. Endogenously generated proteins are degraded in the cytoplasm by the action of a macromolecular proteasome complex. Endogenous peptides are transported into the endoplasmic reticulum (ER) by specialized peptide transportors, TAP, and loaded on to new MHC class I molecules (consisting of class I heavy chain and b2m). The loading of peptides is under the control of a loading complex composed of several ER resident chaperons (including tapasin, calnexin, and calrecticulin), which retard the intracellular transport of peptide-free class I molecules. The assembled trimolecular complex (peptide, heavy, and b2m chains) is transported through the golgi complex to the plasma membranes via the constitutive secretory pathway for surface expression. Abbreviations: MHC, major histocompatibility complex; TAP, transporter in antigen processing.

Figure 4 Class II major histocompatibilty complex class antigen. (A) Schematic illustration of the a and b chains, each contains the membrane-distal a1 and b1domains that form the peptide-binding cleft, and the membrane-proximal a2 and b2 domains. Each is followed by a transmembrane and an intracytoplasmic domain. (B) Schematic illustration of the peptide-binding cleft formed by two separate a1 and b1 domains, each containing approximately 90 a.a. One a-helix and four b-strands are contributed by each domain. NH2 and COOH, amino- and carboxy-terminal ends.

Chapter 5:

Physiologic Basis of Transplantation

95

class II molecules followed by the association of the peptides with the a/b heterodimers (15,16). Vesicularly transported class II a/b-peptide complexes are then expressed on the cell surface for antigen presentation (Fig. 6). Class II molecules exhibit limited distribution to vascular endothelium and cells of lymphoreticular origin, specifically B-lymphocytes, monocytes, APCs (including macrophages, B-cells, DCs, and langerhans epidermal cells), and immune-activated T-lymphocytes.

Figure 5 Schematic illustration of peptides binding to class I or class II molecules. The continuity between a1 and a2 domains of the class I molecules provides a closed peptide-binding groove that limits binding to peptides that are 8 to 10 a.a. long. Class II molecules exhibit an open peptide-binding groove formed by two separate a1 and b1 domains, thus allowing longer peptides (12–24 a.a.) to bind and protrude beyond the peptide-binding groove. Abbreviation: a.a., amino acids.

an exogenous assembly pathway links class II molecules to the antigenic peptides generated after endocytosis and endosomal digestion of antigens by proteases including cathepsins and asparaginyl endopeptidases (14). The class II chains synthesized intracellularly associate in the ER with a nonpolymorphic, non-MHC–encoded chain, termed ‘‘invariant chain’’ (li, 30 kDa). Three invariant chains combine to form a homotrimer, with each subunit binding to a newly synthesized class II a/b heterodimer to form a nine-chain complex. The invariant chain serves to make the class II a/b heterodimers more compact, and reduces the binding of the class II molecules to endogenous peptides in the ER. The invariant chain then guides the class II complexes to the lysosomal compartments of the exogenous pathway, which contain the proteolytically cleaved, exogenous antigenic peptides. The acidic environment of the endosomes allows the dissociation of the invariant chain from

Blood Group Antigens: A Minor Histocompatibility Antigen Complex Red blood cell carbohydrate antigens, which are considered as minor histocompatibility antigens, vary in their tissue distribution and degree of expression. Rh antigens are found exclusively on red cells, while ABO antigens are widely distributed on other tissues and body fluids. The ABO system of blood typing is the only non-HLA histocompatibility system that has been identified to mediate rejection in humans (17). Renal transplantation across an ABO incompatibility is almost always unsuccessful (18). The recipient responds as a presensitized host, because he bears circulating isoantibodies toward foreign blood group antigens, thereby resulting in hyperacute rejection (see below). Renal function ceases within minutes to hours. Recently, the development of techniques for removal of anti–A and anti–B isoantibodies by plasmapheresis renewed some interest in ABO incompatible kidney transplants. Alexandre et al. reported a series of successful ABO incompatible, living, related and unrelated kidney transplants (19). Interestingly, after treatment, the isoagglutinin titers returned to near preoperative levels, even in successful grafts. A successful outcome of cadaveric renal transplantation from donors with the blood group A2 to recipients with blood group O has been reported, a success attributed to the lower density of the A2 form of antigen expressed on the donor kidney. Lewis (Le) Ags, which are blood group–related complex carbohydrate antigens consisting of 1,3 fucosylated N-acetylglucosamine groups within repeating lactosamine subunits, may also influence renal allograft survival. They result from a complex interaction between gene products of the ABO, Rh, Secretor, and Le loci. The Le antigens exist in a soluble form in the serum (Lea and Leb) and body fluids but not on erythrocytes. Oriol et al. implicated incompatible

Figure 6 Schematic illustration of antigen processing and presentation by class II molecules. The class II chains synthesized intracellularly associate in the ER with a nonpolymorphic, non-major histocompatibility complex–encoded chain, termed as the invariant chain (li). Three invariant chains combine to form a homotrimer, with each subunit binding to a newly synthesized class II a/b heterodimer to form a nine-chain complex. The invariant chain then guides the class II complexes to the lysosomal compartments of the exogenous pathway, which contain the proteolytically cleaved, exogenous antigenic peptides. The acidic environment of the endosomes allows the dissociation of the invariant chain from class II molecules followed by the association of the peptides with the a/b heterodimers. Vesicularly transported class II a/b peptide complexes are then expressed on the cell surface for antigen presentation. Abbreviation: ER, endoplasmic reticulum.

medwedi.ru

96

Part One: General Considerations

Le Ags as the cause of renal allograft failure in presensitized hosts bearing anti-Le antibodies following multiple blood transfusions (20). Although Le and HLA disparities display negative additive effects on transplant survival, HLA identity cannot override the deleterious influence of a Le Ag mismatch. Le Ags are expressed on lymphocytes and on epithelial cells of both the distal convoluted tubules and collecting ducts. Spitalnik et al. reported that eight Le-negative individuals with circulating anti-Le antibodies, who received Le-incompatible grafts, all displayed allograft rejection (21). In contrast, Rh incompatibility in renal transplantation plays a minor role in allograft survival, except possibly in a presensitized Rh(-) recipient (17). Currently, ABO incompatibility between donor and recipient is routinely avoided by blood grouping, but Le mismatches are only sought if there has been an extensive recipient transfusion history. T-Lymphocytes T-Cell Receptor. There are two forms of T-cell receptor (TcR): the a/b heterodimers, which are expressed on the majority of mature peripheral blood T-cells (Fig. 7), and the g/d heterodimers, which are expressed on 10% of intestinal T-cells and 5% of peripheral blood T-cells. The a/b TcR recognizes processed peptides presented by classical polymorphic class I or class II MHC molecules in order to activate a wide variety of T-cell–mediated immune mechanisms, including the alloimmune response. Activation of a/b T-cells is thus ‘‘restricted’’ by the recognition of the appropriate MHC antigens. T-cells expressing the g/d TcR are not restricted by the conventional polymorphic self-MHC,

but may recognize the nonpolymorphic MHC-like molecules. The function of the g/d T-cells is largely unknown; they may play a role in the initiation of the immune response to some commonly encountered microbial antigens at the epithelial boundaries. The a/b TcR consists of two polypeptide chains (Fig. 7), the a chain (40–50 kDa) and the b chain (40–45 kDa), which bear striking similarities to Igs. Both chains have variable (V) and constant (C) domains with appropriately spaced cysteine residues, to allow the formation of interchain disulfide bonded loops similar to Ig V and C domains. Thus the TcR and many other membrane proteins, structurally homologous to Ig domains, are referred to as members of the Ig superfamily (IgSF), and the genes encoding these molecules are termed the Ig gene superfamily (Table 2). The C-terminal end of the V region in both chains (the junction between the V and C domains) is encoded by a joining (J) segment gene, and in case of the b chain only, by an additional diversity (D) segment gene. The presence of V, D, J, and C regions is also characteristic of Igs. The similarity between the TcR and Ig may reflect the common function of both structures to detect foreign antigens. The Ig domain of the C region of both chains is followed by a hinge region that forms a disulfide linkage between the two chains. The transmembrane segments exhibit positively charged side chains that interact with the negatively charged residues in the CD3 polypeptides. The carboxy terminus of the C regions of both the a and b chains forms a 5 to 12 a.a. intracytoplasmic tail, which is too short for signal transduction, rather this function is performed by the TcR-associated CD3 complex. TcR-Associated Proteins. The CD3 complex contains three (g, d, e) peptide products. The g, d, and e chains, encoded on chromosome 11, are nonpolymorphic, highly homologous peptides of 20 to 26 kDa (Fig. 6). Each chain exhibits an Ig-likeextracellular domain (79–104 a.a.), a transmembrane segment containing a negatively charged aspartic acid residue important for association with the TcR, and a cytoplasmic domain ranging from 43 to 55 a.a. The TcR x chain encoded on chromosome 1 is a 16 kDa peptide that exists primarily as a disulfide-linked homodimer, and is structurally and genetically distinct from the CD3 subunits. x chain has a short extracellular domain of only 9 a.a. and long cytoplasmic tail of 113 to 155 a.a.; its dimerization occurs through the single cysteine residue located at the extracellular boundary of the plasma membrane. The TcR, currently

Table 2 Immunoglobulin Superfamily Members

Figure 7 Schematic illustration of the T-cell receptor (TcR) complex. The TcR consists of two chains a and b, each containing an immunoglobulin-like variable domain (V) and a constant domain (C). Each chain has a transmembrane and a short intracytoplasmic segment. The TcR-associated proteins consist of the CD3 complex d, g and e chains associated with z chain homodimer. The transmembrane segments of the TcR a and b chains exhibit positively charged side chains (þ) that interact with the negatively charged residues (–) in the transmembrane portions of the g, d, e, and x chains. Antigen recognition activation motifs containing sites for tyrosine phosphorylation (P) are present in the cytoplasmic tails of the g, d, e, and x chains.

IgG Major histocompatibility antigens (class I, class II) TcR CD3 (g,d,e) Invariant chain (li) CD4, CD8 Thy-1 CD2 (LFA-2) ICAM-1, ICAM-2 VCAM-1 CD28, CTLA-4, B7/BB1, B7.2 IL-1R Abbreviations: ICAM, intercellular adhesion molecule; IgG, immunoglobulin; IL-1R, interleukin-1 receptor; LFA-2, lymphocyte function-associated antigen-2; TcR, T-cell receptor; VCAM-1, vascular cell adhesion molecule-1.

Chapter 5:

Physiologic Basis of Transplantation

97

viewed as an octomer model of receptor structure, consists of four relatively stable dimmers: ab, CD3-de, CD3-ge, and zz (Fig. 7). The cytoplasmic tails of the CD3-g, CD3-d, CD3-e, and TcR z chains, essential for the TcR signal transduction, contain a critical signaling motif known as the immunoreceptor tyrosine-based activation motif (ITAM). The concensus sequence for an ITAM is YxxL(x)6–8YxxL, (single-letter code for a.a. with x denoting any a.a.). The tyrosine residues undergo phosphorylation during TcR activation. This motif occurs once in the tails of CD3-g, CD3-d, and CD3-e chains, and thrice on the tail of the TcR z chain. Rearrangement and Expression of TcR a and b Genes. Genomic sequences encoding the b chain are located on human chromosome 7 (Fig. 8). Each Cb gene is associated with a 50 cluster of six Jb genes and one Db gene. Vb segments (75–100) are located at the 50 of the D J C clusters. The a-chain sequences on human chromosome 14 contain a single Ca gene associated with at least 60 different Ja genes and 75 Va gene segments, grouped in 12 different families (Fig. 8). The assembly of the multiple units of the V, D, and J segments (somatic recombination) is mediated by the products of the recombination activator genes RAG -1 and RAG-2 (22), found only in the immature T- and B-cells. The multiple combinatorial associations of different V, D, and J segments during TcR rearrangement allows a broad TcR diversity. Further, the ‘‘N-region diversification,’’ involving the random addition of nucleotides that are not a part of the genomic sequences at the VJ, VD, and DJ junctions, and the pairing of aa/b chains serve to multiply the diversity of the TcR. Thus, the potential size of the generated T-cell repertoire may exceed 1015 specificities. T-Cell Maturation and MHC Restriction. After migration from the bone marrow, T-cells mature in the thymus where rearrangement and expression of the TcR genes occur. The CD4 and CD8 molecules expressed on mature T-cell subsets are commonly used as markers for thymocyte maturation. Most immature cells in the thymic cortex

Figure 8 Genomic sequences encoding the TcR a and b chains. Vb segments are located 50 of the D J C clusters, while each Cb gene is associated with a 50 cluster of six Jb genes and one 30 Db gene. The a chain sequences contain a single Ca gene associated with multiple Ja and Va gene segments. The assembly of different V, D, and J segments with the C gene segments results in multiple genomic sequences encoding a and b chains with different specificities. Abbreviation: TcR, T-cell receptor.

are the rapidly dividing thymocytes, which lack CD4 and CD8 molecules (CD4CD8, double negative), but are actively rearranging the a- and b TcR genes (Fig. 9). The majority of the double-negative cells (80%) beginning to express CD4 and CD8, thus develop into CD4þCD8þ (double positive). The vast majority of double-negative cells die in vivo, and only 20% of such cells develop into CD4þ TcR a/b or CD8þ TcR a/b MHC–restricted (single positive) mature T-cells, which are predominantly detected in the medulla. These single positive T-cells constitute the vast majority of the T-cells in the peripheral circulation. A small proportion of double-negative T-cells will never express CD4 or CD8 and rearrange the g/d but not the a/b TcR genes, giving rise to the g/d TcR–expressing T-cells, which are not restricted by the conventional polymorphic self-MHC. T-cells maturing in the thymus exhibit a broad range of specificities, including clones potentially reactive to

Figure 9 T-cell maturation in the thymus. In the a/b T-cell lineage, double-negative (CD4CD8) thymocytes develop into CD4þCD8þ (double positive). The majority of double-positive thymocytes die in vivo and the remaining minority ultimately gives rise to the CD4þ TcR ab or CD8þ TCR ab self-major histocompatibility complex (MHC)– restricted (single positive) mature T-cells that recognize foreign antigen in association with self-MHC. Positive selection allows thymocytes with TcRs that recognize self-MHC molecules to survive and eliminates all non–self-MHC–reactive cells. Negative selection eliminates all T-cells that recognize self-antigens in association with selfMHC. A small population of double-negative thymocytes expresses the g/d TcR and develops into CD4CD8 non–MHC-restricted T-cells. Abbreviation: TcR, T-cell receptor.

medwedi.ru

98

Part One: General Considerations

Figure 10 Interaction of TcR complex and accessory molecules with target ligands. (A) Interaction of CD4þ T-helper cell with APC. (B) Interaction of CD8þ T cytotoxic cell with target cell. LFA-1 binds to ICAM-1, CD2 to LFA-3, and CD28 to B7. The antigen-binding site of the TcR complex interacts with both the peptide and the peptide-binding groove of the MHC molecule. CD4 and CD8 molecules bind to MHC class II or class I, respectively. Abbreviations: APC, antigen presenting cell; ICAM, intercellular adhesion molecules; LFA, leukocyte function–associated antigen; MHC, major histocompatibility complex; TcR, T-cell receptor.

self-antigens. Thus, the second important event in the thymic T-cell maturation is the selection of T-cells that are tolerant to self-antigens, yet reactive to foreign antigens. On the one hand, there is selection of T-cells with the receptors recognizing foreign antigens in association with self-MHC molecules (positive selection) (23). On the other hand, there is selective elimination of T-cells (negative selection) that bind with high affinity to self-antigens, in association with self-MHC (24,25). Such self-reacting T-cell clones undergo clonal deletion by a Ca2þdependent process of cell death or apoptosis (26). Thus, thymic selection results in a T-cell repertoire recognizing foreign antigens, including alloantigens, in the context of self-MHC.

of the Src oncogene family p56lck. Rapid phosphorylation of the serine residues in the cytoplasmic tail upon antigenspecific stimulation of the T-cell (MHC–peptide complex interaction with TcR) underlines the role of CD4 in signal transduction. Binding of the CD4 coreceptor to the lateral surface of the MHC molecule augments signaling via the TcR up to 100-fold. However, ligation of the CD4 molecules alone, without TcR activation, inhibits T-cell activation (27). This dual opposing behavior presumably reflects an interplay between p56lck and the cytoplasmic tails of the CD3 z chains. The major function of CD4þ T-cells (65% of the a/

Accessory Molecules. The binding of the peptidehistocompatibility antigen assembly to the TcR is complemented by at least three sets of independent, accessory receptor–ligand interactions: coreceptor, CD4 to class II MHC molecules or CD8 markers to class I (Fig. 10); costimulatory molecules such as B7 to CD28; and adhesion molecules such as leukocyte function–associated antigen-1 (LFA-1) of the integrin gene family to intercellular adhesion molecules (ICAM-1 or ICAM-2). Although the TcR–CD3 complex are the key molecules in the antigen-specific recognition of the MHC–peptide complex and T-cell activation, binding of the accessory molecules is necessary for modulation of signal transduction, as well as to increase the affinity of cellular interactions with T-cells, as evidenced by the capacity of blocking antibodies directed against accessory molecules to inhibit T-cell activation. Coreceptor Molecules, CD4 and CD8. These nonpolymorphic transmembrane glycoprotein members of the Ig gene superfamily are expressed in a mutually exclusive fashion on mature T-cell subsets, which are either CD4þ or CD8þ. The CD4 (T4, L3T4) molecule (55 kDa), encoded on chromosome 12, contains four extracellular Ig-like domains, a transmembrane domain, and an intracytoplasmic tail (Fig. 11). The two N-terminal Ig-like domains only bind to the b2 domain of class II MHC, thus imposing a restriction of CD4þ T-cell interactions to class II MHC–bearing cells such as APCs. The intracytoplasmic tail is physically associated with a lymphocyte-specific protein tyrosine kinase

Figure 11 Schematic illustration of coreceptor molecules. The CD4 molecule (55 kDa) is expressed on cellular membranes as a monomer, which consists of four extracellular immunoglobulin-like domains, a transmembrane domain, and an intracytoplasmic tail. The two membrane-distal domains contain the binding sites for class II major histocompatibility complex (MHC) b2 domain, while the intracytoplasmic domain is associated with p56lck src protein kinase. The CD8 molecule is mostly expressed as a heterodimer of a (34 kDa) and b (34 kDa) chains that contain the class I MHC–binding domain in the extracellular domains. Similar to CD4, the CD8 intracytoplasmic domain is associated with p56lck.

Chapter 5:

b mature T-cells) following antigen-specific stimulation is the secretion of cytokines that act on other T-cells, B-cells, macrophages, neutrophils, and vascular endothelium. These cells are thus designated helper–inducer T-cells (Th). The CD8 (T8, Lyt-2) molecule exists in two forms: either as a homodimer of CD8a chain (34 kDa) or as a heterodimer of CD8a and CD8b (34 kDa) chains (Fig. 11) encoded by genes located on chromosome 2. The extracellular domains contain the binding sites to MHC class I a3 domain, resulting in restricted interaction of CD8þ T-cells (35% of the a/b T-cells) with class I MHC–bearing cells. Similar to the CD4 molecule, the intracytoplasmic domains of CD8 undergo serine phosphorylation following antigenspecific stimulation of CD8þ T-cells due to the physical association of p56lck. The CD8 marker is expressed on killer or cytotoxic T-lymphocytes (CTL; Tc), which constitute the effector T-cell population that ultimately contribute to allograft destruction. Cytokines involved in the differentiation and induction of CTLs include interleukin (IL)-2, interferon (IFN)-g, and IL-6. The division of T-cells into Th or CTL populations based on the expression of CD4 or CD8 molecules, while convenient, is not exclusive. Cytotoxic activity has been shown to be mediated by CD4þ T-cells, while helper activity can be provided by CD8 cells. Animal studies utilizing antibodies directed against CD8 or CD4 have demonstrated that rejection of class I allo-disparate grafts is primarily mediated by CD8þ cells, while CD4þ cells are responsible for rejection of class II–disparate allografts (28). However, CD4 and CD8 cells cooperate in nearly all episodes of clinical graft rejection. Costimulation Molecules. As we will discuss next, T-cell activation requires two essential signals to fully drive their proliferation and differentiation. TcR and its associated

Physiologic Basis of Transplantation

99

molecules (CD3, CD4, or CD8) interacting with MHC– peptide complex provides the first and antigen-specific signal. At the same time, a secondary and non–antigen-specific signal is required, which acts synergistically by either delivering a qualitatively distinctive intracellular signal or simply enhancing the endogenously weak TcR engagement. The second signal is provided by costimulation molecules on T-cell side interacting with their ligand or receptor counterparts on APCs. Currently, there are two major families of well-characterized costimulation molecule pairs: IgSF (29), such as CD28-B7, and TNF-receptor (TNFR) superfamily, such as CD40L–CD40 (30) (Fig. 12). With the identification of a multitude of costimulation molecules in each of these two families, and the discovery of the regulated expression of costimulation molecules depending on the stages of T-cell differentiation and the types of inflammatory environment, the current hypothesis of costimulatory mechanism of T-cell activation acknowledges the necessity of multiple costimulations and the variation of costimulation, despite redundancy. The existence of these many costimulation pathways may meet the need of at least three in vivo scenario, which are: (i) requirement of several signals simultaneously at any one time in responding T-cells, (ii) requirement of different signals at different times and/or stages of T-cell responses, or (iii) promotion of different effector functions (Th, Tc, Treg, Tmemory, etc.). (a) IgSF. Members of this family can be categorized into CD28-like molecules expressed on T-cells and B7-like molecules expressed on APCs. CD28 and its relatives including inducible costimulator (ICOS), CTLA-4, PD-1, CD7, and TIM1 are characterized by a single V-like Ig domain extended by a stalk from the T-cell surface (Fig. 12). They form homodimers and, except PD-1 (in 2q37.2), have their genes coded in the 2q33. On the other

Figure 12 Two superfamilies of T-cell costimulatory molecules. Costimulation molecules on T-cell side are interacting with their ligand– receptor counterparts on APCs. Two major families of well-characterized costimulation molecule pairs are: IgSF, such as CD28-B7, and TNFR superfamily, such as CD40L–CD40. Abbreviations: APCs, antigen-presenting cells; IgSF, immunoglobulin superfamily; TNF, tumor necrosis factor; TNFR, TNF-receptor.

medwedi.ru

100

Part One: General Considerations

hand, B7-like molecules, B7-1, B7-2, B7H, and PD-L1/2, are made of a distal V-like and a proximal C-like Ig domain and probably also form homodimers. They are coded in the 2q23 region. CD28 is the first, well-characterized costimulatory molecule expressed constitutively on the surface of both na€ve and activated T-cells. Currently, there are two known ligands, B7-1(CD80) and B7-2(CD86), which have different expression pattern and induction kinetics on APCs. Ligation of CD28 can reduce the number of TcRs that must be engaged for a response, lower the activation threshold, and allow a response to low-affinity peptide. CD28 signaling can also alter the balance between Th1 and Th2 cell differentiation and prevent the induction of nonresponsiveness (anergy) and cell death (apoptosis). Although it has been shown that na€ve or primary T-cell responses are dependent on CD28 costimulation for optimal production of cytokines and proliferation, it is now also clear that secondary or memory T-cell responses are less dependent or independent of CD28 molecule. Other costimulatory molecules, such as ICOS, can substitute CD28 to provide necessary costimulation for memory T-cell activations. CTLA-4 was identified soon after CD28 as one of its close relatives, and binds to the same ligands but with much higher affinity. In contrast to CD28, CTLA-4 was not expressed constitutively on T-cells: resting T-cells express little surface CTLA-4, but its surface level is induced upon T-cell activation (particularly by CD28 costimulation) via both redistribution of an intracellular pool and increased synthesis. Most importantly, ligation of CTLA-4 delivers a negative signal to T-cells and inhibits T-cell proliferation and IL-2 synthesis in response to stimulation with anti-CD3 and anti-CD28 antibodies in vitro. Interference of CTLA-4–B7 interaction enhances T-cell responses, both in vitro and in vivo. Deficiency of CTLA-4 in mice leads to the development of massive lymphoadenopathy, autoimmunity, and early death. Thus, it has been hypothesized that CTLA-4 sets the threshold of T-cell activation and is the master switch of self-limiting T-cell activation: na€ve T-cells without CTLA-4 are activated by TcR and costimulatory signals, which accompany the induction of CTLA-4 to prevent overreaction of T-cells and eventually shut down T-cell response. The existence of CD28-independent costimulation pathways is indicated by the facts that mice lacking CD28 are still able to mount effective responses to some virus, acutely reject various kinds of allografts, and produce near normal levels of cytokines by their T-cells, particularly memory type, upon activation. ICOS was first identified in a screen for unique molecules expressed on human peripheral blood T-cells following activation. Thus, unlike CD28, ICOS is expressed on activated but not resting na€ve T-cells. Memory T-cells express ICOS constitutively, and its level is further increased following activation. Although ICOS costimulation might support activation of na€ve T-cells, it seems to be more important for enhancing ongoing and recallproliferative responses. ICOS costimulation does not induce IL-2 production but increases secretion of IL-4, IL-5, IL-10, IFN-g, and TNF-a, suggesting its primary role in inducing T-cell effector function. ICOS is structurally related to CD28 but does not bind to B7-1 and B7-2 molecules. Instead, it binds to a novel B7 family member, B7H, which is regulated differentially from B7-1 or B7-2 on APCs. Importantly, B7H expression can be induced in fibroblasts in culture, and in nonlymphoid tissues in mice, by treatment with the inflammatory agents LPS and TNF-a, whereas B7-1 or B7-2 are not induced in these same tissues by similar

treatment. Thus, inflamed peripheral tissues would be able to stimulate memory, but not na€ve, T-cells, due to the differential regulation of the ligands for CD28 and ICOS. PD-1 was initially cloned due to its involvement in apoptosis. Unlike other members of the CD28 family, PD-1 is widely expressed on hematopoietic-derived tissues. It expresses on T-cells, B-cells, monocytes, and myeloid cells following activation. The functional role of PD-1 is not completely understood. Although, like CTLA-4, it may deliver an inhibitory signal to T (and B)-cells, it works only under certain conditions and in certain aspects of immune responses. PD-1–deficient mice become ill owing to the inappropriate activation of lymphocyte, particularly production of autoreactive IgG3 (C57Bl/6) or IgG1 (Balb/c). In marked contrast to CTLA-4–deficient mice, all of which died within three to four weeks after birth, severe autoimmune symptoms are only observed in half of the PD-1 deficient mice and occur late after birth (up to 14 month). All of these suggest that PD-1 is not the primary inhibitory signal for T-cells, and is less potent compared with CTLA-4. The ligand for PD-1 was recently cloned (B7H1) and shares structural homolog with B7-1 or B7-2. It is constitutively expressed on both nonlymphoid tissues, including heart, lung, kidney, skeletal muscle, and placenta, and some hematopoietic tissues, such as macrophage and T-cells. Its expression is upregulated on DCs by LPS and IFN-g, as well as on nonlymphoid tissues such as keratinocytes. The expression pattern of B7H1 suggests that PD-1 might function to inhibit lymphocyte responses in nonlymphoid tissues. (b) TNF/TNFR Superfamily. The first member of this large family of costimulatory molecules is CD40–CD40L pair. The TNFR-like CD40 has been known for long-time presence on B-cells and other APCs, including DCs, monocytes, macrophages, mast cells, fibroblasts, and endothelial cells. Its engagement is critical for B-cell clonal expansion, as well as APC activation that enables them to activate na€ve T-cells. Its ligand, TNF-like CD40L, is induced on na€ve T-cells within a few hours of their activation by TcR-mediated signal 1 alone, and this induction is enhanced by CD28-mediated signal 2. The ligation of CD40L on T-cells leads to the upregulation of cell surface CD28 expression and later to induce ICOS. The importance of this costimulatory pathway is manifested by the disorders observed in the human hyperIgM syndrome, an X-linked immunodeficiency where the CD40L molecules is nonfunctional. Using CD40 or CD40L KO animals or blocking antibodies, it has been shown that CD40–CD40L interactions are critical for the development of the CD4 T-cell–dependent, cell-mediated immune responses at multiple levels. Lack of these interactions results in greatly reduced activation of CD4 T-cells resulting from inefficient priming and expansion of antigen-specific T-cells, due to a lack of induction of costimulatory activity on APCs and a failure in the activation of APC to produce cytokines such as IL-12. This will lead to the impairment of many CD4 T-cell effector functions, including help for B-cells and activation of monocytes, macrophages, and DCs, which in turn affect the activation of CD8 T-cells. Additionally, CD40–CD40L interaction upregulates expressions of adhesion molecules on endothelia, and its blockade in vivo will inhibit the migration of T-cells to secondary lymphoid organs and inflamed tissues. At the effector stage, CD40– CD40L interactions could amplify immune responses by upregulating costimulation and promoting secretion of inflammatory cytokines. Thus, CD40–CD40L interaction is mandatory for primary APC–T-cell cooperation, and plays

Chapter 5: Physiologic Basis of Transplantation

a central role in CD4 T-cell help to B-cells, as well as cytotoxic CD8 T-cells. This family of costimulatory molecules is expanded rapidly in recent years, and now it includes at least five other pairs (TNFR–TNF) (30): OX40–OX40L, CD27–CD70, CD30– CD30L, 4-1BB–4-1BBL, and HVEM–LIGHT (Fig. 12). A simplified pattern of the cellular expression of these new, paired molecules on lymphocytes is that TNFR family members are expressed by T-cells, and their TNF-family ligands are expressed by APCs. However, each ligand can also be expressed by T-cells. Additionally, there are two patterns of expression kinetics of these TNFR family members by na€ve T-cells: constitutive low-to-medium level expression, such as CD27 and HVEM, and inducible expression, which occurs several hours after signal 1 engagement and often peaks for two to four days into the responses, such as OX40, 4-1BB, and CD30, depending on antigens and the environment during T-cell responses. None of the TNF-family ligands is expressed constitutively on T-cells. TcR-mediated signal 1 is sufficient to induce the inducible TNFR-family molecules, however, CD28 signaling augments their kinetics and levels. Corresponding to the receptor-like molecules on T-cells, their ligands on APCs also have two expression patterns. OX40L, 4-1BB, CD70, and CD30L are not constitutively expressed by resting or immature APCs, but are inducible 24 hours to several days after activation by CD40, LPS (on DCs), and BCR (on B-cells), coinciding with the peak level of expression of their receptors by T-cells. LIGHT is expressed by immature DCs, and unlike others, it is downregulated during the process of maturation. Thus, functionally, the constitutive expression of HVEM–LIGHT pair indicates their possible role in the initial activation of T-cells and APCs, while other inducible pairs involve more likely either in clonal expansion phase or to sustain the ongoing responses of T-cells. Adhesion Molecules. The ICAM-1 (114 kDa) contains five Ig-like extracellular domains, and is expressed on T- and Bcells, fibroblasts, and endothelial cells (Fig. 13). ICAM-1 contains the binding sites for the adhesion molecules LFA-1 and macrophage antigen-1 (Mac-1), both members of the b2 integrin family. The binding of LFA-1 to ICAM-1 may deliver a costimulatory signal to T-cells, thus enhancing the TcR-mediated signal for T-cell activation. ICAM-2 bears only two Ig-like extracellular domains, and can only bind to LFA-1. CD2 [T11, LFA-2, Tp50, and sheep red blood cell receptor (SRBC); 50 kDa] is expressed on mature T-cells, on 50% of thymocytes, and on NK. CD2 binds to a molecule that is structurally similar to itself: leukocyte function–associated antigen-3 (LFA-3, CD58; 55 kDa), which is expressed on a wide variety of hematopoietic cells. CD2 binding to LFA-3 is important for the binding of Th cells to APCs or CTLs to their targets. In addition to its adhesive function, CD2 plays an important role in T-cell activation, as evidenced by the ability of some anti-CD2 antibodies to stimulate T-cell proliferation and cytokine production. This led to the hypothesis that CD2 may mediate an alternate pathway for T-cell activation, independent of the TcR. The vascular cell adhesion molecule-1 (VCAM-1), expressed on activated endothelial cells, contains seven Ig-like extracellular domains. VCAM-1 is the ligand for very late activation (VLA)-4 (b1 integrin) expressed on T-cells. The VCAM-1–VLA-4 interaction is critical for T-cell migration from the blood stream into the sites of inflammation, and may further provide a costimulatory signal for T-cell activation.

101

Figure 13 Adhesion molecules of the immunoglobulin (Ig) gene superfamily. These are characterized by the presence of the Ig homology unit, demonstrated schematically as a loop that is stabilized by a disulfide bond (–S–S–), contributed by conserved cysteine residues. Members of this family include ICAM-1, ICAM-2, CD2, VCAM-1, CD28, and B7 molecules. Each molecule contains multiple Ig-like domains, a transmembrane region, and an intracytoplasmic segment. NH2 and COOH, amino- and carboxyterminal ends. Abbreviations: ICAM, intercellular adhesion molecules; VCAM-1, vascular cell adhesion molecule-1.

Selectins (lectin adhesion molecules), a family of three closely related proteins L-, E-, and P-selectin, provide a calcium-dependent specific recognition signals upon interaction with carbohydrate (31), but not with protein, leading primarily to the adhesion of leukocytes to endothelial cells. All three selectins are single chain, transmembrane glycoproteins that share similar structural features (Fig. 14A): first, a lectin-binding domain at the N-terminus, then an epidermal growth factor–like domain and a number of tandemly repeated domains homologous to the complement regulatory proteins, followed by a transmembrane domain and a short intracytoplasmic tail. The L-selectin (CD62L, MEL-14, LAM-1; 90 kDa) expressed on leukocytes serves as a homing receptor for lymphocytes to attach to lymph node– high endothelial venules. It also binds leukocytes to cytokine (TNF, IL-1, and IFN-g)-activated endothelial cells at the site of inflammation. E-selectin (CD62E, ELAM-1; 110 kDa) is exclusively expressed by cytokine-activated endothelial cells. Its ligand is a complex sialylated carbohydrate group related to Lex antigens. P-selectin [CD62P, PADGEM, guanosine monophosphate (GMP) -140; 140 kDa] is present in the secretory granules of platelets and endothelial cells. Upon activation of endothelial cells, P-selectins are rapidly distributed to the cell surface in order to bind circulating monocytes and neutrophils. P- and E-selectins recognize similar ligands. Integrin superfamily members are heterodimeric cell surface proteins composed of two noncovalently associated a (120–200 kDa) and b chains (90–110 kDa; Fig. 14B) (32). The integrin b chains contain tandem repeats of a cysteine-rich domain. The globular heads of the a chains contain a series of divalent cation–binding regions important for receptor function, because many integrins have been shown to

medwedi.ru

102

Part One: General Considerations

Figure 14 Schematic illustration of selectins and integrins. (A) The extracellular regions of L-, E-, and P-selectin consist of the characteristic lectin-binding domain and an epidermal growth factor–like domain, followed by a variable number of short consensus repeats similar to the complement-regulatory proteins. Each molecule contains transmembrane and short intracytoplasmic domains. (B) Integrins are heterodimeric complexes of noncovalently associated a and b chains, with characteristic globular heads that contribute to interchain linkage and ligand interaction. Stalks extend from the heads to the cellular membrane, followed by transmembranous and cytoplasmic segments.

require divalent cations for ligand binding. The extracellular domains of the two chains bind to a wide variety of ligands including extracellular matrix glycoproteins, including fibronectin and vitronectin, other cell surface proteins, and complement components. The three original integrin subfamilies were defined based on the b subunits, which were believed to bind several distinct nonoverlapping sets of a chains. Recently, at least eight forms of the b-chain have been identified; furthermore, several a chains have been shown to pair with more than one b subunit. The VLA molecules or b1 integrins (CD49a–f CD29) display six different a chains (CD49a–f) linked to the same b1 chain (CD29). VLA-4 (a4b1, CD49d CD29) mediates adhesion of T-cells to endothelial cells by binding to the VCAM-1. In addition, VLA-4 (a4b1, CD49d CD29) and VLA-5 (a5b1, CD49e CD29) bind to fibronectin, and VLA-6 (a6b1, CD49f CD29) binds to laminin in the extracellular matrix. Such interactions may be important for the retention of T-cells in the tissues following extravasation from the intravascular compartment. Further, the binding of VLA-4 to VCAM-1 and extracellular matrix proteins can provide costimulatory signals for T-cell activation. The three b2 integrins—LFA-1 (CD11a CD18), Mac-1 (CR3; CD11b CD18), and p150, 95 (CR4; CD11c CD18)— share the same b2 subunit (CD18) that combines with three different a chains (CD11a, CD11b, and CD11c). These molecules play an important role in the adhesion of lymphocytes to other cells, such as the APCs and vascular endothelium. Ligands for LFA-1 include ICAM-1 and ICAM-2 (members of the Ig gene superfamily). Mac-1 also binds to ICAM-1. Anti–LFA-1 antibodies inhibit a wide variety of lymphocyte functions including APC induced Th cell activation and CTL target cell lysis. This is presumably due to inhibition of the conjugate formation between the involved cells. TcR-specific stimulation results in functional modulation of integrins, resulting in an increase in their binding affinity to their corresponding ligands. The increased affinity may be caused by phosphorylation of the integrin intracytoplasmic tails. In addition, following ligand binding, integrins deliver stimulatory signals to cells. The critical role of the integrin function is demonstrated in the familial disease leukocyte deficiency-type 1, which occurs as a result of genetic

mutation of the b2 chain (CD18). Afflicted individuals display a deficiency in all b2 integrins, leading to recurrent bacterial and fungal infections due to lack of polymorphonuclear leukocyte accumulation and adhesion-dependent lymphocyte function. Adhesion molecules play an important role in the migration of cells from the vascular compartment to the sites of inflammation (33). Inflammatory cytokines (mainly TNF) induce this complex process leading to the activation of endothelial cells, which regulate the extravasation of neutrophils, monocytes, and T-cells. Endothelial cells release vasodilators such as prostacyclin (PGI2) and nitric oxide (NO), which increase blood flow at the inflammatory site. TNF production enhances PGI2 synthesis, increases NO production, and induces endothelial cell surface E-selectin expression. E-selectin–mediated interaction with neutrophils results in slowing and rolling of cells (Fig. 15). Endothelial cell expression of VCAM-1 and ICAM-1, which occurs approximately four to six hours after the initiation of the inflammatory response, is critical for the attachment of leukocytes. The T-cell ligand for ICAM-1 is LFA-1, and VLA-4 for VCAM-1, while neutrophils engage ICAM-1 through Mac-1. Chemokines, secreted by the endothelial cells under the effect of TNF-a such as IL-8 and monocyte chemotactic protein-1, induce leukocyte flattening and cell locomotion. TNF-a and IFN-g cause endothelial basement membrane changes that allow migration and extravasation of cells as well as other macromolecules such as fibrinogen. Once leukocytes enter the tissues, VLA-4, VLA-5, and VLA-6 encourage cell binding to the extracellular matrix proteins. The extravasation of neutrophils and monocytes accompanied by the deposition of fibrin result in induration at the site of inflammation or graft rejection. Such induration is characteristic of a delayed type hypersensitivity (DTH) reaction, which is apparent 18 hours after the deposition of antigen eliciting the inflammatory response, and reaches a maximum at 24 to 48 hours. Antigen-activated CD8þ or CD4þ T-cells can adoptively transfer DTH-like reactions. Monocytes deposited in the tissues differentiate into macrophages, which are the main effector cells in DTH. IFN-g is the main cytokine in DTH due to its macrophage activating capacity. IFN-g augments the phagocytic

Chapter 5: Physiologic Basis of Transplantation

Figure 15 Transendothelial migration of leukocytes. 1. Rolling: inflammatory cytokines (TNF) induce the expression of L- and E-selectins on endothelial cells, which initiate rolling of leukocytes. 2. Attachment: ICAM-1 expressed on endothelial cell surfaces binds to MAC-1 on neutrophils or LFA-1 on T-cells. VCAM-1 engages VLA-4 on T-cells. IL-8 and MCP-1 induce leukocyte conformational changes. 3. Migration: attached leukocytes migrate into the interstitial space. Abbreviations: ICAM, intercellular adhesion molecule; IL, interleukin; LFA, leukocyte function–associated antigen; MCP, monocyte chemotactic protein; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VLA, very late activation.

activity of macrophages and increases the expression of the high-affinity receptors for the Fc portion of Ig molecules, thereby enhancing phagocytosis of opsonized bacteria. Activated macrophages display more efficient APC function, express higher levels of class II, ICAM-1, and LFA-3, and release platelet-activating factor, prostaglandins, thrombin, transforming growth factor (TGF) -b, fibroblast growth factor (FGF), tissue factors that initiate the extrinsic clotting cascade, and other inflammatory mediators. DTH results in tissue destruction (necrosis) followed by angiogenesis and fibrosis when the antigen is eliminated. Dendritic Cells Dendritic cells are bone marrow–derived APC that are found both in lymphoid and nonlymphoid tissues. They are the most critical cellular component bridging innate and adaptive immunity (34). DCs at immature stage reside in most peripheral tissue, particularly at sites of interface with the environment, where they take up 1% to 2% of the total cell numbers. In the absence of ongoing inflammation and immune responses, DCs patrol constantly through the blood, peripheral tissues, lymph, and secondary lymphoid organs. Although they are capable to take up self- and non–self-antigens via endocytosis or phagocytosis, immature DCs are quite inefficient in presenting antigens and are not able to fully activate T-cells. They have to go through a maturation process, which is induced during infection or inflammation by bacterial or viral products, inflammatory cytokines, as well as some self-molecules, identified in recent literatures as endogenous danger signals. Via specific cell surface receptors (e.g., TLRs, CD40, TNFR, FcR), stimulated DCs dramatically increase their surface expression of T-cell costimulation molecules, and the efficiency of antigen presentation (by enhancing antigen uptake, intracellular transport and degradation, and the intracellular traffic of MHC molecules, leading to increased peptide loading half-life and delivery to the cell surface of MHC molecules). Matured DCs are the

103

most potent APCs and the only ones capable of activating na€ve T-cells and initiating adaptive immune response. Concomitant with the modification of their antigen presentation abilities, maturation also induces massive migration of DCs out of peripheral tissues. Alterations in the expression of chemokine receptors and adhesion molecules, as well as changes of the cytoskeleton organization, contribute this migration of DCs through afferent lymph to secondary lymphoid organs where they interact with T-cells. DCs represent a heterogenous cell population. Improved techniques for the isolation of DCs from various tissues have led to the identification of at least five types of DCs, based on their phenotypes and functions (35). They are myeloid or monocytoid DC (CD11cþCD1aþCD123–), plasmacytoid DC (CD11c–CD1a–CD123þ), Langerhans cell– derived DC (CD11cþCD1a–CD123–), B-cell–like DC, and follicular DC in humans, and CD8a- (myeloid) and CD8aþ DC, B-cell–like DC, plasmacytoid DC, and Langerhans cell–derived DC in murines. Although they all express MHC class II and CD40 (and CD11c in mice), different DC subsets and DCs at different maturation stages express distinct surface molecules and secrete different cytokines. Human plasmacytoid DC are the principal IFN-producing cells of the immune system, and monocytoid DC produce IL-12. In mice, although both CD8a– and CD8aþDC mature into potent immunostimulatory APCs, CD8aþCD11b-DC secrete IL-12 and prime na€ve CD4 T-cell secrete Th1 cytokines and promote antiviral immunity by inducing CTL via secretion of IFN-g; CD8-CD11bþDC, on the other hand, stimulate Th2 responses and secrete neither IL-12 nor IFN-g. In transplantation models, alloantigen presentation by immature DC has been shown to promote graft tolerance. Thus, during antigen presentation, DCs can determine selectively the type of induced immune responses.

Central Limb: Proliferation and Differentiation Although multiple effectors, both cells and molecules, contribute to allograft rejection, the most critical one is the T-cell. It is not only able to directly reject grafts by itself, but also influences other effectors in reacting to grafts. In this section, we will discuss both biochemical and structural mechanisms of alloreactive T-cell activation, in particular CD4þ T-helper subset.

T-Cell Activation Two Signal Hypothesis for T-Cell Activation The two-signal model was originally proposed by Bretscher and Cohn in 1970 as a hypothesis to account for self-tolerance in the peripheral. The current form of this model assumes that T-cells require two signals to be activated by APCs. The first signal is delivered via TcR upon antigen presentation. The second signal has two important features: it has no cognition of the antigen, and it can be produced by distinctive molecular interactions between an APC and a T-cell. Lymphocytes stimulated through the antigen receptor alone fail to produce cytokines, are unable to sustain proliferation, and often undergo apoptosis or become nonresponsive to subsequent stimulation. Early studies found soluble factors, such as cytokines (IL-1, IL-2, and IL-4), could enhance the activation of both T- and B-cells. Now, it is clear that interactions between receptor–ligand pairs of cell surface molecules on the responder lymphocyte and an APC represent the critical event, costimulation, in the activation process. The binding of TcR with a peptide-loaded MHC molecule is very brief. To fully activate a primary T-cell with signal 1 alone, it

medwedi.ru

104

Part One: General Considerations

has been calculated that the engagement of 8000 TcR were required. However, with the costimulation of CD28, the number of TcR engagements required is lowered to 1000 (36). Biochemically, the secondary costimulation may deliver a qualitatively distinct activation signal, or act synergistically with the first signal (see below for details). As discussed above, amultitude of costimulation molecules have been identified. Although hierarchy and redundancy exist, these different molecules may function in different types of T-cells (e.g., CD4, CD8, Th, Treg, and Tc) and/or at different stages of T-cell differentiation (na€ve, effector, and memory). The Immunological Synapse and Lipid Raft Effective TcR interactions with MHC–peptide complex occur in the nanometer-scale gap between T-cells and APCs, referred to as an immunological synapse (IS) (37). T-cell activation requires sustained interactions with APCs with signaling duration on the order of hours, while individual receptor–ligand pair between these cells has half-lives only on the order of seconds. IS provides a molecular organization that helps make the longevity and specificity of the T-cell–activation signaling possible. The mature IS has been defined by the bull’s eye arrangement of supramolecular activation clusters (SMACs) that form within a few minutes of T-cell–APC contact. SMACs are detected by fluorescence microscopy and appear as increased densities of specific molecules. The center of the bull’s eye or cSMAC is enriched with TcR (including CD3 and CD4/8) and MHC–peptide complexes. The ring of the bull’s eye or pSMAC contains the integrin LFA-1, its major counter-receptor ICAM-1, and CD2. The cSMAC also includes the signaling molecules on the T-cell cytoplasmic side of the IS, including protein kinase C y and the src family kinase lck (see below for detail). Interestingly, costimulatory molecule, CD28, is also localized in the cSMAC. The structural basis to form IS is the preexisting membrane domain, lipid raft, which segregates proteins and lipids into liquid-ordered domains with distinct biophysical properties. Experimentally, these membrane domains are relatively insoluble in Triton X-100 detergent at low temperature, which are also referred to as detergent-insoluble, glycolipid-enriched domains, or glycosphingolipid-enriched membranes. Crucial signaling proteins are enriched in these lipid rafts. They include palmitoylated or myristoylated src kinase, ras-related proteins, such as RAC and CDC42, and adaptor proteins, such as palmitoylated linker for activation of T-cells (LAT). TcR is only weakly associated with lipid rafts in unstimulated state. However, engagement of TcR with antigen promotes the entry of receptors into the lipid rafts, and early TcR-induced tyrosine phosphorylation is restricted within the lipid raft. Coreceptor CD4 and CD8 are strongly associated with lipid rafts and may play an important role in the initial alternations in the lipid and signaling environment of the TcR. Costimulation modulates lipid raft accumulation in IS such that CD28 coligation with TcR enhances the process, while CTLA-4 potently inhibits TcR and TcR–CD28–mediated raft expression. Biochemical Basis of T-Cell Activation As previously discussed, TcR is a multisubunit complex consisting of ligand recognition component of polymorphic ab chains noncovalently associated with the signal transduction component of invariant CD3-g, CD3-d, and CD3-e and TcRz chain dimer. All of these molecules are integral TcR components and as such are required for TcR expression. The nonpolymorphic signal transduction chains are

members of a family of immunoreceptor signal transduction subunits that contain signaling motif ITAM, as described above. Each of the CD3-g, CD3-d, and CD3-e subunits contain one ITAM, and TcRz contains three ITAM. The tyrosine residues within each ITAM become rapidly phosphorylated upon optimal TcR engagement (Fig. 7), which is mediated by two members of the Src family of protein tyrosine kinases (PTKs) found in T-cells. Lck is the predominant enzyme involved in ITAM phosphorylation, while Fyn also has this capacity. The phosphorylated ITAM becomes subject to binding by additional molecules, most importantly zetaassociated protein (ZAP)-70. ZAP-70 is a cytoplasmic PTK exclusively expressed in T-cells and NK cells. It contains two SH2 domains in its N-terminal, both of which are essential for its binding to two phosphorylated tyrosines in a signal ITAM. Once bound to the TcR, ZAP-70 is activated by phosphorylation at multiple sites mediated by the Src PTKs, which then acts as both kinase and binding sites for other proteins. The activated TcR is thus characterized by phosphorylated ITAMs associated with phosphorylated, activated ZAP-70 (Fig. 16) (38). One of the most critical substrates of ZAP-70 is LAT (39), which is a type-III membrane protein without a signal sequence. There are two Cys residues, which undergo palmitoylation and localize this protein to the plasma membrane. LAT contains a very short extracellular domain and a long cytosolic region with nine tyrosine residues. Tyrosine phosphorylations of LAT lead to recruitment of a number of key, downstream signaling molecules, including Grb2 family proteins, SLP-76, and phospholipase C-g1. Both Grb2 family proteins and SLP-76 are adapter molecules, which themselves do not have any enzyme activities but contain SH3 domain to recruit other effector molecules, including SOS, Cbl. Additionally, SLP-76 contains multiple tyrosine residues at its amino-terminals, which can be phosphorylated by ZAP-70 and become binding sites for other proteins with SH2 domains, noticeably Vav, Nck, and Itk. It was shown recently that Itk plays a critical role in the activation of PLCg1 recruited to LAT. PLCg1 catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate into inositol-1,4,5-triphosphate and diacylglycerol (DAG). Phosphatidylinositol 3 (PI3) induces release of Ca2þ from ER via its receptors. The deprivation of intracellular Ca2þ storage triggers the opening of the cytoplasmic Ca2þ release– activated Ca2þ channels and leads to influx of Ca2þ from the extracellular environment. Elevated intracellular Ca2þ activates calcineurin, a Ca2þ/calmodulin (CaM) -dependent phosphotase, which dephosphorylates NFAT family of transcription factors. Increase of DAG activates RasGRP and protein kinase y. Activated RasGRP directly interacts with Ras and induces guanosine diphosphate–guanosine triphosphate exchange, which may be involved in the initiation of extracellular signal–regulated kinase activation, leading to c-fos induction, a AP-1 component. Protein kinase y was shown to play an essential role in NF-kB activation via activation of IkB kinase (IKK)b that phosphorylates IkB proteins and induces their degradation. NFAT, AP-1, and NF-kB are all essential transcription factors for IL-2 production (Fig. 16), a hallmark of complete T-cell activation. Costimulation contributes to T-cell activation. The signaling pathways downstream of costimulation molecules have been difficult to characterize and have only recently begun to be elucidated. CD28 is the primary costimulation molecule for na€ve CD4 T-cells. Despite being short, its cytoplasmic domain contains multiple binding motifs for various signaling molecules, including PI3-kinase (PI3K,

Chapter 5: Physiologic Basis of Transplantation

105

Figure 16 Biochemical basis of T-cell activation. Following T-cell antigen recognition, the tyrosine residues within each immunoreceptor tyrosine-based activation (ITAM) become rapidly phosphorylated by Lck and Fyn. The phosphorylated ITAM become subject to binding by zeta-associated protein (ZAP-70). Once bound to the TCR, ZAP-70 is activated by phosphorylation at multiple sites mediated by the Src PTKs, which then act as both kinase and binding sites for other proteins. One of the most critical substrates of ZAP-70 is LAT, whose tyrosine phosphorylations lead to recruitment of a numbers of key downstream signaling molecules, including Grb2 family proteins, SLP-76, and phospholipase C-g1. SLP-76 contains multiple tyrosine residues at its amino-terminals, which can be phosphorylated by ZAP-70, and become binding sites for other proteins with SH-2 domains, including Vav, Nck, and Itk. Itk plays a critical role in the activation of PLCg1 recruited to LAT. PLCg1 catalyzes hydrolysis of PIP2 into IP3 and DAG. PI3 induces release of Ca2þ from ER via its receptors. The deprivation of intracellular Ca2þ storage triggers the opening of the CRAC and leads to influx of Ca2þ from the extracellular environment. Elevated intracellular Ca2þ activates calcineurin, a Ca2þ/calmodulin–dependent phosphotase, which dephosphorylates NFAT family of transcription factors. Increase of DAG activates RasGRP and protein kinase y. Activated RasGRP directly interacts with Ras and induces GDP–guanosine triphosphate (GTP) exchange, which may be involved in the initiation of ERK activation leading to c-fos induction, a AP-1 component. Protein kinase y plays an essential role in NF-kB activation via activation of IKKb that phosphorylates IkB proteins, and induces their degradation. NFAT, AP-1, and NF-kB are all essential transcription factors for IL-2 production, a hallmark of complete T-cell activation. Abbreviations: CRAC, cytoplasmic Ca2þ release–activated Ca2þ channels; DAG, diacylglycerol; ER, endoplasmic reticulum; GDP, guanosine diphosphate; IL, interleukin; IP3, inositol-1,4,5-triphosphate; PIP2, phosphatidyl inositol 4,5-bisphosphate.

via its adaptor subnit p85, SH2), ITK (SH3), LCK (SH3), and GRB2/GADS (SH2 and SH3). CD28 phosphorylation subsequent to TcR activation is required for the recruitment of these proteins. Three intracellular signal transduction pathways have been attributed biochemically to the costimulatory effects of CD28 (29). Central to all three pathways are the D3 lipid products of PI3K, phosphatidylinositol (3,4)bisphosphate and phosphatidylinositol (3–5) trisphosphate, which anchor to the inner face of the plasma membrane where they bind and recruit various proteins with pleckstrin-homology domains. (i) Phosphoinositide-dependent kinase–protein kinase B (PKB)–glycogen synthase kinase-3 pathway prevents T-cell apoptosis, increases cellular glycolysis, and enhances IL-2 gene transcription [via nuclear factor of activated T-cells (NFAT)]. (ii) VAV-MEKK1-JNK pathway also upregulates IL-2 transcription [via activating protein-1 (AP-1)], and additionally induces cytoskeleton remodeling. (iii) PKB–MEKK1–MAGUK–mediated NF-kB pathway, as the third avenue, also contributes to the induced transcription of IL-2 and some antiapoptosis genes. Enhanced degradation of inhibitor of NF-kB and increased activity of IKK promotes translocation of NF-kB to the nucleus after CD28 ligation (Fig. 16). T-Helper Cell Activation and Differentiation Central to host adaptive immunity, Th cell activation and differentiation defines the nature of developing immune responses. Although oversimplified, the paradigm that

activated CD4 T-cells differentiate into distinctive subsets producing different arrays of cytokines provides us vital insights into the pathogenesis of immune-mediated diseases (40). As we discussed above, T-cell activation requires two essential signals to drive their proliferation. At the same time, the environment of T-cell activation provides a third signal, which will determine the characters of the descendent T-cells. It is now clear that Th differentiation is regulated at multiple levels. Although the natures of antigens and costimulation molecules, as well as the key transcription factors all play important roles, cytokine condition is the most important regulator in initiating the differentiation processes and determining the types of Th cells generated (41,42). The classical Th subsets include Th1 and Th2 (Fig. 17). Th1 effector cells produce IFN-g and mediate macrophage activation and DTH, which are collectively termed proinflammatory or cell-mediated immune responses, critical to control intracellular pathogens. In contrast, Th2 effector cells produce IL-4 or IL-5, promote secretion of IgG1 and IgE from B-cells, and mediate immediate-type hypersensitivity reactions (allergy), which are collectively termed humoral immunity. Recently, a third type of Th cell has been defined as Treg, which exerts immune regulatory functions. IL-12 is the classical cytokine used for in vitro differentiation of Th1 cells from naive precursors. It is a heterodimeric cytokine composed of two subunits, p35 and p40. The p35 subunit is expressed ubiquitously and

medwedi.ru

106

Part One: General Considerations

Figure 17 Cytokine induced differentiation of T-helper cells. The classical Th subsets include Th1 and Th2. Th1 effector cells produce IFN-g and mediate macrophage activation and DTH, which are collectively termed proinflammatory or cell-mediated immune responses. In contrast, Th2 effector cells produce IL-4 or IL-5, promote secretion of IgG1 and IgE from B-cells, and mediate immediate-type hypersensitivity reactions (allergy), which are collectively termed humoral immunity. IL-12 is the classical cytokine used for in vitro differentiation of Th1 cells from niave precursors. The transcriptional factor Stat4 is critical to IL-12R signaling, which upon activation by phosphorylation may directly interact with IFN-g promoter and induce its production. T-bet is another important transcriptional factor that mediates the positive feedback loop of IFN-g production. IL-4 is the major known factor regulating Th2 differentiation. TSLP in human can activate DCs to prime na€ve CD4 T-cells to produce IL-4 and other Th2 cytokines. IL-4 binding to their receptors activates Stat6, which is the central transcriptional factor driving Th2 differentiation. The activated Stat6 influences the remodeling of the IL-4 or IL-13 locus and induces another transcription factor GATA-3. GATA-3 can directly bind to the promoters of IL-5 and IL-13 genes and activate their transcriptions. Abbreviations: DTH, delayed type hypersensitivity; IFN, interferon; TSLP, hymic stromal lymphopoietin; IL, interleukin; MHC, major histocompatibility complex; TcR, T-cell receptor; TNF, tumor necrosis factor; CTL, cytotoxic T-lymphocytes; Ig, immunoglobulin.

constitutively at low levels, while the p49 production is highly regulated and induced by products of infectious microorganisms in monocytes, neutrophils, macrophages, and DCs, via TLRs. IL-12 is also induced by the engagement of CD40 on APCs. The IL-12 receptor expressed by T-cells consists of two subunits, b1 and b2, both of which are not expressed in resting T-cells but induced upon T-cell activation. Critical to IL-12R signaling is the transcriptional factor Stat4, which upon activation by phosphorylation may directly interact with IFN-g promoter and induce IFN-g production (Fig. 17). T-bet is another important transcriptional factor, which mediates the positive feedback loop of IFN-g production. Synergized with TcR signaling, IFN-g activates Stat1 and upregulates expression of T-bet, which alters the chromatin structure of IFN-g locus and stabilizes expression of IL-12Rb2. This permits the cells’ continued responsiveness to IL-12, which further induces IFN-g production and Th1 differentiation (43). Other cytokines produced by APCs in response to pathogens and capable of inducing Th1 differentiation include type-1 IFNs, IL-18, and two newly identified IL-12 homolog IL-23 and IL-27. In contrast to the multiplicity of cytokines produced by DC to promote Th1 differentiation, there are few clear initiators produced by APCs in response to pathogens to drive Th2 differentiation. In human, it appears that thymic stromal lymphopoietin, which is highly expressed by epithelial cells, can activate DCs to prime na€ve CD4 T-cells to produce IL-4 and other Th2 cytokines (41). The dose of antigen is another determinant that may initiate Th2 differentiation. Low doses of antigen induce Th2 polarization. Currently, IL-4 is the major known factor regulating Th2 differentiation, both in vitro and in vivo. However, it is unclear as to which sources, including eosinophils, mast cells, and NK1.1 T-cells, and CD4 T-cells polarizing towards Th2, produce the initiating IL-4. Na€ve CD4 T-cells stimulated through TcRs in the presence of IL-4 develop into Th2 effector cells capable of producing IL-4, IL-5, and IL-13. IL-4 is also a potent suppressor of IFN-g–producing Th1 cells. Two types of IL-4 receptors exit, both using IL-4Ra chain.

The type I receptor comprises the IL-4Ra and the common g chain, and the type II receptor comprises IL-4Ra and IL-13R. IL-4 binding to either of these receptors activates Stat6, which is the central transcriptional factor driving Th2 differentiation (Fig. 17). The activated Stat6 influences the remodeling of the IL-4 or IL-13 loci, and induces another transcription factor GATA-3 (43). GATA-3 can directly bind to the promoters of IL-5 and IL-13 genes and activate their transcriptions. GATA-3 does not affect IL-4 gene expression as a cis-acting transcriptional regulator, but rather by influencing chromatin remodeling, as T-bet to IFN-g gene. Another transcription factor preferentially expressed in Th2 cells is the proto-oncogen c-Maf, which strongly transactivates the IL-4 promoter but not the IL-5 or IL-13 promoters. Other cytokines capable of inducing Th2 differentiation include IL-13 and a newly described cytokine IL-21, related to IL-2/-4/-15 family.

Alloimmune Recognition Allorecognition refers to T-cell recognition of genetically encoded polymorphisms between individuals of the same species. The principal targets of the allorecognition are MHC molecules. Additionally, minor histocompatibility antigens, peptides derived from allelically polymorphic host proteins, presented in the groove of MHC class I and II are also recognized by host T-cells. Vigorous T-cell responses initiated by multiple T-cell clones expressing a wide variety of receptor genes in response to alloantigen are the essential components of graft rejection. In contrast to the low frequency of T-cells (< 0.1%) responding to nominal antigens, as much as 10% of host T-cells can respond to alloantigen. Molecular Basis of Allorecognition The a.a. sequence variation between donor and recipient polymorphic class I or class II MHC alloantigens induces rejection. This variability is mainly confined to a.a. present on the top, sides, and floor of the peptide-binding groove of MHC molecules (Fig. 18A) (44). Polymorphic a.a. residues

Chapter 5: Physiologic Basis of Transplantation

within the peptide-binding groove serve as sites for peptide binding and/or TcR recognition, with the TcR recognizing a complex formed of a peptide anchored in the peptidebinding groove (Fig. 18A) (45). Normally, thymic selection allows for a T-cell repertoire that is tolerant to self-peptides presented on self-MHC (Fig. 18B, Panel 1), but is activated by foreignc peptides presented on self-MHC molecules (Fig. 18B, Panel 2). Thus, MHC–peptide complexes that exhibit a.a. differences from self-peptide–MHC complexes trigger the alloimmune response (46). T-cells recognize alloantigens either as intact molecules expressed on the graft (direct recognition) or as processed allopeptides presented by self-MHC (indirect recognition) (47–49). Acute allograft rejection is conventionally thought to be mediated largely by direct recognition of allo-MHC– peptide complexes, which is a unique type of immune

Figure 18 Molecular basis of allorecognition. (A) TcR recognition sites. Polymorphic amino acid (a.a.) present in the MHC peptide-binding groove serve as sites for peptide and TcR binding. The TcR binds to a.a. present in both the peptide and the MHC-binding groove. (B) Direct recognition. Host TcRs are tolerant to self-MHC molecules presenting self-peptides (Panel 1), but are reactive to self-MHC molecules presenting foreign peptides (Panel 2) or allo-MHC–peptide complexes that resemble foreign peptide self-MHC complexes (Panel 3). (C) Indirect recognition. MHC alloantigens are processed and presented as allopeptides on self-MHC molecules to stimulate host T-cells. Abbreviations: APC, antigen-presenting cell; TcR, T-cell receptor; MHC, major histocompatibility complex.

107

response occurring only in allogeneic transplantation settings. The vigorous response observed when MHC-incompatible lymphocytes are cocultured (mixed lymphocyte reaction, MLR) is the result of this direct allorecognition. In the model of direct recognition (Fig. 18B), it is believed that the three-dimensional surface determinant formed by alloMHC–peptide complex (Fig. 15B, Panel 3) resembles that of a foreign peptide bound to self-MHC (Fig. 15B, Panel 2), which optimally binds to and activates host TcR, but differs from the self-MHC–peptide complex to which the T-cell is tolerant (Fig. 18B, Panel 1). Thus, direct recognition of alloantigens represents cross-reactivity for a TcR selected to recognize foreign antigen in the context of self-MHC. The presence of multiple a.a. differences between allo-MHC– peptide and self-MHC–peptide complexes generates numerous determinants that trigger multiple, cross-reactive T-cell clones. An important concept arising from the direct recognition model is that alloreactive T-cells are the same cells involved in foreign antigen recognition. Thus, the allospecific and antigen-specific T-cell–repertoires are one and the same. There are two major hypotheses to account for the unusually high precursor frequency of alloreactive T-cells involved in this particular antigen recognition pathway (49,50). The first one (high determinant density) proposes that the ligand of the alloreactive T-cells is the allogeneic MHC molecule itself, independent of what peptides are bound. Thus, every foreign MHC molecule of a given type could act as a ligand for the alloreactive T-cells, creating a very high ligand density. As a consequence, the affinity of the alloreactive T cell’s receptor could afford to be substantially lower than that required for a peptide– self-MHC complex, thereby calling into play the alloreactive T-cell–repertoire T-cells with low, medium, and high affinity, and creating a high precursor frequency. The second hypothesis (multiple binary complex) suggests that alloreactive T-cells are specific for individual peptide–allo-MHC complexes. Given that MHC molecules at the cell surface are known to be occupied by a diverse array of peptides, a single allogeneic MHC molecule could stimulate a large range of alloreactive T-cells, each specific for an individual peptide–MHC complex. Despite these hypotheses, the role of direct allorecognition in vivo has not been definitively proven until recently. It is now also realized that the relevance of na€ve direct alloreactive T-cells in rejecting allografts may be limited to the very early stage of transplantation due to the availability of donor-derived DCs. On the other hand, recent evidence suggests that indirect recognition plays an important role in both the initiation and amplification of the rejection process (47,51). In the indirect recognition model, class I or class II MHC alloantigens undergo cellular digestion, processing, and presentation as allopeptides by host APCs (Fig. 18C), in a similar fashion to foreign antigens. Thus, peptides derived from MHC alloantigens trigger the alloimmune response when presented on self–class II. A single alloantigen may produce multiple peptides exhibiting variable lengths and a.a. composition. Each cell can display up to 104 copies of an individual peptide, and up to 102 to 103 different peptides bound to the same MHC molecule (46). Furthermore, each peptide may specifically bind to different MHC molecules. It is estimated that a heterozygous individual can express 10 to 20 different class II and six different class I molecules per cell. Thus, binding of numerous selfpeptides to allo-MHC molecules, or conversely, processing and presentation of multiple allo-peptides derived from allo-MHC molecules on self-MHC molecules result in a vast

medwedi.ru

108

Part One: General Considerations

diversity of MHC–peptide complexes that differ from selfMHC–peptide complexes. This diversity accounts for the large number of T-cell clones responding to a single alloantigen. Nevertheless, several reports have observed that one or several Vb segments of the responding TcRs recur with a high frequency (52), suggesting the dominance of some epitopes displayed by the MHC–peptide complexes in triggering the alloimmune reaction. The model of indirect alloantigen recognition is currently under intense investigation because recent evidence suggests that modified MHC-derived allopeptides may deliver an inhibitory (53) rather than an immunogenic signal to the TcR that results in tolerance, rather than rejection of allografts (54,55). Cellular Basis of Allorecognition A unifying perspective in the alloimmune response is that rejection is initiated by disparate histocompatibility antigens (class I, class II, or both), which activate cytokine-producing Th cells, and is executed by cytokine-dependent cytolytic lymphocytes (CTL), although many phenotypes of cells may participate. The mixed lymphocyte culture (MLC) reaction (Fig. 19) seems to provide an in vitro correlate of the in vivo rejection response to dissect the contribution of individual elements. MLC Reaction. A ‘‘two-way’’ allogeneic MLC is induced by culturing mononuclear leukocytes (T-cells, B-cells, mononuclear phagocytes, and DCs) obtained from peripheral blood of one individual (donor cells) with a similar population of cells obtained from another individual (recipient cells). These cultures display proliferation of both cell populations, if there are allelic differences at MHC loci. In a ‘‘one-way’’ MLC, donor lymphocytes are gamma irradiated to inhibit their proliferation, thereby allowing one to selectively measure the proliferative response of responder host cells (measured by 3H-thymidine incorporation) toward stimulator donor cells. Two major populations of alloreactive

Figure 19 Mixed lymphocyte culture (MLC) reaction. The MLC is an in vivo determination of histoincompatibility. Proliferative responses of responder lymphocytes toward donor stimulators are determined by 3H-thymidine incorporation.

T-cells emerge during the MLC. The first is IL-2–producing CD4þ T-cells specific for allogeneic class II molecules (HLADR, DP, and DQ), which undergo the proliferative response. In practice, HLA-D disparity is detected by the proliferative response of recipient to donor cells. The magnitude of the proliferative response seems to correlate well with the length of graft survival: living, related donor–recipient combinations producing high MLC stimulation indicative of a significant class II Ag mismatch have a lower one year survival than low MLC responders (56). However, treatment with cyclosporine (CsA) and prednisone resulted in excellent graft survival in MLC high-responder, living, related recipients (56). The second cell type CD8þ T-cells function as cytolytic T-cells–recognizing foreign class I MHC product namely HLA-A, B, or C. Each individual CTL is specific for only one class I MHC gene product. However, the bulk population contains CTLs directed against most class I differences between the stimulators and responders. CTLs produce IL-2, IFN-g, TNF-a, and LT. It is the cooperation between these two distinct cell populations that ultimately leads to allograft destruction. It is emphasized that the functional subdivision of alloreactive T-cells into CD4þ helper and CD8þ CTLs is not absolute; both CD4þ CTLs and CD8þ helper cells have been identified to participate in MLR response.

Cytokine Network Cytokines are a diverse group of proteins that regulate both the specific and nonspecific phases of the immune response. They are produced by a variety of cells and act on target cells in an autocrine (same secreting cell), paracrine (nearby cell), or endocrine (distant cell) fashion. Their short-lived effect is mediated by their binding to high affinity receptors on a wide variety of cells. Most cytokines are pleiotropic, where a single cytokine exhibits a wide range of biological effects on various tissues and cells. Conversely, a single cell has different receptors for multiple cytokines and can interact with more than one cytokine. Cytokines also function in a redundant fashion; different cytokines act on the same cell to produce similar effects. This complex, intercellular cytokine network allows T, B, and/or hemopoietic cells to be differentially activated and to produce varied responses. Based on their origin, sequence of discovery, and chromosome location, cytokines have been subdivided as ILs, IFNs, colony-stimulating factors (CSFs), TNFs, TGFs chemokines, and other growth factors (Table 3) (57). Structurally, cytokines may be grouped into large families that share conserved motifs or sequence homologies. For example hematopoietins comprise the set of molecules IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, and IL-12, granulocyte macrophage–colony-stimulating factor (GM–CSFq), granulocyte– colony-stimulating factor, and erythropoietin. These molecules contain a four a-helix bundle motif, which is also shared by growth hormone prolactin, and a ciliary neurotrophic factor (58). Similarly, IL-1a, IL-1b, FGF, and keratinocyte growth factor exhibit a b-trefoil motif, whereas NGF, TGF-b, and platelet-derived growth factor assume a cysteine knot motif (two pairs of antiparallel b-strands anchored by three cysteine bridges) (59). Table 4 illustrates the most important cytokines and their prominent features. Functionally, cytokines may be organized into three broad overlapping categories: cytokines that influence T- and B-cell activation, cytokines that mediate nonspecific immunity and inflammation, and cytokines that stimulate hematopoiesis (60).

Chapter 5: Physiologic Basis of Transplantation

Table 3 Cytokine Families Interleukins IL-1a, b IL-2 IL-3 IL-4 IL-5 IL-6 IL-7 IL-9 IL-10 IL-11 IL-12

CSFs and TNFs

Interferons IFN-a IFN-b IFN-g

Chemokines

TGF-b

GM–CSF G–CSF M–CSF EPO TNF-a LT (TNF-b) LT-b

TGF-b1 TGF-b2 TGF-b3 TGF-b4 TGF-b5 Activins Inhibins BMPs

IL-8 MCP-1

Growth factors EGF TGF-a FGF KGF PDGF NGF

Abbreviations: BMP, bone morphogenic protein; CSF, colony-stimulating factor; EPO, erythropoietin; EGF, epidermal GF; FGF, fibroblast GF; GF, growth factor; G–CSF, granulocyte-CSF; GM–CSF, granulocyte macrophage–CSF; IL, interleukin; IFN, interferon; KGF, keratinocyte GF; LT, lymphotoxin; M–CSF, macrophage–CSF; MCP, monocyte chemotactic protein; NGF, nerve GF; TGF, transforming growth factor; TNF, tumor necrosis factor; PDGF, platelet derived GF.

Efferent Limb: Alloreactive Effectors and Graft Destruction The rejection process (Table 5), which is initiated by Ag recognition and lymphocyte activation, is ultimately effected by: (a) antigen-specific cytotoxic T cells reacting specifically

109

with donor class I (CD8 CTL) or class II (CD4 CTL) Agbearing cells; (b) antigen-nonspecific effector cells activated by a lymphokine mechanism, e.g., macrophage (61); and/or (c) humoral antibodies, including a variety of complementdependent and lymphocyte-dependent moieties. As we discussed above, the outcome of T-cell recognition of antigens depends on the nature of cellular interactions and the surrounding milieu. In vivo, a third dimension of T-cell activation, i.e., location, also determines the outcome of this antigen encounter, as shown recently that peripheral secondary lymphoid organs, i.e., LN and spleen, are critical for eliciting alloimmune responses after transplantation (62). Clinically, graft rejection is classified on the basis of its timing as hyperacute, accelerated, acute, or chronic.

Multiple Pathways for Allograft Rejection Central to the allograft rejection cascade is the activation of alloreactive T-cells. After organ transplantation, there are two-way traffics of lymphocytes in and out of the graft, directed by proinflammatory chemokines or cytokines. Critical to the acute graft rejection, donor DCs migrate to recipient’s draining LNs or spleen to initiate the activation of na€ve alloreactive T-cell, directly recognizing alloantigens. At the same time, recipient’s DCs travel through the graft, pick up and process donor antigens, and present to na€ve alloreactive T-cell, indirectly recognizing alloantigens in the recipient’s draining LNs or spleen. While alloreactive CD4 T-cells are activated by DCs only, the alloreactive CD8 T-cell

Table 4 Major Cytokines and Their Function Cytokine

Gene number

IL-1 (17 kDa) Monomer

2(IL-1a IL-lb)

IL-2 (17 kDa) Monomer

1

IL-3 (26 kDa) Monomer IL-4 (20 kDa) Monomer EL-5(20kDa) Homodimer IL-6 (26 kDa) Monomer IL-7 (25 kDa) Monomer IL-10 (18kDa) Homodimer

1 1 1 1 1 1

IL-12 (40 kDa) Heterodimer

2

Type I IFN (a, b)(18 kDa) Monomer

20 IFN-a 1 IFN-b

Type II (IFN-g) (24 kDa) Homodimer

1

TGF-b (14 kDa) Homodimer Chemokines (8–10 kDa) Monomer

Multiple Multiple

TNF (17 kDa) Homotrimer

1

LT (TNF- b)(24 Kda) Monomer GM-CSF (22kDa) Homodimer

1 1

M-CSF (40 kDa)

1

G-CSF (19 kDa)

1

Cell source

Function

Macrophages, APCs

Facilitates activation of Th cells, acute phase reactants CD4 þ T cells Autocrine and paracrine T cell growth and differentiation, activation of NK and B cells CD4 þ T cells Growth and differentiation of hematopoietic stem cells CD4 þ T cells B-cell differentiation, IgE production, mast cell growth T cells B-cell and eosinophil differentiation, IgA production Macrophages, Th cells B-cell differentiation, acute phase reactants Bone marrow, stromal cells Growth and differentiation of B-cell progenitors T cells Inhibit TNF, IL-1 production by macrophages, B cell activation Macrophages Activation of NK cells, CTL activation, Th1 differentiation Macrophages a fibroblasts b Inhibit viral replication, cell proliferation, increase class I expression and NK activity T cells Activation of macrophages, T, B, NK, and endothelial cells. Increases class I and class II expression, anti-viral activity Macrophages, T cells Inhibition of macrophages and T cells Endothelial cells, T cells, phagocytes, Leukocyte chemotaxis, activation fibroblasts Macrophages, T cells Activation of neutrophils, endothelial cells, fever acute phase reactants, cachexia T and B-cell stimulator Activated T cells Similar to TNF Endothelial cells, T cells, phagocytes, Acts on marrow progenitors for growth and fibroblasts differentiation of granulocytes and monoclear phagocytes. Granulocyte activation Phagocytes, fibroblasts, endothelial Differentiation to mononuclear phagocytes cells Phagocytes, fibroblasts, endothelial Differentiation granulocytes cells

Notes: Mononuclear phagocytes include monocytes and macrophages; granulocytes include esinophils, basophils and neutrophils. Abbreviations: CSF, colony stimulating factors; CTL, cytotoxic T-lymphocytes; Ig, immunoglobulin; IL, interleukin; kDa, kilodalton; NK, natural killer cells; TNF, tumor necrosis factor.

medwedi.ru

110

Part One: General Considerations

Table 5 Clinical Types of Rejection Rejection

Time course

Clinical signs and symptoms

Mechanism

Pathology

Hyperacute

Sudden onset, min/hr after vascularization

Abrupt loss of function; no perfusion

Humoral with preformed anti-HLA antibodies

Accelerated

Rapid loss of function, 72–100 hr after transplantation

Abrupt loss of function; tender, swollen graft

Acute

First 3 mo after transplantation

Graft swelling, fever, and oliguria

Cellular presensitization: destruction by specific Tc cells or ADCC Cellular; Tc cells and DTH mechanism

Fibrin thrombi within arterioles. Endothelial sloughing, platelet aggregation Interstitial hemorrhage. Fibrinoid necrosis of small arterial vessels

Chronic

Gradual decline in graft function

Progressive loss of function, hypertension, and glomerulopathy

Humoral

Interstitial and perivascular mononuclear infiltration, tubulitis, and interstitial edema Obliterative vascular changes, interstitial fibrosis

Response to therapy () Irreversible

()

(þ) Reversible

() Irreverisble

Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; DTH, delayed-type hypersensitivity; HLA, human leucocyte antigen.

activation may require additional CD4 help, which is either cytokine, such as IL-2, or costimulatory interaction with DCs, such as CD154–CD40. The activation of alloreactive B-cells is mediated by activated CD4 T-cells via direct CD154–CD40 interactions. Activated T-cells are now able to infiltrate into the graft and exert their effector functions (63). Cytotoxic CD8 T-cells recognize donor MHC class I molecules expressed on the graft, and kill the cells preferentially by the perforin/granzyme pathway; cytotoxic CD4 T-cells, on the other hand, recognize donor class II molecules, which can be induced by inflammatory cytokines on certain types of cells, e.g., endothelia, and kill the cells by the Fas/FasL pathway. Additionally, activated T-cells, in both direct as well as indirect allorecognition pathways, produce proinflammatory cytokines, such as IFN-g, which induce the delay-type hypersensitivity reaction where macrophages release toxic molecules, e.g., NO, TNF-a, and oxygen species. Antibodies reactive to donor MHC molecules will mediate complement activation, such C6, or antibodydependent cell-mediated cytotoxicity, e.g., FcR-mediated NK cytotoxicity. While the cytotoxic T-cell–mediated allograft rejection is the dominant effector mechanism of Th1-type alloimmune response, Th2-type immune response is also able to reject allografts. In addition to alloreactive antibodies, IL-4, IL-5, or IL-13 mediate eosinophil recruitment and activation within grafts, and the release of cytotoxic granules from activated eosinophils can directly damage allografts (64).

Hyperacute Rejection This is characterized by the cessation of graft function minutes to hours after graft revascularization. This form of rejection is thought to be secondary to host presensitization, i.e., to the presence of host preformed antidonor antibodies. Furthermore, it is not amenable to any form of pharmacologic immunosuppressive agents. A classic setting for hyperacute rejection is ABO incompatibility wherein circulating antidonor hemagglutinins rapidly thrombose the graft after binding to endothelial cells, and through their Fc tails activate complement. Damaged endothelial cells secrete high-molecular-weight forms of von willebrand factor that mediates platelet adhesion and aggregation and granulocyte activation. Although, anti-ABO antibodies do not present a clinical problem due to pretransplant ABO

typing, preformed antibodies toward HLA or endothelial E–M antigens are the more usual causes of hyperacute rejection. These antibodies may be induced by prior transplants, blood transfusion, or pregnancy. Correlation between a positive pretransplant microcytotoxicity cross-match (an assay for detection of recipient antidonor antibodies) and the occurrence of hyperacute rejection is well documented (65). Pretransplant testing of recipients for antidonor antibodies has markedly reduced the incidence of hyperacute rejection in clinical allotransplantation. On the one hand, renal and heart transplants are particularly susceptible to hyperacute rejection. Thus, a negative T-cell cross-match and ABO compatibility are usual prerequisites. On the other hand, the liver is less susceptible to hyperacute rejection, and liver transplants have been performed in the face of ABO incompatibility and positive cross-matches. Microscopically, hyperacutely rejected transplants show fibrin thrombi within the small arteries and arterioles, capillary dilation, endothelial cell sloughing, platelet aggregation, and adhesion of polymorphonuclear leukocytes. Both animal and human renal allograft studies suggest that rejection is initiated by a primary immune injury to the vascular endothelium. Circulating antibodies bind specifically to the class I histocompatibility Ags exposed on the vascular endothelial cell surface and activate complement. Platelet aggregation and subsequent release of platelet factors and vasoactive substances occur at the site of injury. The initial vasoconstrictive response progresses to thrombosis after aggregation of platelets, red blood cells, and polymorphonuclear leukocytes, followed by fibrin deposition. The ischemic cascade obviates perfusion to the transplanted organ. Sometimes the reaction is not immediate but rather occurs 24 to 48 hours after transplantation, in which case it is denoted as ‘‘delayed hyperacute’’ rejection. Presumably, these cases reflect initial low titers of antibodies with a prompt secondary response. Thus, delayed hyperacute rejection appears to be the result of a qualitatively weaker immune response than that which causes hyperacute rejection.

Accelerated Rejection Accelerated rejection frequently produces rapid loss of graft function; in many cases, it is refractory to antirejection

Chapter 5: Physiologic Basis of Transplantation

therapy. The graft usually functions satisfactorily for 72 to 100 hours, before graft function declines precipitously. Histologically, there are vascular lesions of capillary disruption with interstitial hemorrhage, hemorrhagic infarcts, and fibrinoid necrosis of small arterial vessels. Two pathogenic mechanisms appear to mediate the response: cellular presensitization with rapid graft destruction by specific T-cytotoxic cells, or a secondary antibody production of a moiety that depends on lymphocytes to execute cytotoxicity (antibody-dependent cell-mediated cytotoxicity). In such a reaction, antibody acts as a bridge between donor tissue and cytotoxic cells, an interaction that results in activation of the lytic mechanism of the cytotoxic cell with subsequent tissue destruction.

Acute Rejection Acute rejection, unlike the accelerated or hyperacute mechanisms, tends to be reversible with therapy. Acute rejection episodes are the most common type, affecting 30% of renal allografts and usually occurring during the first three months following surgery with a peak incidence at five weeks. Acute rejection is uncommon after the first year unless there is noncompliance to the drug regimen by the patient or an inappropriate reduction of immunotherapy by the physician. The clinical features of cell-mediated renal allograft rejection including graft swelling and tenderness, fever, oliguria, and hypertension are rarely obscured in the CsA era. Laboratory assessment reveals an increased serum creatinine, and the diagnosis may be confirmed by percutaneous needle biopsy. However, attenuation of the clinical picture by CsA therapy has led to greater reliance on laboratory data and imaging studies. The greatest dilemma is the differentiation between acute rejection and CsA-induced nephrotoxicity. Furthermore, anuria secondary to acute tubular necrosis (ATN) may occur immediately following operation or within the first few weeks after transplantation. In general, a 25% rise in serum creatinine demands immediate evaluation (66). Imaging studies include the evaluation of the physiologic status of the allograft by nuclear renograms or ultrasound examination enhanced by color flow Doppler (CFD). Nuclear renograms include three phases that utilize two radiolabeled compounds (99mTc-DTPA and 99m Tc-MAG3). The first phase evaluates renal perfusion, which should be evident within four seconds of the aortic blush following the administration of 99mTc-DTPA. The second phase quantitates graft flow by the interval between injection and the appearance of parenchymal activity. The third phase evaluates the excretory function by comparing the amount of the isotope in the bladder relative to the graft. In acute rejection, there is decreased perfusion, poor parenchyma uptake, and excretion. Good perfusion with impaired parenchymal uptake is common in ATN. The findings in early CsA toxicity are similar to those of ATN. In severe CsA toxicity, altered perfusion may be present due to the alpha-agonist effect of CsA. Thus, the diagnosis of CsA toxicity is tentative until rejection and ATN are ruled out. Ultrasound examination with CFD accurately detects allograft swelling common to both ATN and rejection, but it is less helpful than nuclear scans in differentiating both entities. It also demonstrates ureteric or renal pelvic dilatation secondary to obstruction or accumulation of perinephric fluid collections that contribute to the declining renal allograft function. CFD sensitively detects the increase in vascular resistance, which is associated with

111

rejection, but is not an early feature of CsA toxicity. However, CFD is operator dependent, and the evaluation of acute rejection often demands histopathologic examination. Histologic features of acute rejection include prominent interstitial and perivascular mononuclear infiltrates with interstitial edema and tubulitis (Fig. 20A). Macrophages and T-lymphocytes, specifically cytotoxic T-cells, are the predominant infiltrating cell types. In addition, CD4 helper cells mediating delayed-type hypersensitivity mechanisms are important contributors. Significant interstitial cellular infiltration with moderate tubulitis (greater than four mononuclear cells/tubular cross section) constitute grade I ‘‘mild’’ acute rejection. Grade II ‘‘moderate’’ rejection demonstrates significant interstitial infiltration, severe tubulitis, and/or intimal arteritis, while ‘‘severe’’ grade III rejection involves transmural arteritis, medial smooth muscle necrosis, and/or focal infarction and interstitial hemorrhage. In mild-to-moderate cellular rejection, two cell types predominate within the interstitial cellular infiltrates (67): macrophages, comprising 40% to 50%, and T-lymphocytes, 30% to 40%. Microscopically, infiltrating T-cells include cytotoxic T-cells (Tc) bearing the CD8 cell surface marker and helper CD4 cells. In severe cellular rejection, the cellular infiltrate is composed of 60% macrophages, 20% to 30% polymorphonuclear leukocytes, and 15%

Figure 20 Renal allograft rejection. (A) Acute rejection demonstrating prominent interstitial and perivascular mononuclear infiltrates with interstitial edema. (B) Chronic rejection characterized by interstitial fibrosis and obliterative vascular changes.

medwedi.ru

112

Part One: General Considerations

T-lymphocytes, the majority of which are Tc cells. Although there are no classical histological changes of acute CsA toxicity, inclusion bodies, peritubular capillary congestion, tubular vacuolization, microcalcifications and thrombotic microangiopathy have been described. ATN is a difficult histologic diagnosis, although swelling of tubular cells and disrupted tubules in the absence of signs of rejection or drug toxicity is helpful information. After activation of CD4 and CD8 lymphocytes, circulating immune cells recognize the allograft at the periphery. The CD4 cells play a critical role by releasing lymphokines that recruit and activate immunologically incompetent lymphocytes and macrophages toward the allograft through a delayed-type hypersensitivity mechanism. This mechanism is specific, although the target cytotoxic cell activated by lymphokines is not. On the one hand, the delayed-type hypersensitivity effector CD4 cell does not directly mediate allograft damage but secretes lymphocytotoxins responsible for cellular destruction and lymphokines that attract and activate macrophages, lymphocytes, and NK cells to produce cellular necrosis. On the other hand, cytotoxic CD8 lymphocyte displays specific activity against class I alloantigen on the graft, thereby participating in the tissue destruction. Although the CD8 Tc cell is the predominant specific lymphocyte involved in cellular rejection, the CD4 helper cell is an important component of the process because of its ability to magnify the cellular response by recruitment of other immune elements. In summary, cytotoxic T-cells specifically react with the class I alloantigen disparity, whereas the delayed-type hypersensitivity mechanism of CD4 helper cells causes a nonspecific response in recognition of the class II alloantigen disparity. Acute rejection episodes may be precipitated by viral syndromes that are caused by the following (68):

low serum complement levels suggest that the humoral antibodies mediate a glomerular lesion. The Ig deposits appear to produce obliterative vascular changes (Fig. 20B) eventuating in interstitial fibrosis (65). Chronic rejection tends to be a separate pathologic and clinical entity reflecting an alloantibody response frequently triggered by but not due to recurrent acute rejection episodes. In recent years, the role of T-cells recognizing alloantigens indirectly has been implied (69–71). At least three lines of evidence support the case: first, by manipulating animal models (e.g., class I KO recipients of MHC class II KO graft), it was shown that indirect allorecognition alone was able to mediate graft rejection; second, by analyzing lymphocytes from those animal models, it was confirmed that there was a small population of self-MHC–restricted T-cells responsive to donor-derived peptides; third, in clinical patients, it has been demonstrated that there is a positive correlation between T-cell reactivity to synthetic allopeptides derived from the donor MHC and chronic graft rejection. It is now clear that the nature of antigenic stimulations from an allograft changes over time. At the late stage of transplantation, processed alloantigen becomes the dominant type, because the donor-derived APCs residing in and emigrating from the graft diminish, and all of the parenchymal cells of the graft can serve as a substrate for host APC processing. Due to the fact that the T-cell precursor frequency in indirect allorecognition pathway is several orders of magnitude less than that in the direct allorecognition pathway, the indirect alloimmune response represents a more slow-paced immune reaction, consistent with the natural history of chronic rejection.

IMMUNOSUPPRESSIVE THERAPY

From the opposite standpoint, allograft rejection sometimes produces activation of a latent viral infection, caused either by viral transformation of lymphocytes or by release of virus from damaged donor kidney cells.

The ultimate goal in organ transplantation is to achieve immunologic tolerance of the host to the graft, thereby obviating any rejection process. Although there have been important experimental leads toward the goal of decreasing graft immunogenicity, only the recipient immunosuppressive approach has proven clinical efficacy. The ideal immunosuppressive regimen would specifically dampen host responses toward donor, but not toward third-party transplants. Currently, the immunosuppressive modalities used for organ transplantation are nonspecific, altering host responses not only toward histocompatibility but also toward an array of other antigens. In general, two types of agents are used in clinical practice: pharmacologic agents exemplified by corticosteroids, CsA, and antiproliferative agents, and biologic agents such as antilymphocyte sera (ALS) and monoclonal antibodies. Irradiation, although utilized in the early days of clinical transplantation, has no current applications.

Chronic Rejection

Mechanisms of Pharmacologic Agents

1. 2.

3.

Direct viral damage, e.g., as in mumps or influenza viral syndromes, releasing increased amounts of histocompatibility Ags from the graft. Viral Ags expressed during a clinical infection may cross-react with donor histocompatibility Ags. Thus the immune response directed against the virus can potentially result in graft rejection. The virus may augment the host’s immune system by acting as an adjuvant, making him more susceptible to an acute rejection episode, although in most cases, particularly with cytomegalovirus, the infection tends to induce immunodepression.

Chronic rejection is characterized by a gradual decline in graft function and tends to be unresponsive to steroid antirejection therapy and to eventuate in transplant failure. Although CsA has reduced the incidence of acute renal allograft rejection, it has failed to reduce the previously observed 10% incidence prior to its use (66). The clinical syndrome of progressive deterioration of graft function following renal transplantation includes hypertension and glomerulopathy with hematuria and/or proteinuria. Graft damage has been ascribed to a humoral process based on detection of donorspecific circulating antibodies in recipient sera. Deposition of Igs and complement on glomerular capillary walls and

Current clinical and experimental immunosuppressive agents (72) seek to inhibit the recognition of alloantigens, destroy alloreactive T-cells, or alter the regulatory events leading to maturation and differentiation of mature alloreactive elements (Fig. 21).

Inhibition of Antigen Recognition, Processing, and Presentation Corticosteroids The first step in the development of transplant rejection is the generation of costimulatory activity by APCs, an event necessary for T-cell activation. Corticosteroids impair transcription

Chapter 5: Physiologic Basis of Transplantation

113

evidence suggests that the activated ligand–receptor complex impedes the activation, but not the binding, effects of AP-1 and NFAT DNA–binding proteins on the IL-2 gene promoter region. Because of their tendency to inhibit nonspecific resistance more intensively than specific resistance (low immunosuppressive index), and their pleiotropic toxicities due to widespread utilization of GRE in other gene transcription units (an unfavorable therapeutic index), steroids are the weakest link in present clinical regimens. Steroid therapy may produce multiple, severe side effects such as hypertension, cushingoid syndrome, steroid-induced diabetes, osteoporosis, avascular necrosis of bones, weight gain, growth retardation, poor wound healing, cataracts, pancreatitis, peptic ulceration, colonic perforation, gastrointestinal bleeding, and psychosis.

Lymphokine Synthesis Inhibitors (Calcineurin Inhibitors) Figure 21 Sites of action of immunosuppressive drugs in relation to the cell cycle. Steroids and 15-DSG block initial activation events at the G0 phase. CsA and FK506 (Tacrolimus) inhibit G0 to G1 progression, by inhibiting IL-2 transcription. RAPA acts during the late G1 phase by blocking cytokine signal transduction. Aza, MM, MTX, and MZB inhibit purine, while BQR inhibits pyrimidine synthesis at the S phase. Abbreviations: 15-DSG, 15-deoxyspergualin; Aza, Azathioprine; BQR, Brequinar; CsA, cyclosporine; MM, Mycophenolate Mofetil; MTX, Methotrexate; MZB, Mizorbine; RAPA, Rapamycin.

of the IL-1b gene, cause rapid degradation of IL-1 mRNA, as well as reduce IL-6 transcription, thereby inhibiting the generation of the costimulatory signal (73). Moreover, steroids also inhibit the gene transcription and expression of IL-2, TNF, and IFN-g. These compounds diffuse intracellularly and bind to cytoplasmic receptors that exist in association with the 90 kDa HSP. Steroid binding induces the dissociation of the HSP from the complex and translocation of the ligand– receptor complex into the nucleus. The activated complex reversibly binds to DNA sites, collectively called glucocorticoid response elements (GRE), which exhibit the TGTTCT DNA motif and are present on multiple promoter regions of several cytokine genes including the IL-2 promoter. Recent

Cyclosporine CsA (1202 Da; 74) is a cyclic endecapeptide, extracted from the soil fungus Tolypocladium Inflatum Gams, which exhibits a hydrophobic exterior and a hydrophilic center shielded in the interior of the structure. CsA binds to a cytoplasmic protein, cyclophilin (CYP; Fig. 22), which displays cis– trans peptidyl-propyl-isomerase activity, which everts the hydrophilic CsA site from the interior to the exterior of the molecule, presumably converting the prodrug into the active moiety. CsA inhibits processes dependent upon an increased cytoplasmic calcium burst. CsA binding to CYP changes the substrate affinity of the isomerase such that it complexes with and inhibits calcineurins (CaN) A and B, serine–threonine phosphatases associated with Ca2þ, and CaM. The formation of the complex CaN A–CaN B–Ca2þ– CaM–CsA–CYP prevents the dephosphorylation, activation, and nuclear translocation of NFATc, the first regulatory protein controlling the enhancer region of the IL-2 gene (75). CsA inhibits T-cell synthesis of not only IL-2, but also IL-3, IFN-g, IL-6, and IL-7. IL-1 synthesis and IL-2-receptor (IL-2R) generation appear to be calcium independent and therefore CsA resistant. T-helper and T-cytotoxic cell functions are downregulated by CsA in addition to the generation of regulatory T-cells that appear to enhance allograft survival in animal models (74). The lack of inhibitory effects of CsA on the generation, proliferation, or function of

Figure 22 Proposed mechanism of action of calcineurin inhibitors on the regulatory sequences of the IL-2 gene. The promoter region of the IL-2 gene contains binding sites for the Oct-1, AP-1, OAP, and NF-kB DNA–regulatory proteins. NFIL-2A and NFIL-2E sites bind Oct-1/OAP and NFAT proteins, respectively. CD28RE, CD28 responsive element. The pentameric complexes CaN A– CaN B–Ca2þ–CaM–CsA–CYP or CaN A–CaN B–Ca2þ–CaM– FK506–CYP prevent activation and nuclear migration of NFATc, which normally binds to NFATn to induce activation of the IL-2 promoter at the NFIL-2E site. Abbreviations: Ca2þ, calcium; CaM, calmodulin; CaN, calcineurin; CsA, cyclosporine; CYP, cyclophilin; FKBP, FK506 binding protein; NFAT, nuclear factor of activated Tcells; IL, interleukin.

medwedi.ru

114

Part One: General Considerations

nonspecific host resistance elements produces a high immunosuppressive index. CsA exhibits a variety of side effects that include nephrotoxicity, hypertension, hyperkalemia, hyperuricemia, hypercholestrolemia, hypertriglyceridemia, hyperglycemia, hemolytic uremic syndrome, hepatotoxicity, and mild neurologic symptoms such as insomnia, hyperactivity tremors, and depression. Further, the concentration of CsA is affected by several drugs that enhance or inhibit CsA metabolism through the cytochrome P-4503A enzyme system. Rifampin, phenobarbital, phenytoin, and valproic acid increase CsA metabolism, whereas erythromycin, verapamil, and ketoconazole reduce CsA metabolism. It has been difficult to optimize CsA therapy because of the agent’s marked interindividual variations in pharmacokinetics and in pharmacodynamics. Among renal transplant recipients, there is a sixfold span of drug clearance rates and a ninefold span of relative oral bioavailability. Thus, CsA doses are based upon measured drug levels or calculated pharmacokinetic parameters, rather than on fixed weight- or surface area–adjusted amounts. CsA whole blood levels are more reproducible than plasma levels. CsA levels are measured by either fluorescence or radioimmunoassays that measure primarily the parent compound and about 15% of its metabolites, or by high-performance liquid chromatography, which measures only the parent compound. Some centers tailor CsA therapy based on trough levels (175–225 ng/mL for renal and 350–450 ng/mL for hepatic transplants). However, clinically obtained trough levels do not show a good correlation with areas under the concentration curve (AUC; 76). Nevertheless, in clinical practice, AUCs are often difficult to obtain and trough levels are widely utilized to guide dosing protocols. The use of the new glycol-furan microemulsion formulation of CsA (Neoral) has facilitated dose prediction. Neoral absorption appears to be independent of bile and food composition. Tacrolimus (FK506, Prograf) Tacrolimus is a polycyclic macrolide antibiotic produced by Streptomyces tsukubaensis that inhibits T-cell production of IL-2, IL-3, IL-4, and IFN-g, 10- to 100-fold more potently than CsA. Furthermore, it blocks the expression of IL-2R and inhibits the synthesis of TNF-a GM–CSF, and c-myc. Tacrolimus, like CsA, inhibits Ca2þ-dependent intracellular pathways mediated by interactions with an intracellular binding protein [FK506 binding protein (FKBP); Fig. 22], which, like CYP, is a member of the cis–trans propyl isomerase ‘‘immunophilin’’ family. This interaction ultimately results in inhibition of IL-2 production (75). Tacrolimus and CsA exhibit in vitro and in vivo antagonism, which may be explained by the fact that they share a common intracellular pathway. The two drugs, however, may not act by precisely the same mechanism, because, in experimental models, Tacrolimus inhibits, whereas CsA facilitates the induction of regulatory cells. Tacrolimus absorption, following oral administration, is less bile dependent than CsA. This may be beneficial during the biliary diversion with T-tube drainage following hepatic transplantation. This may explain, in part, the wider utilization of Tacrolimus as the primary immunosuppressive agent in liver transplantation when compared with CsA (77). In the recent years, Tacrolimus has been widely utilized in clinical pancreatic and renal transplantation. Similar to CsA, Tacrolimus dosing is guided by whole blood trough concentrations.

Side effects of Tacrolimus therapy include nephrotoxicity caused by decreased renal cortical blood flow and reduced glomerular filtration rates and drug-induced hyperkalemia and hypertension, findings previously reported with CsA therapy. Excessibely high doses of Tacrolimus may be associated with neurotoxicity, which includes expressive aphasia, coma, and seizures, nephrotoxicity, new onset diabetes mellitus, and, rarely, lymphoproliferative disorders. Thus, Tacrolimus appears to have an equivalent immunotherapeutic effect to CsA. Although immunosuppressive protocols that avoid calcineurin inhibitors may be utilized in the future, most clinicians currently utilize either agent as the primary immunotherapeutic medication. The choice between CsA and Tacrolimus is mostly based on clinical preference and the experience of the center with each drug.

Inhibitors of Late T-Cell Function (TOR Inhibitors) The inhibitors of mammalian target of rapamycin (mTOR) are a relatively new class of immunosuppressants (78). This class includes two drugs: sirolimus and everolimus. Sirolimus (Rapamycin, RAPA, Rapamune1; Wyeth Pharmaceuticals) Sirolimus (79) a macrolide antibiotic produced by the actinomycete Streptomyces hygroscopicus is structurally related to FK506. Unlike CsA and Tacrolimus, which influence the G0 to G1 progression, Sirolimus does not affect lymphokine synthesis, but rather inhibits their effects on the G1 build-up phase to the S phase (Fig. 21). Thus, RAPA inhibits a broad array of calcium-independent activation events mediated via CD28, protein kinase C, and lymphokine stimulation. Although Sirolimus binds to FKBP to form RAPA–FKBP complex, the target of its inhibitory effects on isolated lymphocytes is unknown. Various authors report retarded endocytosis of receptor complexes or inhibited PI3-kinase activity necessary to generate the 3-phosphorylated phosphoinositides (PI-3-P, PI-3,4-P2, and PI-3,4,5-P3), which function as growth and division signals. RAPA also inhibits the IL-2 stimulated T-cell S-phase entry (80) by blocking p70S6 or the p34cdc2 kinases, thereby blocking the proliferative but not the differentiation events induced by IL-2. The clinical utilization of RAPA has been based, in part, upon its synergistic immunosuppressive effect with CsA. Thus, the combination of RAPA and CsA may have allowed the utilization of both drugs at extremely low doses to produce a high immunosuppressive index with a low toxic profile. In renal transplantation, RAPA is widely used in conjunction with CsA in ‘‘steroid-sparing’’ immunosuppressive protocols. Unfortunately, a black-box warning has been placed on RAPA in liver transplantation after the initial clinical trials resulted in a high rate of side effects that included hepatic artery thrombosis and delayed wound healing. Side effects most commonly documented with sirolimus include nausea, vomiting, and elevated liver enzymes, cholesterol, and triglycerides. Everolimus (Certican1, RAD-001; Novartis) Everolimus has a mechanism of action identical to that of sirolimus. Once inside the cell, it binds to FKBP-12. The complex then binds mTOR, inhibiting activation of p70S6 kinase and arresting the cell cycle at the G1 to S phase. This results in a blockade of growth factor–mediated, IL-2 and IL-5–driven proliferation of T- and B-lymphocytes and vascular smooth muscle cells.

Chapter 5: Physiologic Basis of Transplantation

Drug–drug interactions must be considered with the mTOR inhibitors. Coadministration with CsA increases exposure to everolimus, but this interaction does not appear to be as severe as that seen with CsA and sirolimus. Nevertheless, withdrawal of CsA will require retitration of the everolimus dose. Everolimus is metabolized by the cytochrome P450 3A4 enzyme system, resulting in a potential for important interactions with drugs such as macrolide antibiotics, azole antifungals, and phenobarbital or phenytoin. Currently, this drug is in clinical trial with very promising results (81).

Nucleoside Synthesis Inhibitors Azathioprine Aza, a purine analog, is a nitroimidazole derivative 6-mercaptopurine (6-MP). It was first used at the Peter Bent Brigham Hospital in Boston and rapidly became the cornerstone of chemical immunosuppression in the 1960s (72). Aza must be metabolized in the liver via conversion to 6-MP and then to its active metabolite 6-thioinosinic acid. It exerts its immunosuppressive effect by broadly inhibiting DNA and RNA synthesis by preventing the synthesis of adenosine monophosphate and GMP from inosinic acid (de novo purine synthesis) and blocking the interconversion among the precursors of purine nucleotides (salvage pathway). However, Aza exhibits multiple limitations. Because Aza can be incorporated into DNA as a fraudulent base, it carries an increased proclivity to malignancy and papillomatosis. Aza also produces a hepatotoxicity that can potentiate the CsA injury. Because Aza acts as a competitive enzyme inhibitor of both de novo and salvage pathways, it must be used at high concentrations, resulting in bone marrow depression to a greater degree than its immunosuppressive effect. The limitations of Aza as an immunosuppressive drug led to an urgent need to identify new nucleoside synthesis inhibitors that (a) acted noncompetitively to inhibit synthesis of either purines [Mizorbine (MZB) and Mycophenolate Mofetil (MMF)] or pyrimidines [Brequinar (BQR)], (b) were not incorporated into DNA, and (c) showed reduced myelotoxicity. In the early days of transplantation, Aza–steroid regimens displayed a low therapeutic index, with 90% of renal allograft recipients experiencing rejection episodes and only 50% one-year graft survival. Following the advent of CsA, Aza was utilized as a third agent with the CsA–steroid regimen. Currently, the clinical use of Aza has been largely replaced by MMF. MMF (RS-61443, Cellcept1; Hoffmann–La Roche) MMF is a semisynthetic morpholinoethyl ester of mycophenolic acid (MPA), which is produced by the fungus Penicillin glaucum. It was introduced in the mid-1990s after a series of clinical trials showed its superiority to Aza in preventing allograft rejection in kidney transplant recipients (82). It is now commonly used for maintenance immunosuppression in various regimens containing calcineurin inhibitors, steroids, and/or sirolimus (83). It is rapidly absorbed following oral administration and hydrolyzed to form MPA, its active metabolite. MPA inhibits the de novo pathway of guanosine nucleotide synthesis through reversible inhibition of inosine monophosphate dehydrogenase (IMPDH) and possibly also GMP-synthetase, two crucial enzymes in the de novo purine synthesis pathway, thereby depleting phosphoribosyl pyrophosphate (PRPP). Depletion of PRPP inhibits generation of hypoxanthine guanine phosphoryl ribosyl transferase, an important intermediate in the major purine salvage

115

pathway. The result is a relatively selective antiproliferative effect on lymphocytes, because they rely heavily upon this de novo pathway for purine synthesis. Initial reports suggested that MMF does not produce significant hepato- or nephrotoxicity. The most problematic adverse events associated with this agent include gastrointestinal effects (diarrhea, abdominal pain, nausea, vomiting, and dyspepsia) and hematologic disorders (leukopenia, anemia, and thrombocytopenia). In most cases, these effects respond promptly to dose reductions. The drug is now widely utilized in all solid organ transplants, as a third agent in conjunction with steroids in CsA- or Tacrolimus-based triple immunosuppressive regimens. Moreover, MMF has been successfully utilized with either CsA or Tacrolimus in steroid-sparing immunosuppressive protocols. MPA Sodium (Myfortic1, ERL-080; Novartis) Mycophenolate acid sodium is an enteric-coated formulation of the sodium salt of MPA. It is considered a second generation IMPDH, with a mechanism of action that is the same as that described above for MMF. Because it is enteric coated, it allows a delayed release of MPA into the small intestine. This is hoped to ameliorate some of the upper gastrointestinal side effects associated with MMF’s immediate release of MPA into the stomach. A dose of 720 mg of mycophenolate acid sodium offers systemic exposure equivalent to 1000 mg of MMF. Two pivotal, Phase III, multicenter trials were conducted in renal transplant recipients to assess tolerability and efficacy (84). In each of these trials, mycophenolate acid sodium (ERL-080) 720 mg, twice daily, was compared to MMF 1000 mg, twice daily, in combination with CsA and corticosteroids. Both groups demonstrated equivalent rates of biopsy-proven acute rejection, graft loss, and patient death. The ERL-080 group, however, seemed to have fewer moderate or severe acute rejection episodes. No significant difference in the incidence or frequency of GI adverse events was noted at three or six months. The group receiving ERL080, however, had a lower incidence of severe neutropenia, fewer serious adverse events, and fewer serious infections. Myfortic has been recently approved for clinical utilization. MZB; Bredinin MZB is an imidazole nucleoside antibiotic isolated from Eupenicillum brefeldianum, and is converted to its active monophosphate form by adenosine kinase (72). It has been used experimentally and, to a limited extent, clinically in Japan as an immunosuppressive agent. MZB noncompetitively inhibits IMPDH, which converts IMP to xanthine monophosphate, an intermediate compound in the synthesis of GMP. Thus, like Aza and MMF (MM), MZB progressively depletes intracellular GMP stores. Its immunosuppressive capacity is estimated to be comparable to that of Aza, whereas associated marrow depression is less prominent. The drug is not metabolized in the liver and demonstrates no significant hepatotoxicity. Its use has been associated with significant anorexia and subsequent weight loss in the canine model. As yet no clinical trials have been published outside of Japan, and worldwide distribution of the drug is not anticipated. Leflunomide (Arava1; Aventis) Leflunomide is currently approved for use in rheumatoid arthritis and previous data suggested a promising role for

medwedi.ru

116

Part One: General Considerations

it in organ transplantation. Leflunomide is rapidly and extensively metabolized to A77 1726, an active metabolite that is responsible for most of the drug’s activity (85). It inhibits de novo pyrimidine synthesis by reversibly blocking dihydro-orotate dehydrogenase (DHODH). This inhibition blocks T- and B-cell proliferation and strongly suppresses the production of IgM and IgG antibodies. Doses required for use in kidney and liver transplantation are significantly higher than those used for rheumatoid arthritis. Leflunomide carries a black box warning against use in pregnancy and is not suggested for use in patients with significant hepatic dysfunction or positive hepatitis B or C serologies. Within the field of organ transplantation, leflunomide has been studied in a variety of different capacities. It has been shown to control and reverse acute rejection, control the aggressive antibody responses in xeno-rejection, reverse an established chronic rejection response in rodents, have synergistic or additive effects with the calcineurin phosphatase inhibitors, and have the ability to halt replication of herpes viruses including cytomegalovirus (CMV) and herpes simplex virus (HSV). Due to its adverse event profile, however, it may not be widely used in transplantation. Toxicity, including anemia and elevations in liver function tests, correlates with serum concentration. ‘‘Public Citizen,’’ a consumer watchdog group, has petitioned the FDA to remove leflunomide from the market, citing 130 cases of severe liver dysfunction and up to 22 deaths associated with its use. FK778 (Fujisawa) FK778 is an analogue of A77 1726—leflunomide’s active metabolite. It is a novel molecule with a mechanism of action similar to leflunomide. Like leflunomide, it appears to have antiviral effects and has been effective in preventing acute allograft rejection in animal models (86). Compared to the parent compound, FK778 has demonstrated an equivalent or higher immunosuppressive effect with a shorter half-life in vitro and in vivo. FK778 is currently in Phase II clinical trials in Europe. Brequinar BQR is a synthetic difluoroquinoline carboxylic acid derivative, which was originally developed as an antineoplastic drug. It reversibly inhibits the mitochondrial enzyme DHODH, the fourth enzyme in the de novo pyrimidine biosynthesis pathway. The greater potency of BQR than that of MM, MZB, or Aza is probably due to the 100fold lower concentration of pyrimidine than of purine precursors (72). Oral drug administration prolongs the survival of heart, kidney, and liver transplants in rat models. BQR exhibits synergistic interaction with CsA, both in vitro and in vivo. Although high-dose BQR therapy in cancer patients produced gastric toxicity, Phase I study only showed thrombocytopenia, which can be avoided by the use of lower drug doses. Unfortunately, Phase II trials to assess its efficacy in combination with CsA and steroids were suspended. Its clinical future is therefore doubtful. Methotrexate MTX is an antimetabolite that antagonizes folic acid metabolism by binding dihydrofolate reductase, thereby inhibiting DNA synthesis (72). The immunosuppressive effects have been attributed to inhibition of macrophage migration due

to decreased IL-1 production and to reduced accumulation of inflammatory cells and/or immune mediators. Combined low-dose treatment with MTX and CsA downregulates the transcription of some gene products that mediate cytotoxicity, including TNF-a, LT, and some serine proteases, thereby prolonging transplant survival. However, utilization in clinical practice is limited.

Other Agents FTY720 (Novartis) is a novel agent with a structure that is completely different from conventional immunosuppressants and a mechanism of action that is equally unique. After oral administration, it is metabolized by sphingosine kinase to FTY720-phosphate, the active metabolite. This metabolite acts as an agonist at four of five receptors for sphingosine 1-phosphate, where it increases the intrinsic mobility of cells. This results in a reversible redistribution of lymphocytes from the periphery to lymphoid tissues (87). It does not impair T-cell activation or expansion, or memory to systemic viral infection. Rather, its immunosuppressive activity is a result of altered chemokine response and resultant removal of T- and B-cells from circulation while sequestering them in lymph nodes and Peyer’s patches. Administration of FTY720 results in a rapid, dosedependent decrease in peripheral blood lymphocyte counts. This occurs within hours and is reversible upon discontinuation of the drug. Doses of FTY720 in clinical studies have ranged from 0.125 to 5 mg, administered orally, once daily. FTY720 exhibits low interpatient variability compared with other immunosuppressants, and it is believed that therapeutic drug monitoring will not be necessary. It is extensively and completely metabolized by the liver with an elimination half-life of approximately seven days (88). Dose adjustments may only be necessary in patients with severe hepatic insufficiency. To date, clinical studies with FTY720 have been conducted solely in renal transplant recipients. A multicenter, randomized, open-label, dose-finding study compared FTY720 to MMF in combination with CsA and corticosteroids. FTY720 doses of 2.5 mg reduced the rate of biopsyproven acute rejection below that of MMF 2 g/day (89). Another study showed that FTY720 doses of 5 mg/day may allow for reduced-dose CsA with equivalent immunosuppressive efficacy. The major adverse event noted was bradycardia (12%), occurring within hours of the first dose. It is suspected that this is caused by a direct effect of FTY720 on the sinus node, and the toxicity is enhanced by concomitant b–blocker therapy. Phase III trials are underway.

Biologic Agents Polyclonal Antibodies Potent, nonspecific, immunosuppressive antibodies can be produced by immunizing a xenogeneic host, i.e., a speciesdivergent host, with human lymphocytes. These sera contain polyclonal antibodies, which opsonize the corresponding peripheral blood cellular elements, including T-cells, leading to their autodestruction in the liver and spleen. In addition, antibody binding onto lymphocytes may ‘‘blind’’ them to antigenic stimuli. The resulting in vivo depletion or inactivation of T-lymphocytes interferes with Tcell–mediated reactions, including allograft rejection, delayed hypersensitivity (DTH), and graft versus host reactions. Immunosuppression with ALS or purified globulin fractions (ALGs) has been demonstrated in experimental animal trials to prevent skin allograft rejection in mice, rats, and

Chapter 5: Physiologic Basis of Transplantation

primates and to prevent rejection of vascularized allografts in experimental canine renal and hepatic transplantation. Polyclonal antilymphocyte preparations have been conventionally used for prophylactic therapy during the first week after transplantation, to reduce the frequency and severity of early rejection episodes. However, clinical studies have not yielded unequivocal evidence supporting the use of ALS prophylactically. Some centers demonstrated improved graft survival and fewer rejection episodes, with a relative paucity of the reported side effects of serum sickness, anaphylactoid reactions, vascular thrombosis, or infection. On the other hand, other well-controlled studies suggest no therapeutic benefit from prophylactic ALG, but rather a significant risk of fatal infections. Alternatively, polyclonal antibodies can be used for therapy of acute renal allograft rejection episodes. The use of ALG in conjunction with high-dose steroids to reverse acute renal allograft rejection episodes produces a 13% increased incidence of viral sepsis and a 13% incidence of serum sickness, but an improved one-year allograft survival. Therefore, sequential rather than simultaneous use of ALG and high-dose steroids is recommended for rejection therapy. In clinical utilization, ALS and ALG preparations have been replaced by thymoglobulin, which is obtained by immunization of rabbits with human thymocytes. Like the previously used polyclonal antibodies, thymoglobulin requires central venous access for administration. Adverse events of thymoglobulin include fever, chills, and leukopenia and viral, bacterial, and fungal infections. The incidence of malignancies (less than 3%) is also comparable to other polyclonal antibodies.

Monoclonal Antibodies A second class of biologic agents that disrupt early activation events are monoclonal antibodies (MAb) directed toward surface receptor (abTcR, CD3) or coreceptor (CD4) epitopes present on T-cells or on APCs, such as B7, LFA-1, or ICAM-1. Immunosuppressive therapy with MAb reagents inactivates cell surface epitopes that mediate alloreactivity. Hybridoma technology, which was initially reported by Kohler and Milstein (90), yields readily standardized, specific xenogeneic murine MAb of greater purity and molecular specificity than polyclonal reagents. Unfortunately, clinical utilization of MAb produced in the mouse may result in the production of human antimouse antibodies (HAMA) that preclude retreament. Two innovations have been adopted to avoid the production of HAMA following administration of mouse MAbs. Chimeric antibodies combine the variable regions of mouse antibodies with human antibody constant regions and, therefore, present fewer foreign a.a. sequences to the host. However, one-third of the structure is still of mouse origin, which may stimulate the production of anti-idiotypic antibodies. Humanized antibodies combine only the smallest part of a mouse antibody that is required for target recognition, the distinctive complementarity-determining regions, with human variable and constant region frameworks (Fig. 23). However, humanized antibodies may exhibit reduced affinity to antigen epitopes and their beneficial effects can be clarified only by randomized clinical trials. Anti-CD3 and TcR MAbs OKT3 is a murine IgG2a MAb that dampens alloantigen recognition and cytolytic function of T-cells, by modulating

117

Figure 23 Schematic illustration of chimeric and humanized antibodies. The murine portions of the antibody is shown in black and the human portions in white. Abbreviations: CDR, V (variable); C (constant) regions; CDR, complementarity-determining region.

or ‘‘blinding’’ cell surface CD3 epitopes, thereby reversing allorejection episodes. However, OKT3 therapy may evoke the production of HAMA including anti-idiotypic and antiisotypic varieties (91) that preclude retreatment with mouse antibodies. Further, the administration of OKT3 may be associated with fever, chills, diarrhea, headache, pulmonary edema, wheezing, hypotension, aseptic meningitis, seizures, or even coma due to the release of IFN-g, IL-1, and TNF. In addition to the acute cytokine release reactions, excessive OKT3 therapy predisposes to cytomegalovirus infections and post-transplant lymphoproliferative diseases (PTLD). Second generation MAbs seek to avoid the severe systemic reactions due to the cytokine release that follows OKT3 administration, and the proclivity toward lymphoma development. Visilizumab (NuvionTM, HuM291; Protein Design Labs) and huOKT3g1 (R. W. Johnson Pharmaceutical Research Institute) are two new humanized anti-CD3 monoclonal antibodies. These modified agents may exhibit less mitogenic and less cytokine-releasing activity than muromonab-CD3. Visilizumab, in a Phase I study in de novo live donor renal transplant recipients, induced a rapid, dose-dependent, marked depletion of peripheral T-cells within two hours. At higher doses, this effect lasted for approximately one week. Most adverse events were mild to moderate, occurred within the first few hours after administration, and were likely related to cytokine release (92). In a separate phase I study, huOKT3g1 showed the ability to reverse acute rejection episodes in kidney transplant and kidney–pancreas transplant patients. Minimal first-dose reactions occurred and anti-OKT3 antibodies were not detected (93). T10B9 and BMA 031 are two MAbs that are putatively directed against the ab TcR, which represents the initial site of T-cell recognition. Both antibodies are currently under clinical evaluation, the former for use in acute rejection episodes and the latter for prophylaxis of rejection. A major limitation of treatment with anti-TcR antibodies is the rapid development of HAMA. MAbs Against Accessory Molecules Alternate approaches seek to utilize MAb directed against accessory T-cell molecules. OKT4A IgG2a MAb, which reacts with the CD4 coreceptor on Th cells, appears to provoke fewer side effects than OKT3 (94). Unfortunately, OKT4A also generated strong HAMA. The lack of efficacy of the original murine antibody seems to be overcome with the humanized variant of OKT4A.

medwedi.ru

118

Part One: General Considerations

A second target is the molecular pair LFA-1 on T-cells and ICAM-1 (CD54) on monocytes. A phase I clinical trial of anti-CD54 MAb induction therapy in ‘‘high risk recipients’’ demonstrated a 78% renal allograft survival, in contrast to 56% with conventional immunosuppression (95). AntiLFA-1 MAb successfully reversed steroid-resistant acute graft versus host reactions in man. These promising results using MAbs directed against T-cell/monocyte coreceptors await confirmation in controlled clinical trials. The CD28–B7 interaction is perhaps one of the best understood of the costimulatory pathways. CTLA-4-Ig and LEA29Y (Bristol-Myers Squibb and Novartis) are fusion proteins and homologues of CD28. They bind the B7 molecule, thereby blocking the interaction with CD28. LEA29Y is considered a second-generation CTLA-4-Ig and has shown to be more effective for inhibiting T-cell effector functions in vitro than CTLA-4-Ig. Early trials are not yet published, and Phase II and III clinical trials are currently in progress. IL-2R Antagonists The newest monoclonal antibodies for induction in solid organ transplantation are the IL-2 receptor blockers daclizumab and basiliximab. These agents share a similar pharmacologic mechanism. The differences between these agents lie in the amount of murine antibody sequences, with basiliximab being a chimeric molecule and daclizumab being a humanized molecule that contains fewer murine antibody sequences. Also, these agents have different dosing guidelines based on the study designs from the currently available literature. Both of these agents have demonstrated a very low occurrence of adverse reactions found to be essentially equal to placebo-treated patients without the cytokine release syndrome commonly seen with the traditional induction agents, mainly OKT3. These agents have proven efficacy in reducing the incidence of acute rejection episodes in renal transplantation, when used in combination with maintenance immunosuppression. Emerging Anti–B-Cell MAbs Alemtuzumab (Campath1; Schering AG) is an anti-CD52 monoclonal antibody currently approved for treatment of B-cell chronic lymphocytic leukemia. It targets T- and B-lymphocytes as well as monocytes. After intravenous (IV) administration, alemtuzumab rapidly and completely depletes lymphocytes from circulation and from the periphery. The most significant adverse event is a profound, prolonged lymphopenia and the subsequent increased risk of opportunistic infections. However, excessive adverse events associated with immunosuppression were not seen despite extremely low CD4 counts (96). Preliminary data suggest a trend toward a reduced incidence and severity of rejection episodes in renal, liver, and multivisceral transplant recipients. Rituximab (Rituxan1; Genentech) is a murine/human chimeric monoclonal antibody approved for use in treating non-Hodgkin lymphomas. It is specific for the CD20 surface marker on B-cells. Within the field of transplantation, it has been used primarily in cases of PTLD. It is currently under investigation for utilization in antibody-mediated rejection episodes as well as in B-cell induced disorders in transplantation.

Irradiation The immunosuppressive effect of irradiation is caused by the inhibition of DNA synthesis and cellular replication. Total

body irradiation of renal transplant recipients has been employed in the early days of clinical transplantation with limited but unequivocal success. However, total body irradiation was abandoned in favor of local graft radiotherapy, because of its associated toxicity including severe bone marrow depression and fatal infections. Subsequent clinical trials demonstrated that local graft irradiation increased the rate of reversal of allograft rejection but adversely affected the ultimate fate of the graft when used in combination with steroids. These findings, coupled with the superiority of other emerging immunologic strategies in managing graft rejection, resulted in very limited clinical application of local graft irradiation, which was ultimately abandoned. Because of the potent immunodepressive effect of radiotherapy and the need to minimize other organ toxicity, a regimen called total lymphoid irradiation (TLI) that focuses on cervical, axillary, mediastinal, para-aortic, splenic, and ilioinguinal nodes was devised and first applied for treatment of Hodgkin’s disease. After therapy, hosts displayed a state of immunosuppression characterized by T-lymphocytopenia, decreased alloreactivity, and induction of nonspecific T-suppressor cells. A decreased number and function of T-cells were documented for years after therapy. Although TLI decreases cell-mediated immunity and prolongs allograft survival in mice, success in large mammal models has not been consistent. Even if the logistic issue that TLI must be performed before transplantation is ignored, the complications associated with its administration (i.e., nausea, vomiting, possible increased incidence of lymphoma, and opportunistic infections) have limited its application in the clinical arena.

Risks of Immunosuppression Neoplasia Immunodeficiency states predispose to the development of de novo cancers since the first report of this association in 1969. The incidence of neoplasms in renal allograft recipients varies between 1% and 16%, far greater than the general population matched for age (97). Nonmelanotic skin and lip cancers, lymphoproliferative diseases, and cervical carcinomas account for 60% of the total cancers (98). Conversely, the malignancies that are most commonly encountered in the general population, namely carcinoma of the breast, lung, prostate, and colon are relatively uncommon in transplant recipients. There is an increased incidence of de novo skin and lip cancers in transplant recipients, 39% of which are squamous cell and basal cell carcinomas. Melanomas, which comprise only about 5% of skin cancers, behave in a similar fashion to the general population. OKT3 treatment poses a particularly high risk for PTLD, which encompasses a wide morphologic spectrum of Epstein–Barr virus (EBV)– induced B-cell diseases ranging from reactive, polyclonal hyperplasia, to true monoclonal malignant lymphoma. A common picture in renal allograft recipients (97) shows non-Hodgkin’s lymphomas containing TcR-b gene rearrangements consistent with monoclonal T-cell proliferation. Treatment with Aza, prednisone, and/or MTX, as well as the high frequency of herpes virus infections predispose recipients to cervical dysplasia and carcinoma in 21% of women who develop post-transplant cancers. Treatment is based on surgical extirpation of the tumors, if possible, together with reduction of immunosuppressive therapy. Conflicting data suggest that immunosuppression potentiates the growth of existing cancers. Based on recurrence rates of neoplasms posttransplantation, a two-year

Chapter 5: Physiologic Basis of Transplantation

waiting period between treatment of cancers and transplantation is justified for most neoplasms, except incidentally discovered renal carcinomas, in situ carcinomas, low-grade bladder cancers, and basal cell skin cancers.

Infections Over 80% of transplant recipients develop at least one infection after transplantation, and 40% of deaths are due to infectious complications occurring alone or following rejection and treatment. About 55% of posttransplant infections are caused by bacterial agents, 30% are by viruses, and 15% are by fungi (99). Most bacterial infections arise in the urinary tract, plastic venous catheters, the surgical wound, or intra-abdominal sites due to a spectrum of gram-negative and gram-positive agents akin to those occurring in other surgical patients. The most common viral infections after transplantation are caused by DNA viruses of the herpes virus family including CMV, EBV, HSV, and varicella zoster virus (HSV). Viral infections tend to be latent but are potentially oncogenic. Symptomatic CMV is associated with intense immunosuppression, particularly the use of ATG or OKT3, exhibiting a peak incidence at six weeks posttransplantation. In addition, CMV constitutes a risk factor for subsequent rejection episodes and bacterial, fungal, and parasitic (particularly Pneumocystis carinii) super-infections. The reduced incidence of such infections under CsA rather than Aza therapy may reflect both the less frequent rejection episodes requiring monoclonal or polyclonal intervention (31) as well as its capacity to spare nonspecific immune elements. Candida albicans is the most common fungal infection, although Candida globrata is seen with increasing frequency. Aspergillus fumigates and A. flavus are the second most common causes of fungal infections and present as pulmonary infiltrates. Other less common agents include Coccidioides immitis, Histoplasma capsulatum, and Nocardia asteroides. The protozoan parasite P. carinii has become an important cause of pneumonia in the immunocompromised patient. However, prophylaxis with trimethoprim–sulfamethoxazole has nearly eliminated these infections in transplant patients.

Clinical Application Unfortunately, current clinical practices are based upon empiric rather than scientific foundations. In spite of the widely disparate intrinsic immunogenicity of various organs, the various degrees of donor-to-recipient incompatibility, and the well-recognized interindividual variations in host immunosuppressiveness, transplant centers tend to utilize uniform initial induction and early maintenance immunosuppressive regimens.

Induction Immunosuppression The first two weeks post-transplant pose the greatest challenge, due to the requirement to promptly establish adequate immunosuppression in order to avert an acute allograft rejection episode. Many clinicians initiate CsA therapy either prior to or immediately after the transplantation procedure because experimental data suggest that CsA exerts maximal benefit at the time of antigen presentation. Others cite the proclivity of CsA to produce renal and/or hepatic dysfunction as the basis for delayed CsA administration, preferring sequential initiation protocols with antilymphocyte antibodies that provide rapid T-cell depletion with significant effects on granulocytes and platelets. Selective effects on T-cells may be

119

achieved by OKT3, although its early administration carries the risk of development of HAMA that precludes its subsequent administration. Most workers, therefore, prefer the polyclonal reagents for the initial induction and reserve the use of the MAb for subsequent acute rejection episodes. Antilymphocyte induction protocols carry several penalties: delayed hospital discharge due to postponing optimization of CsA regimen, delayed onset (but not reduced incidence) of acute rejection episodes, and proclivity for viral infections and post-transplant lymphoproliferative disease.

Short-Term Maintenance Immunosuppression The short-term immunosuppressive regimen utilizes the dual drug combination of calcineurin inhibitors (CsA/ Tacrolimus) and steroids to avert allograft rejection during the first 90 days posttransplant. The most popular strategy starts with an 8 to 10 mg/kg CsA divided as a twice a day (BID) regimen. The dose is adjusted based upon measured trough levels. Most clinician’s strive for whole blood parent CsA compound concentration of 175 to 350 ng/mL. When Tacrolimus is utilized, trough levels of 10 to 15 ng/mL are usually targeted in the early postoperative period. Tripple immunosuppression regimens combine either MMF or RAPA in addition to calcineurin inhibitors and steroids. The combination of corticosteroids with calcineurin inhibitors is based upon both clinical and experimental data that suggest a synergistic effect. Almost all steroid regimens include a massive (250–1000 mg) intraoperative dose of methylprednisolone to dampen graft tissue injury and reduce T-cell activation. During the immediate postoperative period, steroid doses are rapidly tapered from 200 mg to 20–30 mg by day 7, followed by a more gradual taper to 15 mg between 30 and 90 days.

Antirejection Immunosuppression The principles of treatment for rejection episodes are relatively uniform across organs and among transplant centers. Most centers demand histopathological evidence of rejection, due to the significant penalties of excessive treatment of an adequately immunosuppressed patient. Steroid regimens combine large IV doses of methyl prednisolone with an oral prednisone taper. Delivery of IV steroids achieves high plasma concentrations and rapid reversal of symptoms. The risks of therapy include exacerbating or inducing diabetes mellitus, gastrointestinal irritation/ perforation, and triggering psychosis. Administration of more than 7 g of methyl prednisolone within the first 30 days posttransplantation constitutes a risk factor for survival, due to the pronounced depression of the nonspecific immune resistance of the host. It is important to reduce the level of steroids to the pretherapy dose within one month, as long-term administration of high doses predisposes to gastrointestinal bleeding, myopathy, osteoporosis, bacterial/fugal infections, and hypertension. The advantages of steroid treatment are the low medication costs and the 90% efficacy rate. After three to five days of steroid treatment, most centers assess the success based upon remission of symptoms and improved graft function. However, this assessment is not clinically easy. On the one hand, blood chemistry values, which reflect tissue damage end points, slowly reverse even after control of the immune process; on the other hand, delay in the delivery of adequate immunosuppression may result in graft failure or severe permanent impairment. If the

medwedi.ru

120

Part One: General Considerations

response to steroids is deemed inadequate, and if the transplant biopsy documents persistent rejection, the physician proceeds with the administration of an antilymphocyte preparation. Most workers use OKT3 rather than polyclonal sera. To minimize the toxicity of OKT3 due to cytokine release, our regimen employs a split dose approach, delivering 1, 2, and 2 mg IV Q eight hours for the first day, followed by 2.5 mg Q 12 hours on the second day, and 5 mg/day thereafter. Each dose is administered with an anti-inflammatory pretreatment cocktail of 100 mg hydrocortisone, 50 mg benadryl, and 120 mg acetaminophen. Additionally, administration of monoclonal antibodies is always combined with a CMV prophylactic protocol. An intermediate point for the efficacy of OKT3 therapy is the reduction of T-cells bearing the CD3 marker from about 65% to < 10%, determined by flow cytometry analysis of whole blood samples with a fluoresceinated OKT3 reagent. Unfortunately, there are no secure algorithms for the length of OKT3 therapy, because there is a delay in the therapeutic effect by 7 to 10 days and in the toxic effects by 14 to 30 days.

Long-Term Maintenance Immunosuppression Although CsA reduced the incidence and severity of graft rejection episodes, it has had little impact on the 10% incidence of chronic rejection observed under Aza–Pred therapy. While it is possible that the failure represents inadequate CsA therapy due to suboptimal dose adjustments, it is more likely that host B-cell responses are less CsA sensitive than T-cell responses. Long-term management schemes show more variation than short-term regimens—there are advocates for CsA-only, CsA–Pred, CsA–Aza, and Aza–Pred strategies. Although no data suggest a difference in outcome, there have not been truly randomized trials. More recently, tacrolimus have been substituted for CsA in renal, liver, pancreas, and mutlivisceral organ transplant recipients. Furthermore, AZA use has been replaced by either MMF or RAPA.

CLINICAL TRANSPLANT OUTCOMES The modern era of organ transplantation began with the first successful grafting of a kidney between identical twins in 1954 (46). Subsequent advances in knowledge concerning the pathogenesis of rejection and the ability to manipulate this immune response by various therapeutic strategies have allowed transplantation to proceed to a point where many diseased organs can now be replaced with a minimum of difficulty. Kidney transplantation is relatively commonplace throughout the United States and many other countries, and organs such as the liver and heart are now being transplanted with increasing frequency. Although allograft rejection continues to be an important problem, CsA has done much to improve graft survival rates. Thus, for many organs, the availability of donors has posed more of a problem than the potential difficulties surrounding the rejection process. To gain an insight into the advances that have been made in organ transplantation over the last three decades, this section will briefly review the current status of organs that are transplantable. For purposes of discussion, three types of donor grafts should be recognized. These include: (i) grafting between twins in which the immunologic match is identical between host and donor, (ii) living, related grafts in which there is considerable immunologic similarity between the host and donor, but not to the same

degree as with twins, and (iii) cadaveric grafts obtained from unrelated individuals (i.e., subjects who are brain dead, but in whom function of the organ to be potentially transplanted is normal) in which immunologic matching between host and donor may be quite dissimilar, even though every attempt is made before transplantation to optimize this match as much as possible. For renal transplantation, all three types of grafts have been used. For transplantation of organs such as the heart, it is obvious that only cadaver grafts can be used.

Renal Transplantation Approximately 6000 to 10,000 new patients annually develop end-stage renal disease in the United States, srequiring treatment with either chronic dialysis or renal transplantation. For patients aged 70 years or lesser, renal transplantation has emerged as the treatment of choice. This relates to the recent advances in immunosuppression, particularly the discovery of CsA, which has drastically improved both renal allograft and patient survival (66). Before the availability of CsA, survival rates for patients receiving cadaveric allografts approached 90%, whereas graft survivals approximated 50%. With the advent of CsA, graft and patient one-year survival rates of 80% and 95%, respectively, have been routinely achieved in cadaveric transplantation. Similar results have been obtained in patients receiving living, related donor kidneys. With HLA-identical grafts, graft survival has approached 90% to 95%, and for all other living, related grafts, 75% to 85% graft survival has been obtained. Historically, patient survival following renal transplantation with a kidney from a living, related donor always exceeded that achieved with hemodialysis. In contrast, patient survival after cadaveric transplantation generally paralleled that associated with hemodialysis. With the use of CsA, however, a clear improvement in patient survival following cadaveric transplantation has been observed, when compared to that in hemodialysis. In addition, renal transplant patients demonstrated a significantly improved rehabilitation rate. Without question, both the longevity and quality of life have been clearly improved with this therapeutic modality. The renal transplanted kidney is usually placed in the retroperitonium of the iliac fossa through a lower abdominal incision (Fig. 24). Generally, the blood supply is assured by anastomosing the renal artery to the external iliac artery in an end-to-side or to the hypogastric artery in an end-toend fashion. The renal vein is anastomosed to the iliac vein end-to-side. Urinary tract continuity is usually established by a ureteroneocystostomy by placing the ureter either through a submucosal tunnel or by a direct implant that prevents the subsequent development of reflux. The success of this surgical approach has been clearly demonstrated in the thousands of kidneys that have been transplanted over the last 30 years.

Cardiac Transplantation Since the performance of the first human cardiac transplant by Dr. Christian Barnard in December 1967, thousands of heart transplants have been performed to prolong the life expectancy of patients with end-stage cardiac disease. Although enthusiasm for cardiac transplantation has waxed and waned over the last two decades, the use of CsA to treat rejection clearly improved the clinical outcome and rejuvenated interest in this procedure. The impact of CsA was

Chapter 5: Physiologic Basis of Transplantation

Figure 24 Renal transplantation. The donor kidney is placed in the retroperitonium of the iliac fossa. The donor renal artery and vein are anastomosed to the recipient iliac artery and vein, respectively in an end-to-side fashion. Ureteroneocystostomy establishes urinary continuity.

evidenced by the worldwide increase in cardiac transplant centers. Currently, cardiac transplantation is routinely performed in many centers in the United States. Patients considered as suitable candidates for cardiac transplantation are those with end-stage heart disease, provided that they have no other disease condition that potentially affects long-term survival. Generally, candidates for cardiac transplantation should be under the age of 65, and without an underlying malignant disease, insulindependent diabetes mellitus, severe peripheral vascular disease, morbid obesity, or an active infectious process. In addition, a high fixed pulmonary vascular resistance is usually considered a contraindication for this procedure. Cardiac allotransplantation (100) is usually performed orthotopically; the recipient heart is removed, leaving a remnant of the right and left atria posteriorly. The atria, pulmonary artery, and aorta from the donor heart are then anastomosed primarily. Heterotopic cardiac transplantation has also been performed in which the allograft is connected in parallel with the native heart. The theoretic advantage of this latter procedure is the maintenance of the native myocardium to sustain the recipient for reimplantation, if the organ comes from a suboptimal donor or if it undergoes acute irreversible rejection. The current overall patient survival rate exceeds 85% and 70%, with graft survival rates of 85% and 70% at one and five years, respectively. Regularly scheduled right endocardial biopsies in conjunction with cardiac catheterization and coronary angiography are used to evaluate the status of the transplanted heart. Although fever, hemodynamic instability, signs of congestive heart failure, arrhythmias, and electrocardiographic alterations are clinical indices suggesting rejection, histologic evaluation of the endocardium is usually necessary to rule out a rejection episode. Although rejection may occur at any time following transplantation, late graft failure is often associated with atherosclerotic coronary artery disease and chronic rejection of the transplanted heart.

Hepatic Transplantation Liver transplantation is now considered an accepted therapeutic modality for a number of hepatic disorders, and, in

121

certain conditions, the treatment of choice. As with heart transplantation, the general acceptance of this procedure has paralleled the significant improvement in survival resulting from the development of the surgical procedure and the use of CsA. Before CsA, Starzl and coworkers, pioneers in clinical hepatic transplantation, reported a one- and five-year survival rate of 32.9% and 20%, respectively, between 1963 and 1980. Immunosuppression with CsA has drastically improved these results, with the actuarial survival rates at one and five years now being 75% and 70%, respectively. When liver transplantation is carried to improve the quality of life in noncritically ill patients, the one-year survival is in excess of 90% (101). Indications for liver transplantation are now clearly defined. In the pediatric population, biliary atresia is the most common clinical condition in which this procedure is used. Because clinical success with hepatic transplantation has exceeded that of the Kasai procedure for biliary atresia, it is now considered by some researchers to be the treatment of choice for this pediatric disease. Other pediatric conditions in which hepatic transplantation offers a therapeutic alternative include various inborne errors of metabolism such as Wilson’s disease, tyrosinemia, glycogen storage disease, and the alpha1-antitrypsin deficiency. However, the severe shortage of pediatric liver donors has limited the expansion of liver transplantation in the pediatric population. The development of new surgical approaches including reduced-size liver transplant, split-liver transplantation, and living, related donors has increased the supply of organs for the pediatric population. End-stage liver disease (ESLD) caused by hepatitis C virus infection has become the most common indication for transplantation of the liver. Other indications include ESLD caused by cryptogenic and primary biliary cirrhosis, sclerosing cholangitis, alcohol related liver disease (Lannec’s cirrhosis), fulminant hepatic failure, hepatitis B, primary hepatocellular carcinoma, and hemangioendothelioma. Although the literature is replete with examples of transplantation in patients with cholangiocarcinoma, the relatively high recurrence rate in patients with this neoplastic disease has questioned the value of this procedure. As a general rule, patients with hepatic malignancy secondary to an extrahepatic source are no longer considered acceptable candidates for liver transplantation. Individuals with significant cardiopulmonary disease, advanced alcoholic disease, sepsis, or those deemed psychologically unfit for transplantation because of potential difficulty with immunologic drug compliance are also eliminated as acceptable transplant candidates. Age greater than 70 years currently constitutes a relative contraindication for liver transplantation. Liver transplantation (Fig. 25) is a formidable procedure conducted in three phases. The first phase involves dissection and removal of the recipient liver through a bilateral subcostal incision with an upper midline extension. During the second anhepatic phase, the venovenous bypass employed by most centers, decompresses the splanchnic bed, lower extremities, and kidneys by establishing venous flow from the portal vein and inferior vena cava to the axillary vein via a centrifugal pump. The third phase of hepatic implantation involves four vascular anastomoses including the inferior vena cava above and below the liver, the portal vein, and the hepatic artery. The most common biliary reconstruction is a choledochocholedochostomy followed by a choledochoenteric anastomosis via a standard Roux-en-Y choledochojejunostomy. Reported complications following liver transplantation ranged from 14% to 55%. These include

medwedi.ru

122

Part One: General Considerations

have been patients with end-stage pulmonary vascular disease such as primary pulmonary hypertension, and those with severe parenchymal disease, including chronic obstructive pulmonary disease, respiratory burns, pulmonary fibrosis, toxic pneumonitis, and bronchiectasis.

Pancreas Transplantation

Figure 25 Hepatic transplantation. Vascular continuity is established through four anastomoses that include the IVC above and below the liver, the portal vein, and the hepatic artery. Biliary tract reconstruction is obtained by a choledochocholedochostomy performed over a T-tube. Abbreviation: IVC, inferior vena cava.

postoperative hemorrhage, vascular thrombosis, biliary leak and obstruction, bowel obstruction and perforation, gastrointestinal bleeding, and wound complications (101). In deciding whether a patient is a suitable candidate for hepatic transplantation, the most important determinants are clearly the extent to which the patient’s underlying disease is interfering with quality of life and how transplantation will ultimately influence the long-term prognosis of this disease.

Lung Transplantation Transplantation of the lung can be performed either by itself or as an en bloc heart–lung combination. Clinical experience with solitary lung transplants has been fraught with considerable problems, including infection, hemorrhagic consolidation, and severe rejection, although this latter problem appears to be less noteworthy with the availability of CsA. Most centers in which solitary transplants have been performed have had few survivors beyond one month. For this reason, the heart–lung combination transplant has gained in popularity. Not only does the combined transplant ensure a better blood supply to the transplant bronchus, which has historically been a major problem with solitary pulmonary transplants in which anastomotic dehiscence of the bronchus has frequently occurred, but the operation is also technically more feasible than the solitary transplant and provides a maximum amount of lung parenchyma to optimize function of the allograft. However, in the last decade, lung transplantation outcomes have dramatically improved. Currently, lung grafting boasts one- and three-year survival rates approaching 78% and 60%, respectively. Survival following combined heart–lung procedures is approximately 70% and 40%, at one and three years, respectively. Although clinical experience with lung transplantation has been limited when compared with kidney, heart, or liver transplantation, potential recipients include those individuals with irreversible and terminal pulmonary failure. Among individuals who have received lung transplants

More than one million patients in the United States currently suffer from insulin-dependent diabetes mellitus. An additional 10,000 to 15,000 new cases can be expected each year. Despite exacting control of the serum glucose by exogenously administered insulin, serious complications are associated with this disease. The microangioplastic lesions resulting from aberrant diabetic carbohydrate metabolism produce severe retinopathy that may ultimately lead to blindness, nephropathy eventuating in renal failure, and peripheral vascular disease that is commonly associated with neuropathy and limb loss. Pancreatic transplantation in rodent models has successfully prevented and, in some cases, halted the progression of these microangiopathic lesions; thus it is not surprising that enormous efforts have been made to develop successful means of transplanting pancreatic tissue in humans. The first pancreatic transplant was performed by Kelly at the University of Minnesota in 1960. The one-year survival for all pancreas transplants between 1966 and 1980 was 21%, the outcome being influenced greatly by the magnitude of the rejection process. The advent of CsA, has renewed interest in this endeavor. Currently, approximately 1200 pancreatic transplantation are performed yearly in the United States in type 1 diabetic (T1D) patients. The most common procedure is simultaneous pancreas and kidney transplant in T1D recipients with renal failure. Pancreas transplantation alone is generally reserved for T1D patients who exhibit severe diabetes-related complications, but no evidence of renal failure. Rarely, the procedure is employed for type 2 diabetes, which is considered a contraindication for transplantation by most researchers. Presently, one-year patient and graft survival rates approximate 95% and 85%, respectively. Whole organ pancreatic transplants (102) include en bloc placement of the pancreas and a portion of duodenum surrounding the papilla of Vater to the urinary bladder in order to provide a means of exocrine drainage (Fig. 26). More recently, enteric drainage of the duodenal portion of the transplanted pancreas has been widely adopted because of the high complication rates and electrolyte imbalance associated with bladder drainage. The splenic artery and vein are then anastomosed to the hypogastric artery and external iliac vein, respectively, to reestablish blood supply. Pancreas transplantation is associated with higher morbidity than that encountered in renal transplant recipients. Such complications include vascular thrombosis and duodenal leaks that frequently necessitates allograft removal. In addition to the vascularized pancreatic allograft, treatment of diabetes has also been attempted with transplantation of isolated pancreatic islet cells. It is estimated that approximately 500,000 islets are required for normal carbohydrate metabolism. For this procedure, the pancreas is mechanically and enzymatically disrupted to harvest the islet cells. These cells are then transferred to the donor. A variety of donor sites have been used, including the testes, peritoneal cavity, beneath the renal capsule, spleen, and portal vein, the latter being the most often used. Although this technique has been quite successful experimentally in preventing or halting the metabolic consequences of diabetes in various animal models, clinical trials to date in diabetic

Chapter 5: Physiologic Basis of Transplantation

123

have recently been successful in preventing the rejection process and GVHD in various experimental models include CsA or FK506 administration, donor organ irradiation, and microsurgical excision of mesenteric lymph nodes. In the 1960s, several attempts have been made clinically to transplant human intestine. However, all patients died because of technical difficulties associated with the operation, sepsis, graft rejection, or a combination of these factors. Interest in SBT in the 1970s faded due to the advent of total parenteral nutrition (TPN). In the 1980s, interest in SBT was renewed due the realization of TPN limitations and the success of CsA in prolonging SBT survival in experimental animals. Current attempts of isolated SBT or combined liver/small bowel transplants have utilized high doses of FK506 and prostaglandin E1 with a 70% actuarial graft and patient survival (103). However, this is associated with a 90% incidence of bacterial infections, 43% viral infections, and an increased rate of lymphoproliferative disorders.

Bone-Marrow Transplantation Figure 26 Pancreas transplantation. Donor portal vein is anastomosed to the recipient iliac vein. Donor iliac ‘‘Y’’ graft connects donor SMA and donor splenic artery to recipient iliac artery. The duodenal segment is anastomosed to the recipient urinary bladder. Abbreviations: SMA, superior mesenteric artery; SMV, superior mesenteric vein.

human subjects have failed to abrogate the need for insulin, although some groups reported total insulin independence for one year. Thus, despite its potential advantage, islet transplant is still in its infancy.

Small Bowel Transplantation Annually, thousands of patients become victims of the short gut syndrome, usually secondary to thrombosis or embolization of the superior mesenteric artery, necessitating massive intestinal resection. The minimal digestive absorptive capacity with which these patients are left is often inadequate to maintain a normal nutritional status, requiring the use of long-term parenteral alimentation for survival. Obviously, replacement of this missing intestine with a small bowel transplant would be highly desirable. Experimentally, small bowel transplantation (SBT) has been successfully performed in animals since 1959. Lillehei, Goott, and Miller were the first to describe this technique with a canine model. Continuing experimental refinements have made the technique of SBT quite feasible from a technical standpoint. As with other organ transplants, the major problem in making SBT a clinically useful modality concerns the control of rejection. The magnitude of this problem directly relates to the length of intestine transplanted. Large segments of small intestine have resulted experimentally in a graft-versus-host disease (GVHD) reaction, because of the large amount of lymphoid tissue contained in intestinal mesenteric lymph nodes, peyer’s patches, and lamina propria that are capable of mounting an immune response against the host. In humans, the typical erythematous rash of GVHD develops concurrently with the appearance of donor lymphocytes in the recipient’s peripheral circulation. When small segments of intestine are transplanted, this is less of a problem, but the allograft still undergoes the standard rejection process. Immunosuppression regimens that

The indications for bone-marrow transplantation include severe inherited immune deficiency disorders, bone marrow failure, and certain malignancies. The potentially fatal inherited diseases for which bone marrow transplantation has been used include various hemoglobinopathies such as thalassemia and sickle cell disease, immunodeficiency states, and certain enzymatic disorders such as mucopolysaccharoidosis, osteopetrosis, chronic granulomatous disease, adenosine deaminase deficiency, and Diamond–Blackfan anemia. Acquired disorders of marrow failure responding to bone-marrow transplantation have included aplastic anemia and various malignancies such as acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, neuroblastoma, multiple myeloma, and acute myelofibrosis. Marrow transplantation has also been used in selected cases of marrow failure secondary to toxic chemotherapeutic agents. Human bone-marrow transplantation have stressed the use of HLA-histocompatible marrow between donor and recipient, as determined by serologic typing for the alleles of HLA-A, HLA-B, HLA-DR, and HLA-D loci and nonreactive MLC. Bone marrow for transplantation has been obtained from syngeneic, allogeneic, and autologous sources. Whereas syngeneic marrow transplantation refers to a transfer of bone marrow between genetically identical twins, allogeneic marrow transplantation is usually accomplished between HLA-identical siblings who inherited the same haplotype of chromosome 6 from each parent. The chance of HLA identity between siblings is one in four. Recipients of allogeneic or syngeneic marrow are pretreated with immunosuppressive agents and myeloablative drugs, if the underlying cause of marrow failure is a malignancy. In autologous transplantation, marrow is harvested from the patient during remission and cryopreserved. The marrow is then replanted following myeloablative antineoplastic therapy to eliminate residual malignant cells. Of interest, autologous transplantation has been as effective as the allogeneic or syngeneic marrow transplantation, in treating acute nonlymphocytic and chronic myelogenous leukemia. The major complications associated with bonemarrow transplantation have included rejection of the grafted marrow, GVHD, and potentially lethal infections. If the transplanted marrow functions only briefly and a marrow biopsy reveals the absence of marrow elements, this

medwedi.ru

124

Part One: General Considerations

indicates that the recipient has rejected the donor marrow because of presensitization, usually resulting from prior blood transfusions. GVHD results from the transplanted T-cells reacting to the genetically different host cells. The lymphohematopoietic system, including the skin, liver, and gastrointestinal tract, are primarily affected by the graft versus host response, which is manifest clinically as dermatitis, diarrhea, alterations in liver function, weight loss, and a high susceptibility to infection. GVHD occurs in 30% to 70% of allogeneic marrow transplant recipients and results in death of 20% to 40% of those individuals affected. The infectious complications following bone-marrow transplantation usually occur within the first several weeks before the production of granulocytes by the grafted marrow. The recipient is susceptible to all types of infections, including those caused by bacteria, fungi, and herpes simplex. After the first month following grafting, the increase in the peripheral white blood cell count suggests the engraftment of the donor marrow. Subsequent infections include cytomegalovirus and P. carinii infections, both of which are usually manifested as interstitial pneumonias. The use of prophylactic trimethoprim–sulfamethoxazole has greatly reduced the incidence of interstitial pneumonia secondary to Pneumocystis. Those patients having cytomegalovirus as the offending organism are much less fortunate, and many of these individuals will die because no current effective treatment exists. Thus, to prevent cytomegalovirus infections, hyperimmune globulin is usually administered prophylactically, early after transplantation.

Corneal Transplantation Corneal transplantation, also referred to as corneal grafting or penetrating keratoplasty, is performed in the United States at a rate of approximately 10,000 operations per year. The success of this procedure is limited only by the technical skills of the surgeon and not by the immune response. This is because the cornea is an immunologically privileged structure in which oxygen is derived from the oxygen content of the internal aqueous humor rather than from specific blood vessels. Consequently, circulating antibodies are isolated from the transplanted cornea. When they occur, rejection episodes are usually mild and develop at a rate of only 10% to 12%. If rejection becomes a problem, it is usually ablated by the use of topical steroids. In over 90% of operations performed, corneal transplantation proves to be successful. Currently, corneal transplantation is the procedure of choice for all patients suffering from opaque corneas. It is limited only by the availability of donor corneas. The persistence of the immunologically privileged status of the transplanted cornea depends on the vascularity of the graft. Scarring of the cornea results in an increased vascularity and consequently an increased risk of rejection. Under this circumstance, the cornea has a 25% incidence of irreversible rejection. Rejection occurs primarily through a cellular immune response. Previous corneal grafting resulting in corneal scarring and increased vascularity has been associated with graft failure. Histocompatibility matching is not routinely necessary, but is beneficial in the presence of heavily vascularized corneas.

SUMMARY Successful transplantation of organs or tissues rests on an understanding of the immunologic rejection process. The events leading to allograft rejection consist of afferent,

central, and efferent limbs. The presentation and recognition of foreign antigens are manifestations of the afferent limb. The central limb encompasses the proliferation, differentiation, and production of lymphokines by T-cells and of humoral antibody by B-cells, whereas the efferent limb represents the activation of various cell populations that ultimately lead to the rejection of the transplanted tissue or organ. Clinically, allograft rejection is classified as hyperacute, accelerated, acute, or chronic. A variety of immunologic strategies have been used to avert, minimize, or reduce the rejection response of the host or the immunogenicity of the allograft. The latter approach has only had limited success experimentally with nonvascularized grafts. Host immunosuppression by means of chemical substances (i.e., corticosteroids, CsA, and Aza) nonspecifically diminishes the immune response. More recently, new potent immunosuppressive medications (Tacrolimus, MMF, and RAPA) have gained wide application in transplantation. Biologic agents (i.e., ALS and monoclonal antibodies) provide both generalized and specific immunosuppressive effects. ALS nonspecifically depletes the host of lymphoid cells, whereas monoclonal antibodies deplete a specific T-cell subset. To date, immunologic manipulation to achieve transplantation tolerance has not progressed to a level satisfactory for clinical use. Continued research in basic immunology provides foundations for further advances in immunosuppressive manipulations. The next era of transplantation will witness progress from the nonspecific immunosuppressive strategy that is associated with a high morbidity to a strategy that seeks to alter regulation of the immune response, in order to selectively downregulate antidonor responses to achieve immunological tolerance, the ideal state of immunosuppression (104).

REFERENCES 1. Kahan BD. Transplantation timeline. Mankind’s three millennia—one maverick’s three decades in the struggle against biochemical individuality. Transplantation 1991; 51:1–21. 2. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med 2000; 343:338–344. 3. Fox A, Harrison LC. Innate immunity and graft rejection. Immunol Rev 2000; 173:141–147. 4. Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002; 8:582–587. 5. Beg AA. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002; 23:509–512. 6. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003; 21:335–376. 7. Proudfoot AE. Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol 2002; 2:106–115. 8. DeVries ME, Hosiawa KA, Cameron CM, et al. The role of chemokines and chemokine receptors in alloantigenindependent and alloantigen-dependent transplantation injury. Semin Immunol 2003; 15:33–48. 9. el-Sawy T, Fahmy NM, Fairchild RL. Chemokines: directing leukocyte infiltration into allografts. Curr Opin Immunol 2002; 14:562–568. 10. Rammensee HG, Falk K, Rotzschke O. Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 1993; 11:213–244. 11. Yewdell JW, Reits E, Neefjes J. Making sense of mass destruction: quantitating MHC class I antigen presentation. Nat Rev Immunol 2003; 3:952–961.

Chapter 5: Physiologic Basis of Transplantation 12. Gromme M, Neefjes J. Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways. Mol Immunol 2002; 39:181–202. 13. Brown JH, Jardetzky TS, Gorga JC, et al. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 1993; 364:33–39. 14. Germain RN. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994; 76:287–299. 15. Villadangos JA. Presentation of antigens by MHC class II molecules: getting the most out of them. Mol Immunol 2001; 38:329–346. 16. Hiltbold EM, Roche PA. Trafficking of MHC class II molecules in the late secretory pathway. Curr Opin Immunol 2002; 14:30–35. 17. Flye MW. Immunohematology. In: Flye MW, ed. Principles of Organ Transplantation. Philadelphia: WB Saunders, 1989. 18. Sheil AG, Stewart JH, Tiller DJ, May J. ABO blood group incompatibility in renal transplantation. Transplantation 1969; 8:299–300. 19. Alexandre GP, Squifflet JP, De Bruyere M, et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc 1987; 19:4538–4542. 20. Oriol R, Cartron J, Yvart J, et al. The Lewis system: new histocompatibility antigens in renal transplantation. Lancet 1978; 1:574–575. 21. Spitalnik S, Pfaff W, Cowles J, Ireland, JE, Scornik, JC, Blumberg N. Correlation of humoral immunity to Lewis blood group antigens with renal transplant rejection. Transplantation 1984; 37:265–268. 22. Lin WC, Desiderio S. Regulation of V(D)J recombination activator protein RAG-2 by phosphorylation. Science 1993; 260: 953–959. 23. Benoist C, Mathis D. Positive selection of the T cell repertoire: where and when does it occur? Cell 1989; 58:1027–1033. 24. Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell 1987; 49:273–280. 25. Nossal GJ. Negative selection of lymphocytes. Cell 1994; 76: 229–239. 26. Finkel TH, Kubo RT, Cambier JC. T-cell development and transmembrane signaling: changing biological responses through an unchanging receptor. Immunol Today 1991; 12:79–85. 27. Janeway CA Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell 1994; 76:275–285. 28. Auchincloss H Jr, Mayer T, Ghobrial R, Winn HJ. T-cell subsets, bm mutants, and the mechanisms of allogeneic skin graft rejection. Immunol Res 1989; 8:149–164. 29. Rudd CE, Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 2003; 3: 544–556. 30. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?. Nat Rev Immunol 2003; 3: 609–620. 31. Tiemeyer M, Swiedler SJ, Ishihara M, et al. Carbohydrate ligands for endothelial-leukocyte adhesion molecule 1. Proc Natl Acad Sci USA 1991; 88:1138–1142. 32. Springer TA. Adhesion receptors of the immune system. Nature 1990; 346:425–434. 33. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994; 76:301–314. 34. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392:245–252. 35. Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002; 2:151–161. 36. Lanzavecchia A, Lezzi G, Viola A. From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 1999; 96:1–4. 37. Bromley SK, Burack WR, Johnson KG, et al. The immunological synapse. Annu Rev Immunol 2001; 19:375–396. 38. Weissman AM. The T-cell antigen receptor: a multisubunit signaling complex. Chem Immunol 1994; 59:1–18.

125

39. Samelson LE. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annu Rev Immunol 2002; 20:371–394. 40. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383:787–793. 41. Agnello D, Lankford CS, Bream J, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol 2003; 23: 147–161. 42. Farrar JD, Asnagli H, Murphy KM. T helper subset development: roles of instruction, selection, and transcription. J Clin Invest 2002; 109:431–435. 43. Ansel KM, Lee DU, Rao A. An epigenetic view of helper T cell differentiation. Nat Immunol 2003; 4:616–623. 44. Bjorkman PJ, Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem 1990; 59:253–288. 45. Chien YH, Davis MM. How alpha beta T-cell receptors ’see’ peptide/MHC complexes. Immunol Today 1993; 14:597–602. 46. Sherman LA, Chattopadhyay S. The molecular basis of allorecognition. Annu Rev Immunol 1993; 11:385–402. 47. Shoskes DA, Wood KJ. Indirect presentation of MHC antigens in transplantation. Immunol Today 1994; 15:32–38. 48. Gould DS, Auchincloss H Jr. Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol Today 1999; 20:77–82. 49. Rogers NJ, Lechler RI. Allorecognition. Am J Transplant 2001; 1:97–102. 50. Lechler R, Lombardi G. The structural basis of alloreactivity. Immunol Res 1990; 9:135–146. 51. Ghobrial R, Hamashima T, Kloc M, Etkin L, Stepkowski SM, Kahan BD. Membrane-bound or soluble truncated RT1.Aa rat class I major histocompatibility antigens induce specific alloimmunity. Transplantation 1995; 60:602–610. 52. Shirwan H, Chi D, Makowka L, Cramer DV. Lymphocytes infiltrating rat cardiac allografts express a limited repertoire of T cell receptor V beta genes. J Immunol 1993; 151:5228–5238. 53. Evavold BD, Sloan-Lancaster J, Allen PM. Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today 1993; 14:602–609. 54. Ghobrial R, Hamashima T, Stepkowski SM, Kahan BD. Induction of transplantation tolerance by perioperative injection of "quasi-self" chimeric class I MHC antigen combined with a short cyclosporine course. Transplant Proc 1995; 27: 239–240. 55. Nisco S, Vriens P, Hoyt G, et al. Induction of allograft tolerance in rats by an HLA class-I-derived peptide and cyclosporine A. J Immunol 1994; 152:3786–3792. 56. Kerman RH. Relevance of histocompatibility testing in clinical transplantation. Surg Clin North Am 1994; 74:1015–1028. 57. Miyajima A, Kitamura T, Harada N, Yokota T, Arai K. Cytokine receptors and signal transduction. Annu Rev Immunol 1992; 10:295–331. 58. Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell 1994; 76:253–262. 59. McDonald NQ, Hendrickson WA. A structural superfamily of growth factors containing a cystine knot motif. Cell 1993; 73:421–424. 60. Abbas AKLA, Pober JS. Cytokines. In: Abbas AKLA, Pober JS, eds. Cellular and Molecular Immunology. Philadelphia: WB Saunders, 1994. 61. Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in vivo model of immune-mediated tissue destruction. Annu Rev Immunol 1992; 10:333–358. 62. Lakkis FG, Arakelov A, Konieczny BT, Inoue Y. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 2000; 6:686–688. 63. Le Moine A, Goldman M, Abramowicz D. Multiple pathways to allograft rejection. Transplantation 2002; 73:1373–1381. 64. Le Moine A, Goldman M. Non-classical pathways of cellmediated allograft rejection: new challenges for tolerance induction? Am J Transplant 2003; 3:101–106.

medwedi.ru

126

Part One: General Considerations

65. Jeannet M, Pinn VW, Flax MH, Winn HJ, Russell PS. Humoral antibodies in renal allotransplantation in man. N Engl J Med 1970; 282:111–117. 66. Browne BJ, Kahan BD. Renal transplantation. Surg Clin North Am 1994; 74:1097–1116. 67. Hancock WW. Analysis of intragraft effector mechanisms associated with human renal allograft rejection: immunohistological studies with monoclonal antibodies. Immunol Rev 1984; 77:61–84. 68. Lopez C, Simmons RL, Mauer SM, Najarian JS, Good RA, Gentry S. Association of renal allograft rejection with virus infections. Am J Med 1974; 56:280–289. 69. Libby P, Pober JS. Chronic rejection. Immunity 2001; 14:387–397. 70. Allan JS, Madsen JC. Recent advances in the immunology of chronic rejection. Curr Opin Nephrol Hypertens 2002; 11: 315–321. 71. Joosten SA, van Kooten C, Paul LC. Pathogenesis of chronic allograft rejection. Transpl Int 2003; 16:137–145. 72. Kahan BD, Ghobrial R. Immunosuppressive agents. Surg Clin North Am 1994; 74(5):1029. 73. Hricik DE, Almawi WY, Strom TB. Trends in the use of glucocorticoids in renal transplantation. Transplantation 1994; 57:979. 74. Kahan BD. Drug therapy. Cyclosporine. N Engl J Med 1989; 321:1725. 75. Sigal NH, Dumont FJ. Cyclosporine A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol 1992; 10:519. 76. Linholm A, Kahan BD. Influence of cyclosporine pharmacokinetic parameters, trough concentrations and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993; 54:205. 77. The U.S. Multicenter FK 506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994; 331:1110. 78. Neuhaus P, Klupp J, Langrehr JM. mTOR Inhibitors: an overview. Liver Transplantation 2001; 7:473–484. 79. Kahan BD, Chang JY, Seghal SN. Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. Transplantation 1991; 52:185. 80. Kuo CJ, Chung J, Fiorentino DF, Flangan WM, Blenis J, Crabtree GR. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 1992; 358:70. 81. Kovarik JM, Kaplan B, Tedesco-Silva H, et al. Exposureresponse relationships for everolimus in de novo kidney transplantation: defining a therapeutic range. Transplantation 2002; 73:920. 82. Sollinger HW, Belzer FO, Deierhoi MH, et al. RS-61443 (mycophenolate mofetil): a multicenter study for refractory kidney transplant rejection. Ann Surg 1992; 216:513. 83. European Mycophenolate mofetil study group. Placebocontrolled study of mycophenolate mofetil combined with cyclosporin and corticosteroid for prevention of acute rejection. Lancet 345:1321. 84. Granger DK. Enteric-coated mycophenolate sodium: results of two pivotal global multicenter trials. Transplant Proc 2001; 33:3241. 85. Williams JW, Mital D, Chong A, et al. Experiences with leflunomide in solid organ transplantation. Transplantation 2002; 73(3):358.

86. Jin MB, Nakayama M, Ogata T, et al. A novel leflunomide derivative, FK778, for immunosuppression after kidney transplantation in dogs. Surgery 2002; 132:72. 87. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002; 296:346. 88. Kahan B. Update on pharmacokinetic/pharmacodynamic studies with FTY720 and sirolimus. Therap Drug Mon 2002; 24:47–52. 89. Tedesco H, Kahan BD, Mourad G, et al. FTY720 combined 1 with Neoral and corticosteroids is effective and safe in prevention of acute rejection in renal allograft recipients—interim data. Am J Transplant 2001; 1(suppl 1):243. 90. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody or predefined specificity. Nature 1975; 256:495. 91. Jaffers G, Fulkler T, Cosimi AB, Russell P, Winn H, Colvin RB. Monoclonal antibody therapy, anti-idiotypic and anti-isotypic antibodies to OKT3 arising despite intense immunosuppression. Transplantation 1986; 41:572. 92. Norman DJ, Vicenti F, de Mattos AM, et al. Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors. Transplantation 2000; 70(12):1707–1712. 93. Woodle ES, Xu D, Zivin RA, et al. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1 (Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 1999; 68(5):608–616. 94. Murine OKT4A immunosuppression in cadaver donor renal allograft recipients: a coopertive clinical trials in transplantation pilot study. Transplantation 1997; 63(9):1243–1251. 95. Haug CE, Colvin RB, Delmonico FL, Auchincloss H Jr, et al. A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAB in renal allograft recipients. Transplantation 1993; 55:766. 96. Tzakis AG, Kato T, Nishida S, et al. Preliminary experience with Campath 1H (C1H) in intestinal and liver transplantation. Transplantation 2003; 75(8):1227. 97. Hanto DW, Shelton MW, Simmons RL. Cancer in recipients of organ allografts. In: Williams GM, Burdick J, Solez K, eds. Kidney Transplant Rejection: Diagnosis and Treatment. 2d ed.. New York: Marcel Dekker, 1991. 98. Penn I. Development of new tumors after transplantation. In: Cerelli GJ, ed. Organ Transplantation and Replacement. Philadelphia: JB Lippincott, 1988. 99. Johnson M, Flye MW. Infectious complications in renal transplant patients. In: Flye MW, ed. Principles of Organ Transplantation. Philadelphia: WB Saunders, 1989. 100. Frazier OH, Macris MP. Progress in cardiac transplantation. Surg Clin North Am 1994; 74(5):1169. 101. Wood RP, Ozaki CF, Katz SM, Monsour HP, Dyer CH, Johnston TD. Liver transplantation. Surg Clin North Am 1994; 74(5):1133. 102. Sollinger HW, Geffner SR. Pancreas transplantation. Surg Clin North Am 1994; 74(5):1183. 103. Asfar S, Zhong R, Grant D. Small bowel transplantation. Surg Clin North Am 1994; 74(5):1197. 104. Merrill JP, Murray JE, Harrison JH, et al. Successful homotransplantation of human kidney between identical twins. JAMA 1956; 160:277.

6 Surgical Infection: Principles of Management and Antibiotic Usage Christina Paylan and Rodney Durham

INTRODUCTION The prevention and treatment of microbial infections are important components of the surgeon’s clinical practice. Patients may first present to a surgeon because of an infection requiring drainage or some other form of surgical treatment. In addition, postoperative infections are among the most common complications of surgical therapy, even in patients whose original problem was noninfectious in nature. For these reasons, it is important for the surgeon to have an understanding of the basic pathophysiology of infection, as well as the fundamental principles of management, including antibiotic therapy.

PATHOPHYSIOLOGY OF SURGICAL INFECTIONS Infections result when the balance between pathogenic organisms and the host’s defense mechanisms is disrupted. Large numbers of bacteria and other microorganisms colonize many of the epithelial surfaces of the body, including the skin, most portions of the upper aerodigestive tract, the gastrointestinal (GI) tract below the duodenum, the vagina, and the lower genitourinary tract. Overall, approximately 1014 bacteria colonize the human body, or about 10 bacteria for every eucaryotic cell (1). Anaerobic bacteria predominate over aerobic bacteria by a 10:1 ratio, and this ratio may be even higher in the lower GI tract. These endogenous microorganisms prevent colonization of epithelial surfaces by more pathogenic organisms, but can themselves be pathogenic under appropriate circumstances. Furthermore, endogenous flora is responsible for many of the infections observed in surgical patients. The virulence of a particular microbe is related to many different properties. Specific molecules on the microbial surface may allow an organism to adhere to an epithelial surface, thereby initiating an infection. For instance, Escherichia coli strains bearing specific types of fimbriae can attach to the urinary epithelium; these strains are much more likely to produce clinical urinary tract infections than strains not bearing those structures. Other microbial products may facilitate invasion of the host tissues. Streptokinase, hyaluronidase, and collagenase are enzymes secreted by some types of bacteria that allow spreading infections to occur. Finally, many microorganisms have mechanisms that allow them to escape the host defenses. Thus microbial proteins that disrupt chemotaxis by white blood cells, interfere with phagocytosis, or prevent intracellular killing have been identified. Thus, certain intracellular pathogens, such as Listeria, actually survive within the phagocyte.

Various exotoxins and endotoxins may be responsible for many of the deleterious effects of microbial infections. Many times, the actual infection itself is of little consequence, but the potent toxins released lead to fulminant disease. Examples of such infections are those produced by diphtheria, cholera, and tetanus bacteria. Microbial toxins produce a variety of effects on the host. Some exotoxins are cytotoxic for eucaryotic cells, such as the exotoxins produced by Clostridium difficile. Other toxins trigger an overwhelming host response, and it is the host response rather than the actual infection that results in damage to distant tissues. For instance, many of the pathogenic effects of lipopolysaccharide, the complex endotoxin of gram-negative bacteria, are thought to be mediated by this overwhelming host response. There are numerous mechanisms by which the host prevents these pathogenic microorganisms from producing frank infection (2). The intact epithelium of the skin or mucosal surface presents the initial barrier against microbial invasion. Both physical and chemical components contribute to this barrier function. Tight junctions and other components of the intercellular adhesion complex prevent microorganisms from gaining access to internal tissues. Mucosal surfaces are protected by a surface layer of mucus, which prevents bacterial attachment, and the dry, somewhat acidic, keratinized surface of the skin inhibits bacterial proliferation. In addition, epithelial cells secrete a number of substances, such as lysozyme, which are also inhibitory for microbial growth. Finally, some epithelial surfaces have mechanical mechanisms, by which to directly remove microorganisms, as is seen with the mucociliary apparatus of the respiratory epithelium. Microbial organisms that breach the epithelial barrier or otherwise gain access to interior tissues have to face both nonspecific and specific humoral and cellular defense mechanisms. Nonspecific humoral components of the inflammatory response, such as the complement cascade, the kallikrein–kinin system, and the coagulation system, are activated. This activation helps to localize the invading microorganisms and also signals for the recruitment of phagocytic cells, such as neutrophils and macrophages, to the site of invasion. The nonspecific inflammatory response is accompanied by the development of the specific immune response. The humoral arm of the immune response is represented by the various immunoglobulin molecules produced by B-lymphocytes and plasma cells, and the cellular arm by specific cytotoxic T-lymphocytes and natural killer cells, among others. Many aspects of surgical treatment interfere with these host-defense mechanisms. The most obvious of these is the surgical incision through intact skin or mucosa.

medwedi.ru 127

128

Part One: General Considerations

The placement of intravenous and other vascular access catheters also breaks the intact skin barrier. Other devices, such as endotracheal tubes and indwelling urinary catheters, provide microorganisms with direct access from sites of heavy colonization to normally sterile areas. Ischemic and devitalized tissues produced as a result of a surgical procedure provide a haven for the growth of bacteria, because they may be inaccessible to phagocytic cells. In addition, the presence of blood in areas of damage provides essential nutrients for bacterial growth. The use of prophylatic antibiotics for many operative procedures, while undeniably reducing the risk of wound infections, may also change the resident microbial flora, allowing a pathogen to proliferate. This has been well demonstrated in the development of antibiotic-associated colitis (AAC). The patient’s preexisting medical condition can also interfere with host-defense mechanisms. For instance, the presence of diabetes mellitus or the prior use of corticosteroid or immunosuppressive medications may impair the development of an adequate inflammatory or immunologic response. Severe malnutrition is also associated with an increased risk of postoperative infections. Finally, the pathologic process that has necessitated the surgical procedure may increase the risk of a significant infection. There is a high likelihood of developing an intraabdominal abscess or surgical wound infection when massive peritoneal contamination, for instance, from a free colonic perforation, has occurred. Shock and hypothermia also result in a generalized impairment in the function of phagocytic cells, as well as in the cellular immune responses, and predispose patients to postoperative infections.

SYSTEMIC INFLAMMATORY RESPONSE The local inflammatory response generated as a result of an infection is usually accompanied by a systemic response of the organism. This systemic response to a proinflammatory stimulus, whether infectious or noninfectious, is now referred to as the systemic inflammatory response syndrome (SIRS) (3). SIRS is considered to be present if a patient has two or more abnormalities in temperature, heart rate, respiratory function, or white blood cell count (Table 1). When an infection is the cause of SIRS, sepsis is considered to be present. Although alterations in these four parameters suffice to define the clinical syndrome of SIRS, the systemic response to infection involves changes in many more physiologic parameters. In general, this systemic response includes the development of a hyperdynamic cardiovascular state characterized by increased cardiac output and decreased systemic vascular resistance and a hypermetabolic state characterized by increased oxygen consumption and carbon dioxide production, production and utilization of glucose, mobilization of free fatty acids, and breakdown of the body’s muscle protein stores (4). This overall systemic response is important in ensuring the organism’s survival during an infectious episode. Indeed, in experimental settings, it has been shown that the development of fever is associated with increased survival following a normally lethal bacterial challenge (5). It has also been observed in clinical studies that the inability to develop an adequate cardiovascular or metabolic response has an adverse impact on patient survival during sepsis (6,7). The mechanisms by which the systemic inflammatory response is generated have been extensively investigated in recent years. It is apparent that a large number of endogenous

Table 1 Definitions Infection: Microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organism Bacteremia: The presence of viable bacteria in the blood SIRS: The systemic inflammatory response to a variety of severe clinical insults. The response is manifested by two or more of the following conditions: Temperature >38 C or <36 C Heart rate >90 beats/min Respiratory rate >20 breaths/min or PaCO2 <32 Torr (<4.3 kPa) WBC >12,000 cells/mm3, <4000 cells/mm3, or >10% immature (band) forms Sepsis: The systemic response to infection. This systemic response is manifested by two or more of the following conditions as a result of infection: Temperature >38 C or <36 C Heart rate >90 beats/min Respiratory rate >20 breaths/min or PaCO2 <3 Torr (< 4.3 kPa) WBC >12,000 cells/mm3, <4000 cells/mm3, or >10% immature (band) forms Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status Septic shock: Sepsis with hypotension, despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured Hypotension: A systolic blood pressure of <90 mmHg or a reduction of <40 mmHg from baseline in the absence of other causes for hypotension MODS: Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention Abbreviations: MODS, multiple-organ dysfunction syndrome; SIRS, systemic inflammatory response syndrome. Source: From Ref. 3.

mediators are involved in this response. Such mediators include neurotransmitters and hormones (such as catecholamines, glucagon, and glucocorticoids), various proinflammatory mediators (including lipid-derived mediators such as eicosanoids and platelet-activating factor), and polypeptide mediators (such as activated components of the complement system). Of particular importance in triggering the systemic response to infections are certain peptide regulatory factors referred to as cytokines. Cytokines that may be especially important in the development of this response include tumor necrosis factor (TNF), lymphotoxin, colonystimulating factors, and various interleukins [particularly interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8), and, interferon-a, interferon-b, and interferon-g] (8). The importance of these agents has been demonstrated in experimental studies in which endotoxin was infused into laboratory animals or human volunteers. Endotoxin infusion was found to be followed by the sequential release of TNF, IL-1, and IL-6 (9). Inhibition of TNF using a neutralizing antibody abrogated the release of the other cytokines and also suppressed many of the physiologic changes typical of the systemic inflammatory response (10). In clinical studies, however, circulating levels of IL-6 rather than TNF have been found to correlate most closely with an adverse clinical outcome, but the combined inflammatory score based on circulating concentrations of

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

endotoxin, TNF, IL-1, and IL-6 appeared to be the best predictor of outcome in patients with the sepsis syndrome (11). Given the importance of these proinflammatory mediators in the development of the clinical manifestations of infections, it is not surprising that antagonists of these cytokines have been developed and subjected to clinical trials. In general, however, the use of antiendotoxin antibodies, anti-TNF antibodies, and an IL-1 receptor antagonist has not proved beneficial. There are several potential reasons why these agents have not been useful clinically. First of all, although the experimental infusion of endotoxin produces an orderly release of cytokines with TNF playing a primary role, most clinical infections, even those due to gram-negative organisms, are likely to involve a much more complicated pattern of mediator release. Second, the therapeutic use of cytokine antagonists may occur too late, because much of the initial wave of cytokine release occurs within a few hours of the infusion of bacteria or endotoxin. It is only under very special circumstances, in which an antagonist can be given prior to the expected release of the mediators, that anticytokine therapy has proved beneficial (12). Finally, from the biologic viewpoint, it should be noted that the systemic inflammatory response has evolved in vertebrates as a mechanism to counteract infectious and other damaging stimuli. Accordingly, this reaction should ultimately be advantageous for survival, even though acutely it increases the physiologic demands placed on the organism. Thus it is certainly possible that counteracting this response may not benefit the patient.

f.

g.

h.

i. j. k.

l.

OVERALL APPROACH TO SEPSIS In March of 2004, an international panel of critical care and infectious disease specialists published guidelines for the management of patients with severe sepsis and septic shock under the auspices of Surviving Sepsis Campaign (13). The multimodality approach to sepsis outlined by Surviving Sepsis Campaign is as follows:

m. n.

a.

Goals at initial resuscitation within the first six hours include the following:

b.

c.

d. e.

CVP of 8–12 mmHg Mean arterial pressure of 65 mmHg Urine output greater than 0.5 cc/kg/hr Mixed venous saturation greater than 70%

If mixed venous saturation of more than 70% is not achieved within the first six hours with fluid resuscitation to a central venous pressure of 8 to 12 mmHg, then transfusion with one unit of packed red blood cells to achieve a hemotocrit of more than 30% is recommended. This goal can also be attempted by administration of dobutamine if necessary. Goals at diagnosis include drawing appropriate cultures before any antimicrobial therapy is begun. At least two types of blood cultures, one drawn percutaneously and one drawn through each vascular access device, are recommended. Intravenous antibiotic therapy should be started within the first hour of recognition of severe sepsis after appropriate cultures are obtained. Initial empirical anti-infective therapy should be directed against the likely bacterial or fungal organisms. Antimicrobial regimen should always be reassessed after 48 to 72 hours with the aim of streamlining to

o. p. q.

r. s. t.

129

prevent development of resistance and to reduce toxicity as well as costs. Source control should be evaluated in every patient presenting with sepsis. In this regard, drainage of an abscess, debridement of infected necrotic tissue, and the removal of a potentially infected device should not be delayed. Fluid resuscitation is important and may consist of natural or artifical colloids or crystalloids. There is no evidence-based support for one type of fluid over another. Vasopressor therapy is important when fluid resuscitation becomes inadequate to control blood pressure. Either norepinephrine or dopamine is the first choice as a vasopressor agent to correct hypotension in septic shock. However low-dose dopamine should not be used for renal protection as part of treatment for severe sepsis. All patients requiring vasopressors should have an arterial catheter placed as soon as practical. Vasopressin may be considered in patients with refractory shock despite adequate fluid resuscitation. Inotropic therapy is recommended in severe sepsis when the cardiac output is low. Dobutamine is the agent of choice, and if used in the presence of low blood pressure, it should be combined with vasopressor therapy. Intravenous corticosteroids (200–3000 mg/day for seven days in three divided doses or by continuous infusion) are recommended in patients with septic shock, who despite adequate fluid replacement require vasopressor therapy to maintain adequate blood pressure. Some experts use 250 mc adrenocorticotropic hormone (ACTH)–stimulation test to identify responders (9 mg/dL increase in cortisol 30–60 minutes post–ACTH administration). Human-activated protein C, known as Xigris, is recommended in patients at high risk of death. Blood product administration should only occur when red blood cell concentration falls below 7 g/dL. Erythropoietin is not recommended as a specific treatment of anemia associated with severe sepsis, but may be used when septic patients have other accepted reasons for administration, such as renal failure–induced compromise of red blood cell production. In addition, routine use of fresh frozen plasma to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures is not recommended. High tidal volumes coupled with high plateau pressures should be avoided. Hypercapnia can be tolerated in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Unless contraindicated, mechanically ventilated patients should be maintained semirecumbent with the head of bed at 45 to prevent the development of ventilator-associated pneumonia (VAP). Neuromuscular blockers should be avoided due to the risk of prolonged neuromuscular blockade following discontinuation. Blood glucose levels should be maintained at less than 150 mg/dL by using continuous infusion of insulin. In acute renal failure, and in the absence of hemodynamic instability, continuous venovenous hemofiltration and intermittent hemodialysis are considered equivalent.

medwedi.ru

130

Part One: General Considerations

u. Bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements is not recommended. v. Deep vein thrombosis therapy is recommended with unfractioned or low-molecular-weight heparin. w. Stress ulcer prophylaxis should be given to all patients with severe sepsis. H2 receptor inhibitors are more efficacious than sucralfate and are the preferred agents.

DEFINITIONS OF SURGICAL INFECTIONS In 1992, the Centers for Disease Control and Prevention revised its definition of surgical wound infections. At this time, it was proposed to change the terminology from wound infection to surgical-site infections (SSI) (14). This latter terminology was designed to take into account both incisional (superficial and deep) infections and infections of organs or body spaces (e.g., subphrenic abscesses). More distant infections (e.g., postoperative pneumonia), excluding blood infections directly related to SSI, are classified as postoperative complications. Superficial incisional infections involve only the skin and subcutaneous tissues. Deep incisional infections involve the fascial and muscle layers, and organ or space infections involve any organs or body cavities that were manipulated during the surgical procedure. To be considered an SSI, the infection must occur within 30 days of the procedure, unless an implant is in place, in which case the time period is lengthened to one year. Characteristics of the different types of infection are listed in Table 2. Infections that arise in tissues begin as a cellulitis. This is manifested clinically by local tenderness, heat, swelling, redness, and pain. Because this type of infection has no localized areas of pus formation, it does not lend itself to drainage and can often be managed by rest, application of local heat, and antibiotic therapy, and elevation if an extremity is involved. If left untreated, cellulitis may spread through adjacent tissue planes (as occurs with b-hemolytic Streptococcus) or remain localized to form an abscess (as

may occur with Staphylococcus). In contrast to cellulitis, an abscess denotes a local collection of necrotic tissue, white blood cells, and bacteria, designated clinically as pus. The increased osmotic pressure that exists within a walled-off abscess can lead to movement of water into the area from adjacent tissues, resulting in pressure that is seen clinically as severe pain and tenderness. All abscesses should be drained to prevent the risk of bacterial spread along adjacent tissue planes or through the blood or lymphatic vessels and to provide symptomatic relief. Adjunctive antibiotic therapy is indicated to treat associated areas of cellulitis and to control any bacteria that may have entered the lymph or blood during the drainage process. Not uncommonly, products of infection from areas of cellulitis or abscess formation gain access to the blood and lymph systems. Occasionally, during the spread of infection, lymph channels may become infected and are seen clinically as hyperemic streaks. This condition is called acute lymphangitis, colloquially referred to as blood poisoning. If this infection is not controlled, the involved lymph nodes may later abscess and progress to a more severe state of infection known as suppurative lymphangitis. Invasion of vascular channels by bacteria is referred to as bacteremia. Because of the direct consequences that may result from bacterial spread, both lymphatically and through the vascular system, aggressive treatment including appropriate antibiotic therapy and local management of the source of infection with drainage of any abscesses is indicated. Approximately 30% of surgical patients either enter the hospital with an infection or develop one subsequently during the course of their postoperative care. Operative intervention is usually required in patients who are admitted to surgical services with evidence of infection. Infections of this nature include such diseases as appendicitis, cholecystitis, diverticular abscess, and gangrene of the leg. Although antibiotics are used as an adjunct to surgery in these patients, antibiotics by themselves are usually not efficacious in controlling the infectious process. The most frequent types of infection encountered in surgical patients are postoperative infections. In general, this classification

Table 2 Characteristics of Surgical Site Infections Superficial incisional SSIs Infection occurs within 30 days after the operation and infection involves only skin and subcutaneous tissue of the incision and at least one of the following: (i) Purulent drainage, with or without laboratory confirmation, from the superficial incision (ii) At least one of the following signs or symptoms of infection: Pain or tenderness, localized swelling, and redness, or heat, and superficial incision is deliberately opened by surgeon, unless culture result of incision is negative Deep incisional SSIs Infection occurs within 30 days after the operation if no implant is left in place or within 1 yr if implant is in place and the infection, appears to be related to the operation and infection involves deep soft tissues (e.g., fascial and muscle layers) of the incision (i) A deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has at least one of the following signs or symptoms: Fever (higher than 38 C), localized pain, or tenderness, unless culture result of the incision is negative Diagnosis of a deep incisional SSI by a surgeon or attending physician Organ or space SSIs Infection occurs within 30 days after the operation if no implant is left in place or within 1 yr if implant is in place and the infection, appears to be related to the operation and infection involves any part of the anatomy (e.g., organs or spaces) other than the incision, which was opened or manipulated during an operation and at least one of the following: (i) Purulent drainage from a drain placed through a stab wound into an organ/space (ii) Organisms isolated from an aseptically obtained culture or fluid or tissue in the organ or space (iii) An abscess or other evidence of infection involving the organ or space on direct examination, during reoperation, or by histopathologic or radiologic examination (iv) Diagnosis of an organ or space SSI by a surgeon or attending physician Abbreviations: NNISS, National Nosocomial Infection Surveillance System; SSI, surgical site infection. Source: From Ref. 14.

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

implies a hospital-acquired infection, commonly referred to as a nosocomial infection. Of all nosocomial infections, as many as 70% occur in surgical patients (16). Approximately 40% of these infections occur at the surgical site, 42% originate in the urinary tract, 14% are respiratory infections, and 4% are blood stream infections. As discussed in the preceding section, nosocomial infections are most commonly caused by the patient’s normal endogenous flora and are a consequence of breaches in the patient’s host defenses from the surgical procedure itself or secondary to other invasive procedures such as the placement of intravenous catheters. However, if the patient has been hospitalized for a period of time, colonization of the patient with hospital-acquired organisms occurs and may result in infections that are resistant to multiple antibiotics (17). Nosocomial infections are less frequently caused by organisms acquired directly from the hospital environment. Examples include infections derived from contaminated respiratory equipment resulting in pneumonia, intravenous fluid contamination resulting in sepsis, and the infrequent situation in which hospital personnel may be the source of infection.

EVALUATION OF SUSPECTED INFECTION IN THE SURGICAL PATIENT An understanding of the clinical manifestations and types of infection that develop postoperatively assists greatly in expediting the diagnosis and in instituting appropriate therapy for the infectious process. Normal body temperature is maintained by the thermoregulatory center in the hypothalamus within narrow limits (98.6 0.9 F) and varies only slightly throughout a given 24-hour period. An elevation in temperature above normal daily fluctuations represents the presence of fever. Although fever in the postoperative period may be due to numerous causes (Table 3), the presence of fever should be assumed to be due to infection until proved otherwise. The timing of the onset of fever is a classic aid in determining the possible cause of these infections. A temperature elevation in the first day or two following surgery is usually related to atelectasis involving one or both lungs. In the next 24 to 48 hours, urinary tract manifestations may become apparent. Under most conditions, wound infections do not cause fever until four to six days postoperatively, although streptococcal and clostridial wound infections can be seen as early as 24 hours after surgery. Thrombophlebitis almost never occurs before the third postoperative day and usually does not become apparent until a week to 10 days following surgery. Venous disorders involving the lower extremities as a cause of postoperative fever are generally less commonly encountered than those associated with phlebitis secondary to upper-extremity venous catheter placement (i.e., intravenous lines). A mnemonic to assist in remembering this sequence of fever onset is wind (pulmonary), water (urinary), wound, and walking (phlebitis). Despite the convenience of these guidelines, they should not preclude careful examination of other potential sources for infection. Furthermore, exceptions to the timing of these guidelines and fever patterns are legion so that the rational assessment of postoperative fever should begin with an organized approach to diagnosis (Fig. 1). In addition to elicitation of the patient’s history, a careful physical examination focusing on likely sources of infection is mandatory. Wounds and drain sites must be

131

Table 3 Causes of Postoperative Fever Respiratory tract infections Atelectasis Pneumonia Urinary tract infections Wound infections Early wound infections Streptococcus species Clostridium species Late wound infections Staphylococcus species Mixed aerobic–anaerobic organisms Thrombophlebitis Upper extremity (almost always catheter-related infections) Lower extremity (usually related to venous stasis and not infected) Intra-abdominal causes Peritonitis Abscess Miscellaneous causes (considerably less common) GI infections Blood transfusion reaction Allergies Dehydration Undrained sterile fluids (e.g., pleural fluid and hematoma) Pancreatitis Blood transfusion–related infections (e.g., non-A hepatitis, non-B hepatitis, and cytomegalovirus infection) Abbreviation: GI, gastrointestinal.

inspected carefully. Patients with urinary bladder catheters should be examined for signs of urinary tract infection (e.g., flank pain and cloudy urine). Intravenous catheter sites may be a source of serious infection even though the evidence for inflammation at the catheter site may be subtle. Swelling in the arm distal to a subclavian catheter might indicate septic thrombophlebitis. The skin should be carefully examined for rashes, which may be allergic or infectious in origin. Infection lesions should be uncapped, and a Gram stain and culture of the pustular contents should be performed. Careful assessment of the lung and chest tube sites, if present, is mandatory to exclude pneumonitis and other pulmonary infections such as empyema. Evaluation of the abdomen may disclose peritonitis or a suspected subphrenic or other deep abscess. The rectal and pelvic examinations must not be excluded; otherwise, perirectal and pelvic abscesses might be missed. Appropriate laboratory and radiologic studies are obtained based on the clinical findings after completion of elicitation of the history and physical examination.

ROLE OF THE LABORATORY IN INFECTION DIAGNOSIS Stress caused by trauma, burns, or infections result in a nonspecific host response that has been referred to as the acute phase response (18,19). This response occurs within hours to days after tissue injury and may last indefinitely, depending on the persistence of the disease. This response results in metabolic changes in numerous organ systems (hepatic, hematologic, endocrine, and neurologic systems), some of which may be detected by laboratory tests. One of the more sensitive indicators of the acute phase response is an increase in the number and a decrease in the maturity of circulating neutrophils. Many surgical infections are

medwedi.ru

132

Part One: General Considerations

Figure 1 Approach to the clinical management of the surgical patient with postoperative fever.

characterized by leukocytosis with a left shift in the differential count. However, white blood cell counts by themselves can be misleading. As noted in the definitions of sepsis discussed in Table 1, a low white blood cell count, especially in the elderly or compromised host, may be associated with particularly severe episodes of sepsis. A number of other nonspecific laboratory tests may also be indicative of infection. An increase in hepatic protein synthesis results in elevated levels of C-reactive protein and an increase in the erythrocyte sedimentation rate during the acute phase response. In addition, abnormalities of glucose metabolism during sepsis can lead to both hypoglycemia and hyperglycemia (20,21). Laboratory tests may also support the presence of specific disease processes. Liver function studies may reveal elevated levels of bilirubin and alkaline phosphatase secondary to infections of the liver such as ascending cholangitis, cholecystitis, liver abscess, or hepatitis. However, the range of overlap in liver function derangements in fundamentally different disease states is so high that these tests may be difficult to interpret clinically. For example, exceedingly high aminotransferase levels (i.e., in the thousands) are virtually diagnostic of hepatitis (usually A, B, and

non-A/non-B), lower levels (i.e., in the hundreds) can be seen in hepatitis caused by cytomegalovirus infections, Epstein–Barr viral disease, syphilis, and toxoplasmosis. These lower levels can be seen in alcoholic hepatitis, liver abscess, and, occasionally, gallbladder disease, among other disease states. If hepatitis is considered a possibility, more specific serum tests, such as hepatitis B surface antigen and cytomegalovirus titers, should be obtained. Although the history, physical examination, radiographic tests, and nonspecific laboratory tests are valuable in establishing the presence and defining the focus of infection, identifying the offending organism depends on obtaining stains and cultures of relevant material. Care must be taken to ensure appropriate collection of these specimens (22). Many surgical infections occur adjacent to mucous membranes or other areas where colonizing flora may be confused with causal flora. Classic examples of inappropriate and irrelevant cultures are as follows: culturing sputum for anaerobes in necrotizing pneumonia, culturing chest tube contents rather than percutaneously obtained pleural space material when empyema is suspected, swabbing wounds for culture rather than aspirating underlying abscesses through intact skin or cellulitic areas, and

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

culturing sinus tracts rather than obtaining bone biopsies without contamination from the tract when osteomyelitis is suspected. Direct examination of a specimen either as a wet mount or as a stained specimen is often useful in the diagnosis of infection. Wet mounts examined with an ordinary light microscope are useful in the identification of protozoa and fungi (23). Gram’s stain is the most widely used procedure for the direct examination of a specimen. Stained smears can demonstrate the presence of inflammatory cells and bacteria. The presence of inflammatory cells may be useful in determining the adequacy of a specimen, particularly in Gram’s stains of sputum in which the presence of inflammatory cells suggests pneumonia, whereas a stain demonstrating squamous epithelial cells and a wide variety of organisms suggests that the specimen has been contaminated with saliva (23). With experience, many causative agents can be predicted, and the Gram’s stain result can guide empiric therapy. For instance, clumps of staphylococci are clearly different from chains of streptococci. Clostridial species have a characteristic appearance of plump, gram-positive rods. Among surgical infections, mixed anaerobic–aerobic infections are common; the Gram’s stain result may be the only clue to the presence of an anaerobe that may fail to grow in culture. Traditionally, urine, sputum, and blood cultures in addition to cultures of any infected material obtained from debridement or aspiration have been used to evaluate patients suspected of having a postoperative infection. However, if negative urinalysis results are obtained and the patient has no symptoms relating to the urinary tract, urine cultures may be omitted. In addition, routine culturing of the patient need not include a sputum sample if there is no realistic concern for pulmonary infection (i.e., no cough, no rales during pulmonary auscultation, and a normal chest radiogram). Finally, the utility of routine culturing of the blood in patients with postoperative fevers in the absence of clinical signs of sepsis or neutropenia has been questioned. Theuer et al. (24) found the yield of positive blood cultures per patient febrile event was only 5% when routine blood cultures were obtained. Of interest, bacterial cultures in patients receiving broad-spectrum antibiotics were uniformly negative. Because many patients were begun on antibiotic coverage after obtaining one set of cultures, reculturing the patient was not productive if initial cultures did not reveal the source of fever. As a result, appropriateness of antibiotic therapy could not be evaluated in these patients. Therefore, it has been suggested that antibiotic therapy be withheld until there is a defined bacterial source of infection in patients who are not neutropenic or septic. Empiric antibiotic therapy can and should be initiated in these patients if clinical deterioration occurs. The approach outlined above is designed to have an organism available in the laboratory so that tests can be performed on it to verify that the correct antibiotics have been chosen and to allow for appropriate changes in antibiotic coverage if the organism proves to be resistant. To predict antibiotic susceptibility of an organism, most microbiology laboratories use the disk diffusion test in which an antibiotic impregnated in a paper disk diffuses into the Mueller– Hinton agar plate on which bacteria are plated (25,26). The utility of this test is limited to organisms that grow rapidly on this agar (staphylococci, Enterobacteriaceae, pseudomonads, and Haemophilus influenzae). This method is not reliable for determining susceptibility of anaerobic

133

bacteria. In 24 hours, a sizable clear zone (no growth) around the disk indicates that the organism is susceptible to that antibiotic. It must be noted, however, that the amount of antibiotic in a disk has been chosen so that the result of the test predicts that an organism in the blood stream can be killed or its growth inhibited by concentrations of antibiotic achievable in the blood stream. The minimum inhibitory concentration (MIC) must be exceeded in the blood stream to penetrate an abscess and kill susceptible organisms. Conversely, a urinary tract infection caused by an ‘‘antibiotic-resistant’’ organism may actually be cured by that antibiotic because the antibiotic is excreted, and thereby concentrated, in the urine. The apparent susceptibilities of certain organisms are also subject to the exact number of organisms placed on the agar plate (i.e., inoculum effect). Susceptibilities of organisms such as Pseudomonas aeruginosa are very dependent on control of the cationic content of the media. Finally, a slow-growing organism may appear falsely susceptible to antibiotic therapy by disk diffusion testing. Additional information about antibiotic susceptibility can be obtained by dilution susceptibility testing, which may be performed in agar or broth. A highly controlled inoculum (often in serum to control the effects of protein binding) is exposed to specific antibiotics in twofold dilutions. The MIC and minimum bactericidal concentration of the antibiotic can then be defined and related to the measured or anticipated concentration of antibiotic achieved or achievable in target tissues (27,28). This kind of data is useful for testing of slow-growing bacteria, when the duration of antibiotic therapy is long (i.e., osteomyelitis and endocarditis), or if another antibiotic must be substituted because of the development of adverse reactions. Automated systems using both the disk diffusion and the dilution method can produce susceptibility results in three to seven hours. However, results for important isolates should be confirmed by conventional methods, which require 24 to 48 hours to perform. Most surgical infections can be well managed by using standard antibiotic susceptibility data. One very important exception to this rule is the apparent susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) to cephalosporins when tested by the disk diffusion method (29). MRSA may appear to be susceptible, but when checked by dilution susceptibility testing, the MICs are found to be high. Consequently, clinical failures can occur when MRSA infection is treated with even higher doses of cephalosporins. For this reason, many laboratories no longer report the cephalosporin susceptibility of MRSA.

TYPES OF POSTOPERATIVE INFECTIONS Respiratory Infections Pneumonia is the second most common nosocomial infection after urinary tract infections but is the leading infectious cause of morbidity and mortality in hospitals in the United States. Nosocomial pneumonias related to surgery have been noted to occur in 5.4 to 11.2 cases per 1000 discharges, depending on the type of operation performed (30). Nosocomial pneumonia is now characterized to include the spectrum of (i) hospital acquired-pneumonia (HAP), (ii) VAP, and (iii) healthcare associated pneumonia (HCAP). Since the initial 1996 American Thoracic Society guidelines, a number of new developments have appeared requiring a new evidence-based guideline for HAP, VAP, and HCAP.

medwedi.ru

134

Part One: General Considerations

Some of the key recommendations and principles in this new-evidence based guideline are as follows: &

&

&

&

&

&

&

&

&

&

&

&

&

&

HCAP is included in the spectrum of HAP and VAP, and patients with HCAP need therapy for multidrugresistant (MDR) pathogens. A lower respiratory tract culture needs to be collected from all patients before antibiotic therapy, but the collection of cultures should not delay the initiation of therapy in critically ill patients. Either semiquantitative or ‘‘quantitative’’ culture data can be used for the management of patients with HAP. Lower respiratory cultures can be obtained bronchoscopically and nonbronchoscopically and can be cultured quantitatively or semiquantitatively. Quantitative cultures increase specificity of the diagnosis of HAP without deleterious consequences. Negative lower respiratory tract cultures can be used to stop antibiotic therapy in a patient who has had cultures obtained in the absence of an antibiotic change in the past 72 hours. Early, appropriate, broad-spectrum antibiotic therapy should be prescribed with adequate doses to optimize antimicrobial efficacy. An empiric therapy regimen should include agents that are from a different antibiotic class than that the patient has recently received. Combination therapy for a specific pathogen should be used judiciously in the treatment for HAP, and consideration should be given to short-duration (5 days) aminoglycoside therapy, when used in combination with a b-lactam to treat P. aeruginosa pneumonia. Linezolid is an alternative to vancomycin, and unconfirmed, preliminary data suggest that it may have an advantage for proven VAP due to MRSA. Colistin should be considered as therapy for patients with VAP due to a cabapenem-resistant Acinetobacter species. Aerosolized antibiotics may have value as adjunctive therapy in patients with VAP due to some MDR pathogens. De-escalation of antibiotics should be considered once data are available on the results of lower respiratory tract cultures and the patient’s clinical response. A shorter duration of antibiotic therapy (7–8 days) is recommended for patients with uncomplicated HAP, VAP, or HCAP, who have received initially appropriate therapy and have had a good clinical response, with no evidence of infection with nonfermenting gramnegative bacilli.

A brief discussion of the incidence, pathogenesis, and the modifiable risk factors for each of the three types of nosocomial respiratory infections is warranted to appreciate the extent of the morbidity and mortality that is caused by these infections. HAP is usually caused by bacteria (and currently is the second most common nosocomial infection in the United States) and is associated with high mortality and morbidity (31). HAP increases hospital stay by an average of seven to nine days per patient and has been reported to produce an excess cost of more than $40,000 per patient. Although HAP is not a reportable illness, available data suggest that it occurs at a rate between 5 and 10 cases per 1000 hospital admissions, with the incidence increasing by as much as 6- to 20-fold in mechanically ventilated patients. Time of

onset of pneumonia is an important epidemiologic variable and risk factor for specific pathogens and outcomes in patients with HAP and VAP. Early onset HAP and VAP carries a better prognosis and is defined as pneumonia occurring within the first four days of hospitalization. These are more likely to be caused by antibiotic sensitive bacteria. Pneumonia occurring after five days or more of hospitalization tends to carry a worse prognosis, because they are more likely to be caused by MDR (31). All three types of nosocomial pneumonia may be caused by a wide spectrum of bacterial pathogens, may be polymicrobial, and, rarely are due to viral or fungal pathogens, in immunocompetent hosts. Common pathogens include gram-negative bacilli such as P. aeruginosa, E. coli, Klebsiella pneumoniae, and Acinetobacter species. Infections due to gram-positive cocci, such as Staphylococcus aureus, particularly MRSA, have been rapidly emerging in the United States. Pneumonia due to S. aureus is more common in patients with diabetes mellitus, head trauma, and those hospitalized in intensive care units. The management of nosocomial pneumonia is especially challenging when the pneumonia is caused by multidrug-resistant bacteria. Rates of HAP due to MDR pathogens have increased dramatically in hospitalized patients, especially in intensive care and transplant patients. In dealing with respiratory infections, it is also important to keep in mind that a number of factors predispose surgical patients to the development of respiratory infections. These include suppression of the immune system, which occurs after surgical or accidental trauma, infections occurring at surgical sites remote from the lung, which may lead to ARDS, and mechanical interference with lung function secondary to operative procedures. Thoracic and upper abdominal incisions are particularly likely to impair respiratory function. Pain and splinting from these incisions lead to postoperative hypoventilation and bronchiolar constriction, resulting in atelectasis and a reduction in the functional residual capacity (FRC) of the lung. The extent of the decrease in FRC depends on the type of incision used. Thoracic incisions have been shown to decrease FRC by as much as 65%. Upper abdominal incisions decrease FRC by about 35%, whereas lower abdominal incisions decrease FRC by as little as 7% (32). Atelectasis, defined as areas of alveolar collapse, result in the retention of bronchial secretions and the entrapment of bacteria. Because alveolar macrophages and systemically recruited neutrophils attempt to eradicate these bacteria, fever ensues. Because atelectasis is a common, inciting event leading to the development of postoperative pneumonia, every effort should be directed at preventing or reexpanding collapsed alveoli. This goal may be accomplished through early ambulation, frequent coughing and deep breathing, frequent changes in position when in bed, and the use of incentive spirometry to improve pulmonary expansion. Patient-related risk factors for the development of postoperative pulmonary complications include advanced age, comorbid illnesses (e.g., chronic obstructive lung disease, diabetes, and alcoholism), malnutrition, decreased mental status, and cigarette smoking (33,34). In addition, microaspiration of small volumes of gastric and oropharyngeal secretions colonized with pathogenic bacteria is a common precursor of pneumonia. Whereas microaspiration may occur in up to 45% of normal volunteers, it does not usually lead to pneumonia in the absence of colonization by pathogenic bacteria. As many as 35% of moderately ill patients and about 75% of critically ill patients develop

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

oropharyngeal colonization with pathogenic bacteria, primarily gram-negative enteric organisms, during the course of hospitalization (35).Colonization of gastric secretions is particularly likely in patients receiving acid-reducing therapy for the prophylaxis of stress gastritis. Aspiration of oropharyngeal pathogens or leakage of bacteria around the endotracheal tube cuff is the primary route of bacterial entry into the trachea and may lead to pneumonia. Endotracheal intubation and mechanical ventilation, as mentioned above, in association with discussions of HAP, HCAP, and VAP, is one of the leading factors that predispose the patient to develop pneumonia by interfering with lung defenses and by allowing direct access of bacteria to the bronchial tree. Efforts to minimize the likelihood of aspiration of oropharyngeal and gastric contents are equally important in the prevention of postoperative pneumonia. Thus, removal of tubes that alter the normal function of the gastroesophageal (i.e., a nasogastric tube) and pharyngoesophageal sphincters (i.e., an endotracheal tube) and discontinuation of drugs that depress the central nervous system (CNS) should be effected as early as is safely possible. Clinically, the diagnosis of pneumonia is made by the demonstration of an infiltrate on a chest x-ray examination and the presence of purulent sputum, fever, and leucocytosis (36). If a pleural effusion is identified on chest x-ray examination, a diagnostic thoracentesis should be performed. Computed tomography (CT) scans of the chest are not used routinely but may be useful to identify empyemas, lung abscesses, and other pulmonary pathology in patients who are not responding to therapy. Blood cultures should be obtained and have been shown to isolate the etiologic pathogen in 8% to 20% of cases (37). Gram’s stains and cultures of purulent sputum should be obtained. However, it should be recognized that the utility of sputum cultures in patients with hospital-acquired pneumonia is limited and that the interpretation of culture results is based on how the specimen was collected. Cultures of expectorated sputum are neither sensitive nor specific for identifying the infecting pathogen and are primarily useful to establish sensitivity patterns when resistant organisms are suspected (35). In patients who are intubated, routine nonquantitative cultures are a sensitive but not specific method of identifying possible pathogens, because critically ill patients often have colonization of the lower respiratory tract with pathogenic organisms. The simple recovery of a pathogenic organism in these patients does not establish that organism as the cause of infection. However, these culture results have a significant negative predictive value so that antibiotic regimens may be modified once culture results are available. Quantitative and semiquantitative cultures obtained using fiber-optic bronchoscopy may be useful in some intubated patients. Organisms for culture are obtained by use of a protected specimen brash (PSB) or by bronchoalveolar lavage (BAL). The etiologic pathogen is defined by the recovery of bacteria above a predetermined threshold (PSB > 103 and BAL >104 or 105 colony-forming units per milliliter). However, the role of quantitative culture techniques in the diagnosis of hospital-acquired pneumonia remains controversial, and the techniques for obtaining the cultures and concentration of bacteria that establish the presence of infection have not been standardized. The choice of antibiotics for the treatment of nosocomial pneumonias is based on likely pathogens and the spectrum of activity, pharmacodynamic profile, and adverse reactions associated with individual drugs (38). Likely pathogens may be deduced from the timing of the onset

135

and the severity of the pneumonia, as well as from the presence of patient-associated risk factors. The choice of antibiotic is also influenced by the concentrations of the agent attainable in respiratory secretions. Quinolones attain concentrations in respiratory secretions close to those attained in serum. On the other hand, aminoglycosides penetrate respiratory secretions poorly and should not be used alone to treat gram-negative respiratory infections (39). Clinical improvement should be used as the ultimate end point of therapy. In general, clinical improvement does not occur before 48 to 72 hours after the initiation of therapy. Changes in antibiotics during this period should not be undertaken unless progressive deterioration of the patient’s clinical status is apparent. Every effort should be made to determine the reason for failure in patients who are unresponsive to therapy after this time period (40). The optimal duration of treatment for nosocomial pneumonias has not been established. For gram-negative pneumonias, which are associated with high rates of treatment failure, relapse, and death, 14 to 21 days of treatment has been recommended. Other less virulent organisms may be adequately treated with a 7- to 10-day course of antibiotics.

Urinary Tract Infections The largest percentage of infections that occur on surgery services arise in the urinary tract (approximately 13.3 cases per 1000 hospital discharges) (41). This circumstance is a simple consequence of the placement of urinary bladder catheters. Although serious infectious problems may ensue from the catheterization of the elderly male with an unrecognized prostate infection or obstruction, most urinary tract problems occur because closed urinary drainage systems eventually become colonized by enteric bacteria such as Escherichia from which the patient may become infected. No measure is particularly effective in preventing these catheter-related infections, although a number of approaches have been tried including the administration of antibiotics (both systemic and local), the use of special tubes with irrigants, and various regimens of catheter care (42). Use of prophylactic antibiotics encourages infection by resistant bacteria or the fungus Candida (especially in diabetic patients). Frequent catheter care with cleansing of the urethral meatus leads to an increased frequency of urinary tract infections so that only daily (rather than more frequent) catheter care has become standard practice. The best prevention of urinary tract infections is to avoid prolonged catheterization and to use alternatives such as intermittent catheterization or, in the case of men, condom catheters whenever possible. Regardless of the technique of drainage, patients should be kept well hydrated so that the bladder is constantly flushed, thereby decreasing the number of potentially infecting bacteria. Many physicians overreact to the presence of more than 105 organisms in the patient’s urine without first obtaining a urinalysis to prove the presence (or absence) of pyuria. Colonization without pyuria can usually be resolved without the use of antibiotics, simply by removing the patient’s catheter and maintaining adequate hydration. In the patient with significant bacteriuria and pyuria in combination and a high temperature elevation in the range of 103 to 104 F, a source of infection other than the bladder should be sought. Pyelonephritis with its attendant high frequency of bacteremia may be present under these circumstances and require aggressive antibiotic therapy; simple cystitis rarely causes high fever (43). The majority

medwedi.ru

136

Part One: General Considerations

of catheterized patients with bacteriuria and pyuria have a low-grade fever secondary to a simple catheter-related cystitis. The principles of management in this latter circumstance include removal of the catheter, if possible, and in most instances a single dose of an antimicrobial agent that is excreted in the urine. For those patients in whom catheter placement must remain in the presence of pyuria, the use of a brief course of an antibiotic is warranted to prevent the bladder from becoming a nidus for systemic infection. This latter condition is most likely to occur if the catheter becomes obstructed. Although most postoperative urinary tract infections occur in association with indwelling urethral catheters, occasionally such infections develop in the early postoperative period secondary to urinary stasis and necessitate catheter placement as a therapeutic measure. Patients at risk for this problem include those with prostatic hypertrophy and various neuromuscular disorders such as multiple sclerosis, those who had undergone previous anorectal procedures that have resulted in ineffective postoperative voiding, and those individuals in whom a spinal anesthetic was used. Under most circumstances, a urinary catheter should be prophylactically placed in such patients before surgery to prevent these stasis problems and should be removed as soon as normal voiding can be ensured. If a catheter-associated infection develops, the principles of treatment outlined previously should be followed.

Table 4 NRC Wound Classification Criteria Classificationa

Criteria

Clean (< 2%)

Elective (not urgent or emergency), primarily closed; no acute inflammation or transection of GI oropharyngeal, genitourinary, biliary, or tracheobronchial tracts; no technique break (e.g., elective inguinal herniorrhaphy) Clean contaminated Urgent or emergency case that is otherwise ‘‘clean’’; (< 10%) elective, controlled opening of GI, oropharyngeal, biliary, or tracheobronchial tracts; minimal spillage and/or minor technique break; reoperation via ‘‘clean’’ incision within 7 days: blunt trauma, intact skin, negative exploration (e.g., vagotomy and pyloroplasty) Contaminated (20%) Acute, nonpurulent inflammation (note absence of purulence); major technique break or major spill from hollow organ; penetrating trauma <4 hr old; chronic open wounds to be grated or covered (e.g., acute, nonperforated, nongangrenous appendicitis) Dirty (40%) Purulence or abscess, e.g., preoperative perforation of GI, oropharyngeal, biliary, or tracheobronchial tracts; penetrating trauma >4 hr old (e.g., perforated appendicitis with abscess) a

Wound infection rate after Ref. 44. Abbreviations: NRC, National Research Council; GI, gastrointestinal. Source: From Ref. 45.

Wound and Soft Tissue Infections The development of SSI, usually in the skin and subcutaneous tissues of the operative side, is a common postoperative problem. Overall, it is estimated that 4% to 7% of surgical patients develop these infections postoperatively. These infections contribute to postoperative morbidity and increased length of stay, with attendant increased costs of medical care. The prevention of SSIs relies on correct surgical technique, modification of host risk factors, and adequate antimicrobial prophylaxis. Both local factors, such as the degree of contamination of the wound, and systemic factors, such as the overall condition of the patient, influence the rates of wound infections. Systemic factors, such as hypoxic lung disease, should not be underestimated when evaluating SSI. The degree of contamination of the surgical wound has traditionally been assessed according to the National Research Council (NRC) wound classification scheme. In this system, wounds are classified as clean, clean contaminated, contaminated, or dirty (Table 4). The NRC wound classification does not, however, take into consideration any other risk factors for wound infection (44,45). Additional risk factors for wound infection have been defined. In one prospective study involving nearly 24,000 patients, advanced age, the presence of diabetes, obesity, or malnutrition, and a perioperative hospital stay of more than two weeks were identified as risk factors (46). In other studies, malignancy, alcoholism, recent cigarette smoking, hypoxemia, remote infection, chronic inflammation, prior surgical site irradiation, recent operation, prior use of antibiotics, and recent use of corticosteroids or cytotoxic agents have also been associated with an increased risk of postoperative infection (45,47). The interaction between these and other factors and the NRC wound classification was investigated in two very large epidemiologic evaluations. One of these took place during the Study on the Efficacy of Nosocomial Infection

Control (SENIC) project (48). This analysis of nearly 60,000 patients undergoing surgical procedures identified four factors of nearly equal weight in predicting postoperative wound infection: an abdominal operation, an operation that took longer than two hours, a wound classified as either contaminated or dirty, and the presence of three or more diagnoses at the time of discharge. The surgical wound infection rates in patients ranged from 1.0% in patients with no risk factors to 27.0% in patients with four risk factors (Table 5). Even in patients with clean wounds, the postoperative wound infection rate ranged from 1.1% to 15.8% as the number of risk factors increased from zero to three (49). The second large study involved patients evaluated as part of the National Nosocomial Infection Surveillance System (NNISS), sponsored by the Centers for Disease Control and Prevention (50). In this survey of nearly 85,000 operations, three risk factors were identified: a patient having an American Society of Anesthesiologists (ASA) score of 3, 4, or 5, an operation considered contaminated or dirty-infected, and an operation that took longer than T hours, where the value of T depended on the actual operative procedure and ranged from one hour for a simple procedure such as appendectomy to four hours for complex procedures on the liver, bile ducts, or pancreas. The risk of a surgical wound infection varied from 1.5% to 13% as the number of risk factors increased from zero to three (Fig. 2). In patients with clean wounds, the infection rates varied from 1% to 5.4% as the number of risk factors increased from zero to two. The NNISS data also showed that there was an increased risk of other nosocomial infections, including pneumonias, blood stream infections, and urinary tract infections as the number of risk factors increased. Thus the inclusion of additional factors along with the NRC wound classification predicted the risk of surgical

Chapter 6:

137

Surgical Infection: Principles of Management and Antibiotic Usage

Table 5 Distribution of Patients and Infections by the SENIC Risk Factors and NRC Wound Classification % Infection by NRC wound classification SENIC risk factors 0 1 2 3 4 NRC, % of all patients NRC, % of patients with infection NRC, % of group with infection

SENIC, % of patients with infection

SENIC, % of group with infection

Clean contaminated

Contaminated

Dirty

SENIC, % of all patients

1.1 3.9 8.4 15.8 N/A 55d

0.6 2.8 8.4 17.7 N/A 36

N/A 4.5 8.3 11.0 23.9 2

N/A 6.7 10.9 18.8 27.4 7

46a 32 16 5 1 100

10b 29 35 20 6 –

1c 3.6 8.9 17.2 26.7 –

39e

35

4

22

–

100

–

8.5

12.6

–

–

Clean

2.9f

3.9

4.1

Note: SENIC risk factors include abdominal operations, operations longer than two hours, three or more associated diagnoses, and dirty or contaminated wounds, as defined by NRC wound classification. Patients with contaminated or dirty wounds cannot have zero SENIC risk factors. Patterns with clean or clean-contaminated wounds cannot have four SENIC risk factors. Example statements indicating how to read this table: a Patients with zero SENIC risk factors accounted for 46% of all patients. b Patients with zero SENIC risk factors accounted for 10% of all infected patients. c The infection rate for patients with zero SENIC risk factors was 1%. d The NRC clean wounds accounted for 55% of all patients. e The NRC clean wounds accounted for 39% of all infected patients. f The infection rate for patients with NRC clean wounds was 2.9%. Abbreviations: NRC, National Research Council; SENIC, Study on the Efficacy of Nosocomial Infection Control. Source: From Ref. 49.

wound infection better than did the NRC wound classification scheme alone. Although the variables identified in these two large prospective studies were different, it is apparent that the length of the procedure and the patient’s premorbid condition, as assessed in the SENIC study by the number of discharge diagnoses and in the NNISS study by the ASA classification, have as much bearing on wound infection rates as the NRC wound classification category. Rational interventions designed to decrease the risk of surgical wound infection can be developed on the basis of this risk factor data. Currently, one of the most commonly used interventions is the use of perioperative prophylactic antibiotics. Because of the low rate of infections (approximately 1–3%) usually observed in patients classified as having clean wounds, it had been argued that prophylactic antibiotics were not needed in that group of patients.

Figure 2 SWI rates within categories of the surgical patient risk index. Abbreviations: G, Goodman–Kruskal correlation coefficient; s.e., standard error; SWI, surgical wound infection. Source: From Ref. 44.

However, both the SENIC and the NNISS studies indicate that there are patients with clean wounds who have a much higher risk of wound infection. Thus, selected patients having clean operations might warrant prophylaxis. The use of perioperative antibiotics is discussed in more detail later in this chapter. Other factors might also be subject to modification. The length of the surgical procedure was identified in both studies as a risk factor for the development of surgical wound infection. This might suggest that efforts made by the surgeon to increase the speed of the operation would result in decreased infectious complications. However, it is unclear from these studies if the length of the surgical procedure was actually a surrogate end point for surgical skill or was rather related to the difficulty of the particular procedure as determined by the complexity of the patient’s pathologic condition. Thus if the latter were true, it is unlikely that efforts designed to increase the rapidity with which an operative procedure is carried out would have a significant effect on postoperative infections. From additional studies, it does appear that the prevention of intraoperative hypothermia reduces the likelihood of surgical wound infections. In a recent prospective, randomized study, the maintenance of normothermia during elective colorectal surgery decreased the rate of wound infections threefold (51). It was speculated that hypothermia interfered with blood flow to the surgical wound by triggering vasoconstriction or, in some other way, impaired the immunologic response in those areas. Many of the risk factors related to the patient’s pathologic process and underlying physiologic reserves cannot be readily controlled. However, several factors are related directly or indirectly to nutritional status. Thus interventions designed to improve the patient’s nutritional status, particularly the use of parenteral nutrition, have been

medwedi.ru

138

Part One: General Considerations

proposed as a means of reducing postoperative infectious morbidity. However, preoperative parenteral nutritional support has not been found to benefit the majority of patients and may even contribute to postoperative infections. In the Veterans Affairs Total Parenteral Nutrition Cooperative Study, only the patients with severe malnutrition had a slight benefit from preoperative nutritional support (52). In the remainder of the patients, who had mild-to-moderate malnutrition, preoperative therapy may actually have been detrimental. This investigation did not examine the potential role of oral or enteral nutrition preoperatively, and there is no reason to discourage adequate nutrition during the preoperative period if it does not unnecessarily delay a needed procedure. However, exhaustive efforts to improve nutritional intake, particularly using parenteral nutrition, are unlikely to be useful except in the most severely malnourished patients. One final intervention that appears useful in reducing global rates of surgical wound infections is an effective infection control program (53). This intervention has been estimated to provide reductions in wound infection rates of 20% to 38%. Effective programs should include wound surveillance, both in the inpatient and outpatient setting, to detect the presence of surgical wound infections. However, of greater importance is feedback to individual practitioners with regard to their own wound infection rates and an effective program for policy development and teaching that allows individual practitioners to adapt effective techniques in controlling wound infection rates.

Phlebitis Although phlebitis of the lower extremities may develop in any patient following surgery and result in postoperative fever, it seldom has a bacterial cause. In contrast, catheterrelated phlebitis is a true infection. Bacteremias secondary to intravascular devices occur in as many as 25,000 to 50,000 patients per year in the United States (54). An intravenous catheter breaches local skin defenses and allows several portals of entry for bacteria. The most common portal of entry is along the skin tract on the outside of the catheter. The predominant organisms that gain entry by this route are skin flora (e.g., S. aureus, but also, with increasing recognition, Staphylococcus epidermidis). Contamination of the catheter hub infusion junction has also been implicated as a cause of bacteremia in patients with central venous lines. Again, organisms of the skin flora are the most common ones. Rarely, bacteremias may occur from the infusion of contaminated solutions. These infections are most commonly due to gram-negative organisms (e.g., Pseudomonas and Enterobacteriaceae). Definitive diagnosis of a catheter-related infection can only be made if there is purulence or inflammation at the insertion site with recovery of a pathogen on culture or if blood culture results and culture results from of the catheter tip are positive for the same organism and there is no other identifiable source of bacteremia. The diagnosis is considered probable if (i) there is purulence at the insertion site but no pathogen is recovered, (ii) blood and catheter-tip culture results are positive for the same organism and a separate identifiable source of bacteremia is present, or (iii) bacteremia is present without an identifiable source and the catheter tip and insertion site were not cultured. Catheter-tip cultures are obtained when a blood stream infection is thought to be related to contamination of the catheter. Under these circumstances, the tip of the catheter is cut off with sterile scissors and placed in a sterile

container so that semiquantitative cultures can be obtained. Maki et al. (55) reported that these cultures have a 76% to 96% specificity and a positive predictive value of 16% to 31% for identifying the presence of a catheter-related infection. Prevention of infection requires careful use of sterile technique for the placement of all intravascular catheters and particularly for central venous lines. In addition, the insertion site must be dressed appropriately. A metaanalysis (56) found a significantly increased risk of catheter colonization when transparent semipermeable dressings were used compared with gauze dressings. This study also found a trend toward an increase in bacteremia with the use of transparent dressings, but this difference was not statistically significant. Frequent catheter changes (every 72–96 hours) may be necessary in patients with clinical signs of infection. This is especially true if the catheters are being frequently manipulated to administer medications or to draw blood samples. In the absence of clinical signs of infection and, particularly, if the catheter is dedicated for a single purpose (i.e., total parenteral nutrition administration), the catheters may be left in place indefinitely. Exchange over a guide wire should not be used if a device infection is suspected (57). Three therapeutic decisions involving intravenous catheters are particularly controversial. The first is bacteremia caused by S. aureus, which may be secondary to infected intravenous catheters. S. aureus is notorious for persisting within leukocytes and disseminating widely throughout the body (58). A body of data has suggested that if the focus of infection is removable (e.g., an intravenous catheter that can be removed or a furuncle that can be rapidly drained), the patient can be treated with a relatively short course of antibiotics, specifically, two weeks. Conflicting evidence reveals the occasional case of endocarditis that develops despite adherence to appropriate principles of short-course antistaphylococcal therapy (59). This has led some infectious disease experts to recommend a long (4–6 weeks) course of antibiotics, particularly if the patient is immunocompromised or if the patient has persistent staphylococcal bacteremia. A second and relatively common therapeutic dilemma is the approach to C. albicans fungemia related to an infected intravenous catheter site. Until recently, the usual approach was to remove the catheter and, because C. albicans is an avirulent pathogen, to rely on host defenses to clear the infection. With the introduction of less toxic antifungal agents, therapy is commonly administered to almost all patients with fungemia. Compelling data have documented that fluconazole can replace amphotericin B for the treatment of susceptible fungi in patients without neutropenia (60). Fluconazole should not be used to treat Candida krusei, Torulopsis glabrata, and Candida lusitaniae because of the high incidence of resistance of these organisms to triazoles. In patients with obvious host deficits (e.g., neutropenia and immunosuppressive drugs), the current recommendation is removal of the catheter followed by a short course (7–10 days) of amphotericin B. The third difficulty in the treatment of infected intravenous catheter sites arises when thrombophlebitis supervenes. If a central vein is thrombosed and infected, high-dose antimicrobial therapy often suffices. The incidence of pulmonary embolism in this setting is probably higher than previously thought, and the use of heparin may be appropriate for selected patients. When a peripheral vein is thrombosed, as evidenced by a palpable venous cord, and is believed to be a source of continuing infection, efforts

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

to aspirate the vein are usually unrevealing but worth attempting. In general, treatment consists of a conventional course of antibiotics for approximately 10 days. If the patient does not exhibit a clinical response to antibiotic therapy, excision of the vein may be necessary. It should be recognized that veins that appear grossly normal at the time of surgery may in fact contain multiple microabscesses in their walls when they are examined microscopically.

Intra-Abdominal Infections Intra-abdominal infection may occur with or without contamination of the peritoneal cavity. Infections (e.g., appendicitis and simple cholecystitis) confined to a diseased organ that is resectable are usually easily cured surgically, may not require prolonged antibiotic therapy, and are not associated with diffuse peritonitis. Peritonitis is defined as inflammation of the peritoneum from any cause, with the most common cause being intra-abdominal infection secondary to bacteria or other microorganisms. Bacterial peritonitis has been classified into primary, secondary, and tertiary peritonitis. Primary peritonitis occurs because of seeding of the peritoneum with bacteria from the blood stream or the lymphatic system and occurs most commonly in cirrhotic patients with ascites. It accounts for less than 1% of peritonitis and treatment is primarily medical with antibiotic therapy (61). Tertiary peritonitis is a peritonitis-like syndrome occurring after a patient has had persistent intra-abdominal infection. Organisms causing tertiary peritonitis are generally nosocomial pathogens such as multiply resistant bacteria or fungi. Most of these patients have been on multiple antibiotics and have had numerous abdominal procedures performed. Secondary peritonitis is the most common form of peritonitis encountered by the surgeon and occurs because of a loss of integrity of the GI tract with resultant contamination of the peritoneal cavity by GI contents (62). The natural history of secondary peritonitis has been demonstrated in animal experiments. In these studies, a two-stage process was noted to occur (63,64). The first stage, lasting approximately five days, was a generalized peritonitis in which gram-negative enteric aerobes were the predominate organism. E. coli bacteremia was common, and a mortality rate of 43% occurred during this stage without treatment. The second stage occurred after five days as the peritoneal defenses attempted to wall off the infection. This resulted in multiple intra-abdominal abscesses with grossly purulent material contained within a collagen wall. The predominant organism within these abscesses was Bacteroides fragilis. Antibiotic therapy (e.g., aminoglycosides) directed toward aerobic enteric organisms decreased early mortality and the incidence of E. coli bacteremia, but did not prevent abscess formation. Conversely, treatment directed against anaerobic organisms (metronidazole and clindamycin) did not affect early mortality but prevented the formation of abscesses. Other studies have demonstrated that mortality rates are directly correlated with the E. coli inoculum size. In addition, large inoculums of bacteria within an abscess cavity inactivate antimicrobial agents at a rate proportional to bacterial density and to the individual inactivating ability. Dead bacteria and debris within the abscess cavity can bind to and inactivate antimicrobial agents. Finally inactivation of antibiotics, particularly clindamycin and aminoglycosides, occurs because of the acidic conditions within the abscess. The diagnosis of secondary peritonitis in an alert patient may be made by physical examination, which characteristically demonstrates diffuse tenderness, rebound

139

tenderness, involuntary muscle guarding, and abdominal wall rigidity. The presence of these signs of generalized peritonitis should lead to prompt operation without further diagnostic studies. However, the physical examination may be difficult to interpret in critically ill patients, patients with altered mental status, postoperative patients, and patients with intra-abdominal abscesses. In addition, elderly patients and patients who are immunosuppressed may not exhibit signs of peritonitis even in the face of generalized infection. Ancillary diagnostic tests may be necessary in these patients (65). Plain films may be of use in detecting a perforated viscus if free peritoneal air is demonstrated. In the absence of significant findings on plain films, ultrasonography has been used as the initial procedure to diagnose intra-abdominal infection in some studies. It offers the advantage of the ability to perform the test at the bedside in critically ill patients, low cost, and rapid results. However, interpretation of the scans may be limited by wounds, dressings, ostomies, obesity, and air-filled bowel loops. Ultrasound may be most useful for detecting infections originating in the liver or biliary tree. Overall sensitivity of ultrasound for the detection of intra-abdominal infection is between 75% and 82%. For the majority of patients, CT scan is the most appropriate initial study. Although CT scan is more costly than ultrasound, it has a sensitivity of 78% to 100% for the detection of intra-abdominal infection. Suspicious fluid collections identified on CT scan should be aspirated for gram’s stain and culture. When aspiration is used in conjunction with CT scans, specificity for the identification of intra-abdominal abscesses is 98%. Optimal management of intra-abdominal infection requires physiologic support of the patient, resection or repair of the source of infection, drainage of any established abscesses, and elimination of residual contamination with antimicrobial therapy (66). Patients with diffuse peritonitis exhibit marked sequestration of extracellular fluid within the inflamed peritoneal cavity, and the intestine and may require large amounts of volume resuscitation. In addition, these patients may develop multiple organ dysfunction syndrome (MODS) secondary to intra-abdominal sepsis and require support of other organ systems (i.e., mechanical ventilation and dialysis) while the primary focus of sepsis is being addressed. Operation is usually necessary to control the source of infection. When frank perforation of the GI tract is the source of infection, the operation may involve resection or repair of the intestine with or without anastomoses or exteriorization of the intestine. Established abscesses should be drained to reduce the bacterial inoculum. This may be accomplished by CT-guided percutaneous drainage or by operative drainage (67–69). A safe percutaneous drainage route that avoids puncturing solid or hollow viscera can be identified in 85% to 90% of patients. After successful drainage, there should be prompt clinical improvement within 48 to 72 hours. Failure to improve within this time frame requires a repeat CT scanning. If residual fluid cannot be evacuated with the placement of additional drains, surgical drainage should be performed. The success of percutaneous drainage of well-defined unilocular abscesses ranges from 80% to 90% and CT-guided drainage has become the procedure of choice for these abscesses (63,70). Percutaneous drainage of complex abscesses (i.e., loculated, pancreatic, interloop, or multiple, or abscesses associated with enteric fistula) has been less successful and may require surgery. Based on the experimental data just discussed, antibiotic therapy should be directed toward both aerobic and

medwedi.ru

140

Part One: General Considerations

anaerobic enteric organisms to prevent early mortality and subsequent abscess formation. This may be accomplished with combination therapy or with broad-spectrum single-agent therapy. The requirement for treatment of enterococcus and Candida recovered from intra-abdominal infections continues to be an area of controversy. In animal studies and in past clinical experience, successful treatment of intra-abdominal infection has been accomplished with agents that have no activity against these organisms. However, both organisms are commonly found in the GI tract and have become major nosocomial pathogens over the last 15 to 20 years. Currently, recommendations are that these organisms do not require antibiotic coverage if they are a part of a polymicrobial infection. However, if these organisms are isolated in pure culture or are recovered from the blood stream or, in the case of Candida, if disseminated infection is present, treatment of these organisms should be initiated. A complete discussion of antibiotic therapy in the treatment of intra-abdominal infection is beyond the scope of this chapter but may be found in a consensus statement by the Surgical Infection Society (71).

Miscellaneous Infections Although the foregoing discussion has considered the usual causes of postoperative infection, in reality many other causes can exist. For this reason, the surgeon must always maintain an open mind and frequently reexamine the patient to look for the underlying source of infection if the patient continues to exhibit clinical signs of infection. An unexplained heart murmur may lead to a diagnosis of endocarditis on echocardiogram, whereas unusual obtundation may be secondary to undiagnosed meningitis or brain abscess. In traumatized patients with facial fractures, sinusitis may occur, particularly in patients who are nasotracheally intubated. Parotitis from an obstructed salivary gland duct may also be an incipient source of infection. Conversely, in some patients, fever may not be related to infection at all, but may be secondary to a drug reaction or may be an allergic reaction to a blood transfusion. Finally, an additional type of infectious process is the intrinsic infections of the GI tract that may occasionally occur following surgery. The most common manifestations of these infections are fever and diarrhea. However, these are nonspecific findings, and in some patients, diarrhea may be related to enteral feedings and have nothing to do with the fever. Of more concern to the surgeon is the patient who has received antibiotic therapy and then has developed diarrhea. In many instances, this diarrhea is caused by an overgrowth of C. difficile, which produces a cytotoxin (72,73). Antibiotics that are notably linked with AAC include ampicillin, cephalosporins, and clindamycin, but the syndrome may occur with the administration of almost any antibiotic. AAC may be accompanied by fever and toxicity and is frequently overlooked as the potential source of postoperative fever. Diagnosis includes an assessment of stool for the presence of C. difficile toxin. The fecal leukocyte examination results may be positive, but negative results do not exclude AAC. The diagnosis may also be made by sigmoidoscopy if the typical pseudomembranous lesions associated with this entity are seen. After diagnosis, therapy is oral vancomycin—125 mg four times daily for 10 days. Parenteral vancomycin is not recommended because the object of therapy is to obtain intraluminal levels of antibiotic, which intravenous vancomycin does not provide. An alternative therapeutic option is oral (250 mg four times

daily) or intravenous metronidazole, because both routes of administration of metronidazole are effective. Because Clostridium spores may survive a course of vancomycin or metronidazole, relapses of AAC may occur. These are treated by an additional course of the same antimicrobial agent.

PATHOGENS RESPONSIBLE FOR SURGICAL INFECTION A common approach to characterizing surgical infection is to list the microbial agents that cause such infections. Considering the phenomenal number of organisms that can infect compromised hosts, a list of ‘‘surgical microbes’’ becomes merely a weak attempt at a review of the entire field of microbiology. Equally inappropriate are lists of microbes and the preferred antimicrobial agents to treat them. Memorizing such lists is a relatively fruitless exercise because many surgical infections are polymicrobic; thus the surgeon must more realistically design an empiric therapy with a broad-spectrum agent or a combination of agents The rational approach to surgical microbiology is to learn those microbes that can singly cause important infections and that may have classic clinical presentations. Also the surgeon must learn the combinations of microbes that are frequently encountered in surgical situations so that empiric therapy can be instituted, until the results of appropriate Gram’s stains and cultures are available. Table 6 lists the most common pathogens identified by the NNISS from 1986 to 1989 (74). Among the fungi, C. albicans is the most important and is not infrequently involved in intravenous catheter-related fungemia. A recent multicenter study has documented the efficacy of fluconazole in the treatment of candidemia in non-neutropenic patients (60). In immunocompromised hosts, however, amphotericin B should be used until further data are available. Two new lipophilic preparations of amphotericin B may reduce the toxicity of this agent (75). The easiest way to control Candida infections in routine surgical practice is to prevent their occurrence by choosing the most narrow spectrum antibiotic or combination of antibiotics and using them for the briefest duration consistent with guaranteed clinical success (76). Other fungal pathogens, including Aspergillus and Mucor, are still occasionally problems for the surgeon and may cause systemic infections in debilitated patients The source of these infections (e.g., the burn wound or diabetic abscess) requires aggressive surgical excision in conjunction with high-dose (as much as 1 mg/ kg/day for the 1st week) amphotericin B if effective treatment is to be rendered (77). The role of viruses in surgical infection is poorly studied except for the blood-borne hepatitides such as hepatitis B and C and cytomegalovirus. Cytomegalovirus is a common problem in transplantation recipients. Presently, no effective therapy exists for cytomegalovirus, but new agents are being tested. HIV is an uncommon cause of postoperative infection in surgical patients; however, most surgeons will be called on to treat patients with HIV infections. Although occupational risks for the infection of health care workers is low, all surgeons should be aware of preventive strategies to limit transmission of this disease (78,79). In addition, a number of parasites that are not commonly seen, including Pneumocystis carinii and Toxoplasma gondii, are encountered routinely in AIDS patients, obliging all physicians, including surgeons, to become reacquainted with their clinical presentations.

Chapter 6:

141

Surgical Infection: Principles of Management and Antibiotic Usage

Table 6 Pathogen Distribution for Major Sites of Nosocomial Infection, NNISS, 1986–1989 Pathogen E. coli Enterococci P. aeruginosa S. aureus Coagulase-negative staphylococci Enterobacter sp. K. pneumoniae C. albicans P. mirabilis Streptococcal species Citrobacter sp. Candida sp. S. marcescens

Urinary tract infection 11,135 6720 5127 823 1634 2339 2664 2978 2312 207 812 853 367

(26) (16) (12) (2) (4) (6) (6) (7) (5) (0) (2) (2) (1)

a

Wound

Pneumonia

Blood stream

1951 2645 1668 3439 2472

(10) (13] (8) (17) (12)

946 342 2598 2401 293

(6) (2) (17) (16) (2)

733 1037 543 1984 3384

(6) (8) (4) (16) (27)

1529 618 481 712 539 321 81 271

(8) (3) (2) (4) (3) (2) (0) (1)

1625 1042 615 503 231 226 109 579

(11) (7) (4) (3) (1) (1) (1) (4)

610 548 617 105 465 82 330 152

(5) (4) (5) (1) (4) (1) (3) (1)

Total 14,765 10,744 9936 8647 7783 6103 4872 4691 3632 1442 1441 1373 1369

(16) (12) (11) (10) (9) (7) (5) (5) (4) (2) (2) (2) (2)

Note: A site may have up to four pathogens. a Number (%). Abbreviation: NNISS, National Nosocomial Infection Surveillance System. Source: From Ref. 74.

Knowledge of other parasitic infections may also be relevant to surgical practice. The classic example is the huge solitary liver abscess in the right lobe of the liver. In such cases, amebic disease must be suspected and confirmed by an ameba serology test. Metronidazole is the antibiotic of choice for these infections. Unless such abscesses threaten to rupture, they are usually managed with antimicrobial agents alone, and surgery or percutaneous drainage is generally not necessary (80). When hydatid disease is suspected, it should be confirmed serologically, and serious consideration should be given to treating the patient with benzimidazole compounds (mebendazole and albendazole) before surgery (81).

of a particular antibiotic. It is for these reasons that an antibiotic, although once effective therapeutically against a specific pathogen, may lose its efficacy. A discussion of the various classes of antibiotics is warranted in order to appreciate the understanding of the mechanism by which they are designed to overcome the numerous pathogens causing postoperative infectious complications.

Table 7 Mechanisms of Action Responsible for Efficacy of Antibiotics Against Different Microorganisms

ANTIBIOTICS IN THE MANAGEMENT OF INFECTION

Antibiotic

It is beyond the scope of this chapter to discuss the use of antibiotics in the treatment of infection in a comprehensive fashion. Therefore a brief discussion of the mechanisms of antibiotic action, antibiotic prophylaxis, and the therapeutic use of antibiotics is presented.

Aminoglycoside Inhibit protein synthesis by binding to 30S ribosome b-Lactams Inhibit cell wall synthesis by interleukin with the production or cross-linking of peptidoglycans Clindamycin Binds to 50S ribosome subunits and inhibits peptide bond formation Macrolides Binds to 50S ribosome subunit and inhibits protein synthesis Metronidazole Redox reaction produces toxic metabolites that damage bacterial DNA, inhibits DNA gyrase Quinolones Interfering with DNA replication and repair Rifampin Blocks RNA synthesis by inhibiting DNA-dependent RNA polymerase Sulfonamides/ Blocks folic-acid synthesis; binds to trimethoprim 30S ribosomal subunit and inhibits protein synthesis Tetracyclines Interfering with production of purine and pyrimidine, blocks dihydrofolate reductase Vancomycin Inhibits cell wall synthesis by interfering with peptidoglycan production at a different site from penicillins; also may alter membrane permeability and inhibit RNA synthesis

Mechanisms of Action Differing modes of action are responsible for the efficacy of individual antibiotics against various microorganisms (Table 7). The extent to which these antibiotic effects prevent bacterial growth often influences the efficacy of an antibiotic under a given set of clinical conditions. A bactericidal antibiotic is often preferable to a bacteriostatic antibiotic, which inhibits growth or multiplication of bacteria and allows normal host defenses to actually effect bacterial destruction. In an immunocompromised patient in whom host defenses may be severely depleted, use of a bactericidal drug is even more important. In the same way that antibiotics differ in their modes of action, microorganisms develop bacterial resistance in a variety of ways. These ways may include mutation to a resistant strain or the production of an enzyme such as penicillinase or b-lactamase that can destroy the antibiotic effects of penicillins and cephalosporins, respectively. In addition, a given pathogen may activate a latent biochemical process or acquire, by transfer, a chromosome-like factor, known as a resistance factor that may block the mode of action

medwedi.ru

Mechanism of action

Bacteriostatic/ bactericidal Bactericidal Bactericidal

Bactericidal Bacteriostatic Bactericidal

Bactericidal Bactericidal Bacteriostatic

Bacteriostatic

Bactericidal

142

Part One: General Considerations

b-Lactam Antibiotics b-lactam antibiotics are among the most commonly prescribed drugs, grouped together because of their shared structural feature, the b-lactam ring. They include: & & & & &

Penicillins Cephalosporins Carbapenems Monobactams b-lactamase inhibitors

b-lactam antibiotics cause the inhibition of synthesis of the bacterial cell wall, leaving bacteria without a protective outer shield. Without this protective outer shelf, water from isotonic body fluids move in freely into bacteria, creating a bursting effect. Bacteria with cell wall susceptible to b-lactam antibiotics are typically known as gram-positive organisms. The mechanism of action involves prevention of the normal cross linkage of peptidoglycan, an essential structural component of bacterial cell wall, or by interference of the biosynthesis of peptidoglycans (82). b-lactam inhibition of cell wall synthesis leads to activation of the autolytic system through a twocomponent system, VncR/S, which initiates a cell death program. An understanding of the generational differences among the b-lactams remains essential for the surgeon who is often challenged with the decision to choose from a variety of antimicrobial agents, with the precaution that resistant strains may emerge. Thus, while better and stronger agents have been synthesized and are available to the surgeon today, the surgeon must still remain cognizant of treating simpler infections with the simpler, narrower spectrum antibiotics in order to combat the fight against the emergence of resistant strains. Penicillins Penicillins can be classified into three groups: & &

&

Penicillin G Antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin, and dicloxacillin) Broad spectrum penicillins

Blood spectrum penicillins are further classified into: &

& &

Second generation (ampicillin, amoxicillin, and related agents) Third generation (carbenicillin and ticarcillin) Fourth generation (mezlocillin and piperacillin)

Spectrum of Activity. Penicillin G is effective against &

& &

&

Gram-positive cocci (except penicillinase-producing staphylococci, penicillin-resistant pneumococci and enterococci, and oxacillin-resistant staphylococci) Gram-positive rods such as Listeria Gram-negative cocci such as Neisseria sp. (except penicillinase-producing Neisseria gonorrhoeae) Most anaerobes (with certain exceptions such as Bacteroides)

Antistaphylococcal penicillins inhibit penicillinaseproducing staphylococci but are inactive against oxacillinresistant staphylococci. Broad-Spectrum Penicillins. The broad-spectrum penicillins are distinguished by their-activity against gram-negative

bacilli. These agents have been stratified into the secondgeneration penicillins (ampicillin and amoxicillin), the third-generation penicillins (carbanecillin and ticarcillin), and the fourth-generation penicillins (mezlocillin and piperacillin). None of the broad-spectrum penicillins are effective against penicillinase-producing staphylococci. Second-Generation Penicillins. Ampicillin, amoxicillin, and closely related antibiotics are able to penetrate the porin channel of gram-negative bacteria but are not stable to b-lactamases. These antibiotics are active against the majority of strains of E. coli, Proteus mirabilis, Salmonella, Shigella, and H. influenzae. Whereas a large percentage of encapsulated H. influenzae type b from the blood and cerebrospinal fluid of children are b-lactamase positive (and ampicillin resistant), only 15% of the non–type b isolates from adult patients with community-acquired pneumonia are b-lactamase positive (83). Amoxicillin and ampicillin have an identical spectrum of activity, but amoxicillin is better absorbed from the intestine when administered orally and yields higher blood and urine levels. Amoxicillin is available generically and is preferable to ampicillin for oral use except in the therapy of Shigella infections sensitive to ampicillin. Third-Generation Penicillins. Carbenicillin and ticarcillin also can penetrate the porin channel of gram-negative bacteria in high doses, but they are less active than ampicillin on a weight basis. However, the carboxy group on the side chain of these antibiotics expands the spectrum of activity by rendering them more resistant to the chromosomal b-lactamases of certain organisms, such as indole-positive Proteus species, Enterobacter species, and P. aeruginosa. Third and fourth generation penicillins are most useful in infections caused by these organisms. Ticarcillin has the same spectrum of activity as carbenicillin but is two to four times more active on a weight basis against P. aeruginosa; the normal maximum parenteral dose is 18 g/day. Fourth-Generation Penicillins. Mezlocillin and piperacillin are derivatives of ampicillin. They cover much the same spectrum as carbenicillin and ticarcillin but are more active in vitro on a weight basis. In addition, they have some activity against strains of Klebsiella, although cephalosporins remain the preferred agents. They are more active than carbenicillin or ticarcillin against enterococci and B. fragilis, but other agents are preferred for the treatment of these organisms as well. Mezlocillin is comparable to ticarcillin against P. aeruginosa and somewhat more active against Enterobacteriaceae than carbenicillin or ticarcillin. Piperacillin is as active as mezlocillin against Enterobacteriaceae and more active than mezlocillin or ticarcillin against P. aeruginosa. As with ticarcillin, clinical failures have occurred when these newer penicillins are used as single agents to treat serious Pseudomonas infections. The third- and fourth-generation penicillins are generally considered together as antipseudomonal penicillins and only a single representative employed as standard therapy at a given hospital. Several factors are considered in deciding which of these agents should be chosen: &

The fourth-generation penicillins are more active in vitro on a weight basis in inhibiting bacterial growth but not in bacterial killing; for P. aeruginosa, ticarcillin is more rapidly bactericidal.

Chapter 6: &

&

Surgical Infection: Principles of Management and Antibiotic Usage

The fourth-generation penicillins have little enhanced stability to b-lactamases compared with the thirdgeneration agents. The fourth-generation penicillins, especially mezlocillin, have less effect than ticarcillin on platelet function.

Cephalosporins Cephalosporins include the closely related cephamycin compounds. The parenteral agents are commonly classified into the following categories: & & & &

First generation Second generation Third generation Fourth generation (cefepime)

Spectrum of Activity. Most of the available cephalosporins are semisynthetic derivatives of cephalosporin C, a compound with antibacterial activity produced by the fungus Cephalosporium. The closely related cephamycin compounds (derived from Streptomyces spp.) are regarded as members of the cephalosporin class. In clinical practice, these antibiotics have frequently been grouped into four ‘‘generations’’ based upon their spectrum of activity against aerobic and facultative gram-negative bacilli. First-Generation Cephalosporins. Cephalothin is the oldest of the first-generation cephalosporins and was previously used as the prototype of this group. Cephalothin is active against most gram-positive cocci (including penicillinase-producing staphylococci), but does not have clinically useful activity against enterococci, Listeria, oxacillin-resistant staphylococci, or penicillin-resistant pneumococci. Cephalothin is active against most strains of E. coli, P. mirabilis, and K. pneumoniae, but has little activity against indole-positive Proteus, Enterobacter, Serratia, and the nonenteric gram-negative bacilli such as Acinetobacter and P. aeruginosa. Gram-negative cocci (such as the gonococcus and meningococcus) and H. influenzae are generally resistant. Cephalothin is active against most of the common anaerobic pathogens, with certain exceptions such as Bacteroides species, particularly B. fragilis. Second-Generation Cephalosporins. The second-generation cephalosporins are somewhat less active against grampositive cocci than the first-generation agents, but are more active against certain gram-negative bacilli. This generation of compounds can be divided into two subgroups, one with activity against H. influenzae and the other, the cephamycins, with activity against Bacteroides. Cephamycin Subgroup (Active Against Bacteroides). The cephamycin subgroup of the second-generation cephalosporins includes cefoxitin and cefotetan. This subgroup is active against most strains of E. coli, P. mirabilis, and Klebsiella, like the first generation cephalosporins. Unlike the first-generation cephalosporins, the cephamycins are active against many strains of Bacteroides. The combination of activity against common aerobic and facultative gram-negative bacilli plus Bacteroides has led to the use of the cephamycins in the prophylaxis and therapy of infections in the abdominal and pelvic cavities (where these organisms predominate). The cephamycins have no clear advantages over the first-generation cephalosporins for infections outside of the abdominal and pelvic areas.

143

Cefotetan has a substantially longer serum half-life than cefoxitin, allowing for less frequent dosing for therapy and single-dose prophylaxis. Cefotetan is more active than cefoxitin against aerobic and facultative gram-negative bacilli although not comparable to third-generation cephalosporins, but less active against Bacteroides. Third-Generation Cephalosporins. The third-generation cephalosporin class is marked by stability to the common blactamases of gram-negative bacilli, and these compounds are highly active against Enterobacteriaceae (E. coli, P. mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, and Citrobacter), Neisseria, and H. influenzae. Mutants of Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal b-lactamase, however, are resistant to these antibiotics. The third-generation cephalosporins are less active against gram-positive organisms than the first-generation cephalosporins and are inactive against enterococci, Listeria, oxacillin-resistant staphylococci, and Acinetobacter. Cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third generation cephalosporins as well. In the late 1990s, for example, 25% of strains of Streptococcus pneumoniae in the United States were intermediately or fully resistant to penicillin and 14% were resistant to third generation cephalosporins (84,85). Fourth-Generation Cephalosporins. Cefepime is a member of a new class of cephalosporins. It has a positively charged quaternary ammonium attached to the dihydrothiazone ring, which results in better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third-generation cephalosporins for certain chromosomal b-lactamases of gram-negative bacilli. Cefepime has similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and oxacillin-sensitive S. aureus. Like the earlier third-generation agents, it is active against the Enterobacteriaceae, Neisseria, and H. influenzae, but has greater activity against the gram-negative enterics that have a broad-spectrum, inducible, chromosomal b-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and Serratia). The role of cefepime in therapy of infections due to stably derepressed mutants of these organisms, however, has not yet been fully defined. Cefepime is as active as ceftazidime for P. aeruginosa, and is active against some ceftazidime-resistant isolates. However, cefepime is not yet approved for the therapy of meningitis. Summary of Treatment Indications for Third- or Fourth-Generation Drugs & &

& &

&

Gram-negative meningitis caused by Enterobacteriaceae. Penicillin-resistant gonococcal infections—Ceftriaoxone is therapy of choice, which is also the recommended therapy for Lyme disease involving the CNS or joints. H. influenza that are ampicillin resistant. In renal dysfunction, later-generation cephalosporins are useful alternatives to the aminoglycosides in treating gram-negative infections, particularly, resistant to other b-lactams. Caution should be used, however, in using a latergeneration cephalosporin as a single agent for the

medwedi.ru

144

&

&

Part One: General Considerations

treatment of serious infections with Enterobacter, indolepositive Proteus, Serratia, and Citrobacter, because of the possibility of resistance emerging during therapy. Ceftazidime and cefepime are effective therapies for serious infections due to P. aeruginosa, when the organism is resistant to the antipseudomonal penicillins or the patient is penicillin allergic; as with the antipseudomonal penicillins, however, ceftazidime and cefepime should generally be given in combination with an aminoglycoside for treatment of serious P. aeruginosa infection. Ceftazidime is effective therapy for meningitis caused by P. aeruginosa. Later-generation cephalosporins are not particularly useful in treating infections due to gram-positive cocci (except penicillin-resistant pneumococci) or Acinetobacter. They are not currently recommended for prophylactic use in surgery.

Carbapenems Imipenem and meropenem are carbapenems that are exceedingly resistant to cleavage by most plasmid and chromosomal b-lactamase (86). They have a very broad spectrum of activity encompassing: &

&

&

Gram-positive organisms (including Enterococcus faecalis and Listeria) Gram-negative organisms (including b-lactamase– producing H. influenzae and N. gonorrhoeae, the Enterobacteriaceae, and P. aeruginosa) Anaerobes (including B. fragilis)

Neither drug is generally active against Stenotrophomonas maltophilia (which has a carbapenem-hydrolyzing chromosomal b-lactamase) Although initial isolates of P. aeruginosa are usually susceptible to the carbapenems, resistance may emerge during therapy when these drugs are used as a single agent. Evidence suggests that carbapenems do not traverse the outer membrane of P. aeruginosa through the normal porin channel used by the other b-lactams but rather through a different channel (86). Carbapenem-resistant strains of P. aeruginosa arising on therapy generally have altered permeability to these drugs and specific changes in their outer membrane proteins; such strains are generally not crossresistant to other b-lactams nor do they produce increased or novel b-lactamase activity. Imipenem is inactivated in the proximal renal tubule by the normal human enzyme dehydropeptidase I, with resultant low urinary levels of active drug and necrosis of the proximal tubule in the rabbit model. Such cleavage of imipenem is prevented by coadministration of cilastatin, a specific inhibitor of this dehydropeptidase. Imipenem–cilastatin therapy has been associated with CNS toxicity, including change in mental state, myoclonus, and, particularly, seizures (86). These effects are especially evident in patients with underlying CNS disease or impaired renal function. Imipenem should not be used for the therapy of meningitis. The dosage of imipenem administered should be carefully titrated; patients with glomerular filtration rates of less than 5 mL/min should generally not receive imipenem unless hemodialysis is ongoing or will start within 48 hours. Meropenem is another carbapenem approved for use in the United States; its spectrum of activity is quite similar to imipenem. Meropenem is stable to human renal dehydropeptidase I, and the compound is administered without

cilastatin. Meropenem appears to have a lower risk of producing seizures than imipenem–cilastatin, and it is approved for the treatment of bacterial meningitis. Ertapenem, a new carbapenem, has recently been approved by the U.S. Food and Drug Administration (FDA). This drug has a narrower spectrum of activity than imipenem or meropenem. It is active against most Enterobacteriaceae and anaerobes but less active than the other carbapenems meant for the treatment of infection caused by P. aeruginosa, Acinetobacter, and gram-positive bacteria, particularly enterococci and penicillin-resistant pneumococci. Clinical trials of this new drug have mainly been published as abstracts thus far; its major benefit over other carbapenems is that it has a long half-life and can be administered once daily. Unlike meropenem, ertapenem is not approved for the therapy of meningitis. b-Lactamase Inhibitors Clavulanate, sulbactam, and tazobactam are b-lactamase inhibitors, which have little intrinsic antibacterial activity but inhibit the activity of a number of plasmid-mediated b-lactamases (87). They generally do not inhibit chromosomally mediated b-lactamases. Combination of these agents with ampicillin, amoxicillin, ticarcillin, or piperacillin results in antibiotics with an enhanced spectrum of activity against many, but not all, organisms containing plasmid-mediated b-lactamases. In addition, these compounds inhibit the chromosomal b-lactamase of many Bacteroides species, extending the spectrum of coverage for these organisms as well. Amoxicillin–clavulanate, Unasyn, will inhibit most strains of oxacillin-sensitive S. aureus and b-lactamase–producing H. influenzae in addition to the usual organisms inhibited by amoxicillin alone. At the high drug concentrations achieved in urine, the combination is also active against certain b-lactamase–producing Enterobacteriaceae. Unasyn is a parenteral formulation that expands the spectrum of ampicillin to include most strains of S. aureus and b-lactamase–producing H. influenzae, some Enterobacteriaceae, and anaerobes (including B. fragilis). This combination has been used for prophylaxis and therapy of intra-abdominal and pelvic infections instead of cefoxitin or cefotetan. Randomized, double-blind trials showed ampicillin–sulbactam to be equivalent to cefoxitin in the prophylaxis for abdominal surgery and in the treatment of intra-abdominal and pelvic infections. It has also been used to treat patients with diabetic foot ulcers. Ticarcillin–clavulanate (Timentin) and piperacillin– tazobactam (Zosyn) expand the spectrum of the respective penicillins to include b-lactamase–producing S. aureus, H. influenzae, N. gonorrhoeae, some Enterobacteriaceae, and anaerobes (including B. fragilis) (88). These combinations are generally not effective against ticarcillin- or piperacillinresistant strains of P. aeruginosa. In addition, piperacillin– tazobactam, dosed at 3.375 g every six hours, may not be effective for the treatment of P. aeruginosa infections. Thus, the spectrum and clinical utility of these two agents are similar to ampicillin–sulbactam. Monobactams Aztreonam is a monocyclic b-lactam antibiotic with good activity against the majority of gram-negative aerobic and facultative bacteria, including the Enterobacteriaceae and P. aeruginosa. It has virtually no activity against grampositive organisms or anaerobes: the majority of strains of Acinetobacter and S. maltophilia are resistant, and resistant strains of P. aeruginosa frequently emerge during therapy with aztreonam alone. The spectrum of activity of

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

aztreonam is similar to that of the aminoglycosides. However, it is less reliable therapy than aminoglycosides for the nonenteric gram-negative bacilli such as Acinetobacter, P. aeruginosa, and S. maltophilia. Data support the absence of cross allergenicity between aztreonam and other b-lactam antibiotic (86). However, patients with ceftazidime allergy may be allergic to aztreonam. The clinical situation in which aztreonam is most useful is in place of an extended spectrum penicillin or cephalosporin, in situations when these compounds are indicated but cannot be used because of allergy. Aztreonam is the only monobactam currently marketed. The dosing of these novel b-lactams and dose modifications in patients with renal dysfunction are important considerations in prescribing these drugs. A number of these drugs have unique properties compared to other b-lactams, such as inhibition of b-lactamases or inherent resistance to cleavage by b-lactamases, which extend the spectrum of the combination agents and carbapenems. The monobactams have a narrower spectrum of activity but less cross allergenicity. These agents should not be used widely, to avoid expense and the development of drug resistance. Resistance to b-Lactam Antibiotics Mechanisms of Bacterial Resistance. Three general mechanisms of bacterial resistance to antibiotics, including the b-lactams, have been well characterized: decreased penetration to the target site, alteration of the target site, and inactivation of the antibiotic by a bacterial enzyme (86,87). Decreased Penetration to the Target Site. The outer membrane of gram-negative bacilli provides an efficient barrier to the penetration of b-lactam antibiotics to their target pencillin binding proteins (PBPs) in the bacterial plasma membrane. b-lactams usually must pass through the hydrophilic porin protein channels in the outer membrane of gram-negative bacilli to reach the periplasmic space and plasma membrane. The permeability barrier of the outer membrane is a major factor in the resistance of P. aeruginosa to many b-lactam antibiotics. Alteration of the Target Site. The target sites for the b-lactams are the PBPs in the cytoplasmic membrane. Alterations in PBPs may influence their binding affinity for b-lactam antibiotics and, therefore, the sensitivity of the altered bacterial cell to inhibition by these antibiotics. Such a mechanism is responsible for penicillin resistance in pneumococci, methicillin (oxacillin) resistance in staphylococci, and for an increasing number of bacteria with intrinsic resistance to b-lactams, such as gonococci, enterococci, and H. influenzae (86). Inactivation by a Bacterial Enzyme. Production of b-lactamase is the major mechanism of resistance to the b-lactam antibiotics in clinical isolates. Such bacterial enzymes may cleave predominantly penicillins (penicillinases), cephalosporins (cephalosporinases), or both (b-lactamases). Their production may be encoded within the bacterial chromosome (and hence be characteristic of an entire species), or the genes may be acquired on a plasmid or transposon (and hence be characteristic of an individual strain rather than the species). Bacteria may synthesize the b-lactamase constitutively (as occurring in the case of many plasmid-mediated enzymes) or synthesis may be inducible in the presence of antibiotic (as occurring in the case of many chromosomal enzymes). Inducible b-lactamases may not be reliably detected by initial susceptibility testing, particularly with the newer rapid methods.

145

Chromosomal b-Lactamases. Although virtually all gramnegative bacilli possess a chromosomal b-lactamase gene, certain species produce insignificant amounts of this enzyme, and their susceptibility to b-lactams is largely determined by plasmid-mediated b-lactamases and antibiotic permeability. These include E. coli, P. mirabilis, Salmonella, Shigella, and H. influenzae. K. pneumoniae produces a chromosomal b-lactamase that is primarily a penicillinase; thus, these strains are frequently susceptible to the cephalosporins. The last group of species within the Enterobacteriaceae, including Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, produce an inducible chromosomal b-lactamase that may be difficult to detect on initial susceptibility testing but that can mediate resistance to all currently available b-lactams with the exception of the carbapenems. In addition to inducible production of this chromosomal enzyme, these species may give rise to regulatory mutants that are ‘‘derepressed’’ and produce high levels of this broadspectrum chromosomal enzyme constitutively. Plasmid-Mediated b-Lactamases. The most common plasmidmediated b-lactamases of gram-negative bacteria (such as TEM-1, TEM-2, and SHV-1) mediate resistance to the penicillins and first- and second-generation cephalosporins, but not cefuroxime, cephamycins, third- and fourth-generation cephalosporins, or the novel b-lactam compounds such as the carbapenems or aztreonam. More recently, extended-spectrum plasmid-mediated b-lactamases (derived from the common TEM and SHV enzymes) have arisen, which are capable of cleaving later-generation cephalosporins and aztreonam (86). Originally described in strains of Klebsiella from Europe, these b-lactamases have now been found in a variety of gramnegative bacilli (i.e., E. coli and K. pneumoniae) in several areas of the United States, and the spread of these organisms between patients in intensive care units has been documented. It has also been documented that nursing home patients may be an important reservoir for strains of Enterobacteriaceae producing extended-spectrum plasmid-mediated b-lactamases (89). Although the strains of resistant E. coli and K. pneumoniae usually differ, most harbor a common plasmid encoding the extended-spectrum b-lactamase, suggesting intragenic and intraspecies transfer of the plasmid between strains, rather than transfer of a single strain between patients. These strains are almost always resistant to ceftazidime, gentamicin, and tobramycin, and frequently are also resistant to trimethoprim–sulfamethoxazole and ciprofloxacin. These enzymes mediate high-level resistance to the third- and fourth-generation cephalosporins and aztreonam, but not to the cephamycins (cefoxitin and cefotetan) or the carbapenems. However, use of the cephamycins against strains containing these new enzymes is limited by the development of permeability mutants in the porin protein, OmpF. The b-lactamase inhibitors, clavulanate, sulbactam, and tazobactam, have generally retained the ability to inhibit these newer plasmid-mediated b-lactamases. Another plasmid-mediated b-lactamase has been described in Klebsiella, which is homologous to the chromosomal cephalosporinase of Enterobacter cloacae (89). This plasmid-mediated b-lactamase is capable of cleaving all of the currently available b-lactams (with the exception of the carbapenems), and its activity is not inhibited by clavulanate, sulbactam, or tazobactam. This plasmidmediated b-lactamase confers a broad resistance pattern similar to stably derepressed mutants of Enterobacter.

medwedi.ru

146

Part One: General Considerations

Resistance to b-lactam antibiotics occurs through one or a combination of three mechanisms: production of a b-lactamase, which inactivates the b-lactam ring, alteration of the target penicillin-binding protein of the cell surface, or interference with the antibiotic’s ability to reach the protein target. The problem with resistance to b-lactam antibiotics has been partially addressed by the introduction of a number of b-lactamase inhibitors. These inhibitors are most effective against plasmid-encoded b-lactamases. Enterobacteriaceae produce chromosomal b-lactamases that are only weakly inhibited. Currently, three b-lactamase inhibitors are commercially available: clavulanate, sulbactam, and tazobactam. Although there are some minor pharmacologic differences in these compounds, therapeutic efficacy is similar. These products are only available in fixed combinations with certain b-lactam antibiotics in which the antibacterial activity of the combination is determined by the spectrum of the antibiotic.

Aminoglycosides The aminoglycosides cause a misreading of the mRNA by irreversibly binding to the 30S subunit of bacterial ribosomes (90). This causes a subsequent interference with amino acid replication. Without amino acid replication, bacteria lose their capacity to sustain or proliferate. Nine aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin, neomycin, kanamycin, paromomycin, netilmicin, and spectinomycin) are approved by the FDA for clinical use in the United States. Of these, gentamicin, tobramycin, and amikacin are the most frequently prescribed, although netilmicin possesses comparable efficacy for select indications. The most common clinical application (either alone or as part of combination therapy) of the aminoglycosides is in the treatment of serious infections caused by aerobic gramnegative bacilli (86,91). In addition, selected aminoglycosides have demonstrated clinically relevant activity against protozoa (paromomycin), N. gonorrhoeae (spectinomycin), and mycobacterial infections (amikacin). The aminoglycosides have demonstrated relative stability against resistance, and the emergence of resistance during therapy (especially when used in combination with other agents) is rare. The most frequently encountered toxicity resulting from aminoglycoside administration is nephrotoxicity. Ototoxicity can also result from aminoglycoside administration, but its prevalence and clinical detection are more problematic to determine. These side effects may be reduced by identification and avoidance in patients at risk, and by appropriate dosing and monitoring of serum drug concentration. Neurotoxicity is rarely encountered, but may be severe and life threatening. Newer strategies for dosing include consolidated administration (also known as ‘‘oncedaily’’ administration) in selected patients to take advantage of the postantibiotic effect (PAE), concentration-dependent killing, and the potential for reduced toxicity. This overview will focus on the use of gentamicin, tobramycin, amikacin, and netilmicin against aerobic gram-negative bacilli and for synergy in the treatment of aerobic gram-positive cocci. Mechanism of Action The aminoglycosides are generally considered bactericidal antibiotics. They impair bacterial protein synthesis (90). These drugs work primarily by binding to the 30S ribosomal subunit, leading to misreading of the genetic code and

inhibition of translocation (90). The initial steps required for peptide synthesis are uninterrupted, such as binding of mRNA and the association of the 50S ribosomal subunit, but elongation fails to occur due to disruption of the mechanisms for ensuring translational accuracy (86,90). The ensuing antimicrobial activity is usually bactericidal against susceptible aerobic gram-negative bacilli. Aminoglycosides initially penetrate the organism by disrupting the magnesium bridges between lipopolysaccharide moieties. They are transported across the cytoplasmic membrane in an energy-dependent manner. This step can be inhibited in vitro by divalent cations, increased osmolality, acidic pH, and an anaerobic environment. The microbiologic activity of aminoglycosides is pH dependent. As a result, the antimicrobial effect may be reduced at the low pH found in lung and bronchial secretions. As an example, the MIC of aminoglycosides was increased almost fivefold at pH < 6.5 in one in vitro study. Two important pharmacodynamic properties of aminoglycosides are the PAE and concentration-dependent killing: &

&

The PAE refers to the persistent suppression of bacterial growth that occurs after the drug has been removed in vitro or cleared by drug metabolism and elimination in vivo. Initially described for gram-negative bacilli, aminoglycosides also exhibit PAE against S. aureus but not against other gram-positive cocci. The duration of the PAE [approximately 3 hours (range 1–7.5 hours)] depends upon the method of evaluation and the organism studied. The duration of the PAE is reduced in the absence of polymorphonuclear leukocytes. Concentration-dependent killing refers to the ability of higher concentrations of aminoglycosides (relative to the organism’s MIC) to induce more rapid, and complete, killing of the pathogen. Aminoglycosides exhibit concentration-dependent microbiologic activity in both in vivo and in vitro models. Achieving optimal peak concentrations of aminoglycosides with standard dosing regimens can be difficult, because efforts must be made to avoid sustained elevated trough concentrations (which are believed to be important in avoiding nephrotoxicity). Relative to traditional dosing methods, the consolidated dosing approach is more likely to achieve optimal peak concentrations that result in concentrationdependent killing.

A synergistic effect has been demonstrated in vitro for selected organisms when aminoglycosides are used in combination with other antibiotics, most consistently with cell wall–active agents (e.g., b-lactam antibiotics). Spectrum of Activity Aminoglycosides exhibit potent in vitro activity against a wide range of aerobic gram-negative pathogens, including Enterobacteriaceae, Pseudomonas spp., and H. influenzae. However, in vitro activity against Burkholderia cepacia, S. maltophilia, and anaerobic bacteria is usually poor or absent. Aminoglycosides also demonstrate activity against gram-positive organisms such as methicillin-susceptible S. aureus. However, most authorities believe these drugs are not adequate therapy for serious infections caused by MRSA and S. pneumoniae (see ‘‘Treatment and prevention of methicillin-resistant S. aureus infection’’).

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

Minor differences exist among the in vitro potencies of the various aminoglycosides. Gentamicin usually demonstrates superior in vitro activity to tobramycin against Serratia spp., whereas tobramycin is usually more potent than gentamicin against P. aeruginosa. Clinical Uses. The most frequent clinical use of aminoglycosides (most commonly in combination with other antibacterial agents) is empiric therapy of serious infections such as septicemia, respiratory tract infections, complicated urinary tract infections, intra-abdominal infections, and osteomyelitis caused by aerobic gram-negative bacilli. Once an organism has been identified and susceptibilities determined, aminoglycosides are usually discontinued in favor of less toxic antibiotics to complete a treatment course. Aminoglycosides are also employed frequently in combination (usually with a b-lactam antibiotic to which the organism is susceptible in vitro) for serious infections caused by Serratia spp., Pseudomonas spp., indole-positive Proteus, Citrobacter spp., Acinetobacter spp, and Enterobacter spp., due to the pathogen’s potential to exhibit inducible resistance to the b-lactam. For infections caused by Enterobacter spp., the addition of an aminoglycoside to a third-generation cephalosporin (most frequently associated with ceftazidime) has not been shown to decrease the development of resistance that the latter drug promotes. Combination therapy with gentamicin is frequently used for the treatment of invasive enterococcal infections not exhibiting high-level aminoglycoside resistance (such as bacteremia) and sometimes for serious staphylococcal infections. Prophylactic use of aminoglycosides (in combination with ampicillin or, in penicillin-allergic patients, vancomycin) should be restricted to procedures involving the GI or genitourinary tract. As an example, aminoglycosidecontaining combinations maybe employed for patients undergoing endoscopic retrograde cholangiopancreatography, in patients with biliary obstruction, or those at risk for the developingment of infective endocarditis. Resistance to Aminoglycosides Bacteria become resistant to aminoglycosides by a combination of three mechanisms: prevention of uptake of the antibiotic into the cell, synthesis of enzymes that modify the antibiotic, or change of the ribosomal binding sites. Unlike third-generation cephalosporins in which resistance may emerge during a two- to three-week course of therapy, resistance to aminoglycosides appears to require long periods of exposure or a large inoculum of bacteria, as is found in cystic fibrosis or burn patients.

Quinolone The fluoroquinolones have become an increasingly popular class of antibiotics in clinical use (92). Newer drugs in this class have been developed with a broader spectrum of activity including better coverage of gram-positive organisms and, in one case, even anaerobes. However, toxicities associated with some of the newer agents have limited their use. For instance, Trovafloxacin has limited availability because of risks of hepatic toxicity. Gatifloxacin and moxifloxacin are the two newer fluoroquinolones. Gemifloxacin was approved on April 4, 2003, by the U.S. FDA for the treatment of mild to moderate community-acquired pneumonia and acute exacerbation of chronic bronchitis. Fluoroquinolones are the only class of antimicrobial agents in clinical use that are direct inhibitors of bacterial

147

DNA synthesis. They are also classified as bactericidal agents. Fluoroquinolones inhibit two bacterial enzymes, DNA gyrase and topoisomerase IV, which have essential and distinct roles in DNA replication (93). The quinolones bind to the complex of each of these enzymes with DNA; the resulting complexes, including the drug, block progress of the DNA replication enzyme complex. Ultimately, this results in damage to bacterial DNA and bacterial cell death. Activity Against Conventional Bacteria The greatest activity of the fluoroquinolones is against aerobic gram-negative bacilli, particularly Enterobacteriaceae, and against Haemophilus spp. and against gram-negative cocci such as Neisseria spp. and Moraxella catarrhalis. Relative to nalidixic acid, the fluoroquinolones also have additional activity against nonenteric gram-negative bacilli such as P. aeruginosa and against staphylococci. Ciprofloxacin remains the most potent marketed fluoroquinolone against gram-negative bacteria. The effect of norfloxacin, ciprofloxacin, and ofloxacin against streptococci and many anaerobes is limited. Levofloxacin, gatifloxacin, and moxifloxacin, however, have greater potency against gram-positive cocci, and gatifloxacin and moxifloxacin also have enhanced activity against anaerobic bacteria. Activity Against Mycobacteria Some fluoroquinolones also have activity against mycobacteria. Ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin are active against Mycobacterium tuberculosis, M. fortuitum, M. kansasii, and some strains of M. chelonae, but have only fair or poor activity against M. avium complex. Activity Against Other Bacteria Other bacteria are also inhibited by quinolones in vitro. Ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, and moxifloxacin all have activity against the agents of atypical pneumonias, including Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae, and against genital pathogens such as Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis. Treponema pallidum is resistant to ofloxacin in animal models, and no other quinolone has been shown to have activity against this spirochete. Activity of Newer Quinolones The newer fluoroquinolones have retained much of the activity of ciprofloxacin and ofloxacin against enteric gram-negative bacteria. Ofloxacin is a racemic mixture of two stereoisomers, whereas levofloxacin is composed solely of the active stereoisomer. Thus, levofloxacin has the same spectrum of activity as ofloxacin but is generally twofold more potent. Activity Against Gram-Negative Organisms. Levofloxacin, gatifloxacin, and moxifloxacin generally have gram-negative coverage similar to that of ciprofloxacin, but all may be less active particularly against some strains of P. aeruginosa as well as against some strains of Providencia spp., Proteus spp., and Serratia marcescens. Activity Against Respiratory Pathogens. All of the newer quinolones, as well as ciprofloxacin and ofloxacin, are highly active against H. influenzae and M. catarrhalis. However, levofloxacin, gatifloxacin, and moxifloxacin exhibit increased potency relative to ciprofloxacin and ofloxacin against S. pneumoniae. Other respiratory pathogens, such

medwedi.ru

148

Part One: General Considerations

as L. pneumophila, M. pneumoniae, and C. pneumoniae, are also highly susceptible to all four newer quinolones. Activity Against Gram-Positive Organisms. Although the newer quinolones all have increased potency relative to ciprofloxacin against other gram-positive cocci in addition to S. pneumoniae, they will have a more limited role in the treatment of staphylococcal and enterococcal infections. Among staphylococci, most methicillin-susceptible strains of S. aureus are susceptible to levofloxacin, gatifloxacin, and moxifloxacin. By contrast, many methicillin-resistant strains of S. aureus have acquired high-level resistance to ciprofloxacin, which causes substantial cross-resistance to all of the newer agents. These same patterns of differing quinolone susceptibility have been seen with methicillin-susceptible and methicillin-resistant strains of coagulase-negative staphylococci. Activity against enterococci is marginal. Activity Against Anaerobes. Of all available quinolones, only gatifloxacin and moxifloxacin have sufficient activity against anaerobic bacteria for potential clinical applicability. B. fragilis and other Bacteroides species may be susceptible, but some studies have already noted resistance in 25% to 30% of strains (86).

Vancomycin Vancomycin inhibits cell wall formation by interfering with peptidoglycan synthesis by binding to a cell surface receptor. Vancomycin may also injure protoplasts by affecting cytoplasmic permeability and by interfering with RNA synthesis. Vancomycin is frequently prescribed for patients with suspected or proven, invasive gram-positive infections. Appropriate dosing requires consideration of the site of the infection, patient weight, renal function, and the concomitant use of high-flux hemodialysis (which enhances the clearance of vancomycin from the serum). Careful attention to individualizing therapy must be exercised in selecting the appropriate dose. The potential for vancomycin-induced nephrotoxicity and ototoxicity must be considered in use of this antibiotic especially given the fact that they have been proposed to relate to serum concentrations. Other toxicities have not been associated with specified serum concentrations. Vancomycin-Related Nephrotoxicity Nephrotoxicity associated with vancomycin monotherapy is considered uncommon. Whereas studies have noted that 5% to 15% of patients treated with vancomycin alone develop an acute decline in renal function, it is difficult to isolate such morbidity to the use of vancomycin alone when other comorbidities exist, which may contribute to the cause of such decline in renal function. Relationships between serum vancomycin concentrations and nephrotoxicity have not been clearly established. Whereas the nephrotoxic potential of vancomycin monotherapy is unclear, studies have established an increased incidence and severity of renal insufficiency when vancomycin is administered concomitantly with an aminoglycoside. The incidence of acute renal failure in this setting may be as high as 20% to 30%. Vancomycin-Related Ototoxicity Vancomycin administration and subsequent ototoxicity have been the subject of various case reports. However, ototoxicity secondary to vancomycin has been poorly studied, because few clinical studies have involved serial

audiometric testing. Those that have tested hearing after vancomycin administration have shown inconsistent findings. Although risk factors for ototoxicity have been reported to include preexisting hearing problems, underlying renal dysfunction, older age, and excessive peak concentrations data to support these risk factors are lacking. Resistance to vancomycin occurs primarily because of a plasmid-mediated change in the target protein on the cell surfaced. However, because of its multiple sites of action, resistance to vancomycin has been slow to emerge (94). This has led to vancomycin being widely used in the prophylaxis and treatment of infections caused by MRSA. As a result, vancomycin use increased 20-fold at one teaching hospital in the 10-year period from 1981 to 1991 (95). With the increase in the use of vancomycin, isolated reports of vancomycin resistance in enterococci began to surface in the mid-1980s. Since this time, vancomycin-resistant enterococci (VRE) have become a major problem in the United States. Data from the Centers of Disease Control and Prevention indicate that the incidence of vancomycin resistance in nosocomial isolates of enterococci has risen from 0.5% in 1989 to 10% in 1995, with mortality rates secondary to VRE bacteremia approaching 50% (96). The emergence of VRE is just one example of the increasing emergence of antimicrobial resistance that is rapidly becoming a worldwide crisis. A consensus statement sponsored by the Centers for Disease Control and Prevention and the National Foundation for Infectious Diseases identified excessive and inappropriate prescribing of antimicrobials and the failure to use basic infection control techniques as the primary causes of this crisis. These problems must be resolved to prevent the farther spread of multidrug-resistant organisms (97).

CLINICAL USE OF ANTIBIOTICS An antibiotic may be administered prophylactically to prevent the subsequent development of an infection, empirically to treat presumed infection in a critically ill or neutropenic patient, or therapeutically to treat an infection when it has actually occurred. The following discussion outlines a rational approach to each of these types of antibiotic usage.

Prophylaxis Prophylaxis in the strictest sense refers to the administration of antibiotics prior to the occurrence of contamination. However, this term is also commonly applied to instances in which surgery is the primary treatment for a patient with presumed contamination or with a possible infection (e.g., penetrating abdominal trauma treated within 6 hours, simple acute appendicitis, or cholecystitis). Under these circumstances, antibiotic coverage is limited to 24–48 hours. This prophylactic use of antibiotics to prevent wound infections is currently the most common reason for administration of antibiotics in surgical patients. Surgical wound infections significantly prolong hospital stay, increase cost, and can result in systemic sepsis and death in some patients. Appropriate use of prophylactic antibiotics has been shown to reduce infectious morbidity and hospital costs. However, indiscriminate use of antibiotics does not further decrease the incidence of wound infections and may result in increased costs and in the emergence of resistant infections. An approach to prophylaxis is outlined in Table 8. The use of prophylactic antibiotics is recommended in

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

149

Table 8 Recommendations for Prophylactic Antibiotic Agents by Site Operations Cardiac: all with sternotomy, cardiopulmonary bypass Noncardiac vascular: aortic resection and prosthetic bypass Orthopedic: insertion of prosthetic joints, open operations Neurosurgery Head and neck: operations involving the mucous membranes and deep tissue General thoracic: pulmonary and esophageal Gastroduodenal: bariatric, ulcer patients treated with H2 blockers, bleeding duodenal ulcer, genitourinary or gastric cancer Biliary: all open and laparoscopic procedures (chronically intubated biliary tract) Colorectal: operations that open the colon and/or rectum Appendectomy: simple appendicitis (antibiotics are empiric or definitive for complicated appendicitis) Cesarean section Hysterectomy Abdominal trauma

Intravenous administration of antimicrobial

Bacteria

Dosea

Staphylococcus aureus, S. epidermidis, diphtheroids, gramnegative enterics S. aureus, S. epidermidis, diphtheroids, gram-negative enterics S. aureus, S. epidermidis

Cefazolin (Vancomycin)

l–2 g (1 g slowly) preinduction, 1–2 g every 8 hr for 48 hr

Cefazolin (Vancomycin)

1 g (1 g slowly) preinduction, 2 postoperative doses

Cefazolin (Vancomycin)

1 g (1 g slowly) preinduction

S. aureus, S. epidermidis, oral aerobes and anaerobes, S. aureus, streptococci

Cefazolin

1 g (1 g slowly) preinduction, 2 g preinduction

Oral anaerobes, S. aureus, streptococci, gram-negative enterics Oropharyngeal flora and gramnegative enterics, S. aureus

Cefazolin

1–2 g preinduction

Cefazolin

1–2 g preinduction

Gram-negative enterics, S. aureus, Enterococcus fecalis, clostridia (above plus Pseudomonas species)

Cefazolin (culture-based selection)

1–2 g preinduction (preinduction dose and repeat interval based on drug kinetics)

Enteric aerobes and anaerobes

Oral neomycin or erythromycin (cefoxitin or cefotetan or cefmetazole) Cefoxitin or cefotetan or cefmetazole

Operating room day 1:1 g at 1, 2 and 11 P.M. (1 g preinduction)

Enteric aerobes and anaerobes

Enteric aerobes and anaerobes, E. fecalis, group B streptococci Enteric aerobes and anaerobes, E. fecalis, group B streptococci Enteric aerobes and anaerobes

1 g preinduction

Cefazolin

1 g after umbilical cord is clamped

Cefazolin

1 g preinduction

Cefoxin

2 g preinduction

a

Parenthetic text refers to alternate antibiotic or situation. Current data suggest repeat dosing for operations lasting longer than the serum half-life. Preinduction indicates administration of the drug in operating room before initiating anesthesia. Source: From Ref. 49.

high-risk patients or in high-risk surgical procedures. Patient-related risks include such factors as extremes of age, malnutrition, chronic illnesses [diabetes and chronic obstructive pulmonary disease (COPD)], remote infections, immunosuppression, recent operations, and prior irradiation of the surgical site. Risks have been classified by two scoring systems as previously discussed. In general, the use of the SENIC classification is preferred because it incorporates both wound and patient factors. Patients with clean wounds, as defined by the NRC wound classification, who have two or more patient-related risk factors as defined by the SENIC classification have an 8% to 15% incidence of wound infection (Tables 4 and 5) (49,98). This is similar to the incidence found with clean contaminated wounds using the NRC wound classification and qualifies these patients for the administration of prophylactic antibiotics. This approach also addresses questions that have been raised by Platt et al. (99) concerning the use of prophylactic antibiotics in clean operations. These investigators

found a trend toward a decrease in rates of infection in patients undergoing clean operations (breast and hernia) with the use of prophylactic cefonicid. However, this study has been criticized because patient-related risk factors were not evaluated, all infectious complications (wound, pneumonias, and urinary tract infection) were included in the analysis, and a higher incidence of infection was found with breast operations in this study than has been reported in other studies (100). At present, chemoprophylaxis is not recommended in clean operations unless two or more patient-related risk factors are present as defined by SENIC, or prosthetic materials such as cardiac valves, prosthetic joints, or vascular grafts are being implanted. Although the risk of infections is low in these operations, the use of prophylactic antibiotics is justified because the consequences of infection in terms of morbidity and mortality are great. In addition, although definitive evidence to support the use of chemoprophylaxis is not available, prophylaxis is commonly used in cardiac and

medwedi.ru

150

Part One: General Considerations

Table 9 Suggested Initial Dose and Time to Redosing for Antimicrobial Drugs Commonly Utilized for Surgical Prophylaxis Renal half-life (hr) Patients with normal renal function

Patients with endstage renal disease

Recommended infusion duration

Standard dose

1.5–2

6

3–5 minc, 20–60 mind

1–2 g i.v.

Ciprofloxacin Cefazolin

3.5–5 1.2–2.5

5–9 40–70

60 min 3–5 minc, 15–60 mind

400 mg i.v. 1–2 g i.v.

Cefuroxime Cefamandole Cefoxitin Cefotetan Clindamycin

1–2 0.5–2.1 0.5–1.1 2.8–4.6 2–5.1

15–22 12.3–18e 6.5–23 13–25 3.5–5.0f

3–5 minc, 15–60 mind 3–5 minc, 15–60 mind 3–5 minc, 15–60 mind 3–5 minc, 20–60 mind 10–60 min (do not exceed 30 mg/min)

1.5 g i.v. 1 g i.v. 1–2 g i.v. 1–2 g i.v. 600–900 mg i.v.

Erythromycin base Gentamicin

0.8–3

5–6

NA

2–3

50–70

30–60 min

1 g po 19, 18, and 9 hr before surgery 1.5 mg/kg i.v.g

Antimicrobial Aztreonam

Neomycin

Metronidazole

Vancomycin

2–3 (3% absorbed under normal GI conditions) 6–14

4–6

12–24 or longer

NA

1 g po 19, 18, and 9 hr before surgery

7–21: no change

30–60 min

0.5–1 g i.v.

44.1–406.4 (CCR < 10 mL/min)

1 g over 60 min (use longer infusion time if dose > 1 g)

1 g i.v.

Weight-based dose recommendationa 2-g maximum (adults) 400 mg 20–30 mg/kg (if < 80 kg, use 1 g; if > 80 kg, use 2 g) 50 mg/kg 20–40 mg/kg 20–40 mg/kg If <10 kg, use at least 37.5 mg if >10 kg, use 3–6 mg/kg 9–13 mg/kg

Recommended redosing intervalb (hr) 3–5 4–10 2–5

3–4 3–4 2–3 3–6 3–6

NA 3–6

–g 20 mg/kg

15 mg/kg initial dose (adult); 7.5 mg/kg on subsequent doses 10–15 mg/kg (adult)

NA

6–8

6–12

Note: Data are from Refs. 59, 60, 102. a Data are primarily from published pediatric recommendations. b For procedures of long duration, antimicrobials should be readministered at intervals one to two times the half-life of the drug. The intervals in the table were calculated for patients with normal renal function. c Dose injected directly into vein or via running intravenous fluids. d Intermittent intravenous infusion. e In patients with serum creatinine level of 5 to 9 mg/dL. f The half-life of clindamycin is the same or slightly increased in patients with end-stage renal disease, compared with patients with normal renal function. g If the patient’s body weight is > 30% higher than their IBW, the DW can be determined as follows: DW ¼ IBW þ [0.4 (total body weight IBW)]. Abbreviations: CCR, creatinine clearance rate; IBW, ideal body weight; DW, dosing weight; GI, gastrointestinal.

neurosurgical procedures even when prosthetic materials are not inserted because of the morbidity of sternal or skull infections (101). The choice of a specific antibiotic agent depends on the operation to be performed, the spectrum of coverage, toxicity, and lastly cost. Commonly used drugs for prophylaxis and accompanying dosage schedules are shown in Table 9 (59,60,102). Antimicrobial prophylaxis should be directed toward common bacterial flora encountered in the course of a specific operation and most importantly toward the most common pathogens responsible for infection after a given procedure. Therapy should be tailored to flora endemic to individual hospitals, because patterns of antibiotic use may result in the emergence of resistant organisms. If MRSA or methicillin-resistant S. epidermidis is a common colonizer in a given hospital setting, methicillin would obviously be contraindicated and another prophylactic antibiotic such as vancomycin should be substituted (103–105). Prophylaxis should be limited to common pathogens, because use of antibiotics with an

unnecessarily wide spectrum also leads to the development of resistant strains of bacteria and to the occurrence of difficult-to-treat infections The least toxic antibiotic that has an appropriate spectrum of activity should be chosen. In general, in the absence of allergies, b-lactam antibiotics (particularly cephalosporins) have acceptable safety profiles. Although the use of aminoglycosides for less than 48 hours rarely results in major toxicity, the potential for both renal and ototoxicity is present, and these drugs are best reserved for therapeutic regimens. The timing and duration of antibiotic therapy are critical for successful prophylaxis. Antibiotics are most effective in preventing infection when present in adequate tissue levels at the time of bacterial contamination (106). Parenteral administration is necessary to reliably attain adequate tissue levels. Administration of the antibiotic at intervals greater than one hour prior to operation have been associated with falling antibiotic tissue levels and an increased incidence of infection (107). In most cases, antibiotics should be administered in the operating room no

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

greater than 30 minutes prior to making the incision (103). This approach ensures adequate tissue levels at the time of operation. When administration prior to contamination is not possible (i.e., penetrating abdominal trauma and ruptured viscus), antibiotics should be administered as soon as possible after contamination. Adequate tissue levels should be maintained throughout the procedure. This requires frequent dosing at intervals of two times the plasma half-life for drugs that are rapidly cleared from the circulation (106). For many cephalosporins, dosing at two- to threehour intervals during a procedure may be necessary. Postoperatively, the shortest effective course of antibiotics limits costs, toxicity, and the development of resistant infections. Several studies have demonstrated the efficacy of single-dose prophylaxis in operations (GI, gynecologic, and orthopedic) lasting less than two to three hours (45,103). The need for prophylaxis longer than 24 to 48 hours is extremely rare even in cases of preexistent contamination, such as penetrating abdominal trauma or open fractures (108–110). Finally, it should be remembered that antibiotics are an adjunctive measure for decreasing the incidence of wound infection and do not replace adequate patient preparation, infection control protocols, and the use of eticulous surgical technique.

Other Methods of Prophylaxis Mechanical means to decrease the concentration of infective organisms in the wound should be used whenever possible. For example, in operations involving the large bowel, a period of mechanical cleaning through the use of cathartics and/or enemas before surgery decreases the enteric bacterial count and thereby lessens the risk of infection. In such clean contaminated cases involving the colon, oral antibiotics (neomycin and erythromycin base) administered on the day prior to operation reduce the concentration of bacteria within the colon and provide a significant reduction in the incidence of wound infection with or without the use of systemic antibiotics (111). Topical antibiotic prophylaxis has been most successfully applied to burn wound sepsis (112). The goal with such therapy is not to prevent colonization of the wound but to control bacterial proliferation. The ideal agent possesses a broad spectrum of activity against bacterial and fungal pathogens, penetrates the burn eschar, has limited systemic toxicity, is inexpensive, and is easy to apply and remove. Although none of the available agents meets all these criteria, the most commonly used agents are silver sulfadiazine, silver nitrate, and mafenide acetate.

Empiric Use Empiric antibiotic therapy differs from the therapeutic use of antibiotics in that antibiotics are administered early to treat presumptive infections. Antibiotics have been used in this fashion primarily in immunocompromised patients or in patients with presumed septic shock in an attempt to prevent death during the early phases of an infection before the infecting organism or the source of infection has been identified (38,113–116). In general, broad-spectrum therapy is used to cover the most likely pathogens. This therapy is then tailored to the specific infection, usually after 72 hours, when the culture results are available. In neutropenic patients (granulocyte counts < 500 mm3) prior to the institution of empiric therapy in the 1970s, mortality secondary to gram-negative bacteremias approached 90%. With the early use of antibiotics, mortality has decreased to about 10% currently. The classic organisms associated with

151

infections in neutropenic patients have been the Enterobacteriaceae, specifically Pseudomonas, and more recently Enterobacter species. However, in the 1980s, an increasing incidence of gram-positive organisms, including S. aureus, S. epidermidis, and a-hemolytic streptococci, has been observed (115). In addition, with more prolonged hospitalization, the frequent use of immunosuppressive agents in transplantation recipients, and the frequent previous antibiotic usage, fungal infections, particularly with Candida and Aspergillus organisms, are becoming more common. In patient populations with other disease processes such as AIDS, P. carinii and M. tuberculosis are the most common pathogens. Choices for empiric antibiotic therapy fall into three basic categories: (i) the classic approach of a broad-spectrum b-lactam antibiotic in combination with an aminoglycoside, (ii) the use of two b-lactam antibiotics, and (iii) broadspectrum monotherapy with or without additional gram-positive (i.e., vancomycin) or anaerobic coverage (i.e., clindamycin or metronidazole). Data exist to support each regimen. The first regimen provides broad-spectrum coverage and rapid bactericidal activity and has the advantage of synergy between the b-lactam and the aminoglycoside, thereby limiting the emergence of resistant organisms. Under most circumstances, an antipseudomonal penicillin with an aminoglycoside has been demonstrated to be the best combination. The primary disadvantage of this regimen is the potential toxicity from the use of aminoglycosides. The combination of two b-lactam antibiotics has also been demonstrated to be effective empiric therapy. The primary disadvantage with this regimen is the selection of organisms resistant to lactams. Monotherapy with a number of different agents (extended-spectrum penicillins, third-generation cephalosporins, penicillins, or cephalosporins plus b-lactamase inhibitors, carbapenems, or quinolones) has been used with success. The most extensively studied regimens in neutropenic patients have used imipenem or ceftazidime (113). These regimens have the advantage of ease of administration, lower cost, and toxicity, but again, the occurrence of resistance is the major disadvantage. Regardless of the initial regimen, additions and modifications are frequently necessary when culture results become available. In addition, overall clinical response should be evaluated at 72 hours to determine the effectiveness of the regimen. Patients with documented infections and patients remaining neutropenic after 7 to 10 days of therapy are most likely to require changes in antibiotics (115). For the latter patients, infections with nonbacterial pathogens, particularly viruses and fungal agents, should be considered. Debate continues about the inclusion of vancomycin in the initial empiric regimen. Several randomized studies have demonstrated no survival advantage when all neutropenic patients are considered. However, vancomycin should be included initially in hospitals in which MRSA is endemic. In addition, vancomycin should be added in severely septic patients and in patients in whom MRSA is a likely pathogen (i.e., patients suspected of intravenous line sepsis). In such cases, vancomycin may be deleted after 72 hours if culture results are negative for gram-positive organisms. The optimal duration of antibiotic therapy has also been debated. For patients with negative culture results, in whom the neutropenia resolves, antibiotics may be discontinued after seven days. Antibiotics may be discontinued earlier in nonneutropenic patients with negative culture results, usually after three days. A reasonable approach in patients who remain neutropenic is to continue antibiotics for 14 days or

medwedi.ru

152

Part One: General Considerations

for seven days after they become afebrile. About one-third of these patients become febrile again and require additional therapy. Patients with severe neutropenia (< 100 mm3) may require therapy until granulocyte counts increase above 500 mm3. In conclusion, the regimen chosen must be adapted to the individual patient and the profile of common pathogens in a given institution. Regardless of the initial regimen chosen, the clinician must recognize the need for and the indications to modify initial therapy, based on culture results and the patient’s clinical response.

Therapeutic Use A complete listing of suggested therapy for surgical infections and recommendations for antibiotic therapy of the various pathogens is beyond the scope of this chapter, but may be found in standard texts on infectious diseases. Several aspects of the basic principles governing the therapeutic use of antibiotics to treat established infections are discussed in Table 10. Essential to these principles is a knowledge of the pharmacodynamic effects of antimicrobial agents (117,118). These effects are determined by the drug interaction with the microorganism, as well as by host factors. Bactericidal antimicrobials can be classified as having concentrationdependent or concentration-independent bacterial killing. Overlap exists, with many antibiotics demonstrating both types of behavior depending on the microorganism targeted. In general, aminoglycoside antibiotics are noted for having concentration-dependent killing. Although conflicting data have been reported regarding the usefulness of serum concentrations to titrate therapy, most investigators have found a relationship between serum concentrations and the efficacy, as well as the toxicity, of aminoglycoside (119). Traditionally, for life-threatening infections, peak serum concentrations of 8 to 10 mg/dL and trough concentrations of 1 to 2 mg/dL have been used. More recently, the ratio of peak serum concentration to the MIC, defined as the lowest serum concentration that inhibits bacterial growth, has been directly related to the bacterial killing rate. This increase in bacterial killing is seen up to peak/MIC ratios of about 10

to 12. Early achievement of these therapeutic levels has been associated with improved outcome in patients with intraabdominal infections (71,117). The relationship of serum levels to toxicity is less well defined. Some investigators have reported that both nephrotoxicity and ototoxicity are associated with peak serum concentrations of gentamicin greater than 12 to 14 mg/dL and trough concentrations greater than 2 mg/dL. However, toxicity may occur with therapeutic serum concentrations, and in some patients, it may be difficult to determine if increased serum levels of aminoglycosides are the cause or the result of decreased renal function. To maintain therapeutic aminoglycoside levels, it is important to recognize that critically ill patients have marked interpatient variability in pharmacodynamics, particularly with respect to volume of distribution (Vd) and clearance of the antibiotic. The major factor associated with the increase in Vd in critically ill surgical patients is volume replacement resulting in intracellular fluid shifts. Other factors involved include fever, ascites, peritonitis, vasodilator therapy, and parenteral nutrition. In addition to having increased Vd, critically ill patients have been demonstrated to have lower elimination constants and lower total body clearance of aminoglycosides compared to noncritically ill patients. The increase in Vd and decrease in clearance of the drug result in the need to increase the dose and interval of administration of aminoglycosides in these patients, compared to that followed in conventional regimens (90,119). Chelluri and Jastremski (120,121) demonstrated that a loading dose of 3 mg/kg of tobramycin or gentamicin was necessary to achieve a peak serum concentration greater than 8 mg/dL in 11 of 14 critically ill patients. In addition, it has been recommended that the dose be increased to 7 mg/kg/day, given in divided doses (i.e., every 12 hours) or as a single daily dose. Once-daily dosing is possible in these patients because of the pharmacodynamics and because aminoglycosides exhibit a relatively long PAE (122). The PAE is manifested by the ability of some antimicrobials to suppress bacterial growth despite serum concentrations well below MIC. Several clinical trials have

Table 10 Principles of Antibiotic Therapy The organism should be sensitive to the antibiotic chosen. Obtain an appropriate culture with susceptibility testing to guide possible changes in antibiotic coverage. Recall in vitro/in vivo disparity in susceptibility of some organisms (e.g., cephalosporins are not effective in vivo against MRSA) Antibiotics should be in doses that ensure adequate peak concentrations and tissue penetration. Blood levels should exceed minimum inhibitory concentration, by 2–3 times to ensure penetration of infected tissues Host factors must be taken into consideration (preexisting diseases, allergies, age, immunosuppression, remote infections, etc.) The antibiotic must come in contact with the organism. The blood–brain, prostatic, obstructed bile, and other barriers prevent penetration of some antibiotics Frequency of administration is based on the half-life and the route of elimination of the antibiotic. Inadequate antibiotic serum concentrations at the end of a dosing interval may lead to ‘‘break-through’’ bacteremia. With developing renal or hepatic dysfunction, the dosing interval is lengthened and, as function improves, is shortened again Choose a bactericidal antibiotic when appropriate. Patients with endocarditis and osteomyelitis, and the infected, compromised host with neutropenia require bactericidal antibiotics Use synergistic therapy when appropriate, such as Pseudomonas infections (especially compromised host), serious enterococcal infection, Staphylococcus epidermidis endocarditis, or ventriculoperitoneal shunt infections deserve synergistic therapy Avoid antagonistic combinations of antibiotics. Antagonism is most likely when 2 ‘‘bacteriostatic’’ antibiotics are used together Choose the most-narrow-spectrum antibiotic. Super-infection is minimized. Often cost is less Avoid side effects when possible. Decreasing the side effects should dictate choice of antibiotic more than cost or convenience of administration. Many antibiotics may interact adversely with other drugs (e.g., metronidazole with ethanol) Control potential interfering conditions or substances. Acidic pus may render an antibiotic useless; therefore drain pus. Organisms may survive an antibiotic when a foreign body is present; therefore remove the foreign body Ensure the proper duration of therapy. For many surgical infections, continuing antibiotics 3 or 4 days past the day of afebrility suffices; however, undrained pus may require long therapy, and an unremoved foreign body (e.g., infected vascular graft) may require therapy for life. Clinical response is the most important factor in determining efficacy and duration of treatment Abbreviation: MRSA, methicillin-resistant Staphylococcus aureus.

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

demonstrated efficacy with some decrease in toxicity with once-daily dosing of aminoglycosides. However, the benefits of once-daily dosing have not been conclusively demonstrated, particularly in neutropenic patients. Regardless of the dosing interval, serum concentrations should be followed to maximize efficacy. In contrast to aminoglycosides, most b-lactam antibiotics exhibit concentration-independent bacterial killing (117). For these antimicrobials, the length of time that serum levels remain above MIC, rather than peak concentrations, appears to be the primary determinant of bacterial killing. These characteristics support the use of frequent dosing intervals, with lower doses or alternatively continuous infusions of b-lactam antibiotics, to ensure that serum concentrations remain above MIC for prolonged periods of time. Although several animal and human studies have been carried out, it is difficult to demonstrate a definite benefit of continuous dosing over intermittent dosing at present. However, if continuous dosing is used, a loading dose should be given to ensure that the MIC is rapidly exceeded. As with empiric therapy, there has been a recent trend toward the use of single broad-spectrum b-lactam antibiotics as substitutes for combination therapy with aminoglycosides to treat established infections caused by aerobic, gramnegative bacilli. These organisms are usually a part of a mixed aerobic–anaerobic flora causing intra-abdominal infections. Current recommendations are that all regimens for intra-abdominal infections cover both aerobic, gramnegative organisms and anaerobic organisms. Overall, no clear benefit of combination therapy over monotherapy with broad-spectrum b-lactams has been demonstrated. However, combination therapy should be strongly considered in neutropenic patients with gram-negative bacteremia and in patients with infections secondary to bacteria that are known to develop resistance to b-lactam antibiotics (71,116,123,124). Finally, it cannot be emphasized too strongly that the use of antibiotics in most surgical infections is an adjunct to the proper management of the locus of infection. Thus abscesses must be drained, devitalized tissue must be debrided, and grossly contaminated wounds must be packed and left open to heal by secondary intention. Equally important is the maintenance of the immune system through nutritional support of the infected patient. It is not uncommon for a patient with surgical infection to be grossly malnourished with subsequent compromise of the immune system. In providing optimum care, surgical management of infection and maintenance of metabolic homeostasis are the primary components of therapy and are supported by the adjunctive use of antibiotics.

SUMMARY Despite advances in surgical management and antibiotic therapy, infection continues to be the most important cause of morbidity and mortality in postoperative surgical patients. The most common surgical infections are hospital acquired, and the responsible microorganisms are usually endogenous. If the development of such infections is to be minimized, efforts at preventing derangements in hostdefense mechanisms must be ensured, and meticulous surgical techniques must be employed. When infections do occur, rational treatment should stress the importance of accurate identification of the responsible microorganism, logical investigation of the underlying source of infection, and adherence to sound principles governing antibiotic

153

prophylaxis and treatment. The application of these guidelines to the clinical management of the surgical patient should lead to substantial improvements in the outcome of surgical disorders that are complicated by infection, in terms of both a reduction in complications and an enhancement of survival.

REFERENCES 1. Wells C, Howard K. Overview of etiologic agents of surgical infections. In: Howard R, Simmons R, eds. Surgical Infectious Diseases. 3rd ed. Norwalk, CT: Appleton & Lange, 1995. 2. Heinzelmann N, Scott M, Lam T. Factors predisposing to bacterial invasion and infection. Am J Surg 2002; 183:179. 3. Members of the American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference Committee: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864. 4. Cerra F. Hypermetabolism—Organ failure syndrome: a metabolic response to injury. Crit Care Clin 1989; 5:229. 5. Kluger M, Ringler D, Anver M. Fever and survival. Science 1975; 188:166. 6. Clowes G, Vucinic M, Weidner M. Circulatory and metabolic alterations associated with survival or death in peritonitis: clinical analysis of 25 cases. Ann Surg 1966; 163:866. 7. Shoemaker W, et al. Physiologic patterns in surviving and nonsurviving shock patients: use of sequential cardiorespiratory variables in defining criteria for therapeutic goals and early warning of death. Arch Surg 1973; 106:630. 8. Lowry S. Cytokine mediators of immunity and inflammation. Arch Surg 1993; 128:1235. 9. Hesse D, et al. Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet 1988; 166:147. 10. Fong Y, et al. Antibodies to cachectin/tumor necrosis factor reduce interleukin lB and intetleukin 6 appearance during lethal bacteremia. J Exp Med 1989; 170:1627. 11. Casey L, Balk R, Bone R. Plasma, cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993; 119:771. 12. Fekade D, et al. Prevention of Jarisch-Hexheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med 1996; 335:315. 13. Dellinger RP, et al. Surviving sepsis compaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32:858–873. 14. Horan T, et al. CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Infect Control Hosp Epidemiol 1992; 13:606. 15. Guideline for Prevention of Surgical Site Infection. Infect Contr Hosp Epidemiol 1999; 20:4. 16. Tetteroo G, Wagenvoort J, Braining H. Role of selective decontamination in surgery. Br J Surg 1992; 79:300. 17. Martin M. Nosocomial infections in intensive care units: an overview of their epidemiology, outcome, and prevention. New Horizons 1993; 2:162. 18. Dinarello C. Interleukin-1 and the pathogenesis of the acute phase response. N Engl J Med 1984; 311:1413. 19. Pannen B, Robotham J. The acute-phase response. New Horizons 1995; 3:183. 20. Baker C, Huynh T. Sepsis m the critically ill patient. In: Wells S, ed. Current Problems in Surgery. Chapel Hill, N.C.: Mosby, 1995:1015. 21. Parrillo J. Pathogenetic mechanisms of septic shock. N Engl J Med 1993; 328:1471. 22. Isenberg H, et al. Specimen collection and handling. In: Balows A, et al., eds. Manual of Clinical Microbiology. Washington, D.C.: American Society for Microbiology, 1991:15.

medwedi.ru

154

Part One: General Considerations

23. Balows A, et al., eds. Manual of Clinical Microbiology. 5th ed. Washington, D.C.: American Society for Microbiology, 1991. 24. Theuer C, Bongard F, Klein S. Are blood cultures effective in the evaluation of fever in perioperative patients? Am J Surg 1991; 162:615. 25. National Committee for Clinical Laboratory Standards. Performance Standard for Antimicrobial Susceptibility Testing. Vol Fourth Informational Supplement. Villanova, PA.: NCCLS, 1992. 26. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Villanova, PA: NCCLS, 1993. 27. National Committee for Clinica Laboratory Standards. Methods for Determining Bactericidal Activity of Antimicrobial Agents: Tentative Guideline. Vol Document M26-T. Villanova, PA: NCCLS, 1992. 28. National Committee for Clinical Laboratory Standards. Dilution Procedures for Susceptibility Testing of Aerobic Bacteria. Vol Publication. M7-A3. Villanova, PA: NCCLS, 1993. 29. Benner E, Morthland V. Methicillin-resistant Staphylococcus aureus: antimicrobial susceptibility. N Engl J Med 1967; 277:678. 30. Horan T, White J, Jarvis W. Nosocomial infection surveillance, 1984. MMWR 1986; 35(1SS):17SS. 31. American Thoracic Society. Guidelines for the Management of Adults with Hospital acquired, Ventilator-associated and Healthcare-Associated Pneumonia. Am J Respir Crit Care Med 2005; 171:388–416. 32. Clevenger F. Postoperative pneumonia. In: Fry D, ed. Surgical Infections. Boston: Little Brown, 1995:327. 33. Bergogne-Berezin E. Treatment and prevention of nosocomial pneumonia. Chest 1995; 108:26S. 34. Broughton W, Fones B, Bass JJ. Nosocomial pneumonia—trying to make sense of the literature. Postgrad Med 1996; 99:221. 35. American Thoracic Society: Hospital-acquired pneumonia in adults: Diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med 1995; 153:1711. 36. Bonten MJM, et al. Problems in diagnosing nosocomial pneumonia in mechanically ventilated patients: a review. Crit Care Med 1994; 22:1683. 37. Bryan C, Reynolds K. Bacteremic nosocomial pneumonia. Am Rev Respir Dis 1984; 129:668. 38. Cunha B. Antibiotic treatment of sepsis. Med Clin N Am 1995; 79:551. 39. Honeybourne D. Antibiotic penetration into lung tissue. Thorax 1994; 49:104. 40. Fein A, et al. When the pneumonia doesn’t get better. Clin Chest Med 1987; 8:529. 41. Haley R, et al. Nosocomial infections in U.S. hospitals, 1975– 1976. AM J Med 1981; 70:947. 42. Stamm W, Hooton T. Management of urinary tract infections in adults. N Engl J Med 1993; 329:1328. 43. Wilkie M, Almond M, Marsh F. Diagnosis and management of urinary tract infection in adults. BMJ 1992; 305:1137. 44. Bratzler DW, Houck PM, Richards C, et al. Use of antibiotic prophylaxis for major surgery. Arch Surg 2005; 140:170–182. 45. Page C, et al. Antimicrobial prophylaxis for surgical wounds: guidelines for clinical care. Arch Surg 1993; 128:79. 46. Cruse P, Foord R. A five-year prospective study of 23,649 surgical wounds. Arch Surg 1973; 107:206. 47. Cruse G. Life-threatening surgical infection: its detection and prevention. Ann R Coll Surg Engl 1978; 60:92. 48. Haley R. Nosocomial infections in surgical patients: developing valid measures of intrinsic patient risk. Am J Med 1991; 91:1453. 49. Haley R, et al. Identifying patients at high risk of surgical wound infection. A simple multivariate index of patient susceptibility and wound contamination. Am J Epidemiol 1985; 121:206. 50. Culver D, et al. Surgical wound infection rates by wound class, operative procedure, and patient risk index. Am J Med 1991; 91:1525.

51. Kurz A, Sessler D, Lenhardt R. Perioperative normotherrnia to reduce tile-incidence of surgical wound infection and shorten hospitilization. N Engl J Med 1992; 334:1209. 52. Group VACS. Perioperative total parentetal nutrition in surgical patients. N Engl J Med 1991; 325:525. 53. Condon R, et al. Does infection control, control infection? Arch Surg 1988; 123:250. 54. Maki D. Infection due to infusion therapy. In: Bennett J, Brachman P, eds. Hospital Infections. Boston: Little Brown, 1986:561. 55. Maki D, Weise C, Sarafin H. A semi-quantitative method for identifying intravenous catheter-related infection. N Engl J Med 1977; 296:1305. 56. Hoffman K, Weber D, Samsa G. Transparent polyurethane firm as an intravenous catheter dressing: a meta-analysis of the infection risks. JAMA 1992; 267:2072. 57. Cobb D, et al. A controlled trial of scheduled replacement of central venous and pulmonary artery catheters. N Engl J Med 1992; 327:1062. 58. Melly M, Thomison J, Rogers D. Fate of staphylococci within human leukocytes. J Exp Med 1960; 112:1121. 59. Libman H, Arbeit R. Complications associated with Staphylococcus aureus bacteremia. Arch Intern Med 1984; 144:541. 60. Rex J, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. N Engl J Med 1994; 331:1325. 61. Joefs J, Runyon B. Spontaneous bacterial peritonitis. Dis Mon 1984; 31:1. 62. Wittmann D, Schein M, Condon R. Management of secondary peritonitis. Ann Surg 1996; 224:10. 63. McClean K, Sheehan G, Harding G. Intraabdominal infection: a review. Clin Infect Dis 1994; 19:100. 64. Bartlett J. Intra-abdominal sepsis. Med Clin N Am 1995; 79:599. 65. McDowell R, Dawson S. Evaluation of the abdomen in sepsis of unknown origin. Radiol Clin N Am 1996; 34:177. 66. Nathens A, Rotstein O. Therapeutic options in peritonitis. Surg Clin N Am 1994; 74:677. 67. Dondelinger R, Kurdziel J, Boverie J. Percutaneous management of intraperitoneal, hepatic and other fluid collections. Baillieres Clin Gastroenterol 1992; 6:273. 68. Lambiase R, et al. Percutaneous drainage of 336 consecutive abscesses: results of primary drainage with 1-year followup. Radiology 1992; 184:167. 69. Scheckter S, et al. Computerized tomographic scan-guided drainage of intra-abdominal abscesses. Dis Colon Rectum 1994; 37:984. 70. Malangoni M, et al. Factors influencing the treatment of intraabdominal abscesses. Am J Surg 1990; 159:167. 71. Solomkin JS, McZuski JE, Barron EJ, et al. Infectious diseases societies of America: guidelines for the selection of antiinfective agents for complicated intra-abdominal infections. Clin Infec Dis 2003; 37:997–1005. 72. Fekety R, Shah A. Diagnosis and treatment of Clostridium difficile colitis. JAMA 1993; 269:71. 73. Kelly C, Pothoulakis C, LaMont J. Clostridium difficile colitis. N Engl J Med 1994; 330:257. 74. Schaberg D, Culver D, Gaynes R. Major trends in the microbial etiology of nosocomial infection. Am J Med 1991; 91:3B. 75. Carlson M, Condon R. Nephrotoxicity of amphotericin B. J Am Coll Surg 1994; 179:361. 76. Solomkin J. Pathogenesis and management of Candida infection syndromes in nonneutropenic patients. New Horizons 1993; 1:202. 77. Anaissie E, Solomkin J. Fungal infection. In: Willmore B, et al., eds. Care of the Surgical Patient. New York: Scientific American, 1994. 78. Davis J, et al. The Surgical Infection Society’s policy on human immunodeficiency virus and hepatitis B and C infection. Arch Surg 1992; 127:218. 79. Courington K, Patterson S, Howard R. Universal precautions are not universally followed. Arch Surg 1991; 126:154.

Chapter 6:

Surgical Infection: Principles of Management and Antibiotic Usage

80. Katzenstein D, Rickerson V, Brande A. New concepts of amebic liver abscess derived from hepatic imaging serodiagnosis and hepatic enzymes in 67 consecutive cases in San Diego. Medicine 1982; 61:237. 81. Kammerer W, Schantz P. Echinococcal disease. Infect Dis Clin N Am 1993; 7:605. 82. Solomkin J. Use of new beta lactam antibiotics for surgical infections. Surg Clin N Am 1988; 68:1. 83. Thornsberry C, et al. Regional trends in antimicrobial resistance among isolates of streptococcus pneumonia, Haemophilus influenzae, and Moroxella catarrhalis in the United States: results from the TRUST Surveillance program 1999–2000. Clin Infest Dis 2002; 34(suppl 1):54. 84. Garau J. Treatment of drug-resistant pneumococcal pneumonia. Lancet Infect Dis 2002; 2:404. 85. Whitney CG, et al. Increasing prevalence of multi drugresistant streptococcus pneumonia in the United States. N Engl J Med 2000; 343:1917. 86. Archey GL, Polk RE. Treatment and prophylaxis of bacterial infections. In: Kasper D, et al., eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005: 789–806. 87. Livermore DM. Beta-lactamase-mediated resistance and opportunities for its control. J Antimicrob Chemother 1998; 41(suppl D):25. 88. Solomkin JS, et al. Guidelines for the selection of anti-infective agents for complicated intraabdominal infections. Clin Infect Dis 2003; 37:997. 89. Levison ME. Plasmid-mediated extended-spectrum b-lactamoses in organisms other than Klebsiella pneumoniae and Escherichia coli: a hidden reservoir of transferable resistance genes. Curr Infect Dis Rep 2002; 4:181. 90. Lortholary O, et al. Aminoglycosides. Med Clin North Am 1995; 79:761. 91. Gozalez LS, Spencer JR. Aminoglycosides: a practical review. Am Fam Physician 1998; 58:1811. 92. Oliphant CM, Green GM. Quinolones: a comprehensive review. Am Fam Physician 2002; 61:455. 93. Hooper D, Wolfson J. Mechanisms of quinolone action and bacteria killing. In: Hooper D, Wolfson J, eds. Quionlone Antimicrobial Agents. Washington, D.C.: American Society for Microbiology, 1993:53. 94. Neu H. Emergence and mechanisms of bacterial resistance in surgical infections. Am J Surg 1995; l69:13S. 95. Gold H, Moellering RJ. Antimicrobial-drug resistance. N Engl J Med 1996; 335:1445. 96. Centers for Disease Control and Prevention. Nosocomial enterococci resistance to vancomycin: United States 1989– 1993. Morb Mortal Wkly Rep 1993; 42:597. 97. Goldman D, et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant microorganisms in hospitals. JAMA 1996; 275:234. 98. National Academy of Sciences, National Research Council. Division of Medical Sciences, Ad Hoc Committee on Trauma. Postoperative wound infections: the influence of ultraviolet irradiation on the operating room and of various other factors. Ann Surg 1964; 160(suppl 2):1964. 99. Platt R, et al. Perioperative antibiotic prophylaxis for herniorrhaphy and breast surgery. N Engl J Med 1990; 322:153. 100. Ranaboldo CJ, et al. Antimicrobial prophylaxis in ‘clean’ surgery: Hernia repair. J Antimicrob Chemother 1993; 31:35.

155

101. Waddell TK, Rotstein OD. Antimicrobial prophylaxis in surgery. Committee on Antimicrobial Agents, Canadian Infectious Disease Society. Can Med Assoc J 1994; 151:925. 102. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Project. Infec Dis Clin Prac 2004; 72:384–385. 103. Nichols R. Surgical antibiotic prophylaxis. Med Clin North Am 1995; 79:509. 104. Paluzzi R. Antimicrobial prophylaxis of surgery. Med Clin N Am 1993; 77:427. 105. Leaper D. Prophylactic and therapeutic role of antibiotics in wound care. Am J Surg 1994; 167:15S. 106. Bergamini T, Polk HJ. Pharmacodynamics of antibiotic penetration of tissue and surgical prophylaxis. Surg Gynecol Obstet 1989; 168:283. 107. Galandiuk S. Re-emphasis of priorities in surgical antibiotic prophylaxis. Surg Gynecol Obstet 1989; 169:223. 108. Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg 1990; 72-A:299. 109. Fabian T, et al. Duration of antibiotic therapy for penetrating abdominal trauma: a prospective trial. Surgery 1992; 112:788. 110. Dellinger E. Antibiotic prophylaxis in trauma: penetrating abdominal injuries and open fractures. Rev Infect Dis 1991; 13:S847. 111. Gorbach S. Antimicrobial prophylaxis for appendectomy and colorectal surgery. Rev infect Dis 1991; 13(suppl 10):S815. 112. Pruitt B, McManus A. The changing epidemiology of infection in bun patients. World J Surg 1992; 16:57. 113. Pizzo PA. Drug therapy—Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993; 238:1323. 114. Shands JJ. Empiric antibiotic therapy of abdominal sepsis and serious perioperative infectious. Surg Clin N Am 1993; 73:291. 115. Giamarellou H. Empiric therapy for infections in the febrile, neutropenic, compromised host. Med Clin N Am 1995; 79:559. 116. Dunn DL. Gram-negative bacterial sepas and sepsis syndrome review. Surg Clin N Am 1994; 74:621. 117. DiPiro J, Edmiston C. Pharmacodynamics of antimicrobial therapy in surgery. Am J Surg 1996; 171:615. 118. Solomkin JS, Miyagawa CI. Principles of antibiotic therapy review. Surg Clin N Am 1994; 74:497. 119. Miyagawa C. Aminoglycosides in the intensive care unit: an old drug in a dynamic environment. New Horizons 1993; 2:172. 120. Chelluri L, Jastremski M. Inadequacy of standard aminoglycoside pharmacokinetics in critically ill surgical patients. Crit Care Med 1987; 15:1143. 121. Chelluri L, Warren J, Jastremski M. Pharmacokinetics of a 3 mg/kg body weight loading dose of gentamicin or tobramycin in critically ill patients. Chest 1989; 95:1295. 122. Perriols-Lisart R, Alos-Alminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1995; 53:1141. 123. DiPiro JT, Forston N. Combination antibiotic therapy in the management of intra-abdominal infection. Am J Surg 1993; 165:82S. 124. Shands JW Jr. Empiric antibiotic therapy of abdominal sepsis and serious perioperative infections. Surg Clin N Am 1993; 73:291.

medwedi.ru

7 Hemostasis and Thrombosis in the Surgical Patient Stuart I. Myers, Mark R. Jackson, Michael Sobel, and G. Patrick Clagett

INTRODUCTION The safe practice of surgery requires a fundamental understanding of the concepts of hemostasis. Traditionally, standard textbooks of surgery have focused on the basics of the coagulation pathways and platelet function, with an overview of inherited and acquired defects of these mechanisms. In organizing this chapter, we have sought to summarize these basic concepts and provide additional information on more recent developments that have enhanced our understanding of hemostasis in vivo. The central roles of the tissue factor pathway and thrombin in the coagulation cascade, for example, are emphasized. In addition, newer information on the hypercoagulable syndromes and their role in thrombotic disorders are also presented. Developments in molecular biology are providing unprecedented insight and fundamental understanding of the genetics of inherited bleeding and hypercoagulable disorders that have translated into improved diagnostic testing, such as with resistance to activated protein C and hyperhomocystinemia. Similarly, as the molecular mechanisms of hemostasis are increasingly understood, potent antiplatelet and antithrombotic agents are being developed and made available for clinical use. An appreciation of their therapeutic potential and challenge to surgical hemostasis requires a basic understanding of their mechanisms of action.

MECHANISMS OF HEMOSTASIS Platelets Platelets are anucleate cells produced in the bone marrow by fragmentation of megakaryocytes. The megakaryocytes are located in the subendothelial space of bone marrow vascular sinuses, where proliferation and maturation is regulated. Platelet production is stimulated by thrombopoietin, interleukin-3 (IL-3), and IL-6 (1). Factors that inhibit this process include platelet factor 4 (PF4), transforming growth factor-b, and interferon-a (2–4). Thrombopoiesis is also influenced by circulating platelet mass. The identification, purification, and cloning of thrombopoietin, or the c-Mpl ligand, followed characterization of the c-mpl gene that encodes for a cell surface receptor present on megakaryocytes and platelets (5). Thrombopoietin bound to c-mpl on megakaryocytes stimulates all stages of megakaryocyte maturation, thus leading to platelet production. Thrombopoietin bound to platelet c-mpl aids in its removal from the circulation, a possible mechanism by which platelet mass regulates the plasma concentration of thrombopoietin. Once released into the circulation, platelet hemostatic function is initiated with adhesion of the platelet to the subendothelial matrix of the injured blood vessel (6). Platelet activation is followed by platelet aggregation and secretion,

the end result of which is a hemostatic plug. The two most potent agonists for platelet aggregation are collagen and thrombin. Once platelet activation is initiated, the platelet changes shape from discoid to spherical and develops pseudopods as a result of changes in the platelet cytoskeleton (7). Thromboxane A2 is then produced through the cyclooxygenase pathway of arachidonic acid metabolism and further stimulates platelet aggregation (8). Platelets contain numerous intracellular and membrane components that contribute to their hemostatic function. Platelet activation is initiated following the binding of thrombin or other agonists to the extracellular domain of specific membrane receptors (Fig. 1) (9). As in other cells, platelet receptors for agonists and inhibitors are transmembrane proteins with cell surface and cytoplasmic components. The signal, initiated by receptor occupancy, is then transmitted by the cytoplasmic domain of the receptor through guanosine triphosphate-binding regulatory proteins (G proteins) to membrane-bound, signalgenerating enzymes such as phospholipase C (Fig. 2) (10). Activation of these enzymes induces generation of second-messenger molecules such as inositol 1,4,5triphosphate (IP3) and diacylglycerol (DAG). Inositol triphosphate induces calcium release from the platelet-dense tubular system. A rise in free calcium in the cytosol is a critically important aspect of platelet activation. DAG activates protein kinase C, which in turn promotes protein phosphorylation and causes platelet secretion and the expression of the fibrinogen receptor (GPIIb/IIIa) on the platelet surface that leads to platelet aggregation (11,12). Platelets contain two major types of secretory granules, the most predominate of which is the a-granule. Contents of the a-granule include PF4, transforming growth factor-b, platelet-derived growth factor (PDGF), coagulation factor V, and b-thromboglobulin. The dense granules contain serotonin, adenosine triphosphate, adenosine diphosphate (ADP), and calcium. Release of these biologically active substances occurs by exocytosis during platelet aggregation and results in platelet recruitment to the site of injury, vasoconstriction, and other hemostatic and vascular responses. The platelet membrane contains a number of glycoprotein receptors that bind various ligands during platelet activation, and thereby promote adhesion and aggregation. GPIb/IX functions as a receptor for von Willebrand factor (vWF) at high shear rates such as during arterial injury and allows vWF to bridge the platelet to the subendothelial matrix at the site of arterial injury (13–15). GPIIb/IIIa is the platelet membrane receptor for fibrinogen and is essential for aggregation. GPIIb/IIIa binds fibrinogen only after undergoing a conformational change mediated by the platelet cytoskeleton and actin, its major contractile protein (16,17). Deficiency of GPIIb/IIIa results in Glanzmann’s

medwedi.ru 157

158

Part One: General Considerations

Another function of the platelet is to provide a surface for activation of clotting factors. Many of the reactions in the coagulation cascade are greatly enhanced by the phospholipid surface of the platelet membrane. This enhancement of coagulation by platelets is termed ‘‘platelet coagulant activity’’ and is an important factor during thrombogenesis (20). Because platelets adhere to the site of vascular injury where bleeding occurs, this allows an increased local concentration of clotting factors. Activated factor X (factor Xa) is a pivotal enzyme in the coagulation cascade; when bound to platelet factor Va, its efficiency in thrombin generation is dramatically increased. In addition, factor Xa bound to activated platelets is protected from inactivation by the heparin/ antithrombin III (AT-III) complex.

Coagulation Cascade

Figure 1 The receptor-mediated events of platelet activation, adhesion, secretion, and aggregation. Abbreviations: R, receptor; ADP, adenosine diphosphate; 5HT, serotonin; FG, fibrinogen; vWF, von Willebrand factor; TSP, thrombospondin. Source: From Ref. 9.

thrombasthenia, an autosomal recessive bleeding disorder characterized by absence of platelet aggregation and clot retraction (18,19). Under conditions of low shear stress, such as with venous injury and thrombosis, platelet adherence to subendothelial collagen occurs through the action of receptors GPIa/IIa and GPIb.

In vivo, the primary role in the activation of the coagulation cascade involves the tissue factor/factor VIIa (TF/VIIa) complex (Fig. 3) (21–23). Tissue factor is a 45 kDa transmembrane protein present in the subendothelium and endothelial cells that have been exposed to thrombin or endotoxin. Following vascular injury, factor VII binds to tissue factor and activates small amounts of factor X, which in turn activates additional factor VII. The TF/VIIa complex then activates additional factor X, either directly or through the activation of factor IX. Under basal conditions, the TF/VIIa complex is the primary activator of factors IX and X (Fig. 3) (24,25). Sustained generation of factor Xa requires the factor IXa/factor VIIIa complex. The VIIIa-IXa-X-Ca2þ assembly is known as the Xase (‘‘tenase’’) complex that leads to the rapid conversion of factor X to Xa. Similarly, while TF/VIIa is the primary activator of factor IX, factor XIa is required for sustained generation of factor IXa. Factor XI is autoactivated as well as activated by thrombin in vivo; therefore the contact activation system, or intrinsic pathway, is not required for hemostasis in vivo. Initiation of the intrinsic pathway (termed ‘‘contact activation’’) involves a complex interaction in which factor XII undergoes a conformational change following exposure

Figure 2 Agonists of platelet activation bind to membrane receptors that activate a Gp0, which activates PLC, which in turn stimulates the phosphoinositide pathway. The second messengers, DAG and IP3, lead to exposure of the GPIIb:IIIa complex, platelet secretion, and TXA2 generation. This signal transduction system also regulates intraplatelet cAMPformation.Thrombin stimulates a Gi that inhibits adenylate cyclase and prevents cAMP formation. In contrast, PGI2 interacts with a G5 that stimulates adenylate cyclase activity in the formation of cAMP. cAMP lowers intracellular calcium levels and inhibits platelet activation. Abbreviations: Gp0, G protein; PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol triphosphate; TXA2, thromboxane A2; cAMP, cyclic adenosine monophosphate; Gi, inhibitory G protein; PGI2, prostacyclin; G5, stimulatory G protein.

Chapter 7:

Figure 3 Proposed coagulation pathway under in vivo conditions. Coagulation is initiated by the TF/VII complex, which can activate factor X directly or through the activation of factor IX. Thrombin can reciprocally activate factors XI, V, and VIII. Factor Xa can promote activation of factor VII. The contact system appears to play no role in hemostasis in vivo. Abbreviations: TF/VII, tissue factor/factor VII; factor Xa, activated factor X. Source: From Ref. 15.

to nonendothelialized surfaces. The activation of factor XII occurs principally through the action of kallikrein, with highmolecular-weight kininogen acting as a necessary cofactor. This complicated surface-mediated series of reactions can lead not only to clotting but also to kinin formation, complement activation, and fibrinolysis. In fact, the higher reactions in the intrinsic coagulation cascade are probably more important in triggering inflammatory responses and other defense reactions than they are in hemostasis with. Patients with factor XII (Hageman factor) deficiency have no bleeding diathesis, and patients with factor XI deficiency generally have only mild bleeding. The tissue factor pathway is also referred to as the extrinsic pathway and is the dominant system of the coagulation cascade in vivo. Factor Xa then binds with factor Va to convert prothrombin to thrombin. Assembly of the Va-Xa-IICa2þ complex occurs on the platelet membrane where Va is located, and this thrombin-generating unit is known as the IIase (‘‘prothrombinase’’) complex. Thrombin generation results in the cleavage of prothrombin fragment F1.2, which has been used as a sensitive marker of thrombin generation and hemostatic activation (26). Thrombin then converts fibrinogen to fibrin monomers, which are subsequently cross-linked by factor XIII. The cross-linked fibrin clot is comparatively stable and more resistant to lysis because it incorporates a2-antiplasmin into the clot. The central role of thrombin in the coagulation cascade is demonstrated through its other multiple procoagulant functions, which include the activation of factors V, XI, VIII, and XIII, as well as its potent effect as an inducer of platelet aggregation (27).

REGULATION OF HEMOSTASIS Endothelium The endothelium is a dynamic organ that provides an interface between flowing blood and the vessel wall.

Hemostasis and Thrombosis in the Surgical Patient

159

The endothelium is highly heterogeneous and undergoes ‘‘transdifferentiation,’’ in which the endothelium can be influenced by local factors to acquire specialized characteristics unique to that local environment. ‘‘Thromboregulation’’ is a term that refers to three different basic processes by which cells of the vessel wall and the blood cells interact to facilitate or inhibit thrombus formation (28–31). The initial phase of thromboregulation refers to those vasoactive substances that help to prevent platelet deposition and affect the contractile state of the blood vessel. These early thromboregulators include nitric oxide (NO), eicosanoids, and the ectoADPase/CD39. NO is a potent inhibitor of platelet aggregation and is a potent vasodilator. The endothelial cell eicosanoids include prostacyclin (PGI2) and prostaglandin D2 (32,33). These fatty acid–derived hydrocarbons can inhibit platelet aggregation and cause vasodilatation of the vessel wall. Endothelial cell ectoADPase/CD39 is a membranebased protein that metabolizes ADP in the primary platelet release product, which will then prevent platelet recruitment. In addition to these three early thromboregulators, endothelial cells release endothelins, which are potent vasoconstrictors (34–44). Normal endothelium expresses thrombomodulin (TM), which serves as a binding site for thrombin to activate protein C; heparin-like molecules that can activate AT-III; and ectoadenosine diphosphatase that inhibits platelet aggregation by degrading ADP. Endothelium also produces vWF and releases it into subendothelial matrix, where it mediates platelet adhesions when endothelium is lost. The second group of thromboregulators includes those acting as ‘‘late thromboregulators.’’ These late thromboregulators act to regulate thrombin generation, neutralize thrombin, or lyse clot. These include endothelin, AT-III, tissue factor pathway inhibitor (TFPI), the TM/endothelial cell protein C receptor (EPCR/protein C system), and the fibirinolytic system. Endothelin, as mentioned above, is a potent vasoconstrictor. AT-III is a natural anticoagulant, which inhibits thrombin and factor Xa. TFPI is a protein that inhibits factor VIIa tissue factor activity. The EPCR/protein C system of the vascular wall has direct anticoagulant effects on thrombin. Endothelial cells synthesize and secrete elements of the fibrinolytic system and also regulate the formation of plasmin (45). The third subcategory of thromboregulators includes alterations due to inflammation. These changes include increases in expression of tissue factor and modulation of the TM/EPCR/protein C system. The endothelial cells also upregulate cell adhesion molecules and the selectins. These changes create an interface between the endothelium and various classes of leukocytes. Endothelial injury is accompanied by the loss of antithrombotic, protective molecules and expression of procoagulant properties, white blood cell adhesion molecules, and mitogenic activities that can engender thrombosis, smooth muscle cell migration and proliferation, and atherosclerosis. These multiple endothelial functions and their regulatory effects on platelets, coagulation proteins, and the fibrinolytic system are illustrated in Figure 4 (29–33).

Tissue Factor Pathway Inhibitor The primary regulator of the TF/VIIa complex in hemostasis is the TFPI (22,23). TFPI is present in circulating form and bound to endothelium (Fig. 4). The inhibitory process of TFPI involves two steps (23,34). First, TFPI inactivates factor Xa by forming a TFPI/Xa complex. This complex then binds the TF/ VIIa complex, forming a quaternary Xa/TFPI/VIIa/TF complex, which lacks TF/VIIa activity. Heparin causes the release of TFPI from endothelial stores bound to heparin sulfate or

medwedi.ru

160

Part One: General Considerations

Figure 4 Vasoprotective and procoagulant properties of EC. On the left, inhibition of platelet function and coagulation by several endothelial molecules and factors and the targeted coagulation factors are shown. In addition, activation of fibrinolysis of EC tPA and its PAI-1 is depicted. TM is a surface molecule that binds thrombin, thereby activating PC to aPC, which in the presence of PS degrades factor Va and VIIIa-heparin-like molecules expressed on endothelial surface serve as a cofactor for AT-III, thereby ILa and several other activated coagulation factors shown. On the right, TF expressed on EC surface during activation serves as a cofactor factor VIIa to activate X and IX, respectively. Generated thrombin activates platelets, coagulation, and fibrinolysis. Abbreviations: EC, endothelial cells; tPA, tissue plasminogen activator; PAI-1, inhibition by plasminogen activator; PC, protein C; aPC, activated protein C; PS, protein S; ILa, inactivating thrombin; TF, tissue factor; TM, thrombomodulin; AT-III, antithrombin III. Source: From Ref. 28.

other glycosaminoglycans (46). More TFPI is available from the endothelial source than that circulating in plasma.

Activated Protein C and Protein S Endothelium possesses a thrombin receptor, TM. TM is the cellular cofactor for thrombin and is expressed on endothelial cell surfaces (47,48). TM appears to help prevent thrombosis in intact endothelium in the microcirculation (TM), binds to thrombin and thus helps localize thrombin to endothelial cell surfaces and enhances Protein C activation 1000- to 2000-fold (49–51). Protein S is the cofactor for protein C; both protein S and protein C are vitamin K–dependent proteins. Activated protein C is the major inhibitor of factors Va and VIIIa (Fig. 4) (50–52). Thrombin bound to TM cannot activate factors V, VIII, XIII, fibrinogen, or platelets. The expression of TM is downregulated by endotoxin, tumor necrosis factor, and IL-1.19. Thus thrombosis may be favored at sites of inflammation by a concurrent elevation of tissue factor and a depression in endothelial TM expression.

conversion product plasmin from the natural inhibitor a2-antiplasmin, which efficiently neutralizes plasmin in the fluid phase only. Thus the action of plasmin is localized to the site of clotting or thrombus formation, where fibrin is digested. Free plasmin is thus prevented from escaping into the general circulation. Small amounts of plasmin that leak into the circulation or are generated in flowing blood are rapidly inactivated by the action of a2-antiplasmin and other inhibitors. T-PA is inactivated by plasminogen activator inhibitor (PAI-1), a 52 kDa protein synthesized in the endothelial cell (Fig. 4). PAI-1 is the primary regulator of endogenous t-PA activity (56–59). a2-Antiplasmin is a specific inhibitor of plasminogen and is incorporated into the fibrin clot, thereby rendering it resistant to lysis by plasmin (40). Plasma levels of a2-antiplasmin are less than those of plasminogen, so that depletion of a2-antiplasmin, such as during disseminated intravascular coagulation (DIC), can result in uninhibited plasmin activity and worsening of the coagulopathy.

Nitric Oxide Antithrombin-III AT-III is a 58 kDa glycoprotein that is synthesized in the liver and is the major inhibitor of thrombin and factor Xa. AT-III also inactivates factors XIIa, XIa, and IXa. Heparin accelerates the activity of AT-III by 1000-fold (52–55). Heparin dissociates from AT-III once covalent bonds are formed between AT-III and thrombin or other factors, and is then able to activate additional AT-III. AT-III activity is also accelerated by heparin sulfate present on endothelium (Fig. 4).

Fibrinolytic System Fibrinolysis is stimulated by vascular injury and release of plasminogen activator from endothelial cells (Fig. 4). By the action of tissue-type plasminogen activator (t-PA) or urokinase, the inactive plasma precursor molecule plasminogen is converted to the proteolytic enzyme plasmin, which can digest fibrin and fibrinogen. There are two major forms of circulating plasminogen, lys-plasminogen and gluplasminogen (56–59). Lys-plasminogen selectively binds to fibrin during clotting and is more easily converted to plasmin than is glu-plasminogen. Selective incorporation of lysplasminogen into thrombus also protects the subsequent

NO is a free radical produced from the amino acid L-arginine (L-Arg) and has a half-life of three to five seconds (42–44). NO is produced by the action of NO synthase (NOS), which converts the terminal guanidine group of L-Arg to NO. Two forms of NOS have been identified, an inducible form, found primarily in macrophages, and a constitutive form, found in neuronal tissue, platelets, and vascular endothelium. In addition to its potent vasodilator function, NO interacts with platelets, inhibiting both adhesion and aggregation by increasing intracellular cyclic guanosine monophosphate. Platelets can also release NO, which acts in an autocrine fashion to prevent aggregation. In vivo, platelet deposition at the site of endothelial injury is increased by free hemoglobin, an NO inhibitor, in the cell. This augmented platelet deposition can be blocked by L-Arg, but not by aspirin (60–62).

Prostacyclin Endothelial cells synthesize prostacyclin, which inhibits platelet aggregation and causes smooth muscle relaxation and vasodilation (30,63). Released endothelial cell prostacyclin can react with the platelet surface domain of a specific

Chapter 7:

receptor, thereby initiating a signal transduction pathway that is G protein linked and of the type described for activation of phospholipase C. In this case, the signal-generating enzyme is adenylate cyclase, which catalyzes the formation of the second-messenger cyclic adenosine monophosphate (cAMP) from adenosine triphosphate, resulting in inhibition of platelet function. Continuous, basal endothelial prostacyclin production occurs in vivo, and marked increases are seen in response to increases in shear stress, local thrombin generation, and cytokines. Another product of endothelial prostaglandin metabolism includes lipoxygenase products that inhibit platelet adhesion. By reducing platelet adhesion, inhibiting platelet aggregation, and causing vasodilation, prostacyclin can lead to local increases in blood flow that help to wash away any thrombi that may be forming.

INHERITED DISORDERS OF COAGULATION Inherited disorders of hemostasis are generally characterized by a history of prior bleeding episodes, particularly hemarthrosis, which can result in significant joint damage. Surgical treatment in these individuals is best provided at a center where the expertise of a hematologist and others skilled at providing care for these patients is available. A summary of these deficiencies and their inheritance patterns and treatment are provided in Table 1.

Hemophilia A (Factor VIII Deficiency) Hemophilia A is an X-linked disorder and has an incidence of 10 to 20 cases per 100,000 live births (15, 64–66). As many as 30% of new cases are not associated with a family history, thereby suggesting that the factor VIII gene undergoes frequent mutation. Hemophilia A is suspected in any male with a history of excessive bleeding following trauma or spontaneous hemarthrosis. The severity of hemophilia A is correlated with the level of factor VIII. Patients with factor VIII levels greater than 5% have mild hemophilia and are at reduced risk for spontaneous bleeding but are at increased risk for bleeding following surgery or trauma. Patients with factor VIII levels between 1% and 4% have moderate hemophilia. Patients with factor VIII levels less than 1% have severe hemophilia and are at risk for spontaneous bleeding. Laboratory abnormalities in hemophilia A, other than reduced factor VIII levels, can include a variable prolongation of the activated partial thromboplastin time (aPTT). Analyzing the DNA from blood samples, following amplification using the polymerase chain reaction, can help perform carrier and prenatal testing and then using restriction enzymes that recognize and cleave specific DNA base sequences. The DNA is then analyzed using gel electrophoresis and compared with known patterns of abnormal DNA polymorphism. Treatment of hemophilia A depends on the severity of the disease and the indication (Table 1). For example, patients with mild hemophilia undergoing dental procedures can be effectively treated with desmopressin (DDAVP, 0.3 mg/kg intravenously), which releases stores of factor VIII and vWF and will increase factor VIII to a median level of 62%. DDAVP cannot be used in patients with severe hemophilia A, because they have no stored form of factor VIII. Patients with hemophilia A who are undergoing surgery should be treated with factor VIII concentrates (Table 2). Since 1985, all factor VIII concentrates in the United States have undergone viral inactivation using heat

Hemostasis and Thrombosis in the Surgical Patient

161

or solvent-detergent treatment, which has essentially eliminated the risk of transmitting HIV or hepatitis B and C. Commercial factor VIII concentrates are available in a range of purity and specific activity, depending on their source and methods of purification. The half-life of factor VIII is approximately 12 hours, so replacement therapy should be given at 8- to 12-hour intervals during periods of increased bleeding risk. The Food and Drug Administration (FDA) has approved recombinant factor VIII from genetically engineered mammalian cells.

Hemophilia B (Factor IX Deficiency) Hemophilia B is inherited in an X-linked fashion and has a clinical presentation similar to hemophilia A (15, 65,66). The incidence of hemophilia B is approximately 10-fold lower. As with hemophilia A, spontaneous mutations of the factor IX gene can cause the disorder without a prior family history. Hemophilia B is a heterogeneous disorder characterized by a number of point mutations and deletions of the factor IX gene on the X chromosome. The degree of severity of hemophilia B is categorized as with hemophilia A based on the factor IX levels: severe is less than 1% of normal, moderate is 1% to 5%, and mild is 6% to 60% of normal. Treatment principles for factor IX replacement are similar to those with hemophilia A (Table 1). For major surgery or active bleeding, a factor IX level of 50% to 100% should be achieved using factor IX concentrates. A level of 30% may be adequate for prophylaxis or minor bleeding. The biologic half-life of factor IX is 18 to 30 hours, so concentrates should be readministered at 12- to 24-hour intervals during periods of increased bleeding risk. Replacement therapy for factor IX and VIII can also be guided by periodic assessment of factor levels. The aPTT is inadequate for monitoring factor replacement therapy, because some factor IX products also contain activated clotting factors. The availability of high-purity virally inactivated factor IX concentrates since 1991 has essentially eliminated the risks of viral transmission and thrombogenicity (Table 3). Approximately 50% of patients exposed to factor IX concentrates before the introduction of virus attenuation procedures in 1985 are HIV positive, and virtually all are seropositive for hepatitis C.

von Willebrand Disease The functions of vWF during normal hemostasis are to promote platelet adhesion in conditions of high shear stress (such as in arterial injury) by binding of the subendothelial vWF to the platelet GPIb receptor and the promotion of platelet aggregation by binding of vWF and fibrinogen to the platelet GPIIb/IIIa receptor. vWF is synthesized in the megakaryocyte and in endothelial cells and is then stored in the Weibel–Palade bodies of the endothelial cell and the a-granules of the platelet. von Willebrand disease (vWD) results from a quantitative or qualitative deficiency of vWF and has an estimated prevalence of 0.8%, making this the most common inherited bleeding disorder (7,13,14). It is usually transmitted as an autosomal dominant trait with variable expression. However, there is considerable heterogeneity in the spectrum of this disorder, with at least 20 distinct subtypes (67–70). Clinically, vWD is characterized by easy bruisability, mucosal bleeding, and potentially heavy bleeding during surgery or from trauma. The laboratory diagnosis includes measurement of vWF activity and antigen. The bleeding time is frequently abnormal as is the aPTT (7,13,14,67–70).

medwedi.ru

162

Part One: General Considerations

Table 1 Genetics, Epidemiology, and Therapy of Inherited Coagulation Protein Deficiencies Coagulation protein deficiency Factor I (fibrinogen) Afibrinogenemia Hypofibrinogenemia Dysfibrinogenemia

Inheritance pattern Autosomal recessive Autosomal dominant or recessive Autosomal dominant or recessive Autosomal dominant or recessive

Prevalence Rare (<200 families reported) Extremely rare

Factor V (labile factor) Factor VII

Autosomal recessive Autosomal recessive

Rare (>200 types described) Extremely rare (approximately 25 kindreds) One per million births One per 500,000 births

Factor VIII (antihemophilia factor)

X-linked recessive

One per 10,000 births

Usually autosomal dominant

One per 5000 male births Approximately one per 100 births

Factor II (prothrombin)

Hemophilia A vWF

Type III

Minimum desired level to control active bleeding or prevent surgical bleeding

Replacement sources

100 mg/dL

Cryoprecipitate/FFP

30% of normal

FFP/factor IX complex concentrates

25% of normal 25% of normal

FFP FFP/factor IX complex concentrates 80–100% of normal for life- Factor VIII concentrates; threatening bleeding, 50% desmopressin for mild to of normal for significant moderate disease bleeding, 30% of normal for minor bleeding Total or partial correction of bleeding time and raising vWF activity to 50% of normal

Desmopressin for mild to moderate vWD (except IIB) (variable responses in IIA); cryprecipitate; intermediate-purity factor concentrates containing a full complement of vWF multimers

Factor IX

Severe type III disease usually recessive X-linked recessive

One per 30,000 male births

25–50% of normal depending on extent of surgery or bleeding

Factor IX complex concentrates or factor IX (human) concentrates

Hemophilia B Christmas disease Factor X

Autosomal recessive

One per 500,000 births

10–25% of normal

Approximately 4% of Ashkenazi Jews Extremely rare

20–40% of normal

Factor XII

Autosomal dominant; severe type homozygous Autosomal recessive

FFP or factor IX complex concentrates FFP

Prekallikrein (Fletcher factor)

Autosomal recessive

Extremely rare

High-molecular-weight fibrinogen (Williams, Flaujeac, or Fitzgerald factor) Factor XIII

Autosomal recessive

Extremely rare

Autosomal recessive

One per several million births

Factor XI

One per million births

No replacement therapy required No replacement therapy required No replacement therapy required

5% of normal

FFP or cryoprecipitate

Abbreviations: vWD, von Willebrand disease; vWF, von Willebrand factor; FFP, fresh frozen plasma. Source: From Ref. 15.

There are at least three main types of vWD, each with subtypes. The types are categorized based on a quantitative or qualitative deficiency of vWF. Types I and III are due to quantitative deficiencies, and type II (and other variants) results from a qualitative deficiency in vWF. Type I is most common and is responsible for 70% to 85% of all forms of vWD. Type I vWD results from a quantitative deficiency of vWF of 50% or less of normal. In type IIB, thrombocytopenia can result from treatment with DDAVP because the release of additional abnormal vWF can cause platelet agglutination. Type III vWD is the most

severe and results from greatly reduced levels of vWF caused either by an autosomal recessive homozygous state or double heterozygote with an autosomal dominant mode of inheritance. In addition, a platelet type of vWD is caused by an abnormal platelet GPIb receptor, which has an increased affinity for normal vWF, and is associated with platelet agglutination when more vWF is administered. Patients with type I vWD generally respond well to DDAVP with adequately increased vWF levels for four to eight hours. This effect is presumably mediated through

Chapter 7:

Hemostasis and Thrombosis in the Surgical Patient

163

Table 2 Recombinant and Immunoaffinity-Purified Factor VIII Products Specific activity (U/mg) Recombinanta

Immunoaffinity purifiedb

Product name

Manufacturer

Cell of origin

Recombinate

Chinese hamster ovary

2.2–5

4000þ

Kogenate

Baxter-Hyland Genetics Institute Miles-Cutter

Method of viral inactivation

Final

Discounting albumin

Baby hamster kidney

8–30

4000–6000

Monoclate P

Armour

Pasteurized (60 C, 10 hr)

5–10

3000þ

Hemofil M

Baxter-Hyland

2–11

3000þ

Coagulation FVIII, M method

Baxter-Hylandc

Solvent detergent (TNBP/Triton X-100, 25 C, 10 hr) Solvent detergent (TNBP/Triton X-100, 25 C, 10 hr)

2–11

3000þ

a

Genetically engineered. Derived from human plasma. c Manufactured for the American Red Cross. Abbreviation: TNBP, tri-(n-butyl) phosphate. Source: From Ref. 15. b

the release of endogenous vWF from the endothelium, although the mechanism for this is not completely understood. For patients with type IIA vWD response to DDAVP is unpredictable and should be tested in advance. Use of DDAVP in type IIB and platelet type vWD is contraindicated due to resulting thrombocytopenia. For patients in whom DDAVP is not effective or contraindicated, replacement therapy using cryoprecipitate or intermediate-purity factor VIII concentrates that contain functional vWF is indicated. A retrospective review of the use of cryoprecipitate and factor VIII concentrates in vWD unresponsive to DDAVP in 21 treatment centers showed equivalent efficacy (13,14,69). Because factor VIII concentrates are virally inactivated and cryoprecipitate is not, and because there appears to be no advantage to the use of cryoprecipitate, factor VIII concentrates should be considered the treatment of choice in vWD when DDAVP cannot be used.

INHERITED QUALITATIVE PLATELET DISORDERS Glanzmann’s Thrombasthenia Glanzmann’s thrombasthenia results from a congenital absence of functional platelet GPIIb/IIIa receptor to bind fibrinogen and participate in clot retraction, which is mediated by interaction of GPIIb/IIIa with the platelet cytoskeleton (16,18,19,70,71). The genetic defects that result in Glanzmann’s thrombasthenia are remarkably heterogeneous, can result in abnormal GPIIIa or GPIIb, and are generally inherited in an autosomal recessive pattern (46). A deficiency in either glycoprotein causes a functional abnormality of GPIIb/IIIa. Clinically, the disorder is characterized by a history of excessive bleeding at an early age, easy bruisability, and menorrhagia. Hemarthroses are rare. Laboratory diagnosis is established by the absence of the GPIIb/IIIa receptor by flow cytometry or gel electrophoresis. The platelet count and morphology are normal. Platelet aggregometry reveals agglutination of Glanzmann’s

Table 3 Factor IX Products Product name Coagulation products

Complex concentrates

Activated complex concentrates

Manufacturer

Method of virus inactivation

AlphaNine

Alpha Therapeutic

AlphaNine SD

Alpha Therapeutic

Mononine Konyne 80 Proplex T Profilnine HT (wet method) Bebulin

Armour Miles-Cutter Baxter-Hyland Alpha Therapeutic

Autoplex T

Baxter-Hyland

Heated in N-heptane solution, 60 C, 20 hr TNBP and polysorbate 80, 24–30 C, > 24 hr Sodium thiocyanate, ultrafiltration Dry heat, 80 C, 72 hr Dry heat, 68 C, 144 hr Heated in N-heptane solution 60 C, 20 hr Vapor heated (10 hr, 60 C, 1190 mb pressure plus 1 hr, 80 C, 1375 mb) Dry heat, 68 C, 144 hr

FEIBA VH

Immuno-U.S.

Abbreviation: TNBP, tri-(n-butyl) phosphate. Source: From Ref. 15.

Immuno

Vapor heated (10 hr 60 C, 1190 mb plus 1 hr, 80 C, 1375 mb)

medwedi.ru

Specific activity (U/mg) 84 190 160þ 1.3 47 4.5 2

5 0.8

164

Part One: General Considerations

platelets with ristocetin, but not with ADP, epinephrine, thrombin, or collagen. Treatment of Glanzmann’s thrombasthenia requires antifibrinolytic agents, either e-aminocaproic acid (EACA) or tranexamic acid, for epistaxis, dental surgery, or minor bleeding (19). Oral contraceptives are effective in treating menorrhagia. Platelet transfusions, preferably human leukocyte-matched, are required for surgery. Development of alloimmunization or antibodies to GPIIb/IIIa limits the usefulness of platelet transfusion; so this should be used only when serious bleeding occurs or is likely. DDAVP does not prevent bleeding with this disorder. Although Glanzmann’s thrombasthenia is a rare disorder, the understanding of its molecular basis has led to advances in antiplatelet therapy. Antibody inhibitors of the GPIIb/IIIa receptor are now used as antiplatelet agents and are discussed in a subsequent section.

Bernard–Soulier Disease (Syndrome) Bernard–Soulier disease (syndrome) results from congenital absence of platelet GPIb/IX, the receptor for vWF (72–75). This is a rare disorder, with only approximately 100 reported cases. The pattern of inheritance is usually autosomal recessive, although an autosomal dominant form has been described. These patients have a similar clinical presentation to that of Glanzmann’s thrombasthenia but have thrombocytopenia and large platelets (19). The thrombocytopenia can be as low as 20,000/mL. Because the interaction with vWF is affected, platelets do not aggregate in high shear conditions, such as with arterial injury. Platelet aggregometry reveals agglutination in the presence of ADP, collagen, and epinephrine but not to ristocetin. Aggregation response to thrombin is dose dependent. Treatment principles using oral contraceptives, antifibrinolytic agents, and platelet transfusion are as for Glanzmann’s thrombasthenia. Similarly, DDAVP is not considered effective.

ACQUIRED DISORDERS OF HEMOSTASIS Disseminated Intravascular Coagulation DIC is a hemorrhagic and thrombotic disorder that is triggered by a variety of underlying illnesses, and results in generation of tissue factor with consequent activation of coagulation. Excess thrombin generation and fibrinolysis characterize the disorder. Microvascular thrombosis occurs and can exacerbate underlying tissue and organ injury (76). In surgical patients, multiple clinical settings are associated with DIC and intraoperative coagulopathy. Severe bacterial infections with septicemia and endotoxemia, particularly from gram-negative enteric organisms, can trigger DIC. Gram-positive bacterial infections also can be etiologic. Massive tissue trauma, especially when associated with shock, can flood the circulation with thromboplastic and procoagulant substances and lead to acute consumption of hemostatic elements sufficient to incite bleeding. Localized trauma in the form of brain injury (usually severe and penetrating) and long bone fractures can trigger DIC by similar mechanisms. Malignancy can be associated with acute or chronic DIC. An association between DIC and aortic aneurysms has been well documented (77–82). In one series, 40% of patients with aortic aneurysms had elevated fibrin split products, but only 4% had significant bleeding and laboratory evidence of DIC. The clinician must be careful to look for clinical or laboratory signs of DIC prior to surgical repair to avoid excessive bleeding. The initiation of localized or generalized DIC has been thought

to be caused by activation of tissue factor pathway by the large amount of tissue factor in the atherosclerotic plaque and by loss of clotting factors into the large clot present in many aneurysms. Coagulation defects that are found prior to surgical repair of the aortic aneurysm should be corrected by appropriate replacement therapy and continuous infusion of heparin (83,84). A major transfusion reaction can cause DIC and should be suspected when sudden intraoperative bleeding occurs in the absence of a surgical source during blood transfusion. This can occur with the infusion of as little as 25 mL of mismatched blood. The clinical manifestations of shaking chills, fever, and back pain can be obscured by general anesthesia. Hypotension, diffuse bleeding, and darkening of the urine may be the only clues of intraoperative transfusion reaction. Treatment is directed at (i) stopping transfusion, (ii) restoring normal blood pressure and volume with crystalloid and appropriate pharmacologic support, (iii) attaining alkalinization with sodium bicarbonate, and (iv) administering mannitol to protect against renal tubular necrosis. Fortunately the DIC that attends a major transfusion reaction is transient and usually requires no treatment once the causative agent has been stopped. The laboratory diagnosis of DIC is demonstrated by the evidence of platelet and fibrinogen consumption as well as fibrinolysis. Fibrinogen levels can, however, be normal in up to 57% of patients with DIC (76,85). The prothrombin time (PT) and thrombin times are elevated in DIC. The aPTT is variable depending on the level of factor VIII activation. Elevated levels of fibrinopeptide A indicate conversion of fibrinogen to fibrin. Elevated prothrombin fragment F1.2 indicates thrombin generation from the action of factor Xa on prothrombin. D-Dimer is generated by the lysis of cross-linked fibrin and forms the basis of a sensitive laboratory test (86). Elevation of D-dimer is typically seen in DIC but can occur in other conditions where there is physiologic fibrinolysis. The treatment of all forms of DIC occurring intraoperatively is aimed primarily at supporting normal blood volume and pressure and expeditious removal of the stimulus for DIC. Specific therapies directed against DIC, such as heparinization, have no place in an acutely bleeding patient and are contraindicated in this setting. Heparin may be used in conditions where DIC is not associated with bleeding, such as sepsis or chronic DIC with an intact aortic aneurysm. Likewise, antifibrinolytic agents are not advised, because a degree of fibrinolysis protects against occlusive thrombosis of capillaries and prevents organ ischemia. Most authorities believe that EACA should not be used for DIC unless the patient is heparinized. In a patient with DIC undergoing operation, control of bleeding must, by necessity, be affected by infusion of fresh frozen plasma (FFP), cryoprecipitate, and platelets. The fear of ‘‘fueling the fire’’ and making the process worse has been overemphasized in the past. Component therapy can be lifesaving in this difficult clinical circumstance.

ACQUIRED DISORDERS OF PLATELET FUNCTION Of the long list of substances that have been shown to inhibit platelet function (Table 4), only aspirin has been clearly documented to increase the clinical risk of bleeding. Aspirin irreversibly inactivates cyclooxygenase, thereby preventing the production of thromboxane A2, from arachidonic acid (6–8). One 80 to 100 mg dose of aspirin can totally inhibit thromboxane production for the 10-day lifespan of the platelet (87).

Chapter 7:

Table 4 Acquired Platelet Dysfunction Associated with medication

Associated with medical conditions

Aspirin NSAIDs Cephalosporin antibiotics

Chronic renal failure Cardiopulmonary bypass Disseminated intravascular coagulation Chronic hepatic disease Multiple myeloma Collagen vascular diseases, particularly SLE Chronic myeloproliferative disorders Myelodysplastic syndromes

Penicillins Thrombolytic agents Dextran Prostacyclin (iloprost) b-Blockers Calcium channel blockers nifedipine, verapamil, diltiazem Nitroprusside Nitroglycerin Quinidine Tricyclic antidepressants or antipsychotics Antihistamines Eicosapentaenoic acid (o-3 fatty acids) Ticlopidine

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus. Source: From Ref. 15.

The true impact of aspirin on intraoperative bleeding is difficult to determine. Several trials have shown an increased amount of surgical bleeding in aspirin-treated patients undergoing coronary artery bypass grafting (88–90), but other studies in this clinical setting have shown no increased risk of bleeding (91,92). Results of the Physician’s Health Study on the efficacy of aspirin for primary prevention of myocardial infarction showed an increased risk of bleeding episodes compared to subjects taking placebo (27% vs. 20%) (93). The ubiquitous use of aspirin is reflected in a study that reported that approximately one half of patients undergoing unexpected surgery had taken aspirin within the previous 72 hours (94). In this study, however, there was no increased risk of bleeding or increased use of blood transfusions. However, aspirin can increase bleeding in surgical patients who have other hemostatic problems such as those induced by cardiopulmonary bypass and anticoagulant (e.g., heparin and warfarin) use, and should be used with caution in these settings. Although other nonsteroidal anti-inflammatory drugs inhibit platelet function, they do so reversibly and have not been shown to cause clinically important bleeding. The various penicillins contain a b-lactam ring and a unique side chain. Most penicillins induce an increase in bleeding time in normal volunteers (95,96). Penicillin decreases both platelet secretion and aggregation and ristocetin-induced platelet agglutination. Tests of platelet aggregation are abnormal in 50% to 75% of individuals taking carbenicillin, penicillin G, ticarcillin, ampicillin, nafcillin, and azlocillin, whereas patients taking piperacillin, azlocillin, apalclillin, or mezlocillin demonstrate abnormal aggregation from 25% to 50% of patients (96–99). Penicillins may impair the interaction of agonists (ADP and epinephrine) and vWf with their platelet membrane receptors (100). Penicillins probably inhibit platelet function by binding to one or more membrane receptors necessary for adhesion and aggregation (101). Laboratory tests of platelet function as used by the clinician are the bleeding time and platelet-aggregation

Hemostasis and Thrombosis in the Surgical Patient

165

studies. Platelet aggregometry measures the change in optical density over time in a sample of platelet-rich plasma to which an agonist of platelet aggregation has been added. The optical density decreases as the platelets in suspension cluster into aggregates. Although most acquired disorders of platelet function are associated with abnormal platelet aggregometry, the clinical usefulness of these studies is limited (70). Normal criteria are specific only for individual laboratories (102). Furthermore, abnormalities in platelet aggregometry assays have not always correlated with risk of bleeding (103). Measurement of the forearm template bleeding time is probably the most commonly used laboratory measure of platelet function. The test is performed by making a standard skin incision on the medial aspect of the forearm using a template blade, blotting the incision every 30 seconds, and measuring the time until bleeding stops. While antiplatelet agents generally prolong the bleeding time, a review of the literature shows no clear evidence that a prolonged bleeding time predicts excessive bleeding during surgery (104,105). Bleeding is a serious complication of uremia. In the predialysis era, bleeding was a cause of morbidity in approximately 50% of patients and death in approximately 30% of patients (106,107). Although 90% of patients with renal failure and gastrointestinal hemorrhage have an identifiable source of bleeding, abnormalities with platelet function contribute to the incidence and magnitude of hemorrhage (108). Defects in platelet adhesion, aggregation, and procoagulant activity have been reported in uremia. One defect proposed is that of platelet GPIb–IX complex that is necessary for binding with vWF (109–111). A second platelet defect associated with uremia is platelet activation. Uremic platelets show reduced binding to fibrinogen, aggregation, and secretion in response to agonists. Several of the biochemical abnormalities proposed include a decrease in the rise in cytoplasmic free calcium levels, reduced release of arachidonic acid from membrane phospholipids, decreased conversion of arachidonic acid to thromboxane A2, and a decrease in platelet dense granule content of ADP and serotonin as well as an increase in intracellular cAMP (112–116). Other factors that contribute to hemorrhage in uremia include thrombocytopenia, anemia, and concurrent medications such as aspirin (109,117). Platelet function abnormalities can be improved following dialysis (109,118). DDAVP has been used to correct qualitative platelet dysfunction due to uremia and other causes (109,119).

BLEEDING IN THE SURGICAL PATIENT Preoperative Assessment The most important element in the preoperative evaluation of risk of bleeding is obtaining the patient’s history and physical examination. The history should elicit whether the patient bleeds unusually in response to minor trauma or spontaneously in the absence of trauma (see accompanying box). The responses to major and minor surgery and to dental extractions are particularly helpful. A patient who has recently undergone surgery without bleeding complications has had a far better ‘‘stress test’’ of hemostasis than any laboratory can provide. The manifestations of abnormal bleeding can provide clues to the nature of the underlying hemostatic defect. Easy bruisability, ecchymoses, petechial hemorrhages, nosebleeds, and oral mucosal and gingival bleeding generally indicate thrombocytopenia or a qualitative platelet disorder, whereas joint hemorrhages, deep muscular hematomas, and retroperitoneal bleeding are

medwedi.ru

166

Part One: General Considerations

usually signs of a coagulation defect (congenital factor deficiency or anticoagulant use) (64,65,120). These distinctions are not specific, however, and the presence of any of these abnormalities should prompt a more thorough laboratory evaluation for an underlying hemostatic deficit. The family history is relevant and a pedigree chart of a familial bleeding tendency may provide important clues. The family history is not always positive with the ‘‘inherited’’ clotting disorders. Up to 30% of new cases of hemophilia A are not associated with a positive family history and are thought to represent spontaneous mutation (64,65,120). The routine use of preoperative laboratory screening tests is unnecessary when an underlying coagulation disorder is not clinically suspected. The inability of the bleeding time to predict surgical bleeding has been described previously. Similarly, preoperative assessment of the PT and the aPTT in the absence of a clinically suspected clotting disorder has been shown not to predict surgical bleeding complications (121–123). When evaluating a patient for a major operation that has greater potential to impair clotting mechanisms, such as coronary artery bypass or major vascular reconstruction, or where the consequences of excessive bleeding, are particularly hazardous, such as with neurologic surgery or tissue flaps, it is reasonable to routinely perform basic coagulation tests such as a platelet count, PT, and partial thromboplastin time. This recommendation should not be viewed as a substitute for a proper clinical assessment (Box 1).

Intraoperative and Postoperative Bleeding The most common cause of significant intraoperative bleeding is inadequate surgical hemostasis, the so-called ‘‘silk deficiency.’’ There are no pharmacologic or blood bank substitutes for a careful dissection and attention to technical detail. Even what seems like trivial bleeding from skin edges and subcutaneous tissue can add up, and such bleeding can account for up to 100 to 200 mL of blood loss if unattended (124). Dissection using electrocautery rather than a scalpel has been shown to reduce blood loss (125,126). Intraoperative disorders of hemostasis can be acquired for a number of reasons. Coagulopathy in vascular disorders and trauma has been shown to be related more to hypotension and hypoperfusion than to dilutional factors (127). Tissue hypoxia can cause release of plasminogen activators, thereby stimulating fibrinolysis. Hypothermia may be another contributing factor, particularly in the traumatized patient. Dilutional thrombocytopenia may occur in the massively transfused patient, particularly following 20 or more units of banked or cell salvage blood (128). In a prospective, randomized clinical trial evaluating the efficacy of prophylactic transfusion of either 6 U of platelets or 2 U of FFP given after transfusion of every 12 U of blood, there was no difference in platelet counts or microvascular bleeding (18% in platelet group, 19% in FFP group) between groups, leading the authors to conclude that prophylactic platelet transfusion is unnecessary in the massively transfused patient (129). Of the six patients who developed microvascular bleeding, however, four subsequently required platelet transfusions to correct persistent thrombocytopenia and oozing. This study also illustrates that measured platelet counts are significantly higher following massive transfusion than would be predicted on the basis of dilution alone, indicating that endogenous release of platelets, presumably from the spleen, is responsible for continued release of platelets into the circulation in such patients. Because there was not a control group that did not receive prophylactic

Box 1 Suggested Questions to Determine Bleeding History

Hemostatic Response to Surgery and Trauma 1. What operations have you had, including minor ones, such as tonsillectomy, circumcision, or biopsies? Was bleeding after surgery hard to stop? Have you ever developed unusual bruising in the skin around an area of surgery? 2. Have you ever required a blood transfusion? 3. Have you ever bled for a long time or developed a swollen tongue or mouth after cutting or biting your tongue, cheek or lip? What was the longest time it took to stop bleeding from cuts or scrapes? Has bleeding from a cut or scrape ever restarted after stopping completely? 4. How many times have you had teeth pulled and what was the longest time that you bled afterward? Has bleeding ever restarted the day after extraction?

Spontaneous Bleeding 1. Do you develop bruises larger than a silver dollar without remembering when or how you injured yourself? If so, how big was the largest of these bruises? 2. Do you ever have nosebleeds? 3. Do your gums bleed easily? 4. Do you ever have abnormally heavy menstrual periods or spotting between periods? 5. Do you have blood in your urine or stool? Do you ever have black, tarry stools? 6. Have you ever had bleeding into joints or muscles?

Medication History 1. What medication, including aspirin or any other pills or powders for headaches, colds, menstrual cramps, arthritis, joint pains, back aches, or other pains, have you taken within the last week? 2. Do you take medicine to thin the blood or to prevent blood clots? 3. Have you had a medical problem within the past five years requiring a doctor’s care? If so, what is its nature?

Family History 1. Are there any bleeders in the family? 2. Has any blood relative had a problem with unusual bleeding or bruising after surgery? Were blood transfusions required to control this bleeding?

FFP transfusion, the issue of prophylactic repletion of labile clotting factors was not addressed. Prophylactic treatment with DDAVP did not decrease blood loss and transfusion requirements in a randomized study in patients undergoing aortic surgery (130). However, DDAVP can be useful in patients undergoing complex cardiac operations with prolonged cardiopulmonary bypass (131). Recommendations for platelet and labile clotting factor replacement during surgery are best guided by specific laboratory measurement of coagulation deficiency rather than an arbitrary formula (132). The time delay from when the intraoperative microvascular bleeding is first noticed until laboratory measurements to document the particular coagulation disorder are complete can be problematic. If the surgeon’s clinical judgment is confirmed by the laboratory test, additional blood loss and factor depletion has occurred before the appropriate factor replacement products can be made available. A potential solution to this problem would involve improved near-site monitoring of coagulation function. Despite appropriate factor replacement for acquired and congenital coagulation disorders, nonsurgical bleeding

Chapter 7:

can persist and be difficult to treat. A variety of commercially available topical hemostatic agents have been used in this situation. These topical agents are generally derived from bovine collagen or gelatin, or oxidized cellulose. Although these products create a mechanical template on which clot can form, they are limited by a lack of any inherent coagulation mechanism. Fibrin sealant is a potential alternative topical hemostatic agent. Fibrin sealant mimics the final step in the coagulation cascade by combining thrombin and fibrinogen and factor XIII (generally in liquid form) and can be applied directly to a surgical wound or a vascular anastomosis (133,134). Fibrin sealant can be made in the operating room by combining equal volumes of bovine thrombin (with calcium chloride) and cryoprecipitated plasma using separate syringes for each. Commercially prepared fibrin sealant is made of purified, virally inactivated human thrombin and fibrinogen (in some products fibrinolytic inhibitors have been added), is available in Europe, and is undergoing clinical trials in the United States (135–137).

CONGENITAL DISORDERS OF HYPERCOAGULABILITY Resistance to Activated Protein C Resistance to activated protein C is the most common inherited hypercoagulable disorder, affecting approximately 3% to 5% of populations of Western European origin. It is inherited in an autosomal dominant fashion and is due to a single point mutation in the gene coding for factor V, resulting in an Arg506 to Gln amino acid substitution, rendering it ‘‘resistant’’ to inactivation by protein C. Resistance to activated protein C is common in patient who have venous thrombosis, with a prevalence in this group of 20% to 60% (50,51,138–140). Activated protein C resistance is the most common abnormality associated with deep venous thrombosis during pregnancy, and the diagnosis should be diligently sought in this setting. This disorder is also commonly found among patients with recurrent venous thromboembolism (141). The diagnosis can be made using either a plasmabased clotting assay or a DNA assay. The clotting assay is an aPTT with a mixture of patient plasma and factor V–deficient plasma in the presence and absence of added activated protein C. When the added activated protein C does not prolong the aPTT adequately, resistance is suggested. In the DNA-based assay, DNA is extracted from the patient’s blood and amplified using the polymerase chain reaction. A restriction enzyme that recognizes only the normal factor V DNA is added. Normal and abnormal genotypes can then be determined by the examination of the DNA electrophoretic bands. The effect of anticoagulants on the results of hypercoagulability testing can present a point of confusion. The potential for interference with laboratory assays because of therapeutic anticoagulation is generally only an issue for protein C and protein S, the levels of which are decreased by warfarin, because they are vitamin K–dependent proteins. Because a DNA assay is available for resistance to activated protein C, anticoagulation does not interfere with the results. Generally, all factors can be tested for in the presence of heparin, although AT-III levels may be decreased (Fig. 5). The role of resistance to activated protein C in arterial thrombosis has not been determined. In a cohort study of men in the Physician’s Health Study, resistance to activated protein C was found to be a risk factor for venous

Hemostasis and Thrombosis in the Surgical Patient

167

Figure 5 Laboratory testing for hypercoagulability. AT-III may be decreased in vivo in patients receiving heparin. Test of APC resistance can be performed if heparin is removed; test plasma should be mixed with factor V–deficient plasma. In an assay for lupus anticoagulant, heparin removed or heparin-insensitive assay should be used. Test is performed with 1:1 mixture of patient’s plasma and normal plasma. Abbreviations: ACA, anticardiolipin antibody; APC, activated protein C; AT-III, antithrombin III. Source: From Ref. 142.

thrombosis but not for myocardial infarction or stroke (143). Another study, however, suggested that resistance to activated protein C might be a risk factor for failure of infrainguinal bypass grafts (144).

Protein S Deficiency Protein S, the vitamin K–dependent cofactor of activated protein C, is also associated with thromboembolic disease when deficiency states exist. The deficiency is generally inherited as an autosomal dominant trait; however, several point mutations have been identified (41,50,145). The clinical manifestations are similar to those seen with deficiency of protein C and AT-III, primarily venous thrombotic events. Arterial thrombotic events can also occur but less commonly than venous thrombosis. About 60% of protein S circulates in inactive form bound to C4b-binding protein (146). The remaining 40% is free and is the active form. Increased plasma levels of C4bbinding protein decrease the levels of free protein S and can influence thrombotic events (147). Because C4b-binding protein is an acute phase reactant that increases during inflammatory states and the postoperative period, relative decreases in free protein S may result, predisposing to thrombotic complications. Levels of total protein S in deficient heterozygotes range from 30% to 65% and levels of free protein S range from 15% to 50% of normal (147). Inherited deficiency states characterized by normal total protein S antigen level, normal or reduced free protein S levels, and diminished protein S activity have also been reported (148,149). Patients with protein S deficiency who have sustained thromboembolic episodes are best managed with lifelong anticoagulation.

Protein C Deficiency Protein C is a vitamin K–dependent enzyme that when activated inhibits factors Va and VIIIa. Protein C deficiency is inherited as an autosomal dominant trait with heterozygotes suffering recurrent venous thromboembolism. The initial thrombotic episode occurs spontaneously in approximately 70% of affected individuals. As with protein S deficiency, the relationship to arterial thrombotic events is unknown.

medwedi.ru

168

Part One: General Considerations

Homozygous infants can develop neonatal purpura fulminans. Interestingly, the heterozygote parents infrequently have thrombotic events, suggesting that other factors are involved, which modulate phenotypic expression. As with protein S deficiency states, a number of genetic point mutations have been recognized, which might account for the clinical heterogeneity of this disorder (50,51,150). Laboratory testing is done using a functional assay that measures the ability of activated protein C to inhibit factors Va and VIIIa in a modified aPTT using protein C–deficient plasma that provides the other factors (50,51,142). As with protein S, protein C is a vitamin K–dependent protein, so testing should not be performed while the patient is receiving warfarin therapy. These assays are not influenced by heparin (Fig. 5). Warfarin-induced skin necrosis has occurred in some patients with protein C or protein S deficiency. The clinical and pathologic manifestations are similar to those seen with neonatal purpura fulminans caused by severe protein C deficiency, with skin lesions on the extremities, breasts, trunk, and penis occurring during the first few days of warfarin therapy. The mechanism is thought to be due to a transient hypercoagulable state in which protein C levels decrease faster than factor X levels, as well as a greater effect on hemostatic function from protein C reduction than from factor VII reduction. Because only about one-third of patients with warfarin-induced skin necrosis have an underlying inherited deficiency of protein C (151), heparin is generally administered with warfarin until there is an increase in the PT. Patients with protein C deficiency who have sustained thromboembolism episodes are best managed with lifelong anticoagulation.

AT-III Deficiency Congenital deficiency of AT-III, first described in 1965 (152), has a prevalence of one per 2000 to 5000 and is one of the uncommon hypercoagulable syndromes. Deficiency of AT-III is inherited as an autosomal dominant trait and clinically is characterized by venous thrombosis occurring at an early age. Two-thirds of affected patients have a venous thrombosis by age 35. In the most common form of AT-III deficiency (type I), both the functional and the antigenic levels of AT-III are reduced, resulting from any one of a number of identified mutations (52,53,153,154). Two other types have been identified where the antigenic level of AT-III is normal, but the functional activity is reduced, either because of a defect in the thrombin-binding site (type II) or in the heparin-binding site (type III). Patients with type III AT-III deficiency do not appear to be at increased thrombotic risk unless they are homozygous (142). Patients with AT-III deficiency who have sustained thrombotic episodes are generally treated with lifelong warfarin anticoagulation. Although these patients are often considered to be ‘‘heparin resistant,’’ heparin anticoagulation can be achieved when necessary to acutely treat a thrombotic event. More importantly, AT-III deficiency is the only inherited hypercoagulable disorder for which replacement therapy, comprising concentrates of purified human AT-III, has been approved by the FDA. The concentrates are pasteurized for viral inactivation (115,155). Perioperative replacement therapy with AT-III concentrate is recommended, because 17% to 24% of AT-III–deficient patients undergoing surgery without receiving concentrates develop deep venous thrombosis, even when other forms of prophylaxis are used (52,53,156,157). Despite the commercial availability of the concentrates in the United States since 1990, clinical experience with their perioperative use in

conjunction with anticoagulation has been limited. Successful perioperative use of AT-III concentrates for venous surgery in deficient patients has been described (158).

Hyperhomocysteinemia Homocysteine is an amino acid formed in the metabolism of methionine. Elevated plasma levels of homocysteine can result when there is a deficiency in either one of two enzymes that are involved in cysteine metabolism. A deficiency of cystathione b-synthase prevents adequate transsulfuration of homocysteine. A deficiency of methylenetetrahydrofolate reductase (MTHFR) prevents remethylation of homocysteine to methionine. A number of studies have linked elevated plasma homocysteine levels to an increased risk of premature atherosclerosis and thrombosis (159–166). In the past, much ambiguity has resulted when studies using plasma homocysteine levels as an end point have shown conflicting results regarding the association of homocysteine levels and atherosclerotic risk (167). Recent work has identified a common point mutation in the gene coding for the MTHFR enzyme rendering it thermolabile, resulting in elevated plasma homocysteine levels (168–170). Both homozygotes and heterozygotes have diminished enzyme activity compared to normal, at 30% and 65%, respectively (171). The genomic region of DNA can be amplified using the polymerase chain reaction and then subjected to restriction enzyme analysis, so that genotype can be definitively determined. Populations of Northern European descent have a high prevalence of this mutation, with approximately 10% homozygosity and 40% heterozygosity. It appears that dietary supplementation with folic acid can reduce plasma homocysteine levels in both heterozygotes and homozygotes, which promises a simple and effective therapy for this disorder (170,171). Future studies using these molecular techniques should yield additional insight regarding the role of hyperhomocysteinemia in atherosclerosis and thrombosis, as well as for the potential role of folic acid as a therapeutic agent.

ACQUIRED HYPERCOAGULABLE DISORDERS Antiphospholipid Antibody Syndrome Lupus anticoagulants are antiphospholipid antibodies that have in vitro anticoagulant activity, yet are clinically associated with arterial and venous thrombosis. The constellation of any one of the following clinical manifestations (arterial or venous thrombosis, recurrent abortion, or thrombocytopenia) in the presence of antiphospholid antibodies has been described as the antiphospholipid syndrome (172). When the syndrome occurs in the absence of lupus or other connective tissue disorders, it is referred to as primary antiphospholipid syndrome, and secondary antiphospholipid antibody syndrome when in the presence of lupus or other connective tissue disorders. Drugs such as procainamide, hydralazine, chlorpromazine, quinidine, isoniazid, and methyldopa can also cause antiphospholipid antibodies, with procainamide being most common in the United States (172). When the condition is drug associated, however, there does not appear to be a significant thrombotic risk. The pathogenesis of thrombosis with antiphospholipid antibodies is not completely understood. Proposed mechanisms include platelet activation, inhibition of prostacyclin production, vascular injury, and interference with protein C (172). Alternatively, it is possible that antiphospholipid antibodies are a marker for some other process that is more closely linked with thrombosis. The almost equal tendency for arterial and venous thrombosis with

Chapter 7:

antiphospholipid syndrome distinguishes this disorder from the inherited hypercoagulable conditions where venous thrombosis predominates. Several enzyme-linked immunosorbent assays (ELISAs) for immunoglobulin G (IgG) and immunoglobulin M (IgM) antiphospholipid antibodies are now commercially available and have been standardized (173). The diagnosis of antiphospholipid antibody syndrome can only be confirmed after appropriate laboratory testing on two separate occasions separated by at least 12 weeks (142,174,175). Patients who develop thrombotic complications are generally treated with long-term anticoagulation. Treatment regimens when associated with cerebrovascular thrombosis can also include antiplatelet agents and steroids, although this has not been standardized (172).

HIT (With or Without Thrombosis) Heparin-induced thrombocytopenia (HIT) with or without thrombosis, first recognized in 1973 (176), is associated with morbidity and mortality especially in patients with atherosclerosis, sepsis, and recent surgery (177–179). Recent studies have documented that patients with HIT have antibodies that are directed against complexes of heparin and the heparin-binding cationic protein, PF4, which is secreted from platelet 8 granules and then is bound to platelet and endothelial cell surfaces (180,181). The major factor in the development of HIT (with or without thrombosis) is the formation of antibodies, usually of IgG isotope against the heparin/PF4 complex, which may be localized to the platelet FcgIIa membrane receptor or to other phospholipid surfaces such as heparin sulfates on the endothelial cells. Binding of these antibodies to the complex of heparin and PF4 allows the Fc portion of the IgG molecule to activate platelets through the platelet FcgIIa, which can activate platelet and generate procoagulant membrane microparticles (Fig. 6) (180,181,183–185). Receptor expression can be elevated threefold to fivefold during sepsis or other acute illnesses and returns to normal as the inflammatory process resolves (186). Patients with high levels of receptor expression appear to have the most severe forms of thrombosis with HIT (186). This

Hemostasis and Thrombosis in the Surgical Patient

169

process then initiates thrombosis, which is characteristically rich in platelets, hence the name ‘‘white clot syndrome.’’ Similar to heparin, thrombocytopenia induced from sulfonamides and quinidine cause thrombocytopenia by interacting with the GPIb/IIa and GPIIb/IIIa platelet membrane receptors (180,181,184,187,188). The standard diagnostic test for HIT in most laboratories is the platelet-aggregation test. Although this test is simple and quickly performed, its sensitivity has been questioned. Depending on the reactivity to donor platelets and heparin concentration used in the aggregation test, the sensitivity can range from 29% to 88% (184,189). A more sensitive test appears to be the 14C serotonin release assay (184,190,191). In this test, the release of 14C serotonin from the platelets is measured, rather than the ability of platelets to aggregate, because immune complexes can induce release without causing aggregation. Several laboratories have now developed ELISAs that use heparin/PF4 to detect IgG or IgM antibodies in sera from patients suspected of having HIT (184,192,193). The ELISA for the detection of antiheparin/PF4 antibodies appears to be more sensitive than the 14C serotonin release assay and the platelet aggregation test and has been used clinically to document heparininduced antibodies (184,185). The clinical management of HIT poses many dilemmas, particularly when continued anticoagulation is necessary or desired. Although heparin must be discontinued, few alternatives are readily available. Ideal agents are thrombin-specific inhibitors such as argatroban, hirudin, leprudin, or its analogs. Hirudin is a 65 amino acid polypeptide produced by the salivary gland of the medicinal leech Hirudo medicinalis. Hirudin is the most potent naturally occurring specific inhibitor of thrombin (194–197). Hirudin binds to thrombin at both the N-terminal domain and the C-terminal domain. Natural hirudin, synthetic analogue hirulog, and the recombinant hirudin all contain both of these binding sites. The major indication for leprudin therapy is for the treatment of patients with acute HIT (194–197). Argatroban has also been used successfully as an alternate anticoagulant in patients with HIT. Lowmolecular-weight heparin (LMWH) is now available and

Figure 6 Proposed mechanisms by which heparininduced thrombocytopenia with or without thrombosis occurs. Platelets are activated by thrombin or other agonists and release PF4 from their a-granules. PF4 complexes with heparin on the surface of the platelet. The complex is immunogenic and induces the formation of both IgC and IgM antibodies. The Fc portion of IgG antibodies binds to FcII receptors on platelets and induces further activation and throbocytopenia. FcII receptors are increased by IL-6 and are therefore upregulated in patients with ongoing inflammation. PF4 released from platelets can also bind to heparin sulfate on endothelial cells. IgG or IgM antibodies directed against this complex may cause endothelial cell damage and promote venous or arterial thrombosis. Abbreviations: PF4, platelet factor 4; Ig, immunoglobulin; IL, interleukin. Source: From Ref. 182.

medwedi.ru

170

Part One: General Considerations

seems to be less immunogenic than unfractionated heparin. However, 90% of patients with HIT have antibodies that cross-react with LMWH (196,198), making this a poor alternative when continued anticoagulation is necessary. Heparinoid has been used successfully on a compassionate basis to treat HIT (199). Success has also been reported with the use of ancrod, a rapid-acting defibrinating agent. In patients who have venous thromboembolism as a complication of heparin therapy, placement of a Greenfield filter, thrombolytic therapy, and warfarin treatment is useful. In the absence of alternative parenteral anticoagulants, heparin can be considered for use in the HIT patient but only after repeat test results for the antibody are negative. Heparin has been given successfully to patients with a history of HIT and thrombosis who required cardiac bypass (200). In these patients, the interval between the initial and second exposure has usually been one to two months, and heparin has been administered only during surgery, either alone or in the presence of antiplatelet agents such as aspirin. In those situations where heparin absolutely cannot be used, argatroban or heparinoid should be considered under compassionate use.

Malignancy The incidence of thrombosis in patients with malignancy generally ranges between 5% and 15%, but may be as high as 50% with some tumors, notably pancreatic carcinoma (201–206). The highest incidence of thrombotic manifestations is found in patients with acute promyelocytic leukemia, myeloproliferative disorders, primary brain tumors, and mucin-secreting adenocarcinomas of the pancreas, gastrointestinal tract, lung, and ovary. Episodes of thrombosis, particularly migratory superficial thrombophlebitis, may antedate by months the clinical diagnosis of cancer in some patients and may be the first indication of an underlying malignancy. In addition to venous thrombosis, arterial thromboembolism from nonbacterial thrombotic endocarditis may occur. Multiple coagulation abnormalities predisposing to thrombosis have been identified in patients with malignancy. These include thrombocytosis, shortening of the PT and aPTTs, elevation of plasma coagulation factors (fibrinogen, factors V, VIII, IX, and XI), and fibrinogen–fibrin degradation products, shortened platelet survival, decreased AT-III levels, and increased PAI-1 activity. Many of these changes reflect generalized activation of the clotting system resulting in chronic, partially compensated DIC. In addition, macrophages and endothelial cells stimulated by tumor cytokines can express tissue factor. Cytotoxic chemotherapy can also cause the release of thromboplastic substances from tumor cells. In some cases, the chemotherapeutic agents themselves may contribute to thrombosis (201–206).

ANTITHROMBOTIC THERAPY General Considerations Because of its dependency on coagulation reactions resulting in fibrin formation, venous thrombosis is best treated with the anticoagulants heparin and warfarin. Heparin, heparin-like compounds, and warfarin, given in small doses, prevent the onset of venous thrombosis and can therefore be used successfully as prophylaxis of postoperative deep venous thrombosis in high-risk surgical patients. Agents that are pure inhibitors of platelet function, such as aspirin, are much less successful in prophylaxis of

postoperative venous thrombosis. Methods that prevent venous pooling and stasis of blood in the lower extremities are also beneficial in preventing deep vein thrombosis; augmentation of venous emptying by application of intermittent pneumatic compression boots is as effective as anticoagulants (207–211). In addition to preventing the onset of venous thrombosis, anticoagulants inhibit the growth, propagation, and embolization of established thrombi (207–212). In doing so, these agents are the mainstay of therapy for patients with active venous thrombosis in those who are at risk for pulmonary embolism. Aspirin and other antiplatelet agents are not effective in the treatment of active venous thrombosis. Intracardiac thromboemboli are also responsive to anticoagulant therapy. These thrombi are fibrin rich and form under the relatively static flow conditions of dilated chambers, obstructed valve orifices, areas of low shear associated with prosthetic valves, ventricular aneurysm formation, and poor pumping action with impaired chamber emptying secondary to cardiac failure of dysrhythmia. Acute treatment with heparin and long-term treatment with warfarin reduce the incidence of symptomatic emboli stemming from intracardiac thrombi. Antiplatelet agents are effective in preventing thrombogenesis in areas of high shear and disturbed flow in the arterial circulation; this most commonly involves the surface irregularity or stenoses caused by atherosclerotic plaque. Aspirin is the antiplatelet agent in widest use and has been found to be effective in preventing myocardial infarction in patients with unstable angina and stable coronary disease (213); stroke and transient ischemic attacks in patients with cerebral vascular arteriosclerosis, or after carotid endarterectomy; vein graft thrombosis after coronary artery bypass; and prosthetic bypass thrombosis in patients with femoropopliteal reconstruction. Dipyridamole, a pyrimiopyrimidine compound with vasodilator properties, was introduced for the treatment of angina in 1961. The mechanism of action for dipyridamole is not clear. It inhibits phosphodiesterase and could increase platelet cAMP to levels that could inhibit platelet aggregation (214–216). Dypridiamole has often been combined with aspirin and had generally been found to be ineffective in rigorous clinical trials. There is no indication to use this drug, alone or in combination with aspirin, to prevent arterial thrombosis. Although aspirin retards platelet thrombogenesis on the surface of atherosclerotic plaque, there is no evidence that it prevents plaque formation. Ticlopidine and clopidogrel are structurally related thienopyridine derivatives that inhibit ADP-induced platelet aggregation (217–224). After oral administration both drugs inhibit ADP-induced platelet aggregation, even at high concentrations of agonist (217–231). Both drugs are effective in preventing platelet-dependent arterial thromboembolism. In a randomized secondary prevention trial clopidogel versus aspirin in patients at risk of ischemic events (CAPRIE) (232,233), patients were enrolled with a recent history of myocardial infarction, ischemic stroke, or symptomatic peripheral vascular disease. After a mean follow-up of 1.9 years, aspirin decreased vascular outcome events by 5.83% and clopidogrel decreased ischemic events by 5.32% (relative risk reduction of 8.7%, P ¼ 0.043) (232). Fibrinolytic agents include streptokinase, recombinant t-PA, and urokinase; all act by accelerating the conversion of plasminogen to plasmin. These substances can be given systemically or regionally by means of selective infusion through an intra-arterial catheter, and have been found to

Chapter 7:

be most effective in treating patients with acute myocardial infarction. Clinical trials have demonstrated a reduction in infarct size, preservation of ventricular function, and a reduction in mortality. Clinical benefit has been noted less consistently in venous thromboembolism, acute stroke, arterial bypass graft, peripheral arterial bypass graft thrombosis, and peripheral arterial thrombosis. Because fibrinolytic agents dissolve hemostatic clots along with pathologic clots, they are associated with a much higher incidence of bleeding complications than anticoagulants.

THERAPEUTIC AGENTS Anticoagulants Heparin Heparin is a highly sulfated glycosaminoglycan that exhibits an anticoagulant effect through its interaction with AT-III, which then inhibits thrombin and the activated forms of factors XII, XI, X, and IX. The anticoagulant effect of heparin was first described in 1922 and so named because of its hepatic derivation (234). Mast cell synthesis of heparin results in many structurally diverse polysaccharide chains and variable degrees of sulfation (235). Commercially prepared heparin is a heterogeneous mixture of heparin chains and is obtained from porcine intestinal mucosa or bovine lung. Heparin is not absorbed orally and must be administered parenterally or subcutaneously. Heparin action is immediate following intravenous administration and is delayed 20 to 60 minutes after subcutaneous administration. Following intravenous administration, the average half-life is about 90 minutes and can range from 30 to 360 minutes. Clearance is primarily hepatic, with a small potion excreted intact by the kidneys. Recommended dosing uses an initial intravenous bolus (75 U/kg) to ensure rapid anticoagulation, followed by continuous intravenous infusion (10–25 U/kg/hr). Heparin does not cross the placenta and is considered the drug of choice for long-term anticoagulation during pregnancy. Monitoring of heparin administration is most commonly performed using the aPTT. For active thrombosis (venous or arterial), a range of 1.5 to 2.5 times the normal control value is considered therapeutic. Caution is advised when following therapeutic nomograms and algorithms because of the variability of heparin products and individual response. The aPTT should be checked every four to six hours until a steady state infusion dose can be determined. The most common complication of heparin use is bleeding, the incidence of which ranges from 1% to 7% with continuous infusion and from 8% to 14% with intermittent bolus. Heparin can be reversed using protamine sulfate. One milligram of protamine sulfate neutralizes 100 U of heparin. Another significant potential complication is HIT, with or without thrombosis, which was discussed in a previous section. Other complications include osteoporosis from prolonged heparin use and, rarely, allergic reactions.

Warfarin Warfarin is a vitamin K antagonist that exerts its anticoagulant effect through inhibition of synthesis of the vitamin K–dependent factors, prothrombin (II), VII, IX, and X. The name warfarin is an acronym for the patent holder, Wisconsin Alumni Research Foundation, and ‘‘arin’’ for the chemical structure of the 4-hydroxycoumarin ring. Warfarin inhibits the vitamin K–dependent ribosomal

Hemostasis and Thrombosis in the Surgical Patient

171

posttranslational modification of the precursor proteins of the affected clotting factors and proteins C and S. Under normal circumstances, 10 or more glutamic acid residues near the amino-terminus of each precursor protein must be carboxylated, resulting in the formation of the unique amino acid g-carboxyglutamate, which allows the clotting factor proteins to bind calcium during the coagulation cascade (Fig. 7) (235). Warfarin induces hepatic production of partially carboxylated and decarboxylated proteins. Prothrombin molecules with fewer than six g-carboxyglutamic acid residues have markedly reduced activity. Warfarin action is not immediate, because it has no effect on the existing circulating factors. Plasma warfarin is 98% to 99% protein bound to albumin. It is the remaining 1% to 2% free warfarin that exerts the anticoagulant effect. Metabolized warfarin is excreted in the bile, with a plasma half-life that ranges from 20 to 60 hours. Warfarin is administered orally, where it is more than 95% absorbed through the gastrointestinal tract. Dosage is generally initiated at 5 to 10 mg/day until a steady state is reached, at which time a lower dose can be maintained. Monitoring of warfarin therapy has presented problems because of the significant variability in activity of the numerous available thromboplastins available for PT measurement. This problem with nonstandardized thromboplastins is a particular issue in North America. So that warfarin dosage can be standardized in the presence of the many thromboplastins used in the PT, most laboratories report PTresults as the International Normalized Ratio (INR). The system is based on a standardized thromboplastin

Figure 7 Vitamin K metabolism and the mechanism of action of warfarin. Vitamin KH2 serves as a cofactor for a vitamin K–dependent carboxylase that converts glutamic acid residues in precursor coagulation factors to g-carboxyglutamic acid residues. In addition to vitamin KH2, molecular oxygen and carbon dioxide are required. Vitamin KH2 is oxidized to vitamin K epoxide, KO, which is then converted to vitamin K by vitamin K epoxide reductase. Vitamin K reductase reduces vitamin K to its reduced form, vitamin KH2. Warfarin inhibits vitamin K epoxide reductase and, possibly, vitamin K reductase. The decrease in vitamin KH2 limits g-carboxylation of the vitamin K–dependent proteins and interferes with their function. Source: From Ref. 236.

medwedi.ru

172

Part One: General Considerations

preparation referred to as the World Health Organization primary international preparation of thromboplastin. This system has been accepted as an international standard for clinical use by most western countries. The INR is calculated as follows: INR ¼ (observed PT/control PT). ISI is the International Sensitivity Index and is a measure of the responsiveness of any given lot of a thromboplastin preparation to that of a standard thromboplastin. For most commercial thromboplastins used in North America, the ISI ranges from 2 to 2.8. The relationship between the PT ratio with different thromboplastins and the INR is illustrated with the nomogram in Fig. 8. The recommended therapeutic range of the INR for given clinical indications is listed in Table 5. Portable devices the size of a glucometer are available that can measure the PT and calculate the INR in seconds using a drop of whole blood. As with heparin, the major complication with warfarin is bleeding. The frequency of this complication can vary considerably and is likely related to the degree and duration of desired anticoagulation, underlying illness, concomitant medications, and patient compliance. The risk of major bleeding is generally in the range of 4% to 5% per treatment year, with major bleeding events occurring at 1% to 2% per year (235). Warfarin-induced skin necrosis can occur and is characterized by skin lesions similar to those of neonatal purpura fulminans. This condition is classically associated with homozygous protein C deficiency, as was previously discussed earlier in that section. Warfarin

Table 5 Effectiveness of Oral Anticoagulant Therapy Condition

Minimal effective

Recommended

a

INR Deep vein thrombosis Prevention Treatment Acute myocardial infarction Prevention of stroke Prevention of recurrence Reduction of mortality Atrial fibrillation Prevention of systemic embolism Cardiac valve replacement Tissue valves Mechanical valves Cerebral embolism Native valvular heart disease

1.5–2.5 2.0–2.3

2.0–3.0b 2.0–3.0

2.0 2.7–4.5 2.7–4.5

2.0–3.0 3.0–4.5b 3.0–4.5b

1.5–2.5

2.0–3.0b

2.0–2.3 1.9–3.6 Not evaluated Not evaluated

2.0–3.0 3.0–4.5

a

For thromboplastin with an ISI of 2.3 the INRs and the corresponding PT ratios follow: INR 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0. PT ratio 1.20, 1.35, 1.49, 1.61, 1.72, 1.83, 1.92, 2.01. b A lower range might be effective. Abbreviations: INR, International Normalized Ratio; PT, prothrombin time; ISI, International Sensitivity Index. Source: Adapted from Ref. 237.

crosses the placenta, where it can cause an embryopathy or fetal bleeding, and therefore should not be used during pregnancy.

Low-Molecular-Weight Heparin

Figure 8 Relation between the PT ratio and the INR for thromboplastin reagents over a range of ISI values. The example shown is for a PT ratio of 1.3 to 11.5 for a thromboplastin preparation with an ISI of 2.3. Abbreviations: INR, International Normalized Ratio; PT, prothrombin time; ISI, International Sensitivity Index. Source: From Ref. 237.

LMWH is produced by chemical or enzymatic depolymerization of heparin molecules and has a molecular weight of 3000 to 6000. Unlike heparin, neither LMWH nor heparinoid is fully reversed by protamine. The anticoagulant effect of LMWH is primarily directed against factor Xa. To neutralize thrombin, heparin must interact with and combine to both AT-III and thrombin (208–210,238). LMWH is unable to bind thrombin and AT-III simultaneously, and therefore cannot accelerate the inactivation of thrombin. The combination of LMWH and AT-III can, however, inactivate factor Xa. The LMWHs produce less prolongation of the aPTT than does standard heparin, because this clotting test depends more on the antithrombin effect than the antifactor Xa effect (238,239). There are several advantages of LMWH over conventional heparin. Bioavailability of LMWH is greater due to lack of binding of LMWH to plasma proteins and endothelial cells. Also, LMWH is not inactivated by P4, as is heparin. LMWH has a longer half-life and a more predictable dose response than heparin, allowing for more convenient outpatient treatment of venous thrombosis using a once- or twice-daily subcutaneous dosage. LMWH also appears to be less immunogenic than conventional heparin. In a recent prospective study of the incidence of HIT with unfractionated heparin and LMWH used as prophylaxis during hip surgery in 655 patients, HIT occurred in 2.7% of recipients of unfractionated heparin and in none of the patients receiving LMWH (240). However, as previously discussed, 90% of HIT patients have antibodies that cross-react with LMWH, making this a poor alternative when continued anticoagulation is necessary in patients with an established diagnosis of HIT.

Chapter 7:

Hemostasis and Thrombosis in the Surgical Patient

173

Heparinoid

Ancrod

Heparinoids are nonheparin glycosaminoglycans obtained as a by-product of heparin production from porcine intestinal mucosa (241). The anticoagulant effect of heparinoid is directed primarily against factor Xa. Heparinoid is composed of a mixture of dermatan, heparin, and chondroitin sulfates; heparinoid has a very low degree of sulfation and a reduced molecular weight compared to unfractionated heparin. Heparinoid is less likely to bind to platelets (199,241) or to be immunogenic. In the United States, heparinoid has been obtained for compassionate use from Organon, Inc., in West Orange, New Jersey, U.S.A. Because heparinoid contains a small amount of heparin-like substance that would have the capacity to cause HIT, a test for antibody cross-reactivity should be done before substitution of the heparinoid for heparin (198,199). In a recent review of 230 patients who received heparinoid for HIT, 93% of the recipients were judged to have responded in a satisfactory manner (198,199). Only 10% of the sera obtained from patients with HIT showed cross-reactivity with heparinoid, whereas 90% showed cross-reactivity with LMWH.

Another antithrombotic strategy is to deplete fibrinogen concentration and thus impair fibrin formation. This may be achieved by using a number of snake venom enzymes of which only ancrod (extracted from the Malayan pit viper, Agkistrodon rhodostoma) has been used clinically. Ancrod cleaves fibrinopeptide A, but not fibrinopeptide B, from fibrinogen to produce fibrin that is very sensitive to endogenous fibrinolysis. The fibrin formed by the action of ancrod is deposited in the microcirculation, where it is rapidly lysed by endothelial fibrinolytic mechanisms. Ancrod may be given intravenously, subcutaneously, or intramuscularly. Within hours, marked defibrination occurs and is accompanied by a delayed but striking rise in fibrinogen–fibrin degradation products. Hypofibrinogenemia is sustained by daily administration; however, resistance develops because of the elaboration of neutralizing antibodies when repeated injections are given. A potentially important indication for ancrod use may be HIT, for which there is no established treatment at present.

Argatroban Argatroban, a synthetic derivative of L-Arg, is a reversible, direct thrombin inhibitor with a half-life of approximately 20 to 25 minutes. There is no antidote for argatroban. In a phase I trial, argatroban was shown to prolong the aPTT and thrombin time in a dose-dependent fashion (242). In a more recent phase I dose-ranging clinical trial, argatroban was administered to patients with unstable angina (243). Although there were no significant bleeding complications, there was a rebound effect with recurrence of angina following cessation of argatroban. Argatroban has been used successfully as an alternative anticoagulant in patients with HIT, and its use for this indication is currently under investigation (244). Given its short half-life and direct thrombin inhibition, its potential as an alternative to heparin in patients with HIT is encouraging.

Hirudin and Its Analogs Hirudin is an anticoagulant derived from the saliva of the medicinal leech and directly inhibits thrombin. Interest in hirudin as an anticoagulant has increased since its gene was cloned in 1986 with subsequent production by recombinant techniques (181,195,196,245–247). Hirulog is a 20-amino acid polypeptide that consists of three components: an inhibitor of the active site of thrombin, an inhibitor of the fibrinogenbinding site, and a polyglycine spacer that links the other two segments. In normal human volunteers, hirulog has a half-life of 36 minutes. There is no known inhibitor for use as an antidote for hirudin or hirulog. Unlike the heparin/ AT-III complex, hirudin and hirulog inhibit clot-bound thrombin (181,195,196,248) and do not induce thrombocytopenia. The anticoagulant effects and safety of hirulog have been studied in healthy human volunteers (249). There were no significant bleeding complications. No antihirulog antibodies were noted at 7 and 14 days. In addition to use in animal thrombosis models (250,251), hirulog is being tested in clinical trials and has been used successfully in 291 patients undergoing elective coronary angioplasty (252). Hirulog has been used successfully as an anticoagulant in an animal model of carotid endarterectomy in a dose that allowed inhibition of fibrin deposition without significant bleeding (195,196,253). Hirudin has been used as an anticoagulant during coronary artery bypass surgery (195,196,254).

Antiplatelet Agents Aspirin Aspirin acts by acetylating and inhibiting platelet cyclooxygenase, the enzyme that converts arachidonic acid to the endoperoxide intermediates prostaglandin G2 and H2 (8,255). This process inhibits formation of thromboxane A2, and because platelets are anucleate and incapable of replenishing cyclooxygenase, platelets exposed to aspirin are permanently affected. Because of differential effects on platelets and endothelial cells (platelets being more sensitive), a great deal of effort has been devoted to finding the lowest possible dose of aspirin that inhibits platelet thromboxane A2 production and that allows endothelial PTI2 synthesis to continue. There appears to be no difference in the antiplatelet effectiveness between high- and low-dose aspirin (256). A dose as low as 40 mg daily completely inhibits cyclooxygenase activity and has been shown to reduce the incidence of fatal and nonfatal myocardial infarction in patients with unstable angina (257). Whether this dose provides adequate antiplatelet activity in all patients and for a wide spectrum of indications, however, remains uncertain. Another advantage of a lower aspirin dose appears to be less gastrointestinal bleeding, although this advantage might be realized with enteric-coated preparations. Aspirin is rapidly absorbed in the stomach and upper intestine, with peak plasma levels occurring 15 to 20 minutes after ingestion. Absorption from enteric-coated tablets may be delayed; however, reliable and sustained antiplatelet effects are observed after multiple daily doses of such tablets (258). Although aspirin is moderately effective in preventing arterial thromboembolic complications, it is not helpful in halting the progression of atherosclerosis and the development of intimal hyperplasia (259). Aspirin does not prevent platelet adhesion to collagen and subendothelial vWF, and it does not inhibit a-granule secretion in response to platelet agonists (260). Therefore release of growth factors from the a-granule, such as PGDF and transforming growth factor-b, are unaffected by cyclooxygenase inhibitors.

Ticlopidine and Clopidogrel Ticlopidine and clopidogrel inhibit platelet aggregation by altering the platelet membrane and interfering with the membrane–fibrinogen interaction, thereby blocking the

medwedi.ru

174

Part One: General Considerations

platelet GPIIv/IIIa receptor (261). Unlike aspirin, ticlopidine and clopidogrel do not interfere with the cyclooxygenase pathway. The antiplatelet effect of ticlopidine is maximal at 24 to 48 hours and is not reversible. It prolongs the bleeding time and has no effect on coagulation assays. In trials studying cerebrovascular disease, ticlopidine appears to be marginally superior to aspirin in preventing stroke and transient ischemic attacks (262,263). The use of ticlopidine during coronary artery stenting appears to be associated with fewer thrombotic complications than aspirin (264). The only known serious adverse effect of ticlopidine appears to be neutropenia, which occurs in less than 1% of patients taking the drug. This condition appears during the first months of therapy and reverses when the drug is discontinued. It is therefore recommended that white blood cell counts be monitored during the first months of treatment. Other adverse effects include diarrhea and skin rash, which may occur in up to 20% of patients. Because of these side effects, a ticlopidine analog, clopidogrel, is being developed. Clopidogrel is administered in doses of 50 to 100 mg daily and reaches a steady state inhibition of ADP-induced aggregation in four to seven days. A major advantage of clopidogrel over ticlopidine is the relative infrequent occurrence of serious side effects (232,233). As mentioned previously, the result of the CAPRIE trials show a significant decrease in atherosclerotic ischemic events in patients treated with clopidogrel when compared to aspirin in patients treated for secondary risk reduction following ischemic atherosclerotic events (232,233).

Dextran Dextran is a polysaccharide that is hydrolyzed and fractionated into polymers of variable molecular weight. The preparations most commonly used as an antiplatelet agent has an average molecular mass of 40,000 kDa (dextran 40). Although the drug was first used as a volume expander, it was subsequently found to have an effect on hemostasis and thrombosis. The principal antithrombotic properties are antiplatelet activity through the reduction of plasma vWF and resulting in a mild defect in platelet adhesion, defective fibrin polymerization and increased clot lysis, and increased blood flow through volume expansion (265,266). Dextran has been shown to be useful in the prevention of venous thromboembolism, but is rarely used for this purpose because it must be administered intravenously and its use is cumbersome (267,268). The use of dextran 40 has also been shown to improve early patency following infrainguinal arterial reconstruction (269). Adverse reactions include pulmonary edema from volume expansion, allergic reactions, and rarely anaphylactic reactions.

c7E3 Fab A new class of potent antiplatelet agents inhibit platelet aggregation by binding the GPIIb/IIIa fibrinogen receptor, causing a defect similar to that found in Glanzmann’s thrombasthenia (16,17,19). One of the most promising of such agents is a monoclonal fragment antigen-binding (Fab) fragment of an IgG antibody, chimeric 7E3 (c7E3), that contains the mouse variable regions and the human constant regions (270). The generic name of c7E3 is abciximab and the trade name is ReoPro. Platelet aggregation is profoundly inhibited by c7E3, both in vitro and in vivo (271). In a study evaluating c7E3 with aspirin and heparin during high-risk coronary angioplasty, there was a significant decrease in thrombotic events compared to the use

of aspirin and heparin alone (272). Patients treated with c7E3 had a twofold increase in bleeding complications, but no increase in cerebral hemorrhage or bleeding-related mortality. Antibody formation against the murine component of c7E3 occurred in 6.5%, but there were no allergic or anaphylactic reactions. The FDA has approved c7E3 for use during high-risk coronary angioplasty and atherectomy. The activating clotting time is prolonged with the use of c7E3 (273), and specific assays to monitor dosage are being developed. The results of additional trials defining the optimal dosage of heparin when administered with c7E3 and evaluating the role of c7E3 in the treatment of other thrombotic disorders are eagerly awaited (274).

SUMMARY Because increasing numbers of routine and complex operations are being performed on patients who have diseases that alter hemostasis, the frequency of abnormal bleeding in surgical patients can be expected to increase. Knowledge of the physiologic principles underlying hemostasis and of derangements that precipitate bleeding is important in modern surgical care. Hemostasis depends on interactions among circulating proteins (coagulation factors and inhibitors), cellular elements (platelets and white blood cells), and vascular endothelium and smooth muscle. In the early stages of hemostasis, platelets rapidly adhere and aggregate at the site of vascular injury and form a platelet plug that temporarily stops blood flow. At the same time, the intrinsic and extrinsic coagulation pathways reactivated, resulting in a fibrin network that fortifies the platelet plug and provides a frame for fibroblastic in-growth and ultimate healing of the injury. The hemostatic response is finely regulated to limit clotting to the site of injury and thereby to maintain vascular patency. Inhibitory mechanisms include the fibrinolytic system, plasma serine protease inhibitors (the most important of which is AT-III), and the antithrombotic properties and functions of endothelial cells. Derangements in hemostatic mechanisms can be both congenital and acquired. In surgical patients, acquired bleeding disorders are far more common than congenital ones. To diagnose and treat such disorders adequately, preoperative assessment of hemostatic competence is mandatory in all surgical problems. The keystone to preoperative evaluation for all bleeding disorders is through history and physical examination.

REFERENCES 1. Mazur EM, et al. Human serum megakaryocyte colonystimulating activity appears to be distinct from interleuken-3, granulocytemacrophage colony-stimulating factor, and lymphocyte-conditioned medium. Blood 1990; 76:290. 2. Gewirtz AM, et al. Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOHterminal PF4 peptide. J Clin Invest 1989; 83:1477. 3. Mitjavila MT, et al. Human platelet alpha granules contain a nonspecific inhibitor of megakaryocyte colony formation: its relationship to type b transforming growth factor (TGF-b). J Cell Physiol 1988; 134:93. 4. Chott A, et al. Interferon-alpha-induced morphologic changes of megakaryocytes: a histomorphometrical study on bone marrow biopsies in chronic myeloproliferative disorders with excessive thrombocytosis. Br J Haematol 1990; 74:10.

Chapter 7: 5. Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood 1995; 86:419. 6. Schor K. Antithrombotic drugs in vascular medicine: a historical perspective. Semin Vasc Med 2003; 3(2):97–106. 7. Scharf RE. Congenital and acquired platelet function disorders. Hamostaseologie 2003; 23(4):170–180. 8. Wu KK. Aspirin and other cyclooxygenase inhibitors: new therapeutic insights. Semin Vasc Med 2003; 3(2):107–112. 9. Clagett GP Jr. Occlusive disease: thrombosis. In: Greenfield LJ, et al., eds. Surgery: Scientific Principles and Practice. 2nd ed. Philadelphia: Lippincott-Raven, 1997:1612. 10. Hawiger J, Brass LF, Salzman EW. Signal transduction and intracellular regulatory processes in platelets. In: Coleman RW et al., eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: JB Lippincott, 1994:603. 11. Nurden AT, Nurden, P. GPIIb/IIIa antagonists and other antiintegrins. Semin Vasc Med 2003; 3(2):123–130. 12. Fullard JF. The role of the platelet glycoprotein IIb/IIIa in thrombosis and haemostasis. Curr Pharm Des 2004; 10(14): 1567–1576. 13. Ruan C. Molecular diagnosis of von Willebrand disease. Int J Hematol 2002; 76(suppl 2):145–148. 14. Schlammadinger A, Boda Z. Laboratory screening and diagnosis of von Willebrand’s disease. Clin Lab 2002; 48(7–8): 385–393. 15. Hemostasis and thrombosis: I. Hemostasis. In: Lessin LS, et al., eds. Medical Knowledge Self-Assessment Program in the Subspecialty of Hematology. Philadelphia: American College of Physicians, 1994:194. 16. Steinhuble SR, Moliterno DJ. The role of the platelet in the pathogenesis of atherothrombosis. Am J Cardiovasc Drugs 2005; 5(6):399–408. 17. Andrews RK, Berndt MC. Platelet physiology and thrombosis [review]. Thromb Res 2004; 114(5–6):447–453. 18. Bellucci S, Caen J. Molecular basis of Glanzmann’s Thrombasthenia and current strategies in treatment. Blood Rev 2002; 16(3):193–202. 19. Seligsohn U. Glanzmann thrombasthenia: a model disease which paved the way to powerful therapeutic agents. Pathophysiol Haemost Thromb 2002; 32(5–6):216–217. 20. Walsh PN. Platelet-coagulant protein interactions. In: Coleman RW, et al., eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: JB Lippincott, 1994:629. 21. Weiss HJ, et al. Evidence for the presence of tissue factor activity on subendothelium. Blood 1989; 73:968. 22. Rapaport SI, Rao LVM. The tissue factor pathway: how it has become a ‘‘prima ballerina.’’ Thromb Haemost 1995; 74:7. 23. Price GC, Thompason SA, Kam, PC. Tissue factor and tissue factor pathway inhibitor. Anaesthesia 2004; 59(5):483–492. 24. Bauer KA, et al. Detection of factor X activation in humans. Blood 1989; 74:2007. 25. Bauer KA, et al. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990; 76:751. 26. Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70:343. 27. DiCera E. Thrombin interactions. Chest 2003; 124(3 suppl): 11S–17S. 28. Wu KK, Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annu Rev Med 1996; 47:315. 29. Aierd WC. Endothelium as an organ system. Crit Care Med 2004; 32(5 suppl):S271–S279. 30. Hurairah H, Ferro A. The role of the endothelium in the control of vascular function. Int J Clin Pract 2004; 58(2):173–183. 31. Michiels C. Endothelial cell functions. J Cell Physiol 2003; 196(3):430–443. 32. Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation 2004; 109 (21 suppl 1):1127–1133.

Hemostasis and Thrombosis in the Surgical Patient

175

33. Triggle CR, Hollenberg M, Anderson TJ, et al. The endothelium in health and disease—a target for therapeutic intervention. J Smooth Muscle Res 2003; 39(6):249–267. 34. Marcus AJ, Safier LB. Thromboregulation: multicellular modulation of platelet reactivity in hemostasis and thrombosis. FASEB J 1993; 7:516. 35. Marcus AJ. Platelets: their role in hemostasis, thrombosis, and inflammation. In: Gallin JI, Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates. Philadelphia: Lippincott Williams & Williams, 1999:77. 36. Hamberg M, Svensson J, Samuelesson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 1975; 72:2994. 37. Piper PJ, Vane JR. Release of additional factors in anaphylaxis and its antagonism by antiinflammatory drugs. Nature 1969; 223:29. 38. Moncada S, Gryglewski R, Bunting, S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 1976; 263:29. 39. Whittaker N, Bunting S, Salmon J, et al. The chemical structure of prostaglandin X (prostacyclin). Prostaglandins 1976; 12:915. 40. Maclouf J, Folco G, Patrono C. Eicosanoids and isosicosanoids: constitutive, inducible and transcellular biosynthesis in vascular disease. Thromb Haemost 1998; 79:691. 41. Herschman HR. Prostaglandin synthase 2. Biochem Biophys Acta 1996; 1299:125. 42. Marletta MA. Nitric oxide synthase structure and mechanism. J Biol Chem 1993; 268:12231. 43. Moncada S, Higgs EA. Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J 1995; 9:1319. 44. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharamacology. Pharmacol Rev 1991; 43:109. 45. Wam-Cramer BJ, et al. Modifications of the extrinsic pathway inhibitor (EPI) and factor Xa that affect their ability to interact and to inhibit factor VIIa/tissue factor: evidence for a twostep model of inhibition. Thromb Haemost 1988; 60:453. 46. Sandset PM, Abilegaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 40:803. 47. Broze GJ. Tissue factor pathway inhibitor and the revised theory of coagulation. Annu Rev Med 1995; 46:103. 48. Bajaj MS, Bajai SP. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost 1997; 78:471. 49. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 1996; 93:10212. 50. Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. Hematol Oncol Clin North Am 2003; 17(1):9–36. 51. Van Cott EM, Soderberg BL, Laposata M. Hypercoagulability test strategies in the protein C and protein S pathway. Clin Lab Med 2002; 22(2):391–403. 52. Roemisch J, Gray E, Hoffman JN, Wiedermann CJ. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinol 2002; 13(8):657–670. 53. Witt I. Molecular biological basis and diagnosis of hereditary defect of antithrombin III, protein C and protein S. Hamostaseologie 2002; 22(2):14–24. 54. Bauer KA, Rosenberg RD. Role of antithrombin III as a regulator of in vivo coagulation. Semin Hematol 1991; 28:10. 55. Jordan RE, et al. The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J Biol Chem 1980; 255:10081. 56. Ouimet H, Loscalzo J. Fibrinolysis. In: Loscalzo J, Schafer AI, eds. Thrombosis and Hemorrhage. Boston: Blackwell Scientific Publications, 1994:127. 57. Preissner KT. Biochemistry and physiology of blood coagulation and fibrinolysis. Hamostaseologie 2004; 24(2):84–93.

medwedi.ru

176

Part One: General Considerations

58. Nesheim M. Thrombin and fibrinolysis. Chest 2003; 124 (3 suppl):33S–39S. 59. Aoki N. Natural inhibitors of fibrinolysis. Prog Cardiovasc Dis 1979; 21:267. 60. Rodeberg DA, et al. Nitric oxide: an overview. Am J Surg 1995; 170:292. 61. Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci 2004; 256:639–653. 62. Harrison DG, Cai H. Endothelial control of vasomotion and nitric oxide production. Cardiol Clin 2003; 21(3):289–302. 63. Vane J, Corin RE. Prostacyclin: a vascular mediator. Eur J Vasc Endovasc Surg 2003; 26(6):571–578. 64. Saenko EL, Ananyeva NM, Kouiavskaia DV. Haemophilia A: effects of inhibitory antibodies on factor VIII functional interactions and approaches to prevent their action. Haemophilia 2002; 8(1):1–11. 65. Hermann FH, Wulff K. Haemophilia A: effects of inhibitory antibodies on factor VIII functional interactions and approaches to prevent their action. Haemophilia 2002; 8(1):1–11. 66. Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev 2003; 17(suppl 1):S1–S5. 67. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69:454. 68. Cooney KA, Ginsburg D, Ruggeri ZM. Von Willebrand disease. In: Loscalzo J, Schafer Al, eds. Thrombosis and Hemorrhage. Boston: Blackwell Scientific Publications, 1994:657. 69. Foster PA. A perspective on the use of FVIII concentrates and cryoprecipitate prophylactically in surgery or therapeutically in severe bleeds in patients with von Willebrand disease unresponsive to DDAVP: results of an international survey. Thromb Haemost 1995; 74:1370. 70. Coller BS. Platelets and their disorders. In: Ratnoff OD, Forbes CD, eds. Disorders of Hemostasis. Orlando: Grune & Stratton, 1984:73. 71. Caen JP. Glanzmann’s thrombasthenia. Baillieres Clin Haematol 1989; 2:609. 72. Clemetson KJ, et al. Characterization of the platelet membrane glycoprotein abnormalities in Bernard-Soulier syndrome and comparison with normal by surface-labeling techniques and high-resolution two-dimensional gel electrophoresis. J Clin Invest 1982; 70:304. 73. Nurden AT, Nurden P. Inherited defects of platelet function. Rev Clin Exp Hematol 2001; 5(4):314–334. 74. Balduini CL, Iolascon A, Savoia A. Inherited thrombocytopenias: from genes to therapy. Haematologica 2002; 87(8): 860–880. 75. Kunishima S, Kamiya T, Saito H. Gentic abnormalities of Bernard-Soulier syndrome. Int J Hematol 2002; 76(4): 319–327. 76. Levi M, Jonge E, van der Poll T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann Med 2004; 36(1):41–49. 77. Fine NL, Applebaum J, Elguazabal A, Castleman L. Multiple coagulation defects in association with dissecting aneurysm. Arch Intern Med 1967; 119:522. 78. Fisher DL, Yawn DH, Cawford S. Preoperative disseminated intravascular coagulation associated with aortic aneurysm. Arch Surg 1983; 118:1252. 79. Bieger R, Vreeken J, Stibbe J, Loeliger EA. Arterial aneurysm as a cause of consumption coagulopathy. N Engl J Med 1971; 285:152. 80. Mulcare RJ, Royster TS, Phillips LL. Intravascular coagulation in surgical procedures on the abdominal aorta. Surg Gynecol Obstet 1976; 143:730. 81. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86:2839. 82. Cate JW X, Timmers H, Becker AE. Coagulopathy in ruptured or dissecting aortic aneurysm. Am J Med 1975; 59:171.

83. Aboulafia DM, Aboulafia ED. Aortic aneurysm-induced disseminated intravascular coagulation. Ann Vasc Surg 1996; 10:396. 84. Goto H, Kimoto A, Kawaguchi H, et al. Surgical treatment of abdominal aortic aneurysm complicated with chronic disseminated intravascular coagulopathy. J Cardiovasc Surg 1985; 26:280. 85. Spero JA, Lewis JH, Hasiba U. DIC: findings in 346 patients. Thromb Haemost 1980; 43:28. 86. Bick RL, Baker W. Diagnostic efficacy of the D-dimer assay in DIC and related isorders. Thromb Res 1992; 65:785. 87. Weksler BB, et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 1983; 308:800. 88. Goldman S, et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veteran’s Administration Cooperative Study. Circulation 1988; 77(6):1324. 89. Taggart DP, Siddiqui A, Wheatley DJ. Low-dose preoperative aspirin therapy, postoperative blood loss, and transfusion requirements. Ann Thorac Surg 1990; 50:424. 90. Ferraris VA, et al. Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting. Ann Thorac Surg 1988; 45:71. 91. Rajah SM, et al. Acetylsalicylic acid and dipyrimadole improve the early patency of aorta-coronary bypass grafts: a double-blind, placebo-controlled, randomized trial. J Thorac Cardiovasc Surg 1985; 90:373. 92. Karwande SV, et al. Effect of preoperative antiplatelet drugs on vascular prostacyclin synthesis. Ann Thorac Surg 1987; 43:318. 93. Steering Committee of the Physician’s Health Study Research Group. Final report of the aspirin component of the ongoing Physician’s Health Study. N Engl J Med 1989; 321:129. 94. Ferraris VA, Swanson E. Aspirin usage and perioperative blood loss in patients undergoing unexpected operations. Surg Gynecol Obstet 1983; 156:439. 95. Sattler FR, Weitekamp MR, Ballard JO. Potential for bleeding with the new beta-lactam antibiotics. Ann Intern Med 1986; 105:924. 96. Swattler FR, Weitekamp MR, Sayegh A, Ballard JO. Impaired hemostasis caused by beta-lactam antibiotics. Am J Surg 1988; 155(5A):30–39. 97. Pillgram-Larsen J, Wisloff F, Jorgensen JJ, et al. Effect of high dose ampicillin and cloxacillin on bleeding time and bleeding in open-heart surgery. Scand J Thorac Surg 1985; 19:45. 98. Fass RJ, Copelan EA, Brandt JT. Platelet-mediated bleeding caused by broad spectrum penicillins. J Infect Dis 1985; 155:1242. 99. Cazenave JP, Packman MA, Guccione MA, Mustard JF. Effects of peniciilin G on platelet aggregation, release and adherence to collagen. Proc Soc Exp Biol Med 1973; 142:159. 100. Shattil SJ, Bennet JS, McDonouigh M, Turnbull J. Carbenicillin and penicillin G inhibit platelet function in vitro by impairing the interaction of agonists with the platelet surface. J Clin Invest 1980; 65:329. 101. George JN, Shattil SJ. The clinical importance of acquired abnormalities of platelet function. N Engl J Med 1991; 324:27. 102. Coller BS. Platelet aggregation by ADP, collagen, and ristocetin: a critical review of methodology and analysis. In: Schmidt RM, ed. CRC Handbook Series in Clinical Laboratory Sciences. Section I: Hematology. Boca Raton: CRC Press, 1979:381. 103. George JN, Caen JP, Nurden AT. Glanzmann’s thrombasthenia: the spectrum of clinical disease. Blood 1990; 75:1383. 104. Lind SE. The bleeding time does not predict surgical bleeding. Blood 1991; 77:2547. 105. Rodgers RPC, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16:1. 106. Remuzzi G. Bleeding disorders in uremia: pathophysiology and treatment. Adv Nephrol 1989; 18:171. 107. Rao AK. Uremic platelets. Lancet 1986; 1:913. 108. Weigert AL, Schafer AI. Uremic bleeding: pathogenesis and therapy. Am J Med Sci 1998; 316:94.

Chapter 7: 109. Schetz MR. Coagulation disorders in acute renal failure. Kidney Int Suppl 1998; 66:S96–S101. 110. Weiss JH, Turrito VT, Baumgartner HR. Effect of shear rate in platelet interaction with subendothelium in citrated native blood: shear-dependent increase in adherence in von Willebrand’s disease and the Bernard Soulier syndrome. J Lab Clin Med 1978; 92:750. 111. Sakariassen KS, Bolhuis PA, Sixma JJ. Platelet adherence to subendothelium of human arteries in Pulsatile and steady flow. Thromb Res 1980; 19:547. 112. Remuzzi G, Benigni A, Dodesini P, et al. Reduced platelet thromboxane formation in uremia: evidence for a functional cyclooxygenase defect. J Clin Invest 1983; 71:762. 113. Winter M, Frampton G, Bennet A, Machin SJ, et al. Sytnesis of thromboxane B2 in uremia and the effects of dialysis. Thromb Res 1983; 30:265. 114. Bloom A, Greaves M, Preston FE, Brown CB. Evidence against a platelet cyclooxygenase defect in uremic patients on chronic hemodialysis. Br J Haematol 1986; 62:143. 115. Eknoyan G, Brown CH. Biochemical abnormalities of platelets in renal failure: evidence for decreased platelet serotonin, adenosine diphosphate and Mg-dependent adenosine triphosphate. Am J Nephrol 1981; 1:17. 116. Vlachoyannis J, Schoeppe W. Adenylate cyclase activity and cAMP content of human platelets in uremia. Eur J Clin Invest 1982; 12:379. 117. Shattil SJ, Abrams CS, Bennet JS. Acquired qualitative platelet disorders due to diseases, drugs and foods. In: Beutler E, ed. Williams Hematology. New York: McGrw-Hill, 2001: 1583–1584. 118. Stewart JH, Castaldi PA. Uraemic bleeding: a reversible platelet defect corrected by dialysis. Q J Med 1967; 36:409. 119. Bolan CD, Alving BM. Pharmacologic agents in the management of bleeding disorders. Transfusion 1990; 30:541. 120. Barrai I, et al. The effect of parental age on rates of mutation for hemophilia and evidence for differing mutation rates for hemophilia A and B. Am J Hum Genet 1968; 20:175. 121. Robbins JA, Rose SD. Partial thrombloplastin time as a screening test. Ann Intern Med 1979; 90:796. 122. Eisenberg JM, Clarke JR, Sussman SA. Prothrombin and partial thromboplastin times as preoperative screening tests. Arch Surg 1982; 117:48. 123. Suchman AL, Mushlin AI. How well does the activated partial thromboplastin time predict postoperative hemorrhage? JAMA 1986; 256:750. 124. Spence RK. Bleeding and the vascular surgery patient. Semin Vasc Surg 1994; 7:104. 125. Miller E, et al. Scalpel versus electrocautery in modified radical mastectomy. Am Surg 1988; 54:284. 126. Pearlman NW, et al. A prospective study of incisional time, blood loss, pain and healing with carbon dioxide laser, scalpel and electrosurgery. Arch Surg 1991; 126:1018. 127. Collins JA. Recent developments in the area of massive transfusion. World J Surg 1987; 11:75. 128. Leslie S, Toy P. Laboratory hemostatic abnormalities in massively transfused patients given red blood cells and crystalloid. AJCP 1991; 96:770. 129. Reed RL, et al. Prophylactic platelet administration during massive transfusion. Ann Surg 1986; 203:40. 130. Clagett GP, et al. Does desmopressin improve hemostasis and reduce blood loss from aortic surgery? A randomized, double-blind study. J Vasc Surg 1995; 22:223. 131. Clagett GP. Desmopressin, hemostasis, and vascular surgery. Semin Vasc Surg 1996; 9(4):340. 132. Contreras M, et al. Guidelines for the use of fresh frozen plasma. British Committee for Standards in Haematology, Working Party for the Blood Transfusion Task Force. Transfus Med 1992; 2:57. 133. Rousou J, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study. J Thorac Cardiovasc Surg 1989; 97:194.

Hemostasis and Thrombosis in the Surgical Patient

177

134. Milne AA, et al. Fibrin sealant reduces suture line bleeding during carotid endarterectomy: a randomized trial. Eur J Vasc Endovasc Surg 1995; 10:91. 135. Ortel TL, Charles LA, Keller FG, et al. Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis. Am J Hematol 1994; 45:128. 136. Eyster ME, Gill FM, Blatt, et al. Central nervous system bleeding in hemophiliacs. Blood 1978; 51:1179. 137. Jackson MR. Tissue sealants: current status, future potential. Nature Med 1996; 2:637. 138. Griffin JH, et al. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82:1989. 139. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330:517. 140. Gillespie DL, et al. Resistance to activated protein C: a common inherited cause of venous thrombosis. Ann Vasc Surg 1996; 10:174. 141. Simioni P, et al. The risk of recurrent venous thromboembolism in patients with an Arg506!Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997; 336:399. 142. Jones MP, Alving BA. Laboratory testing for hypercoagulable disorders. Curr Opin Hematol 1996; 3:365. 143. Ridker PM, et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 333:880. 144. Ouriel K, et al. Activated protein C resistance: prevalence and implications in peripheral vascular disease. J Vasc Surg 1996; 23:46. 145. Gomez E, et al. Identification of eight point mutations in protein S deficiency type I: analysis of 15 pedigrees. Thromb Haemost 1995; 73:750. 146. Comp PC. Hereditary disorders predisposing to thrombosis. Prog Hemost Thromb 1986; 8:71. 147. Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb 1992; 12:135. 148. Bauer KA. Inherited hypercoagulable states. In: Loscalzo J, Schafer AI, eds. Thrombosis and Hemorrhage. Boston: Blackwell Scientific Publications, 1994:809. 149. Mannucci P, et al. Familial dysfunction of protein S. Thromb Haemost 1989; 62:736. 150. Reitsma PH, et al. Protein C deficiency: a database of mutations, 1995 update. Thromb Haemost 1995; 73:876. 151. Broekmans AW, et al. Protein C (PC) and coumarin-induced skin necrosis. Thromb Res 1986; 6:137. 152. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13:516. 153. Bock SC, Prochownik EV. Molecular genetic survey of 16 kindreds with hereditary antithrombin III deficiency. Blood 1987; 70:1272. 154. Olds RJ, et al. Novel point mutations leading to type I antithrombin deficiency and thrombosis. Br J Haematol 1991; 78:408. 155. Einarsson M, et al. Heat inactivation of human immunodeficiency virus in solutions of antithrombin III. Transfusion 1989; 29:148. 156. Tengborn L, Bergvist D. Surgery in patients with congenital antithrombin III deficiency. Acta Chir Scand 1988; 154:179. 157. De Stefano V, et al. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, protein S [letter]. Thromb Haemost 1994; 71:799. 158. Jackson MR, et al. Use of antithrombin III concentrates to correct antithrombin III deficiency during vascular surgery. J Vasc Surg 1995; 22:804. 159. Lemesle M, Manceau E, Osseby GV, et al. Ischemic cerebrovascular stroke of arterial origin in the child. Rev Neurol (Paris) 2001; 157(10):1255–1263. 160. Moster ML. Coagulopathies and arterial stroke. J Neuroophthalmol 2003; 23(1):63–71. 161. Thomas RH. Hypercoagulability syndromes. Arch Intern Med 2001; 161(20):2433–2439. 162. Clarke R, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324:1149.

medwedi.ru

178

Part One: General Considerations

163. Fermo I, et al. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med 1995; 123:747. 164. Selhub J, et al. Association between homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332:286. 165. den Heijer M, et al. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis? Lancet 1995; 345:882. 166. Simione P, et al. Hyperhomocysteinemia and deep-vein thrombosis: a case-control study. Thromb Haemost 1996; 76:883. 167. Valentine RJ, et al. Lipoprotein (a), homocysteine, and hypercoagulable states in young men with premature peripheral atherosclerosis: a prospective, controlled analysis. J Vasc Surg 1996; 23:53. 168. Goyette P, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 1994; 7:195. 169. Frosst P, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10:111. 170. Jacques PF, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93:7. 171. Boushey CJ, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995; 274:1049. 172. Alving BM. Lupus anticoagulants, anticardiolipin antibodies, and the antiphospholipid syndrome. In: Loscalzo J, Schafer AI, eds. Thrombosis and Hemorrhage. Boston: Blackwell Scientific Publications, 1994:749. 173. Harris EN, Pierangeli S, Birch D. Anticardiolipin wet workshop report. Fifth International Symposium on Antiphospholipid Antibodies. Am J Clin Pathol 1994; 101:616. 174. Deicher SR, Carman TL, Sheikh, MA, Gomes M. Hypercoagulable syndromes: evaluation and management strategies for acute limb ischemia. Semin Vasc Surg 2001; 14(2):74–85. 175. Kim V, Spandorfer J. Epidemiology of venous thromboembolic disease. Emerg Med Clin North Am 2001; 19(4): 839–859. 176. Rhodes GR, Dixon RH, Silver D. Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg Gynecol Obstet 1973; 136:409. 177. Silver D, Kapsch DN, Tsoi EKM. Heparin-induced thrombocytopenia, thrombosis, and hemorrhage. Ann Surg 1983; 198:301. 178. Laster J, et al. The heparin-induced thrombocytopenia syndrome: an update. Surgery 1987; 102:763. 179. Boshkov LK, et al. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol 1993; 84:322. 180. Warkentin TE. Heparin-induced thrombocytopenia. Curr Hematol Rep 2002; 1(1):63–72. 181. Harenberg J, Jorg I, Fenyvesi T. Heparin-induced thrombocytopenia: pathophysiology and new treatment options. Pathophysiol Haemost Thromb 2002; 32(5–6):289–294. 182. Jackson MR, et al. Diagnosis of heparin-induced thrombocytopenia in the vascular surgery patient. Surgery 1997; 131:419. 183. Warkentin TE, Hayward CPM, Boshkov MC, et al. Sera from patients with heparin-induced thrombocytopenia generate plaelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparininduced thrombocytopenia. Blood 1994; 79:1. 184. Carlsson LE, Santoso S, Baurichter G, et al. Heparin-induced thrombocytopenia: new insights into the impact of FcgammaRIIa-R-H131 polymorphism. Blood 1998; 92:1526. 185. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003; 2(2):148–157. 186. Amiral JA, et al. Pathogenicity of IgA and/or IgM antibodies to heparin-PF4 complexes in patients with heparin-induced thrombocytopenia. Br J Haematol 1995; 92:954.

187. Curtis BR, McFarland JG, Wu G-G, et al. Antibodies in sulfanamide-induced immune thrombocytopenia recognize calcium-dependent epitopes on the glycoprotein Iib/Iia complex. Blood 1994; 84:176. 188. Visentin GP, Newman PJ, Aster RH. Characteristics of quinine- and quinidine-induced antibodies specific for platelet glycoprotein Iib and IIIa. Blood 1991; 77:2668. 189. Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 1993; 69:344. 190. Greinacher A, et al. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71:247. 191. Sheridan D, Carter C, Kelton JG. A diagnostic test for heparininduced thrombocytopenia. Blood 1986; 67:27. 192. Amiral J, et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia [letter]. Thromb Haemost 1992; 68:95. 193. Aylesworth CL, et al. ELISA for detection of antibodies against the platelet factor 4 (PF4)/heparin complex: methods for standardization. Blood 1995; 86:865a. 194. Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74:1. 195. Harenberg J, Jorg I, Koch S, Fenyvesi T. Lepirudin for therapeutic use in heparin-induced thrombocytopenia. Hamostaseologie 2004; 24(2):135–143. 196. Jeske WP, Walenga JM. Antithrombotic drugs for the treatment of heparin-induced thrombocytopenia. Methods Mol Med 2004; 93:61–82. 197. Nand S. Hirudin therapy for heparin-associated thrombocytopenia and deep vein thrombosis. Am J Hematol 1993; 43:312. 198. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993; 70:554. 199. Ortel TL, et al. Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis. Thromb Haemost 1992; 67:292. 200. Olinger GN, et al. Cardiopulmonary bypass for patients with previously documented heparin-induced platelet aggregation. J Thorac Cardiovasc Surg 1984; 87:673. 201. Dvorak HF. Abnormalities of hemostasis in malignant disease. In: Coleman RW, et al., eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: JB Lippincott, 1994:1238. 202. Deitcher SR, Gomes MP. Hypercoagulable state testing and malignancy screening following venous thromboembolic events. Vasc Med 2003; 8(1):33–46. 203. Mandala M, Ferretti G, Cremonesi M, Cazzaniga M, Curigliano G, Barnia S. Venous thromboembolism and cancer: new issues for an old topic. Crit Rev Oncol Hematol 2003; 48(1):65–80. 204. Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies. Semin Thromb Hemost 2003; 29(3):247–258. 205. Kakkar AK. An expanding role for antithrombotic therapy in cancer patients. Cancer Treat Rev 2003; 29(suppl 2):23–26. 206. Gomes MP, Deitcher SR. Diagnosis of venous thromboembolic disease in cancer patients. Oncology (Huntingt) 2003; 17(1): 126–135. 207. Clagett GP, et al. Prevention of venous thromboembolism. Chest 1995; 108(4):312S. 208. Stark JE, Kilzer WJ. Venous thromboembolic prophylaxis in hospitalized medical patients. Ann Pharmacother 2004; 38(1): 365–340. 209. Haas S. The present and future of heparin, low molecular weight heparins, pentasaccharide, and hirudin for venous thromboembolism and acute coronary syndromes. Semin Vasc Med 2003; 3(2):139–146. 210. Chang P. New anticoagulants for venous thromboembolic disease. IDrugs 2004; 7(1):50–57.

Chapter 7: 211. Thorneycroft IH, Goldzieher JW. Venous thromboembolism. A review. J Reprod Med 2003; 48(11 suppl):911–920. 212. Cosmi B, Palareti G. Oral anticoagulant therapy in venous thromboembolism. Semin Vasc Med 2003; 3(3):303–314. 213. Cairns JA, et al. Antithrombotic agents in coronary artery disease. Chest 1995; 108(4):380S. 214. Emmons PR, Harrison MJG, Jonour AJ, Mitchell JRA. Effect of pyridopyrimidine derivative on thrombus formation, platelet adhesiveness and blood pressure in rabbits and rats. Nature 1968; 218:1972. 215. Weiss HJ. Antiplatelet therapy. N Engl J Med 1978; 298:1344, 1403. 216. Fitzgerald GA. Dipyridamole. N Engl J Med 1987; 316:1247. 217. Defreyn G, Bernat A, Delebasse D, Maffrand J-P. Pharmacology of ticlopidine: a review. Semin Thromb Hemost 1989; 15:159. 218. DiMinno G, Cerbone AM, Mattioli OL, et al. Functionally throbasthenic state in normal platelets following administration of ticlopidine. J Clin Invest 1985; 75:328. 219. Herbert JM, Frehel D, Valle E, et al. Clopidogrel, a novel antiplatelet and antithrombotic agent. Cardiovsc Drug Rev 1993; 11:180. 220. Schor K. The basic pharmacology of ticlopidine and clopidogrel. Plaetlets 1993; 4:252. 221. Mills DCB. ADP receptors on platelets. Thromb Haemost 1996; 76:835. 222. Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopdiogrel. Ann Intern Med 1998; 129:394. 223. Weiss HJ. Platelets: Pathophysiology and Antiplatelet Drug Therapy. New York: Alan R Liss, 1982. 224. Schor K. Antiplatelet drugs. A comparative review. Drugs 1995; 50:7. 225. Visseren FL, Eikelboom BC. Oral anticoagulant therapy in patients with peripheral artery disease. Semin Vasc Med 2003; 3(3):339–344. 226. Herbert JM, Savi P. P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med 2003; 3(2):113–122. 227. Bradberry JC. Peripheral arterial disease: pathophysiology, risk factors, and role of antithrombotic therapy. J Am Pharm Assoc 2004; 44(2 suppl 1):S37–S44. 228. Gawaz M, Muller I, Besta F. Combined antithrombotic therapy for acute coronary syndrome. Semin Vasc Med 2003; 3(2):163–176. 229. Moonis M, Fisher M. Antiplatelet treatment for secondary prevention of acute ischemic stroke and transient ischemic attacks: mechanisms, choices and possible emerging patterns of use. Expert Rev Cardiovasc Ther 2003; 1(4):611–615. 230. Behan MW, Storey RF. Antiplatelet therapy in cardiovascular disease. Postgrad Med J 2004; 80(941):155–164. 231. Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003; 26(7): 2181–2188. 232. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348:1329. 233. Hankey GJ. Clopidogrel: a new safe and effective antiplatelet agent. But unanswered questions remain. Med J Aust 1997; 167:120. 234. Howell WH. Heparin, an anticoagulant: preliminary communication. Am J Physiol 1922; 63:434. 235. Freedman JE, Adelman B. Pharmacology of heparin and oral anticoagulants. In: Loscalzo J, Schafer Al, eds. Thrombosis and Hemorrhage. Boston: Blackwell Scientific Publications, 1994:1155. 236. Hirsh J, Ginsberg JS, Marder VJ. Anticoagulant therapy with coumarin agents. In: Coman RW, et al., eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: Lippincott-Raven, 1994:1568. 237. Hirsh J, et al. Oral anticoagulant drugs. N Engl J Med 1991; 324:1865. 238. Scharfstein J, Loscalzo J. Molecular approaches to antithrombotic therapy. Hosp Pract 1992; 27(5):41.

Hemostasis and Thrombosis in the Surgical Patient

179

239. Hodl R, Klein W. The role of low-molecular-weight heparins in cardiovascular medicine. J Clin Pharm Ther 2003; 28(5): 371–378. 240. Warketin TE, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330. 241. Doherty DC, et al. ‘‘Heparin-free’’ cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass. Anesthesiology 1990; 73:562. 242. Clarke RJ, et al. Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 1991; 83:1510. 243. Gold HK, et al. Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol 1993; 21:1039. 244. Matsuo T, et al. Treatment of heparin-induced thrombocytopenia by use of argatroban, a synthetic thrombin inhibitor. Br J Haematol 1992; 82:627. 245. Sawyer RT. Thrombolytics and anticoagulants from leeches. Biotechnology 1991; 9:513. 246. Maraganore JM, et al. Anticoagulant activity of synthetic hirudin peptides. J Biol Chem 1989; 264(15):8692. 247. Maraganore JM, et al. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochem 1990; 29:7095. 248. Weitz JI, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86:385. 249. Fox I, et al. Anticoagulant activity of HirulogTM, a direct thrombin inhibitor, in humans. Thromb Haemost 1993; 69:157. 250. Yao SK, et al. Thrombin inhibition enhances tissue-type plasminogen activator-induced thrombolysis and delays reocclusion (Part 2). Am J Physiol 1992; 262(2):H374. 251. Klement P, et al. Effects of heparin and hirulog on t-PA induced thrombolysis in a rat model. Fibrinolysis 1990; 4(suppl 3):9. 252. Topol EJ, et al. Use of a direct antithrombin, Hirulog, in place of heparin during coronary angioplasty. Circulation 1993; 87:1622. 253. Jackson MR, et al. Antithrombotic effects of hirulog in a microsurgical carotid endarterectomy model. J Surg Res 1996; 60:15. 254. Riess FC, Potzsch B, Bader R. A case report on the use of recombinant hirudin as an anticoagulant for cardiopulmonary bypass in open heart surgery. Eur J Cardiothorac Surg 1996; 10:386. 255. FitzGerald GA. Mechanisms of platelet activation: Thromboxane A2 as an amplifying signal for other agonists. Am J Cardiol 1991; 68:11B. 256. Hirsh J, et al. Aspirin and other platelet-active drugs. The relationship between dose, effectiveness, and side effects. Chest 1995; 108:247S. 257. Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995; 332:238. 258. Jakubowski JA, et al. Cumulative anti-platelet effect of lowdose enteric-coated aspirin. Br J Haematol 1985; 60:635. 259. Clagett GP, Krupski WC. Antithrombotic therapy in peripheral arterial occlusive disease. Chest 1995; 108(4):431S. 260. Rinder CS, et al. Aspirin does not inhibit adenosine diphosphate-induced platelet a-granule release. Blood 1993; 32:505. 261. Di Minno G, et al. Functionally thrombasthenic state in normal platelets following the administration of ticlopidine. J Clin Invest 1985; 75:328. 262. Hass EK, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321:501. 263. Gent M, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1:1215.

medwedi.ru

180

Part One: General Considerations

264. Goods CM, et al. Comparison of aspirin alone versus aspirin plus ticlopidine after coronary artery stenting. Am J Cardiol 1996; 78:1042. 265. Aberg M, Hedner U, Bergentz SE. Effect of dextran on factor VIII (antihemophilic factor) and platelet function. Ann Surg 1979; 189:182. 266. Aberg M, Bergentz SE, Hedner U. The effect of dextran on the lysability of ex vivo thrombi. Ann Surg 1975; 181:342. 267. Harris WH, et al. Prevention of venous thromboembolism following total hip replacement: warfarin vs dextran 40. JAMA 1972; 220:1319. 268. Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg 1988; 208(2):227. 269. Rutherford RB, et al. The efficacy of dextran 40 in preventing early postoperative thrombus following difficult lower extremity bypass. J Vasc Surg 1984; 1:765.

270. Tcheng JE, et al. Pharmacodynamics of chimeric glycoprotein Iib/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994; 90:1757. 271. Coller BS, Anderson K, Weisman HF. New antiplatelet agents: platelet GPIIb/IIIa antagonists. Thromb Haemost 1995; 74:302. 272. The EPIC investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330:956. 273. Moliterno DJ, et al. Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (the EPIC trial). Evaluation of c7E3 Fab in the Prevention of Ischemic Complications Trial. Am J Cardiol 1995; 75:559. 274. Faulds D, Sorkin EM. Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischemic heart disease. Drugs 1994; 48:583.

8 Pathophysiology of Shock Ajai K. Malhotra

Shock: . . . a rude unhinging of the machinery of life . . . Samuel D. Gross, 1870

INTRODUCTION Attempts to define the pathophysiology of shock are as old as the practice of medicine itself. Hippocrates (460–380 B.C.) recognized the state, following traumatic wounds with significant blood loss. He described the Hippocrates facies of a person in the premorbid state from shock, and suggested the use of a tourniquet to control blood loss. Galen (130– 200 A.D.) described ligation of the bleeding vessel to control blood loss, though the technique did not gain widespread acceptance till the work of the French surgeon Ambroise Pare (1510–1590). At about the same time, the groundbreaking work of Andrea Vesalius (1514–1564), and of William Harvey (1578–1657), helped elucidate the anatomy and circulation of the cardiovascular system. The term ‘‘shock’’ itself appeared for the first time in the medical literature in 1743 in an English translation of Henri Francois Le Dran’s (1685–1770) A Treatise, or Reflections Drawn from Experiences with Gunshot Wounds. It referred to a violent physical impact, rather than the physiological changes as a consequence of the impact. The term was used to describe such physiologic sequelae, following major trauma, by George James Guthrie (1785–1856) in his book On Gunshot Wounds of the Extremities, published in 1815. The development of the field of physiology toward the end of the 19th century increased fundamental understanding of the issues involved in shock. George W. Crile (1864–1943) developed animal models of hemorrhagic shock and showed that after hemorrhage the central venous pressure dropped to very low levels. Furthermore, infusion of normal saline resulted in restoration of this pressure and improved survival in his experimental models. He postulated that the increase in central venous pressure, by saline infusion, improved cardiac filling, and thus cardiac output (1). Walter B. Cannon (1872–1945) and William M. Bayliss (1860–1924), two physiologists, made important observations on soldiers injured on the battlefield in World War I. They correlated loss of blood with the development of shock, and also acidosis. Following these observations, they developed animal models of shock caused by injury, and postulated that injured tissue elaborated a toxin that resulted in the state of shock. This concept of traumatic toxemia, prevalent in the early part of the 20th century, was not new because it complemented the centuries-old practice of bloodletting to reverse the

process of shock. In addition to this toxemic theory of shock, other explanations for the state were also offered during this time (2). The next major step in the understanding of the state of shock occurred when Kieth, in 1919, used the dye dilution method to demonstrate that the shock state was accompanied by hypovolemia (3). The concept of hypovolemia being a major determinant of the shock state, however, did not become established until the classic experiments of Alfred Blalock clearly demonstrated that blood and extracellular fluid losses, in the vicinity of a major injury, were sufficient to cause hypovolemia and shock (4). Wiggers, in the 1940s, developed experimental animal models of progressive hemorrhage leading to hypovolemic shock and described irreversible shock—a state from which animals failed to recover despite complete restoration of blood volume. Furthermore, Wiggers attempted to correlate the concepts of cumulative oxygen debt and death (5). During the mid-20th century, resuscitation from shock, using blood, plasma, and balanced salt solutions, became the primary focus of investigation. It was realized that patients suffering from prolonged and severe hemorrhagic shock could survive, provided they were given large volumes of resuscitation fluids early. The pathophysiology as to why these large volumes were required was elucidated by the work of Shires, who, in a series of experiments, demonstrated that in deep and prolonged hemorrhagic shock, cell membrane function was deranged, resulting in the movement of extracellular fluid into the cells (6). This resulted in a profound extracellular fluid deficit that had to be replenished for the organism to survive. With massive resuscitation, a greater number of patients with even severe hemorrhagic shock survived the initial injury; however, other complications, notably sepsis and multisystem organ failure, started to be recognized as delayed complications of shock and massive volume resuscitation. With improved critical care, the ability to support failing organ systems has improved, but other complications of massive crystalloid resuscitation are being reported. Ironically, current research involving cellular and molecular derangements is increasingly focused on systemic inflammation due to shock and the chemical mediators responsible—akin to the toxemic theory of shock.

DEFINITION OF SHOCK Shock may be defined as a syndrome in which tissue perfusion is inadequate to meet the metabolic needs of the body. Because the most immediate metabolic nutrient is oxygen, this inadequate perfusion results in tissue hypoxia that has far-reaching effects on the whole organism, individual

medwedi.ru 181

182

Part One: General Considerations

organ systems, tissues comprising the individual organ systems, and finally the individual cells. Cellular hypoxia leads to cell injury and the initiation of the inflammatory cascade. In situations where the tissue hypoperfusion is rapidly corrected, cell injury is limited; but if treatment is not provided in an expeditious fashion, the shock state may become irreversible with death of the organism. Thus the shock state should truly be viewed as a continuum from subclinical perfusion deficits to frank organ system dysfunction and death. This concept of shock being an imbalance between the body’s oxygen requirements and the ability of the cardiovascular system to provide oxygen is central to the understanding of the pathophysiology of shock. In some situations, the perfusion measurements may be ‘‘normal’’ or even ‘‘supranormal’’; however, due to a state of systemic inflammation, the body’s oxygen requirements may be significantly increased, and a state of shock may thereby exist.

Oxygen Debt The lack of oxygen observed during shock has led some to look at the state of shock as an oxygen debt owed by the cardiovascular system to the tissues. Oxygen debt is the cumulative difference in the volume of oxygen delivered during the state of hypoperfusion and the volume necessary for the organs to function normally. For shock therapy to be successful, oxygen delivery has to be at a suitable level to not only maintain normal function of the organs, but also repay the debt accumulated during shock. If the shock state is prolonged or deep, the oxygen debt can become so high that the cardiovascular system is unable to deliver enough oxygen to repay the oxygen debt and maintain normal functions, and the organism dies. Animal experiments, and some human studies, have shown a very high level of correlation between oxygen debt accrued during shock and survival with resuscitation. However, interventions to massively increase oxygen delivery during resuscitation to rapidly pay off the debt have failed to show improvement in survival (7).

CARDIOVASCULAR PHYSIOLOGY AND TYPES OF SHOCK The cardiovascular system consists of the heart, which pumps the circulating blood volume through a closed system of channels comprising arteries and arterioles carrying blood to capillary networks in all tissues and venules and veins carrying blood back to the heart. There are three requisites for adequate perfusion: (i) adequate circulating volume—preload—with adequate concentration of hemoglobin to transport oxygen; (ii) adequate power of cardiac contraction—contractility—to pump the circulating volume at an adequate perfusion pressure; and (iii) appropriate tone—afterload—of the vasculature, residing principally in the arterioles, to maintain an adequate perfusion pressure at the tissue level. Unlike a pure mechanical preparation where each of the three variables, preload, contractility, and afterload, may be altered individually, in a biological system, as exists within the body, there is a dynamic interplay between the three variables. As a consequence of this dynamic interplay, if one variable changes, not only is the body perfusion affected directly, but the other two variables too may change in response to the change in the first. This dynamism makes it very difficult at times to evaluate the principal problem causing the state of shock—preload, contractility, or afterload. To partly overcome this difficulty, a thermodynamic model of the cardiovascular system was

proposed by Suga et al. (8–11). A fundamental concept in this model was that the volume of blood delivered by the heart (i.e., cardiac output), and the pressure at which it was delivered were both important determinants of overall perfusion adequacy. These two determinants can be combined to arrive at the mechanical work done by the heart or the power output. A pressure–volume diagram (Fig. 1) can be constructed, provided some key volume and pressure measurements are available, and the exact work done by the heart on the vascular system can be calculated. This pressure–volume diagram not only assesses the work done, but also allows for preload, contractility, and afterload to be evaluated individually and independent of the other two. At point A in the pressure–volume loop (Fig. 1), ventricular filling is initiated with the opening of the atrio-ventricular valves, allowing blood to flow from the atria into the ventricles. In the relaxed state, normal ventricles are very compliant; thus the ventricular volume increases, without significant increase in the ventricular pressure—segment AB in the loop. At point B, ventricular contraction causes an increase in ventricular pressure, forcing the closure of atrioventricular valves. Now, outflow tract (aortic root on the left and pulmonary artery root on the right) pressure is much higher than ventricular pressure, and hence both ventricular outflow valves remain closed. With continued ventricular contraction, ventricular pressure rises, without any change in ventricular volume, because no blood can enter or exit the ventricles—isovolumic contraction: segment BC in the loop. At point C, ventricular pressure rises above the outflow tract pressure, allowing the outflow valves to open. With opening of these valves, there is rapid emptying of the ventricles into the outflow tracts, resulting in decrease in ventricular volume—segment CD in the loop. At point D, the ventricles have emptied, and ventricular systole is ending, resulting in a drop in ventricular pressure to less than the outflow tract pressure, causing the outflow valves to close. With continued ventricular relaxation, ventricular pressure falls, but as the atrio-ventricular valves remain closed, no change in ventricular volume takes place—isovolumic relaxation: segment DA. At point A, the ventricular pressure has fallen

Figure 1 Pressure–volume loop as described by Suga et al. The crosshatched rectangle ABCD represents mechanical work performed by the heart on the vascular system to achieve perfusion. The triangle VoAD represents nonmechanical work performed to re-create ionic electrochemical gradients expended during each contraction cycle. The slope of line VoD represents cardiac contractility, and the slope of line BD represents afterload. The three parameters that define perfusion can be quantified individually independent of the other two by constructing such a pressure–volume loop. Abbreviations: Vo, ventricular unstressed volume; ESV, end systolic volume; EDV, end diastolic volume.

Chapter 8:

to a value less than that of the atrial pressure, allowing the atrio-ventricular valves to open and the cycle to start again at point A. In thermodynamic terms, the area enclosed within the pressure–volume loop ABCD is the mechanical work performed by the heart on the vasculature to achieve perfusion. The loop for the left side represents systemic perfusion. In addition to the mechanical work, there is additional energy expenditure involved in re-establishing electrochemical gradients expended to achieve mechanical work. The point V0 represents ventricular unstressed volume (approximately 5 mL in a normal young heart and approximately 10 mL in a normal older heart). The area enclosed within the triangle, V0AD, represents this nonmechanical energy expenditure. In an ideal situation, the area V0AD should be very small, and area ABCD should be large enough to provide adequate perfusion. Modern monitoring allows for the constructing of pressure–volume loops in patients. As described by Suga et al., the slope of the line V0D represents cardiac contractility and slope of the line BD represents afterload. Additionally, experiments have shown that the contractility, as measured on this loop, is load independent. Hence the pressure– volume loop provides accurate independent quantification of the three parameters upon which cardiac function, and hence perfusion, is dependent—circulating volume on the X-axis, and contractility and afterload as the slopes of the two lines BD and V0D, respectively. This quantification can serve as a guide to therapy because it allows prediction as to which intervention—changes in circulating volume, augmentation of contractility, or manipulation of afterload— is the most likely to improve perfusion (increase area ABCD), with least increase in nonmechanical work (area V0AD).

Types of Shock At a pathophysiologic level, shock may be caused by derangements in one or more of the three parameters that define perfusion—preload, contractility, and afterload. In some situations, the shock is relatively ‘‘pure,’’ and is caused by derangement of only one parameter; however in most clinical situations associated with shock, all three are deranged to a lesser or greater degree. Even in situations where shock is caused by derangement of only one parameter to start with, as the shock state progresses, the other two become secondarily affected. For example, a patient suffering from hemorrhage of a major blood vessel, caused by a single stab wound injury, will develop decreased circulating blood volume—decreased preload—resulting in hypoperfusion or shock. If the bleeding is rapidly controlled and resuscitation provided, the patient will recover. On the other hand, in situations where resuscitation and control of hemorrhage is delayed, the decreased venous return to the heart and poor cardiac perfusion will depress cardiac contractility. Later on, tissues starved of oxygen will cause dilatation of vessels, resulting in changes in afterload. Hence shock initially caused by decreased preload will develop a mixed picture with derangements in contractility and afterload. At times it can be extremely difficult to determine the primary insult that initiated shock and the secondary effects contributing to it. The most commonly accepted classification of shock is presented in Table 1.

Pathophysiology of Shock

183

Table 1 Commonly Accepted Classification of Shock, with the Principal Cause of the Hypoperfusion in Parenthesis Hypovolemic shock (loss of preload) Hemorrhagic shock Traumatic shock Cardiogenic shock (loss of cardiac contractility) Neurogenic shock (loss of afterload) Cardiac compressive shock (severe decrease in preload affecting contractility) Septic shock (decreased preload; decreased contractility; deranged afterload)

be caused by loss of blood from the vasculature due to external or internal bleeding—hemorrhagic shock. It may also be caused by nonsanguinous loss of extracellular fluid. This extracellular fluid loss may be external, as seen in diarrhea, vomiting, etc., or internal, as seen in severe inflammatory states as necrotizing pancreatitis. Patients with blunt trauma, with significant blood loss, develop a more severe form of hypovolemic shock—traumatic shock. This is thought to be due to the inflammatory state produced by tissue injury superimposed on the hypovolemic shock due to the hemorrhage.

Cardiogenic Shock Shock due to significant decrease in cardiac contractility causing reduced perfusion is termed ‘‘cardiogenic shock.’’ It is most commonly observed following major myocardial infarction. However, it may also be seen following major blunt trauma to the heart or following viral myocarditis. In late stages of any form of shock, cardiac contractility is affected by cardiac hypoperfusion, and hence a cardiogenic element is often present in the later stages of all forms of shock.

Neurogenic Shock Hypoperfusion as a result of derangement in afterload is termed ‘‘neurogenic shock.’’ It is most commonly observed in cervical spinal cord injury with loss of sympathetic tone to most of the body, resulting in reduction in afterload with decrease in perfusion pressure and shock. Neurogenic shock due to this form of injury, particularly in otherwise young healthy adults, is associated with full and bounding pulse in the face of significant hypotension and bradycardia. The bradycardia is due to loss of sympathetic stimulation to the heart, and the full bounding pulse is due to increased cardiac output in the face of low vascular resistance to cardiac emptying—low afterload. Brief neurogenic shock may also be observed by overactivity of the vagus nerve—vasovagal shock. Any situation that results in major afferent stimulation of the vagus nerve can result in overactivity of the parasympathetic system, suppression of the sympathetic tone resulting in bradycardia, and loss of afterload, with resultant neurogenic shock. Although not considered neurogenic shock in the strictest sense, severe vasoconstriction caused by extraneous administration of sympathomimetic pressor agents can result in tissue hypoperfusion and necrosis; in such situations, a very weak pulse will be observed in the face of ‘‘normal’’ or increased blood pressure.

Hypovolemic Shock

Cardiac Compressive Shock

Any clinical situation causing a reduction in circulating blood volume will result in decreased preload and hypovolemic shock. The decreased circulating volume can

Cardiac compressive shock is a clinical syndrome produced by decreased cardiac filling due to increased pressure within the pericardial or pleural cavities. The increased pressure

medwedi.ru

184

Part One: General Considerations

within the pericardium or pleural cavity inhibits venous return to the heart—decreased preload. In the absence of adequate venous return, there is ineffective cardiac contractions—decreased contractility. The situation may be caused by accumulation of fluid or air within the pericardial or pleural cavities. The amount of fluid or air has to be sufficient to cause reduced cardiac filling. In the normal heart, a very small amount of fluid within the pericardial space is enough to embarrass cardiac filling—cardiac tamponade. In the case of the pleural space a fairly large volume of fluid is necessary to produce cardiac compressive shock. A simple pneumothorax does not produce compressive shock. However, if the pneumothorax is of sufficient volume to produce increased intrathoracic pressure—tension pneumothorax— cardiac compressive shock will be seen. Clinically, the condition may be diagnosed by bulging neck veins (absent in hypovolemic patients) and pulsus paradoxus. In addition, if caused by pericardial tamponade, the heart sounds appear distant on auscultation. When caused by tension within the pleural cavity, there is absence of breath sounds on the affected hemithorax, and hyper-resonance if caused by tension pneumothorax and dullness if caused by fluid.

Septic Shock Septic shock is the term used to denote a complex clinical syndrome affecting, to a lesser or greater degree, all three parameters that define perfusion—preload, contractility, and afterload. It is seen in patients with severe systemic sepsis. It is more common in sepsis due to gram-negative organisms, and hence is often referred to as gram-negative or endotoxemic shock. However the syndrome may also be seen with gram-positive septicemia or fungemia. It is initiated by

microbial products acting in concert with inflammatory mediators causing depression in cardiac contractility, and at the same time causing significant vasodilatation—reduced afterload. In addition, the systemic inflammatory response due to systemic sepsis causes capillaries to become leaky, allowing loss of intravascular circulating volume—reduced preload. All three parameters thus affected result in a severe state of shock, associated with a very high mortality. There is also evidence that sepsis leads to the inability of the tissues to adequately utilize whatever oxygen is available, thus exacerbating the tissue hypoxia that is the hallmark of the shock state.

PATHOPHYSIOLOGIC RESPONSE TO SHOCK The causes and types of shock are many. However, in all shock states, tissue perfusion is inadequate to meet the metabolic demands of the body. Consequently, the body’s responses to shock is similar, irrespective of the cause of shock in an individual. The body responds to the state of inadequate perfusion by mounting a neurohumoral response (Fig. 2) and an inflammatory response. Depending upon the type and etiology of shock, one or the other response may predominate, and in addition the individual components of these responses may differ in degree. However, all forms of shock will, to a lesser or greater degree, have both responses, which are primarily geared toward assuring survival of the organism by maintaining perfusion to essential organ systems, often at the cost of less critical body systems. These responses are blunted at the extremes of age, causing infants and older people to have less

Figure 2 Simplified outline of the neural response (left) and the humoral response (right shaded box) observed in a patient developing shock (hypoperfusion). Abbreviations: GH, growth hormone; TSH, thyroid-stimulating hormone; ADH, antidiuretic hormone; ACTH, adrenocorticotropic hormone; ANH, atrial naturitic hormone.

Chapter 8:

reserves to deal with shock. Some recent research suggests that there may be some gender differences, particularly in the inflammatory response to shock (12). While in the short term, these responses are essential for survival, in prolonged or severe shock, these same responses may prove deleterious and hasten the death of the organism, thus making the early recognition and prompt treatment of shock essential for good outcomes in a variety of clinical situations associated with shock.

Neurohumoral Response A complex neurohumoral cascade of events is initiated within minutes of developing significant hypoperfusion (Fig. 2). This cascade has been best studied in pure hemorrhagic shock models. It is usually initiated by the lowering of blood pressure as detected by the pressure-sensitive receptors in various parts of the cardiovascular system. However it may also be initiated by pain or other noxious stimuli, by lack of metabolic fuels (e.g., glucose), or by the buildup of metabolic end products [e.g., CO2, or Hþ (acidosis)] (13). The end result of this complex cascade is to (i) increase cardiac output and blood pressure to maintain perfusion; (ii) limit fluid losses to maintain adequate circulating volume; and (iii) allow some degree of regional perfusion autoregulation to limit organ injury. The nervous system responds to lowering of blood pressure by a strong sympathoadrenal discharge in an attempt to improve perfusion. Arterial baroreceptors, located in the carotid sinus and aortic arch, respond immediately to changes in blood pressure, by adjusting the sympathetic tone. The low-pressure atrial stretch receptors are sensitive to both stretch and pressure. The afferent pathways from these peripheral receptors converge in the nucleus tractus solitarius, which in turn causes the vasomotor center to reduce its tonic inhibition of the sympathetic system. The combined effects of these changes is to produce vasoconstriction, increasing afterload and causing the blood pressure to rise, and, at the same time, reduce vascular capacity (arterial and venous), leading to the mobilization of blood from capacitance vessels toward the heart, improving cardiac filling and increasing cardiac output. The cardiac output is further augmented by the sympathetic stimulation of the heart, which causes the heart to contract more vigorously and at a higher rate. Arterial vasoconstriction, in response to the sympathetic discharge, is not uniform. It is more severe in the vascular beds of less vital organs such as the integument, or the splanchnic bed, while limited in the cardiac and cerebral circulations. The end result of this disproportionate vasoconstriction is a redistribution of the limited cardiac output to these more vital organs at the expense of other less important organs. Furthermore, local autoregulatory mechanisms continue to regulate the microperfusion in the heart and brain. Cerebral circulation is particularly sensitive to the buildup of CO2 and Hþ (acid). Similarly, systemic chemoreceptors, primarily located in the aortic arch and carotid body, are sensitive to systemic acidosis and lower the arterial partial pressure of oxygen (14). Simultaneous with the neural response, shock also initiates an endocrine response. The vasomotor center, besides coordinating a strong sympathetic nervous system response with secretion of norepinephrine from nerve endings, also causes secretion of epinephrine from the adrenal medulla, complementing the sympathetic nervous system response (15). In addition, the sympathetic nervous system stimulation causes the glucagon–insulin secretory balance within the

Pathophysiology of Shock

185

pancreas to shift toward glucagon (16), and the juxtaglomeruler apparatus in the kidney to secrete renin (17). The atrial stretch receptors, in response to decreased stretch, reduce the secretion of atrial naturitic hormone (ANH). The afferent pathways from the peripheral baro- and chemoreceptors, converging on the nucleus tractus solitarius, cause stimuli to be sent to the hypothalamus. The hypothalamus in turn causes the pituitary gland to secrete adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), thyroid-stimulating hormone (TSH), and growth hormone (GH). ACTH stimulates the adrenal cortex to secrete glucocorticoids, while the renin from the juxtaglomerular apparatus, via the elaboration of angiotensin II results in secretion of mineralocorticoids. The secretion of glucagon and glucocorticoids moves the body toward mobilization of fuel stores to supply the heightened energy needs of the organism under severe stress, while the elaboration of ADH and mineralocorticoids, in concert with reduced secretion of ANH, limits loss of fluid from the body to maintain circulating blood volume. The elevated glucose levels observed in early shock, due to lowered insulin levels and insulin resistance from sympathetic discharge, increase the osmolarity of the extracellular compartment allowing intracellular fluid to move out of cells and augment circulating volume (15). The role of TSH and GH are not well defined. TSH may play a permissive role in the sympathetic response, while GH may act in concert with other hormones to increase blood glucose levels.

Systemic Inflammatory Response Over the past two decades there has been a greater understanding of systemic or generalized inflammation. The human body responds to a variety of insults with localized inflammation at the site of the injury. In situations where either the insult is generalized (e.g., prolonged shock), or the magnitude of the localized insult is large (e.g., necrotizing pancreatitis), the inflammation no longer remains localized. In such situations, the inflammatory process becomes generalized, and has been termed ‘‘systemic inflammatory response,’’ and the consequences of this generalized inflammation termed ‘‘systemic inflammatory response syndrome’’ or SIRS. Inflammation is the first step the body initiates in the healing process. However, when the inflammation is generalized, the same processes cause organ dysfunction and can lead to death of the organism. Systemic inflammation is a complex interplay of activation and inhibition of individual components of the three major cascade systems in the body, namely coagulation, complement, and the immune system. The process of shock can be initiated at the time of hypoperfusion, or at the time of resuscitation (ischemia/reperfusion) (18). In its simplest form, the systemic inflammatory response consists of activation of neutrophils in areas of hypoxia with or without reoxygenation. The activated neutrophils express adhesion molecules on their surface, notably CD11a/CD18 (19). Additionally, under the influence of cytokines, generated by a wide variety of hypoxic cells, the endothelial cells and fixed tissue macrophages (e.g., Kupffer cells), express cellular adhesion molecules on their cell membrane surface (20). These adhesion molecules, expressed on the surfaces of neutrophils on the one hand and endothelial cells and fixed tissue macrophages on the other, cause rolling and sticking of the neutrophils, resulting in tight adhesions between the neutrophils and endothelial cells. Finally, chemoattractants (particularly endothelium-produced interleukin-8) induce the neutrophils to emarginate from the capillaries into the

medwedi.ru

186

Part One: General Considerations

interstitial spaces (21). Once in the interstitial space, the neutrophils generate free oxygen radicals and tissuedestructive enzymes, resulting in tissue injury. Tissue injury may be delayed till the time of resuscitation (reoxygenation) because free-radical production by neutrophils is most active when oxygen is available. The tissue destruction itself causes more cytokines to be produced, perpetuating the inflammatory process. The state of systemic inflammation involves all major organ systems in the body and causes dysfunction of these systems. As can be expected, the dysfunction is worst in organ systems with abundant capillary networks, such as the lungs, liver, and kidneys. Unless the process is arrested early, organ dysfunction leads to death of the individual.

Organ System Effects The lack of perfusion, the hallmark of shock, affects every living cell in the body, causing far-reaching effects on all body systems. These effects are compounded by the inflammation seen in these organ systems.

Central Nervous System As described above, the central nervous system plays a central role in orchestrating the neuroendocrine response to shock. In addition, there are changes seen within the brain as a consequence of hypoperfusion. Beta endorphins are elaborated by the brain, which may alter the pain response (22). The glucose utilization patterns are altered, with discrete brain stem nuclei increasing glucose utilization (23). There is generalized slowing of brain electrical activity in response to hypotension. This presents clinically in the form of reduced cerebral function, and, at times, with anxiety and restlessness. While most of these changes are reversible, particularly when treatment is provided early, if the shock state is deep and prolonged, some activity may be permanently lost (24). Reflex activity also is depressed. The inability to reverse the loss of reflexes has been suggested to be an early indicator of irreversibility of shock despite achieving a ‘‘normal’’ hemodynamic profile (25). The role of cerebral blood flow (CBF) in causing the observed changes has been studied. CBF is preserved in shock, as is the cerebral oxygen consumption. This is because of preserved cerebral autoregulation and the different response of the cerebral circulation, as opposed to the systemic circulation, to sympathetic stimulation (see above) (26). Even though total CBF is relatively preserved, there are regional differences in the distribution of the flow within the brain. The role of these regional differences in causing the functional changes noted above has not been firmly established, but these differences may contribute to the patchiness of neurologic injury seen after prolonged shock (27). There are, however, limits to cerebral autoregulation of blood flow seen during shock. When the shock state is prolonged, CBF decreases, and brain death follows (26).

the juxtamedullary nephrons (22,28). The flow to these nephrons is important in preserving the hyperosmolarity of the renal medulla, which in turn is essential for tubular concentrating function. When the shock state is prolonged, blood flow to these nephrons is affected as well, resulting in loss of medullary hyperosmolarity. At the cellular level, renal cells respond to circulating catecholamines by increasing glucose production by gluconeogenesis. Late in shock, glucose production falls. It is not clear whether there is any relationship between this altered glucose metabolism and renal function. It has been suggested by some that the changes in glucose production correlate with the energy state of the renal cells, which is important for proper function. At the time the glucose production falls, the energy state of the cells is depleted. The lowered energy state of the cells causes depletion of intracellular adenosine triphosphate (ATP) and intracellular acidosis. This in turn depresses glomerular filtration and concentrating ability of the kidneys. The depressed energy state of the cells has been correlated with renal failure (29). Clinically, this renal failure presents either as oliguric failure with decreased urine output and rising creatinine levels, or nonoliguric renal failure associated with normal or high urine output in the face of rising creatinine levels. It is likely that the two clinical types represent a continuum from the most severe insult resulting in oliguric failure and the less severe insult causing the nonoliguric type of failure.

Heart The role of the cardiovascular system and specifically the heart is well documented as a compensatory response to shock (see above). However, the role of cardiac dysfunction in the progression of the shock state is not as well elucidated. Early in shock, perfusion to the heart is preferentially preserved at the cost of other organs, and the proportion of the cardiac output directed to the heart is increased, with maintenance of cardiac blood flow to near-normal levels. With continued hypoperfusion, these compensatory mechanisms fail, with resultant cardiac dysfunction. Even when the overall blood flow to the heart is ‘‘normal,’’ regional differences in perfusion within the heart exist. Most notably there is evidence of reduction in flow to the endocardium (30). This may play a role in cardiac dysfunction, and may be responsible for the subendocardial hemorrhage and necrosis observed in shock (31). Metabolic defects in myocardial glucose utilization are observed in shock and may be due to abnormal glycolysis secondary to relative myocardial oxygen deficiency. This causes a decrease in intracellular ATP, which has been correlated with survival (31). Lastly, plasma from shocked animals is capable of causing cardiac dysfunction in nonshocked animals, suggesting the presence of a circulating mediator that plays a part in the cardiac dysfunction observed during shock (30).

Lung Kidneys The kidneys are very sensitive to shock, and, in moderate shock, are one of the first organs to fail. Initially, the kidneys respond to hypotension by increasing the tone in the efferent vessels while maintaining or decreasing afferent arterial tone (22). This preserves the glomerular filtration pressure and adequate glomerular filtration. Regional changes in blood flow are observed in early shock. The decreased perfusion is much more pronounced in the superficial cortical region, while there is relative preservation of flow to

Post-traumatic pulmonary insufficiency is a well-recognized consequence of shock. This was initially observed in soldiers injured in Vietnam, and termed the ‘‘Da Nang Lung,’’ later changed to ‘‘Shock lung,’’ and currently called ‘‘Adult respiratory distress syndrome’’ or ARDS. ARDS is a complex syndrome associated with severe diffusion deficit resulting in the inability of the alveoli to transfer oxygen from the inspired gas into the pulmonary capillaries. A variety of cellular and humoral mediators have been implicated in the causation of the syndrome. These mediators cause

Chapter 8:

infiltration of neutrophils into the interstitium of the lungs, where they release toxic oxygen radicals and proteolytic enzymes (32). This circumstance results in damage to the alveolar membrane and extravasation of large amount of fluid from the capillaries into the interstitial space. Additionally, the toxic products damage the type I pneumocytes lining the alveoli. The accumulated fluid, in combination with the destruction of pneumocytes, causes a diffusion barrier and hypoxia. This hypoxia, caused by pulmonary dysfunction, compounds the systemic lack of oxygen caused by the shock state. Because the pulmonary failure is often observed two to three days after shock and resuscitation, it remains unclear as to whether the dysfunction is related to the shock state itself or is due to the fluid resuscitation (33). Certain types of resuscitation fluids have been shown to decrease neutrophil sequestration and the amount of fluid that is extravasated in the lungs (34); however, it is unclear whether utilizing those resuscitation regimens will have any beneficial effect on the pulmonary failure (35). In addition to neutrophil infiltration, the lung itself mounts an intense inflammatory response to shock, contributing to the dysfunction (33).

Gastrointestinal Tract The gut is severely affected by hypoperfusion due to shock. Erosion of the mucosa of the stomach and small intestine is well documented (22,36). While in the large majority of patients the erosions are superficial and heal after restoration of blood flow, in some patients the erosions may be deep, and lead to torrential bleeding and death (36). The alteration in splanchnic blood flow, observed in shock, is chiefly due to the body’s compensatory mechanisms diverting limited cardiac output to the heart and brain. This occurs due to intense vasoconstriction of the mesenteric arteries (22,37). Although all vasoconstrictive mediators are involved, the ones most active on the splanchnic circulation are angiotensin II and vasopressin, because the splanchnic vasoconstrictor response to shock is blunted after nephrectomy and hypophysectomy (37,38). The splanchnic vasoconstriction, however, is complex in that there is severe vasoconstriction of arterioles, while at the same time there is dilatation of the mucosal microvasculature, thereby preserving some flow to the mucosa. This vasodilatation in mucosal vessels is believed to be due to the local elaboration of prostaglandins (39,40). A number of investigators have demonstrated that the reduction in splanchnic flow seen during shock often persists despite adequate resuscitation (40–42). This has led some to postulate that microvascular thrombosis and endothelial damage with cell swelling may be an important component of reduced splanchnic flow (38). In some patients, deep and prolonged shock can lead to frank necrosis of parts or the whole of the intestine. Like other areas of the body with large capillary networks, the gut also is prone to neutrophilmediated reperfusion injury (43,44). This injury, probably caused by neutrophil derived oxygen radicals, serves to decrease prostaglandin secretions, compromising mucosal blood flow, and thereby mucosal integrity. The loss of mucosal integrity results in loss of mucosal barrier function, allowing translocation of bacteria and bacterial products across the mucosa into the mesenteric venous beds and lymph nodes (45,46). This translocation of bacteria, observed during shock and resuscitation, has been an area of intense study with some investigators contending that it is responsible for the sepsis and multisystem organ failure

Pathophysiology of Shock

187

seen as a delayed consequence of shock. However, although it is clear that gut translocation does occur, whether this translocation has any pathologic consequences is not clear, with most investigators believing that it is probably innocuous. Nonetheless, gut-derived cytokines in response to mucosal injury may still play a significant role in systemic inflammation observed as a consequence of shock (47,48).

Liver The liver is the most metabolically active organ in the body with important roles in maintaining internal homeostasis. It stands to reason that the liver will be affected in shock. Hepatic perfusion is via two different pathways, an arterial pathway through the hepatic arteries and postintestinal venous pathway via the portal vein. The mesenteric flow is severely compromised in shock, and hence the portal flow is reduced. Although there is partial compensation by increased flow in the hepatic arteries, the overall perfusion is decreased and hepatic oxygen demands are not fully met (49–51). Additionally, despite these macrocirculatory adjustments, microcirculatory flow abnormalities occur with derangement of sinusoidal flow (52). Neutrophil infiltration and leukocyte–endothelial cell interactions further compromise sinusoidal flow (53). Reduced sinusoidal perfusion leads to a decrease in intracellular ATP levels (54), and centrilobular hepatic necrosis (55). Clinically, this necrosis manifests itself as an elevation in the hepatic enzyme levels and mild jaundice. In situations where the shock is prolonged, massive hepatic necrosis and fulminant hepatic failure can be seen (55). Metabolically, the cells respond to the increased level of catecholamines, glucagon, and glucocorticoids by increasing glucose production, first by glycogenolysis, and, when glycogen stores have been exhausted, by gluconeogenesis, raising blood glucose levels. In deep and prolonged shock, the cells lose their ability to raise glucose levels, and hypoglycemia is observed (56). This hypoglycemia, seen in prolonged shock, corresponds to mitochondrial dysfunction and impaired oxidative phosphorylation, with decreased hepatic ATP levels and elevated inorganic phosphate levels (57).

Skeletal Muscle Skeletal muscles are not very metabolically active, yet due to the large mass, relative to body weight, metabolic perturbations in the skeletal muscles can have profound effects on the total body metabolism. In patients with shock, skeletal muscles respond to the circulating catecholamines by mobilizing protein stores and providing the liver and kidney the metabolic fuel for gluconeogenesis (22,55). In the absence of adequate oxygen supply, cells all over the body switch from primarily aerobic metabolism to mainly anaerobic metabolism (see later), resulting in an increase in lactate production (54). The skeletal muscle cells contribute the most to the elevated lactate levels seen during shock.

Integument Integumentary circulation is one of the most expendable circulatory beds in the body, and hence when cardiac output is inadequate to meet the needs of the body, this bed is nearly shut down. This absence of perfusion of the skin is responsible for the clinical observation of cold, clammy, and pale skin of patients in shock. The same phenomenon

medwedi.ru

188

Part One: General Considerations

was observed by Hippocrates, and described as the Hippocrates facies. While in the short term there is no significant harm to the skin, if the state of shock persists, the absence of perfusion makes skin breakdown at pressure points more likely with resultant pressure sores at these points.

Microcirculatory Effects Microcirculation is the distal-most component of the vasculature, where the exchange of nutrients from the blood to the tissues and the removal of metabolic end products from the tissues to the blood take place. It is an area of intense study, because many believe the transition of shock from a relatively compensated state to a decompensated, and then irreversible state, happens at this level. The microcirculation in shock has been most studied in the skeletal muscle due to accessibility, and the belief that because of the large mass, relative to total body weight, changes here have a much more significant effect on the whole body, as compared to changes in smaller vascular beds. The initial response, as in other beds, is that of intense vasoconstriction under the influence of the sympathetic discharge. If the shock persists, however, there is paradoxical vasodilatation (58,59). The cause of this late vasodilatation, associated with rapid clinical deterioration, is not clearly established. It may be related to buildup of metabolic end products such as CO2 and Hþ (acid) (60). At the capillary level, the response to shock is very heterogeneous (59,61). Some capillaries are constantly perfused, others intermittently, and some, not at all (61,62). The absence of perfusion in some capillaries is thought to be due to endothelial cell swelling, microvascular thrombosis, and leukocyte plugging of the lumen (63,64). Additional arteriovenous channels open up allowing blood to be shunted from the arterioles directly into venules, bypassing the capillaries entirely. The sum total of this microcirculatory derangement is loss of effective capillary surface area, affecting diffusion of nutrients from the blood into tissues and metabolic end products from the tissue into the blood. The buildup of metabolic end products causes derangement in the interstitial milieu, ineffective enzyme systems, and cellular dysfunction. Even after resuscitation, some capillaries fail to ‘‘open up,’’ and this phenomenon is termed the ‘‘no-reflow phenomenon’’ (65). The proportion of capillaries demonstrating the no-reflow phenomenon has been correlated with survival. Thus, the more capillaries adversely affected, the less is the chance of survival.

Role of NO In 1980, several researchers postulated the existence of a chemical mediator that acted at the endothelial level, and was responsible for relaxation of the capillary sphincters, thus controlling microvascular perfusion. This unknown chemical was named the endothelium-derived relaxing factor (66). In 1987, this chemical was identified as nitric oxide (NO) (67). Further research showed that it was derived from L-arginine by a family of enzymes collectively called nitric oxide synthase (NOS). At least three forms of the enzyme have been described. The constitutive form, present in the endothelial cells (ecNOS), is responsible for the baseline production of NO. The best-characterized physiologic role of baseline NO is as a moment-to-moment vasodilator, critical in normal control of blood pressure and flow. A second form of NOS, expressed under the influence of proinflammatory stimuli, and also in prolonged shock, is called inducible NOS (iNOS). NO production by iNOS has been shown to occur in many cell types including

macrophages, hepatocytes, vascular smooth muscle cells, endothelial cells, and fibroblasts. Once induced, iNOS can produce large quantities of NO for hours or days. A third form, found mainly in the central nervous system, is called neural NOS and may be responsible for the differences seen in the systemic and cerebral circulation in response to shock. NO, once generated, has a very short half-life and functions in a paracrine fashion. The biologic actions of NO are principally mediated via the guanylate cyclase/ cyclic guanosine monophosphate pathway. Besides its role in controlling capillary perfusion, the L-arginine–NO pathway may play an important role in regulating the inflammatory state of the cell. The role of the L-arginine–NO pathway in the pathophysiology of shock is an area of intense study, particularly in shock associated with sepsis. In hypovolemic and traumatic shock states, NO levels have been shown to be low in the early phases, probably related to production of inhibitors of ecNOS and also to channeling of L-arginine to alternative pathways by upregulation of other enzyme systems, e.g., arginase (68,69). In prolonged shock and septic shock, NO levels are elevated, probably by upregulation of iNOS (70). This is associated with hypotension and the loss of vasoreactivity to catecholamines. These changes are most pronounced in septic shock but are also seen in other forms of shock. Attempts to improve clinical outcomes by modulating the L-arginine–NO pathway by inhibiting NOS activity to reduce the levels of NO, or conversely by providing NO donors and increasing NO levels, are areas of intense study.

The Cell in Shock The fundamental pathophysiological derangement at the cellular level during shock consists of an alteration in the metabolism, affecting cellular energy production and function. Adequate oxygen availability is crucial for normal cellular function. In the presence of oxygen, aerobic metabolism predominates, with generation of high-energy phosphate bonds—ATP—by sequential glycolysis, tricyclic acid (Kreb’s) cycle, and oxidative phosphorylation (Fig. 3). In the absence of oxygen, due to inadequate perfusion, metabolism shifts to an inefficient anaerobic glycolysis, with inadequate production of ATP and near-complete shutdown of the Kreb’s cycle and oxidative phosphorylation. Not only is the process less efficient, but lactic acid, a by-product of anaerobic metabolism, also builds up in the cell, causing the pH to drop, profoundly affecting essential enzyme systems. Intracellular acidosis can also influence the response of cells to various endogenously produced or exogenously administered circulating hormones or chemicals such as catecholamines or corticosteroids (71). Cellular integrity is dependant upon the protection offered by a functioning and intact cell membrane (72). Enzyme systems within the cell membrane maintain ionic gradients that are responsible for the transmembrane potential difference normally present. One of the most important enzyme systems is Naþ-Kaþ-ATPase. Studies have shown that the cell membrane dysfunction with influx of ions and water can be duplicated by ouabain, which directly inhibits the Naþ-Kaþ-ATPase pump (73). In the shock state, probably due to the depletion of ATP, this important system ceases to function properly resulting in the influx of Naþ into the cell. To maintain osmolar equilibrium, water follows, causing a major volume shift from the extracellular to the intracellular compartment. Additionally, the ionic shift results in significant decrease in the transmembrane

Chapter 8:

Pathophysiology of Shock

189

prolonged shock, and the intracellular accumulation of calcium has been shown to induce many of the changes observed in shocked cells (78). In the above discussion, the microcirculation and the cell have been discussed as separate entities, but in reality they are very intimately related. Changes in the microcirculation are responsible for the cellular derangements due to hypoxia, and conversely, deranged cellular physiology affects the microenvironment of the cell, which in turn influences the microcirculation.

Changes in Body Fluid Compartments

Figure 3 Glucose metabolism in the normally perfused (aerobic) and hypoperfused (anaerobic) state. In the well-perfused state with adequate oxygen availability, metabolism proceeds by sequential glycolysis, Kreb’s cycle, and oxidative phosphorylation to generate high-energy phosphate bonds in the form of adenosine triphosphate. In the hypoperfused state with lack of oxygen at the tissue level there is near complete shutdown of Kreb’s cycle and decoupling of oxidative phosphorylation resulting in fewer high-energy phosphate bonds, and generation of lactic acid as a by-product leading to metabolic acidosis. Abbreviations: ATP, adenosine triphosphate; NADH, nicotinamide adenine dehydrogenase.

potential difference (6,74). There are, however, important differences between cells subjected to the same degree of shock. For example, in skeletal muscle cells, all the mentioned changes are observed, except significant decreases in the ATP levels. It is postulated that the maintenance of ATP levels in muscle cells is from the conversion of creatine phosphate to ATP. In contrast, in hepatocytes, the same degree of shock results in significant depletion of ATP levels, because hepatocytes do not possess alternative sources of high-energy phosphate bonds that can be converted to ATP (54). To explain the inadequacy of NaþKaþ-ATPase in the absence of significant decrease in ATP levels, other mechanisms of cell membrane dysfunction have been postulated. One of the suggested alternative mechanisms for Naþ-Kaþ-ATPase dysfunction is primary damage by endotoxin, complement, or some unidentified toxic product of hypoxic cells (75,76). In addition to the cell membrane dysfunction with loss of transmembrane potential and influx of water and electrolytes into the cell, mitochondrial dysfunction has been implicated as a major component of overall cell dysfunction seen during shock. Mitochondrial dysfunction with uncoupling of oxidative phosphorylation and inadequate ATP production may be directly responsible for the energy depletion observed in the shock state. This is especially true for metabolically active tissues such as the liver. These abnormalities in mitochondrial function can persist for a prolonged period of time even after resuscitation and restoration of substrate has occurred (57,77). Abnormalities of calcium hemostasis are also suggested as a major component of cellular dysfunction during shock. Calcium plays a major role in cellular function: in gluconeogenesis, contraction coupling in excitable cells, protease activation, cell and mitochondrial membrane stability, and coupling of electron and hydrogen ion transport essential for oxidative phosphorylation. In addition, calcium acts as a second messenger for several hormones. A rapid influx of calcium has been shown to occur in cells subjected to

Sixty percent of the body weight in a healthy individual comprises water, with two-thirds being present intracellularly and the rest being extracellular. Three-quarters of the extracellular water is present in the interstitial space, and the rest is intravascular (Fig. 4). In early shock, reduced capillary perfusion results in decreased intracapillary hydrostatic pressure. The decreased hydrostatic pressure causes movement of fluid across the capillary membrane from the interstitial space into the intravascular compartment following Starling forces. Later in shock, there is relative hyperosmolarity of the extracellular compartment, produced by hyperglycemia. In response to this hyperosmolarity, there is movement of fluid from intracellular into the extracellular compartment. Both these changes, transcapillary refill and intra- to extracellular fluid movement, are compensatory mechanisms, augmenting circulating volume and improving cardiac output (Fig. 4). If the shock state persists, however,

Figure 4 Fluid shifts observed during various stages of untreated shock. In the normal person, two-thirds of the body water is present intracellularly. Of the extracellular water, three-fourths is in the interstitial compartment, and the remaining intravascular. With loss of volume from the intravascular compartment during hemorrhagic shock, there is contraction of the intravascular volume (uncompensated shock) leading to reduction in the capillary hydrostatic pressure. With compensation, interstitial fluid moves into the vascular compartment along Starling principles (transcapillary refill). With increased osmolarity of the extracellular compartment, contributed to mostly from hyperglycemia, intracellular fluid moves across cell membrane along osmotic gradients to augment interstitial and intravascular volumes. If the state of shock is prolonged, compensatory mechanisms fail. There is loss of cell membrane potential difference and movement of water and electrolytes across cell membrane resulting in increased intracellular space at the expense of extracellular compartments. — — —, Capillary endothelial lining; ——, cell membrane.

medwedi.ru

190

Part One: General Considerations

there is loss of cell membrane potential difference with derangement of ionic gradients and massive shift of fluid from the extracellular compartment into the cells. This intracellular uptake of fluid is the principal site of fluid and electrolyte sequestration seen in prolonged and severe shock (Fig. 4) (6,57,74). In addition, the systemic inflammation induced by prolonged shock results in capillary membrane dysfunction, causing fluid to shift from the intravascular compartment into the interstitium. Once a patient has passed into this phase of shock, for any therapy to be successful, massive volume infusions are required to replenish the extracellular compartment.

Compensated, Decompensated, and Irreversible Shock Wiggers in the mid-20th century performed a series of experiments involving animals with varying degrees of hemorrhagic shock. In his experiments, when animals were bled down to a low blood pressure and maintained in that state, they were relatively fine for a few hours, and completely recovered when the shed blood was returned. This state of shock was termed the ‘‘compensated phase.’’ In this compensated phase of shock, the body’s compensatory mechanisms, especially redistribution of blood flow and increased oxygen extraction, are sufficient to maintain survival. However, if the animals were maintained in shock for a more prolonged period, the animals failed to recover despite reinfusion of all the shed blood. These animals did survive, however, if in addition to the shed blood, they were also given large volumes of balanced salt solution. This state was called the decompensated phase of shock. Finally, if the animals were maintained in the shock state for an even greater length of time, they failed to recover despite reinfusion of all shed blood and infusion of large volumes of salt solution. This phase was termed by Wiggers as ‘‘irreversible shock’’ (6). More recently, these observations have been correlated with derangements at the microcirculatory and cellular level. The decompensated phase of shock occurs at the point when the compensatory mechanisms fail, and fluid shifts from the intravascular compartment to the interstitium across the capillary membrane, and also from the interstitium into the cells across the malfunctioning cellular membrane (6,57,74). The irreversibility of shock, and nonsurvival may be related to the volume of tissue beds that have been occluded for so long that despite resuscitation, too many areas are irretrievable due to microvascular thrombosis, endothelial cell swelling, and leukocyte plugging. While in the nonshocked state, 90% of the capillaries are perfused, shock results in the perfusion of only 30% to 50% of the capillaries. Early in shock, the ability of the organism to compensate and redistribute blood from peripheral beds to vital central organs is dependant on the degree of loss of these capillary beds (61,62). As resuscitation proceeds, arteriolar flow slowly increases with reperfusion of the capillary beds. In survivors, arteriolar flow rates reach 40% to 50% of normal within a few hours. However, in nonsurvivors (irreversible shock), arteriolar flow and consequent capillary reperfusion fails to reach beyond 15% to 20% of normal (65). In concert with these changes, the blood pressure in nonsurvivors fails to reach the levels observed in survivors. At the microcirculatory level, paradoxical dilatation of the precapillary sphincters is observed, with nonresponsiveness to exogenous catecholamines. These later changes are possibly related to upregulation of iNOS, with production of large quantities of NO (70,79).

Investigations into the cause of the no reflow phenomenon seem to implicate endothelial cell dysfunction with swelling, and leukocyte plugging with possible activation and release of toxic products by neutrophils (63,80). In a series of experiments involving animals that were either neutropenic (81) or whose neutrophils were inactivated by a monoclonal antibody directed against the neutrophil adhesion molecule CD18 (82), a higher proportion of animals with absent or nonfunctional neutrophils survived the same degree of shock as compared to normal animals. At autopsy, a significantly higher percentage of no reflow capillaries were noted in the normal (nonsurviving) animals, as compared to the animals with neutropenia, or nonfunctional neutrophils. Because neutrophil-mediated injury is maximum in an oxygen-rich environment, it is unclear how much of the damage is due to mechanical plugging produced by endothelial cell swelling and leukocyte entrapment occurring at the time of shock versus active damage produced by toxic neutrophil products at the time of oxygen abundance seen during resuscitation. Some investigators choose to view shock as a whole-body ischemia reperfusion injury, with neutrophil-mediated organ injury as the most important factor responsible for irreversibility and death (83).

MANAGEMENT CONSIDERATIONS To effectively manage a patient in shock and to reverse the pathophysiology of shock, it is important to be able to (i) diagnose shock by evaluating perfusion adequacy; (ii) treat the state of shock by improving perfusion; (iii) diagnose and treat the cause of shock.

Diagnosis of Shock—Evaluation of Perfusion Shock is a state of perfusion inadequacy, and not merely low blood pressure. In fact, a state of shock (inadequate perfusion) may exist in the face of ‘‘normal’’ blood pressure, while a patient in ‘‘hypotension’’ may have adequate perfusion and not be in shock. A number of relatively simple to fairly complex measures exist to evaluate a patient for adequacy of perfusion. These may broadly be divided into (i) global measures of perfusion adequacy and (ii) organspecific measures of perfusion adequacy. No one measure is perfect and each has its own false negatives and positives, and hence a battery of measures should be taken into consideration when diagnosing shock.

Global Measures of Perfusion Global measures of perfusion are indices that estimate the overall state of perfusion of the body. In situations where these are deranged, a state of shock almost certainly exists. However, if these global measures are within normal limits, there still may be areas in the body where significant hypoperfusion is present.

Lactic Acid The hypoperfusion in shock leads to cellular hypoxia. Cells respond to hypoxia by shifting from aerobic metabolism to anaerobic metabolism, with the generation of lactic acid as a by-product (Fig. 3). Lactic acid is normally cleared by the liver via the Cori cycle to generate bicarbonate. In shock, there is more lactic acid generated, and the liver’s ability to clear this is impaired due to hepatic hypoperfusion. This leads to the accumulation of lactic acid within the body, manifested by elevated serum levels. Elevated lactic acid

Chapter 8:

levels signify a global state of hypoperfusion, but like all global measures, normal levels do not rule out localized areas of hypoperfusion. Lactic acid levels may be elevated without hypoperfusion due to some drugs (Metformin), in liver disease due to poor hepatic clearance, and in acute alcohol intoxication. These drawbacks notwithstanding, the lactic acid level remains an excellent global measure of perfusion adequacy, and has been correlated with the degree of shock, and survival. Studies performed on trauma patients have shown that patients with traumatic shock, who rapidly clear lactic acid from the system in response to resuscitation, have a better outcome, as compared to patients who either fail to clear lactic acid, or do so very gradually (84).

Pathophysiology of Shock

191

the heart and some other similar organs are suffering from inadequate perfusion and lack of oxygen. Hence MvO2, although invasive, is a very sensitive global measure of perfusion adequacy (86). Modern pulmonary artery catheters are capable of continuously measuring the oxygen saturation in the pulmonary artery, thus providing an excellent realtime assessment of overall perfusion. However, MvO2 may be falsely high, suggesting adequate perfusion even in the presence of shock in patients with advanced liver disease due to opening of cutaneous arteriovenous channels, and also in patients with conditions in which the tissues are unable to extract oxygen from the hemoglobin (septic shock, cyanide poisoning, etc.).

Organ-Specific Measures of Perfusion Base Excess A negative base excess (formerly referred to as base deficit) signifies metabolic acidosis. In shock, there is accumulation of lactic acid as a by-product of anaerobic metabolism, resulting in lactic acidosis that manifests itself as metabolic acidosis and negative base excess. Base excess suffers from the same drawbacks as any other global measure. In addition, base excess may reveal significant metabolic acidosis due to causes other than shock-related hypoperfusion (e.g., renal failure or renal tubular acidosis). Base excess has been extensively studied, particularly in patients with traumatic shock, and is an excellent measure of perfusion adequacy, with good correlation with the degree of shock, and survival (85).

Mixed Venous Oxygen Saturation Hemoglobin molecules present within the red blood cells are the principal mode of oxygen transport within the body. Hemoglobin molecules bind oxygen in the lungs and, in the absence of pulmonary insufficiency, hemoglobin in the blood returning to the heart via the pulmonary veins is fully saturated (100%) with oxygen. At the tissue level, oxygen dissociates from the hemoglobin molecule providing the cells with oxygen. In the nonshocked state of adequate perfusion, the degree of oxygen extraction from the saturated hemoglobin molecule differs in different tissues depending upon the oxygen need. There is very little extraction (approximately 10%) in metabolically inactive tissues such as the skin and fat and the hemoglobin in the venous blood from such tissues remains approximately 90% saturated with oxygen. On the other hand, metabolically active tissues such as the heart muscle extract the maximum possible oxygen (approximately 70%) from the hemoglobin, and the coronary venous hemoglobin oxygen saturation is approximately 30%. When venous blood from all over the body is mixed together, the average oxygen saturation is approximately 75%. This is called the mixed venous oxygen saturation (MvO2) and is measured in blood from the pulmonary artery. The percentage of hemoglobin from which oxygen has been extracted is called the oxygen extraction ratio (normal ¼ 25–30%). In the shock state when the perfusion is inadequate to meet the body’s oxygen requirements, one of the earliest responses by the tissues is to increase extraction from hemoglobin. As a result, there is a decrease in MvO2 and a consequent increase in oxygen extraction ratio. While this compensatory mechanism is available to most tissues to maintain oxygen availability in times of inadequate perfusion, it is not possible in the heart where oxygen extraction is maximum even in the resting state. If the MvO2 falls below 60%, it can be presumed that at least

Due to the drawbacks of global measures, organ-specific measures of perfusion were developed, which evaluate perfusion in specific organs. These measures are mostly utilized for organs that the body considers nonvital, and from where perfusion is diverted away in favor of vital organs such as the heart and brain. The reasoning being that if the body is perfusing these organs well, the overall state of perfusion must be satisfactory.

Integument One of the first vascular beds from where perfusion is redirected away is the integument. Hence one of the earliest organs to show evidence of shock is the skin. On examination, the skin of a patient in shock is cold and clammy. More sophisticated measures have shown changes in cutaneous electrical resistance and changes in tissue oxygen tension measured transcutaneously (87). Although fairly sensitive, cold and clammy skin is not specific to shock, and can be seen in any condition that results in sympathetic stimulation.

Brain In shock, the body preferentially directs limited perfusion toward, rather than away from the brain. Nevertheless, higher brain function is extremely sensitive to even the slightest decrement in perfusion. A patient very early in shock will appear restless, agitated, and oftentimes confused. In severe shock the patient will rapidly lose consciousness. As with the skin, other conditions may produce these same findings.

Mucosal Tonometry Mucosal tonometry measures pH within the lining mucosa of internal organs. As with the skin, in shock, blood flow to the gastrointestinal and genitourinary tracts is severely compromised, resulting in acidosis of the mucous membranes lining these tracts. This fact has been utilized to assess perfusion within these tracts. A number of probes have been developed to measure the pH in different mucosal surfaces. The only technique that has been clinically utilized is gastric tonometry, where a probe attached to the gastric tube measures the pH within the gastric mucosa (88). Others have developed probes to similarly assess the pH in other mucous membranes—urinary bladder, sublingual, etc. While attractive in theory, mucosal pH can be altered by the tissue carbon dioxide levels, and the technique can be quite cumbersome in practice.

Treatment of Shock—Improving Perfusion Once it has been determined that perfusion is inadequate, i.e., a state of shock exists, treatment should be directed

medwedi.ru

192

Part One: General Considerations

toward improving perfusion, or reversing the shock state. Among the different types of shock, cardiac compressive shock is an emergency that unless treated immediately can rapidly lead to death. Fortunately, in the majority of instances, cardiac compressive shock can be rapidly diagnosed by a good physical examination. Treatment should immediately achieve decompression of the pericardial or pleural cavities, as the case may be, to rapidly reverse the process and improve perfusion. In all other forms of shock, a systematic approach is essential to elucidate the fundamental derangement—preload, contractility, or afterload—that is responsible for the shock state (Fig. 5). The clinical scenario can provide useful direction as to the most likely derangement. For example, patients with major trauma in most instances would be suffering from hypovolemic shock—reduced preload—due to hemorrhage, while in the presence of high spinal cord injury, neurogenic shock—loss of afterload—is the likely cause. Patients presenting with acute myocardial infarction associated with shock are most likely to have cardiogenic shock— poor contractility—as a cause. However, even in such obvious situations, other derangements should not be ruled out, because a patient presenting in shock following a major motor vehicle collision may have had an acute myocardial infarction that caused the collision.

Evaluation of Preload An adequate circulating volume is essential for adequate cardiac function and perfusion. Adequacy of circulating volume may be assessed clinically by examination for fullness of peripheral veins, auscultation of the chest for rales, examining a chest radiograph for fullness and size of the heart, and the radiolucency of the lung fields. In some situations, the clinical evaluation may be confusing because the variables mentioned are nonspecific and can be affected by other conditions. In such situations, more invasive methods include measurement of the central venous pressure that evaluates cardiac filling on the right side of the heart, and the capillary wedge pressure that evaluates filling on the left side of the heart. However, filling pressures can be affected by the prevailing pressures in the thoracic cavity (e.g., pulmonary and abdominal). Second, the premise of using pressures to evaluate cardiac end-diastolic volume— preload—is that the higher the end-diastolic volume, the higher will be the filling pressures. This premise is based on ‘‘normal’’ pressure–volume relationship of the heart or ‘‘normal’’ ventricular compliance. It is well known that in many disease states, notably sepsis, the ventricular compliance can change from day to day. Hence, filling pressures may give an erroneous estimate of preload. When the clinical picture is confusing, pulmonary artery catheters with

Figure 5 Algorithm outlining the steps in the evaluation and management of shock. Evaluation steps are shown in clear boxes, and action steps in shaded boxes. The callouts to the right show aids used in the suggested evaluation/action.

Chapter 8:

rapid response thermisters can be utilized to directly measure cardiac end-diastolic volume. Using these catheters, it is possible to construct the pressure–volume loop and quantitatively measure all parameters of perfusion. Lastly, a small volume challenge may be necessary to establish whether increasing the preload further will be of benefit or not. If by rapidly infusing a bolus of 250 to 500 mL of crystalloid clinical improvement in the perfusion markers is achieved, the patient will benefit from further increases in circulating volume. If however there is no improvement in the perfusion status, the whole clinical situation should be reevaluated to determine the most appropriate intervention. Experimentally, it has been determined that in patients in shock, who have low preload, volume infusion is the most efficient method of improving perfusion—maximum improvement with least cost in terms of increase in cardiac energy needs.

Evaluation of Contractility After determining that the patient has adequate preload, and yet continues to have poor perfusion—remains in shock—evaluation and improvement in cardiac contractility should be the next intervention in the treatment of shock. The best method to quantify cardiac contractility is to place a pulmonary artery catheter with the rapid response thermister and construct a pressure–volume loop. However, even in the absence of such a catheter, a therapeutic trial of an ionotropic agent may provide the required information. If by augmenting the contractility there is improvement in perfusion parameters, then the agent should be continued. Although improving contractility by using such agents results in significant increase in cardiac oxygen requirements, it is more energy efficient than using pressor agents to manipulate afterload. Intensive monitoring is essential to prevent the development of excessive tachycardia because that can lead to a significant increase in cardiac energy requirements, and even precipitate cardiac ischemia.

Evaluation of Afterload In rare situations, after maximizing preload and optimizing cardiac contractility, the patients still remains in shock. In such situations, afterload manipulations are necessary. Increase in afterload is often necessary in neurogenic shock. In other forms of shock, it should be borne in mind that increasing afterload to increase blood pressure, while sometimes required, places a great strain on the heart. Hence increasing afterload by pressor agents should be performed with extreme caution, and for the shortest possible time. It is advisable to have a pulmonary artery catheter in place to ensure that the patient has a high cardiac output, and introduction of a pressor to increase blood pressure will improve perfusion, and not decrease it further. The situation is most often encountered in patients with septic shock; however, afterload manipulation should only be done after ensuring adequate circulating volume and improving cardiac contractility. On the other hand, in some patients, especially older individuals, afterload reduction may be of tremendous benefit. Afterload reduction improves cardiac performance by decreasing the resistance against which the heart has to pump. If the blood pressure is adequate, the circulating volume replenished, and contractility increased, then an agent to reduce afterload may improve perfusion dramatically, while at the same time reducing the cardiac energy requirements. It should be mentioned that the systemic vascular resistance as calculated by regular pulmonary artery

Pathophysiology of Shock

193

catheter is very unreliable in quantifying the afterload. This value is derived from the measured cardiac output. Hence if the value is high with a low cardiac output, it cannot be presumed that the low cardiac output is secondary to the high systemic vascular resistance. On the other hand, utilizing the pulmonary artery catheter with rapid response thermister will allow the construction of the pressure–volume loop and the measurement of the afterload, independent of the preload and contractility. This may be invaluable in guiding therapy in patients in whom afterload manipulation is necessary to maintain adequate perfusion.

Treatment of the Cause of Shock The causes of shock are many. As the hypoperfusion of shock is being addressed, a systematic effort should be made to determine the cause of the shock and provide appropriate therapy. The specific therapy for each condition leading to shock is adequately dealt with in other chapters of this book.

THE FUTURE Current therapy of shock involves reversing the deranged physiology brought about by prolonged or severe hypoperfusion leading to tissue hypoxia. One of the areas of research involves developing resuscitation solutions that not only provide circulating volume but at the time also carry oxygen. Such solutions will allow a more rapid correction of the deranged physiology, and possibly improve outcome. Another area of research involves elucidating the cellular and subcellular mechanisms that cause some patients with prolonged or severe shock to pass into a phase of irreversibility. Although the causes and exact point at which an individual passes into the irreversible phase is not clearly established, studies suggest that the transition happens at the microcirculatory level. Some researchers are focusing on therapies to improve the microcirculation while the overall macrocirculatory perfusion is being improved by conventional therapy. Lastly, systemic inflammation initiated by shock contributes very significantly toward organ system failure and death. Therapies are being developed to attenuate the runaway systemic inflammatory response and prevent organ system dysfunction and death.

SUMMARY Shock is a state of perfusion that is inadequate to meet the metabolic needs of the body. It represents a continuum from the relatively compensated state of occult hypoperfusion, to the severe irreversible state where the fundamental functions of the cell are so compromised that no recovery is possible. Because no cell in the body can exist for long without adequate perfusion, even a mild state of shock has far-reaching consequences on every cell in the body, and in turn on the functioning of the organ system comprising those cells. The body responds in a predictable fashion to the state of hypoperfusion by initiating compensatory responses to assure survival of the organism. To adequately treat shock, the state of hypoperfusion has to be recognized. Once recognized, a systematic, sequential pathway should be formulated to correct one or more of the deranged parameters that define perfusion—preload, cardiac contractility, and afterload. At the same time as the shock state is being treated—perfusion being improved—the specific cause of shock should be sought and treated.

medwedi.ru

194

Part One: General Considerations

REFERENCES 1. Crile GW. An Experimental Research into Surgical Shock. Philadelphia: JB Lippincott, 1899. 2. Cannon WB, Bayliss WM. Notes on Muscle Injury in Relation to Shock: Special Report of the Medical Research Commission. Vol. 26, 1919:19. 3. Keith NM. Blood Volume Changes in Wound Shock and Primary Hemorrhage: Reports of the Special Investigations Committee on Surgical Shock and Allied Conditions. Vol. 9. London, 1919. 4. Blalock A. Experimental shock, the cause of the low blood pressure produced by muscle injury. Arch Surg 1988; 123:285. 5. Wiggers CJ. Myocardial depression and shock: survey of cardiodynamic studies. Am Heart J 1947; 33:633. 6. Shires GT, Cunningham JN, Baker CRF, et al. Alterations in cellular membrane function during hemorrhagic shock in primates. Ann Surg 1984; 176:288. 7. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330:1717. 8. Suga H, Sugawa K, Shoukas AA. Load independence of the pressure-volume loop of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973; 32:314. 9. Suga H, Sugawa K. Instantaneous pressure-volume relationships and their ration in the excised, supported canine left ventricle. Circ Res 1974; 35:117. 10. Sunagawa H, Maughan WL, Burkoff D, et al. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983; 245:H773. 11. Sunagawa H, Maughan WL, Sagawa K. Optimal arterial resistance for the maximal stroke work studied in isolated canine left ventricle. Circ Res 1985; 56:586. 12. Angele MK, Schwacha MG, Ayala A, et al. Effect of gender and sex hormones on the immune responses following shock. Shock 2000; 14:81. 13. Gann DS, Cross JS. The neuroendocrine response to critical illness. In: Barie PS, Shires GT, eds. Surgical Intensive Care. Boston: Little Brown & Company, 1993:93–134. 14. Cryer PE. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. NEJM 1980; 303:436. 15. Peitzman AB, Billiar TR, Harbrecht BG, et al. Hemorrhagic shock. Curr Probl Surg 1995; 32:925. 16. McLeod MK, Carlson DE, Gann DS. Hormonal responses associated with early hyperglycemia after graded hemorrhage in dogs. Am J Physiol 1986; 251:E597. 17. Ramsay DJ, Keil LC, Sharpe MC, et al. Angiotensin II infusion increases vasopressin, ACTH, and 11-hydroxycorticosteroid secretion. Am J Physiol 1979; 234:R66. 18. Choudhary IH, Ertel W, Ayala A. Alteration in inflammatory cytokine production following hemorrhage and resuscitation. In: Schlag G, Redl H, Traber DL, eds. Shock, Sepsis and Organ Failure. Berlin: Springer-Verlag, 1993:73–77. 19. Spertini O, Kansas GS, Munro JM, et al. Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin. Nature 1991; 349:691. 20. Springer TA, Lasky LA. Cell adhesion: sticky sugars for adhesion. Nature 1991; 349:191. 21. Huber AR, Kunkel SL, Todd RF, et al. Regulation of transendothelial neutrophil migration by endogenous interleukin-8. Science 1991; 254:99. 22. Runcimann WB, Skowronski GA. Pathophysiology of hemorrhagic shock. Anesth Intens Care 1984; 12:193. 23. Svaki HE, Macpherson H, McCulloch J. Alteration in local cerebral glucose utilization during hemorrhagic hypotension in the rat. Circ Res 1982; 50:633. 24. Dora E, Kovach AGB, Nyary I. Hypothalamic and cortical evoked potentials in hemorrhagic shock. Adv Exp Med Biol 1972; 33:481. 25. Peterson CG, Haugen FP. Hemorrhagic shock and the nervous system. Am J Surg 1963; 106:233.

26. Chen RYZ, Fan FC, Schuessler GB, et al. Regional cerebral blood flow and oxygen consumption of the canine brain during hemorrhagic hypotension. Stroke 1984; 15:343. 27. Bronshvag MM. Cerebral pathophysiology in hemorrhagic shock: nuclide scan data, fluorescence microscopy, and anatomic correlations. Stroke 1980; 11:50. 28. Hirasawa H, Odaka M, Tabata Y, et al. Tissue blood flow in brain, liver, renal cortex, and renal medulla in experimental hemorrhagic shock. Crit Care Med 1977; 5:141. 29. Maitra SR, Pan W, Geller ER, et al. Alteration in renal gluconeogenesis and blood flow during hemorrhagic shock. Circ Shock 1993; 41:67. 30. Okada K, Tanokura Y, Tajimi K, et al. MDF: its participation in the pathophysiology of shock. Prog Clin Biol Res 1983; 111:125. 31. Markov AK, Oglethorpe N, Young DB, et al. Irreversible hemorrhagic shock: treatment and cardiac physiology. Circ Shock 1981; 8:9. 32. Thorne J, Blomquist S, Elmer O. Polymorphonuclear leukocyte sequestration in the lung and liver following soft tissue trauma: an in vivo study. J Trauma 1989; 29:451. 33. Claridge JA, Enelow RI, Young JS. Hemorrhage and resuscitation induce delayed inflammation and pulmonary dysfunction in mice. J Surg Res 2000; 92:206. 34. Pascual JL, Kwaja KA, Ferri LE, et al. Hypertonic saline resuscitation attenuates neutrophil lung sequestration and transmigration by diminishing leukocyte-endothelial interactions in a two-hit model of hemorrhagic shock and infection. J Trauma 2003; 54:121. 35. Munrao Y, Hoyt DB, Loomis W, et al. Does the timing of hypertonic saline resuscitation affect its potential to prevent lung damage? Shock 2000; 14:18. 36. Zuckerman GR, Shuman R. Therapeutic goals and treatment options for prevention of stress ulcer syndrome. Am J Med 1987; 83:29. 37. McNeil JR, Stark RD, Greenway CV. Intestinal vasoconstriction after hemorrhage: role of vasopressin and angiotensin. Am J Physiol 1970; 219:1342. 38. Reilly PM, Bulkley GB. Vasoactive mediators and splanchnic perfusion. Crit Care Med 1993; 21:S55. 39. Gosche JR, Garrison RN. Prostaglandins mediate the compensatory responses to hemorrhage in the small intestine of rat. J Surg Res 1991; 50:584. 40. Flynn WJ, Cryer HG, Garrison RN. Pentoxifylline restores intestinal microvascular blood flow during resuscitated hemorrhagic shock. Surgery 1991; 110:350. 41. Scannell G, Clark L, Waxman K. Regional flow during experimental hemorrhage and crystalloid resuscitation: persistence of low flow to the splanchnic organs. Resuscitation 1992; 23:217. 42. Wang P, Hauptman JG, Choudhary IH. Hemorrhage produces depression in microvascular blood flow which persists despite fluid resuscitation. Circ Shock 1990; 32:307. 43. Hernandez LA, Grisham MB, Twohig B, et al. Role of neutrophils in ischemia-reperfusion-induced microvascular injury. Am J Physiol 1987; 253:H699. 44. Parks DA, Bulkley GB, Granger DN, et al. Ischemic injury in the cat small intestine: role of superoxide radicals. Gastroenterology 1982; 82:9. 45. Baker JW, Deitch EA, Li M, et al. Hemorrhagic shock induces bacterial translocation from the gut. J Trauma 1988; 28:896. 46. Redan JA, Rush BF, McCullough JN, et al. Organ distribution of radiolabeled enteric Escherichia coli during and after hemorrhagic shock. Ann Surg 1990; 211:663. 47. Moore EE, Moore FA, Franciose RJ, et al. The postischemic gut serves as a priming bed for circulating neutrophils that provoke multiple organ failure. J Trauma 1994; 37(6):881. 48. Deitch EA, Xu D, Franko L, et al. Evidence favoring the role of the gut as a cytokine-generating organ in rats subjected to hemorrhagic shock. Shock 1994; 1:141. 49. Soini HO, Takala J, Nordin AJ, et al. Peripheral and liver tissue oxygen tensions in hemorrhagic shock. Crit Care Med 1992; 20:1330.

Chapter 8: 50. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol 1985; 249:G549. 51. Hirsch IJ, Rone AS. Hepatic arterial and portal flow in cardiogenic and hemorrhagic shock in awake dogs. Circ Shock 1982; 9:17. 52. Koo A, Liang IYS. Blood flow in hepatic sinusoids in experimental hemorrhagic shock in the rat. Microvasc Res 1977; 13:315. 53. Marzi I, Bauer C, Hower R, et al. Leukpcyte-endothelial cell interactions in the liver after hemorrhagic shock in the rat. Circ Shock 1993; 40:105. 54. Peitzman AB, Corbett WA, Shires GT III, et al. Cellular function in liver and muscle during hemorrhagic shock in primates. Surg Gynecol Obstet 1985; 161:419. 55. Collins JA. The pathophysiology of hemorrhagic shock. Prog Clin Biol Res 1982; 108:5. 56. Maitra SR, Geller ER, Pan W, et al. Altered cellular calcium regulation and hepatic glucose production during hemorrhagic shock. Circ Shock 1992; 38:14. 57. Rhodes RS, DePalma RG. Mitochondrial dysfunction of the liver and hypoglycemia in hemorrhagic shock. Surg Gynecol Obstet 1980; 150:347. 58. Bond RF, Manley ES, Green HD. Cutaneous and skeletal muscle vascular responses to hemorrhage and irreversible shock. Am J Physiol 1967; 212:488. 59. Garrison RN, Cryer HM III. Role of the microcirculation to skeletal muscle during shock. Prog Clin Biol Res 1989; 299:43. 60. Cryer HM, Kaebnick H, Harris PD, et al. Effects of tissue acidosis on skeletal muscle microcirculatory responses to hemorrhagic shock in unanesthetized rats. J Surg Res 1985; 39:59. 61. Haljamae H. Microcirculation and hemorrhagic shock. Am J Emerg Med 1984; 2:100. 62. Amundson B, Jennische E, Haljamae H. Skeletal muscle microcirculatory and cellular metabolic effects of whole blood, Ringer’s acetate, and dextran 70 infusions in hemorrhagic shock. Circ Shock 1980; 7:111. 63. Mazzoni MC, Borgstrom P, Intaglietta M, et al. Luminal narrowing and endothelial cell swelling in skeletal muscle capillaries during hemorrhagic shock. Circ Shock 1980; 29:27. 64. Bagge U, Amumdsom B, Lauritzen C. White blood cell deformability and plugging of skeletal muscle capillaries in hemorrhagic shock. Acta Physiol Scand 1980; 180:159. 65. Zhao KS, Junker D, Delano FA, et al. Microvascular adjustments during irreversible hemorrhagic shock in rat skeletal muscle. Microvasc Res 1985; 30:143. 66. Furchgott RF, Zawadski JW. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288:373. 67. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327:524. 68. Jacob TD, Ochoa JB, Udekwu AO, et al. Nitric oxide production is inhibited in trauma patients. J Trauma 1993; 35:590. 69. Ochoa JB, Bernard AC, Mistry SK, et al. Trauma increases extrahepatic arginase activity. Surgery 2000; 127:419.

Pathophysiology of Shock

195

70. Szabo C. Alterations in nitric oxide production in various forms of circulatory shock. New Horiz 1995; 3:2. 71. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992; 20:80. 72. Choudhary IH, Sayeed MM, Baue AE. Effect of adenosine triphosphate-magnesium chloride administration n shock. Surgery 1974; 75:220. 73. Williams JA, Winthrow CD, Woodbury DM. Effects of ouabain and diphenylhydantom on transmembrane potentials, intracellular electrolytes, and cell pH of rat muscle and liver in vivo. J Physiol 1971; 212:101. 74. Shires GT III, Peitzman AB, Illner H, et al. Changes in red cell transmembrane potential in hemorrhagic shock. Surg Forum 1981; 32:5. 75. Eastridge BJ, Darlington DN, Evans JA, et al. A circulating shock protein depolarizes cells in hemorrhage and sepsis. Ann Surg 1994; 219:298. 76. Jones R, Carlson DE, Gann DS. A circulating shock protein that depolarizes cells in vitro depresses myocardial contractility and rate in isolated rat hearts. J Trauma 1994; 37:752. 77. Choudhary IH. Cellular mechanisms in shock and ischemia and their correction. Am J Physiol 1983; 245:R117. 78. Smith A, Hayes G, Romaschin A, et al. The role of extracellular calcium in ischemia reperfusion injury in skeletal muscle. J Surg Res 1990; 49:153. 79. Thiermann C, Szabo C, Mitchell JA, et al. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci USA 1993; 90:267. 80. Barroso-Aranda J, Schmid-Schonbein GW, Zweifach BW, et al. Granulocytes and no-reflow phenomenon in irreversible hemorrhagic shock. Circ Res 1988; 63:437. 81. Barroso-Aranda J, Schmid-Schonbein GW. Transformation of neutrophils as indicator of irreversibility in hemorrhagic shock. Am J Physiol 1989; 257:H846. 82. Vedder NB, Fouty BW, Winn RK, et al. Role of neutrophils in generalized reperfusion injury associated with resuscitation from shock. Surgery 1989; 106:509. 83. Powell SR, Tortolani AJ. Recent advances in the role of reactive oxygen intermediates in ischemic injury. J Surg Res 1992; 53:417. 84. Abramson D, Scalea T, Hitchcock R, et al. Lactate clearance and survival following injury. J Trauma 1993; 35:584. 85. Rutherford E, Morris J, Reed G, et al. Base deficit stratifies mortality and determines therapy. J Trauma 1992; 33:417. 86. Bishop MH, Shoemaker WC, Appel PL, et al. Prospective randomized trial of survivor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation endpoints in severe trauma. J Trauma 1995; 38:780. 87. Tremper KK, Shoemaker WC. Transcutaneous oxygen monitoring of critically ill adults with and without low flow shock. Crit Care Med 1981; 9:706. 88. Ivatury RR, Simon RJ, Islam S, et al. A prospective randomized study of endpoints of resuscitation after major trauma: global oxygen transport indices versus organ-specific gastric mucosal pH. J Am Coll Surg 1996; 183:145.

medwedi.ru

9 Neoplastic Disease: Pathophysiology and Rationale for Treatment Gregory Kennedy and John E. Niederhuber

INTRODUCTION Our understanding of both cellular and molecular properties of neoplasia has been significantly enhanced by studies using fresh human tissue and clonogenic tumor cells in tissue culture. In this chapter, we describe basic principles of cancer biology modeled in part from a thoughtful review by Hanahan and Weinberg (1). We have used the six traits of a cancer cell (Table 1) as coined by Hanahan and Weinberg to describe the basic tenets of cancer biology. We also demonstrate through a review of the literature how findings in basic research lead to improved therapies for the treatment of cancer. Finally we summarize basic principles underlying the treatment of cancer. By joining insights from basic research to developments in treatment, we hope to provide rationales for the next generation of cancer therapies.

BASIC CONCEPTS OF CANCER BIOLOGY Self-Sufficiency in Growth Signals The ability to grow autonomously was an early-recognized trait of cancer cells. Researchers identified, in cancer cells, mutations that allow the product of a gene to bypass the normally obligate requirement of somatic cells for external mitogenic signals (2). The identification of these genes was assisted by virologists interested in understanding how certain retroviruses transformed normal avian cells (3,4). Identifying the genes responsible for the transformation of the phenotype induced by infection of cells with retroviruses led to the discovery of mammalian homologs of the viral gene products (5,6). It has been observed over the years that mutations within the cellular proto-oncogenes are a requirement for tumor development and have been found to be common in tumors of all types. For example, it is estimated that up to 20% of all human tumors will have undergone an activating mutation in one of the most famous proto-oncogenes, the Ras gene(s) (7). Such mutations allow the Ras protein to function independently of mitogenic signals, thereby providing a constitutive growth signal to the

Table 1 Six Traits of a Cancer Cell Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Evasion of programmed cell death Limitless replicative potential Sustained angiogenesis Tissue invasion and metastasis Source: From Ref. 1.

cell (8). In fact, one group studying H-Ras’ role in the genesis and maintenance of tumors using an inducible murine model of melanoma found the function of Ras to be required for continued cell survival despite the exogenous addition of alternative growth factors (9). This work demonstrates the importance of oncogenic signals in maintaining cellular proliferation and provides hope that functions of the Ras protein may serve as targets for novel therapeutics (10). In fact, many different inhibitors of the Ras protein and the Ras-signaling pathway have been developed and are in clinical trials (10). One such class of drugs is constituted by the farnesyl transferase inhibitors. These drugs work by inhibiting the posttranslational modification of the Ras protein, thereby disrupting its cellular localization. While these drugs have shown great promise in the preclinical phase of their development (11), their use in humans has been somewhat disappointing (10). Another mechanism by which tumor cells frequently achieve autonomous growth is through the modulation of growth factor signals. While most soluble mitogenic growth factors are made by one cell type to stimulate proliferation of another, many cancer cells acquire the ability to synthesize growth factors to which they are responsive, creating positive feedback, often termed ‘‘autocrine stimulation.’’ The idea that tumor cells synthesize, release, and respond to their own growth factors is not novel. A large variety of transformed cells have been reported to produce mitogenic factors, suggesting that this ability of self-stimulation might be important in the establishment and maintenance of transformation. The action of the transforming growth factor peptides is mediated by their distinct membrane receptors, which in turn activate a signaling mechanism eventually leading to a mitogenic response. Such a signaling pathway may be modified by oncogene expression at the receptor or postreceptor levels, as well as by changes in the level of expression of the growth factor itself (12). Indeed, the ability of many oncogenes to render cancer cells independent of growth factors seems to be related to how they alter a signaling pathway, rather than to a primary alteration in the synthesis and release of a specific growth factor. The autocrine action of the effector peptide may be amplified by mechanisms other than an increase in concentration. For example, enhanced cellular responsiveness to a growth factor may also result from a change in the number or affinity of receptors of the growth factor. Thus, very high numbers of epidermal growth factor receptors (EGFrs) are found in squamous carcinoma cells derived from human head and neck cancers (13). Furthermore, different types of sarcomas stained with a monoclonal antibody to EGFr’s demonstrated increased staining in the tumor compared to the stroma (14).

medwedi.ru 197

198

Part One: General Considerations

These types of observations have been furthered by inhibiting the EGFr’s activity with a monoclonal antibody, which resulted in an increased radiosensitivity of squamous cell carcinoma cell lines in vitro (15). Such preclinical observations may have a substantial impact on the treatment of various cancers. Cancer cells can also switch the types of extracellular matrix receptors (integrins) they express, favoring ones that transmit progrowth signals (16,17). In general, cells require anchorage to the extracellular matrix to maintain viability. Integrins can affect viability through the promotion of either cell growth or cell death. For example, integrins can facilitate growth factor–mediated activation of extracellular signal-regulated kinase (ERK), which may be required for cell growth via phosphorylation of the ternary complex factor, which promotes transcription of the immediate-early gene c-Fos (18). On the other hand, loss of attachment to the matrix results in the apoptotic death of many cell types. Mechanisms by which integrins protect cells from apoptosis vary. The integrin a5b1, which binds to fibronectin in the extracellular matrix, protects cells from apoptosis by upregulating the antiapoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) (19). On the other hand, the a5b1 integrin promotes endothelial and melanoma cell survival by the suppression of the p53 pathway and activation of the nuclear factor kappa B transcription factor (20,21). Furthermore, treatment of melanoma M21 cells with antagonists of the integrin a5b3 resulted in their apoptotic death (22). Such observations provide hope that inhibitors of these cell surface proteins may someday prove useful for the treatment of cancer. Tumor growth has traditionally been explored by focusing on isolated genetically deranged cancer cells. While this experimental approach has given us much insight into the biology of cancer, it has ignored any contribution to tumor growth provided by the microenvironment—the apparently normal bystander cells such as fibroblasts, endothelial cells, macrophages, etc. Virtually all cancers are composed of several distinct cell types that appear to communicate via heterotypic signaling. This heterotypic signaling may play a significant role in the initiation of a tumor, as well as in the maintenance of the tumor cell’s continued proliferation. For example, fibroblast cells

constitutively expressing platelet derived growth factor (PDGF) have been shown to induce epithelial tumors when subcutaneously injected into nude mice (23). These findings indicate that successful epithelial tumor cells have the ability to cooperate with their stromal microenvironment, thereby making them more physiologically fit to grow into a tumor. Other studies have found that the initiated cells grown in the presence of stroma isolated from a tumor have a phenotype different from that of the same cells grown in the presence of stroma isolated from normal tissue (24). These observations have been extended by others who have shown that mutations in the tumor suppressor genes p53 and phosphate tensin homolog (PTEN) can be identified in both the tumor and stromal compartments (25); furthermore, these mutations seem to be exclusive of one another. The fact that mutations could be found in these tumor suppressor genes of the stromal cells independent of the epithelial cells is consistent with the stroma contributing through epithelial–stromal cross-talk to tumor development (25). Taken together it is clear that the emphasis formerly placed on isolated tumor cells needs to also include the environment in which the tumor cells reside. Such a shift in paradigm to a ‘‘tissue’’ or ‘‘organ’’ dynamic should result in the identification of new targets for the development of new therapeutic agents.

Insensitivity to Growth-Inhibitory Signals Antiproliferative signals exist to keep the growth of cells in check, thereby preventing tumor formation and achieving tissue homeostasis. These growth-inhibitory signals, like growth-promoting signals, are received by transmembrane receptors coupled to intracellular signaling circuits. To understand fully the mechanism by which antiproliferative signals work, we must first understand the basic cell cycle. The classic cycle of cell division (Fig. 1) can be divided into four ordered and strictly regulated stages: G1 (Gap 1), S (DNA synthesis), G2 (Gap 2), and M (mitosis) (26). Daughter cells generated by mitosis reside in either G1 or G0 (resting or quiescent state) and retain a diploid set of chromosomes. The ultimate molecular regulator of the cell cycle is the retinoblastoma protein (pRb) (27,28). pRb is the classic tumor suppressor protein, the function of which is lost in

Figure 1 A schematic representation of the cell cycle. In the first phase of the cell cycle (G1), the cell is undergoing biochemical changes required for the synthesis of DNA (S). G2 is the second preparatory phase of the cell cycle during which time the cell prepares for mitosis to occur (M). The restriction point of the cell cycle (R) is that point in the cell cycle prior to which mitogenic factors are required for the cell to progress through the cycle. After the restriction point, mitogens are not required for continued progression. G0 is a phase of the cell cycle marked by quiescence. This is a reversible process unless the cell is stimulated to exit the cell cycle permanently commonly through the process of differentiation.

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

patients with retinoblastoma, and was the paradigm for Knudson’s ‘‘two-hit hypothesis’’ (29,30). The essence of this hypothesis is that one mutation within the tumor suppressor gene is inherited with a second ‘‘hit’’ or mutation, resulting in inactivation being required for loss of function. This process is often referred to as loss of heterozygosity or LOH. Tumor suppressor proteins act to regulate growth in a negative manner and are identified when shown to be inactivated by inherited or somatic mutations or through some epigenetic event [for example, promoter methylation (31)] in active cancer cells. Furthermore, the loss of function of a tumor suppressor protein provides a cell with a survival advantage. In the case of pRb, loss of function leads to release of the E2 promoter binding factor (E2F) family of transcription factors, which can then heterodimerize with their binding partners and activate transcription of various E2F-responsive genes, thereby driving the progression of the cell cycle from G1 into the S-phase (32,33). Thus, loss of pRb activity renders cells insensitive to antiproliferative signals that normally would lead to cellular quiescence and arrest of the cell cycle. Antigrowth signals can block proliferation by two distinct mechanisms. The first is characterized by an exit from the cell cycle into a quiescent state. A hallmark of this process of cell cycle exit is reversibility, which can be stimulated by extracellular signals. The process of differentiation is the second mechanism by which proliferation can be blocked. This is a complex, irreversible process. In fact, the genetic events that lead to a state of differentiation are unclear. However, it is clear that tumors can be in various states of differentiation and the inhibition of differentiation plays a role in tumorigenesis. A simplistic way to understand the inhibition of differentiation is to consider a tumor as an aberrant organ initiated by tumorigenic cancer cells that have acquired the capacity for indefinite proliferation through accumulated mutations. This analogy is reminiscent of a normal stem cell giving rise to a normal organ; so we should be able to apply the principles of normal stem cell biology to understand better how tumors develop (34,35). In fact, many observations suggest that analogies between normal stem cells and tumorigenic cells may be appropriate. Both normal stem cells and tumorigenic cells have extensive proliferative potential and the ability to give rise to new tissues. Both tumors and normal tissues are composed of heterogeneous combinations of cells, with different phenotypic characteristics and proliferative potentials (36–39). Because most tumors have a clonal origin (40–43), tumorigenic cancer cells must give rise to phenotypically diverse progeny including cancer cells with indefinite proliferative potential, as well as cancer cells with limited or no proliferative potential. This notion suggests that tumorigenic cancer cells undergo processes that are analogous to the self-renewal and differentiation of normal stem cells. In fact, the hypothesized tumor stem cell population has been identified in breast cancer (44–46). Identification of these populations of cells provides a tantalizing target for the design of new drugs. Therapies that target and efficiently kill populations of pluripotent cells within tumors may ultimately add to the armamentarium of treatment options for some tumors.

Evasion of Programmed Cell Death Apoptosis was initially described by its morphological characteristics, including cell shrinkage, chromatin condensation, and nuclear fragmentation (47–49). The genetic control of

199

this process was initially elucidated through elegant studies using Caenorhabditis elegans (50–52), and similar pathways were quickly identified in human cells (53–55). The genedirected nature of apoptosis implies that cell numbers can be regulated by factors that influence cell survival as well as those that control proliferation and differentiation. Moreover, the genetic basis for apoptosis makes it clear that cell death, like any other metabolic ordevelopmental program, can be disrupted by mutation. In fact, the ability to overcome this innate death signal can contribute to carcinogenesis as well as many other human diseases (49). Induction of apoptosis generally involves the detection of a signal—extrinsic or intrinsic—followed by activation of a proteolytic cascade resulting in cell death (Fig. 2) (56–60). The constituents of the pathway can be classified as either sensors or effectors of apoptosis. The role of the sensor molecule is to receive a signal from either extrinsic [Fas ligand expressed on a neighboring cell or the activation of a tumor necrosis factor (TNF)-receptor, for example] or intrinsic sources (through the detection of DNA damage) and transmit this signal into the effector compartment of the pathway. Upon receiving this death signal, the effectors are activated and carry out their duties, ultimately resulting in the characteristic apoptotic changes. The basic effectors of the apoptotic pathway are composed of a group of cysteine proteases, collectively referred to as the caspases. Caspases can be categorized into initiator caspases (caspases 8 and 9) and the effector caspases (for a thorough review on the signaling of apoptosis please see Ref. 60). The initiator caspases receive the signal from the sensors and initiate the proteolytic cascade by processing and activating the effector caspases (61). Some effector caspases cleave and inactivate certain vital cellular proteins such as DNA repair enzymes, lamin, gelsolin, mouse double minute 2 (MDM2) (an inhibitor of p53), and protein kinase Cd (61,62). The apoptotic pathway can be blocked by a number of mechanisms including disruption of the expression of sensors of the apoptotic signal, disruption of the effector pathway, or the expression of genes whose products protect cells from apoptosis by generally unknown mechanisms. For example, the expression of the antiapoptotic protein Bcl-2 can protect cells from death and, when coupled with other proliferative signals, induces tumor formation (63,64). Disruption of the genes that are responsible for the detection of the apoptotic signals can also provide cells with a survival advantage. One example of sensory genes that detect intrinsic signals are the mismatch repair genes, which are responsible for detecting defects in the synthesis of DNA and also for the induction of the repair process (65). The tumor suppressor protein p53 is also involved in maintaining the integrity of the cellular genome and can, therefore, be considered a sensory gene of apoptosis. An example of this function of p53 can be found in cells treated with the drug PALA (N-phophonacetyl-L-aspartate), which is used to select for the amplification of the carbomylphosphate synthase/aspartate carbomyl transferase/ dihidroorotase (CAD) gene, resulting in the depletion of pyrimidine triphosphate pools, the activation of p53, and ultimately in G1 arrest and apoptosis (66). Cells with wild-type p53 do not undergo gene amplification readily. However, cells with mutant p53 entered S phase and were found to have amplified segments of their DNA. The mechanism by which gene amplification is prohibited by p53 remains unclear, but one possibility is that p53 plays a

medwedi.ru

200

Part One: General Considerations

Figure 2 Schematic diagram for activation of caspases that lead to apoptosis of mammalian cells. The intrinsic and extrinsic pathways are demonstrated. The extrinsic pathway can be activated by a death receptor engaged by its ligand. For example, the Fas receptor bound to the Fas ligand can activate the extrinsic caspase cascade. Activation of caspase 8 results in the proteolytic cleavage of a number of proteins that contribute to cell death. The intrinsic pathway can be activated by DNA damage, which can activate mitochondrial-mediated apoptosis. The APAF-1 contributes to the activation of caspase 9. Both the intrinsic and extrinsic pathways seem to converge and activate caspase 3. The inhibition of activation of caspase 3 can inhibit apoptosis mediated by both the intrinsic and extrinsic pathways of apoptosis. Abbreviation: APAF-1, apoptosis-activating factor-1.

role in monitoring abnormal recombination intermediates and acts to kill such cells by activating the apoptotic cascade (67,68). Disruption of the extrinsic sensors of the apoptotic pathway can also result in escape of programmed cell death. For example, mutations within the Fas receptor gene have been identified in gastric cancer (69), transitional cell carcinoma of the bladder (70), small cell lung cancer (71), and hematologic malignancies (72,73). Other members of the death receptors, such as the TNF and TNF-related apoptosis-inducing ligand-receptors, have been found to be mutated in human cancers (56,74). Inhibition of the effectors of apoptosis can also result in a decreased sensitivity to apoptosis. Because of the critical roles in development likely served by many of the caspases, genetic loss of function of these proteins is likely rare (75,76). However, disruption of caspase function is a common theme used by infectious agents. For example, baculovirus, a virus infecting insects, encodes a protein called P35, which is a general and very efficient inhibitor of the caspases, making it a potent inhibitor of apoptosis (77–79). Human tumor viruses have also been shown to disrupt the apoptotic machinery by various mechanisms. For example, human papilloma virus, the cause of the vast majority of cases of cervical carcinoma, encodes a protein that inhibits the functions of the tumor suppressor gene p53 by both directly binding to and increasing the degradation of p53 (80–82). Another human tumor virus, Epstein–Barr virus (EBV), has also been shown to inhibit apoptosis, a process that can be reversed by the inhibition of an EBV-protein called Epstein-Barr nuclear antigen-1 (EBNA-1) (83). These findings (83), as well as others (84), hold promise that the therapeutic inhibition of single proteins in cancer cells can result in the initiation of the intrinsic apoptotic program, leading to cell death.

Limitless Replicative Potential When normal cells are placed in cell culture, they will undergo limited cell division under the right conditions. For example, primary B-lymphocytes taken from the peripheral blood of a normal human can be induced to proliferate in the presence of interleukin-4 (IL-4) and CD40 (85,86); these conditions support in seven or more population doublings after which the cells will cease to proliferate. Unlike normal B-cells, most tumor cells are immortal and will grow indefinitely in cell culture. Immortalization of cells is a process that is incompletely understood but likely requires multiple genetic alterations. The best understood process of immortalization involves the in vitro infection of primary B-cells with EBV. When primary B-cells are infected with EBV, the virus expresses a number of genes that are required for the induction and maintenance of proliferation (87,88). These cells will replicate for approximately 30 to 60 population doublings and then undergo a ‘‘blast crisis’’ during which time the majority of cells die (89). The few cells that survive this blast crisis are then referred to as ‘‘immortalized.’’ While it is unclear what genetic events are required for these immortalized cells to arise, some studies have indicated that increased telomerase activity contributes to the immortalization process (90). Human telomerase, hTERT, is a reverse transcriptase that uses an intrinsic RNA as a template for the extension of the G-rich strand of the telomeres, which form a protective cap on the ends of chromosomes (91). It has been postulated that telomere shortening is the ‘‘molecular clock’’ that leads to senescence—the cessation of division of human cells—and that the expression of hTERT overcomes senescence and leads to immortalization of cells in vitro and in tumors in vivo. Much correlative data support this hypothesis (92–94). Direct evidence in support of the

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

hypothesis that the telomere loss plays a causal role in in vitro senescence has come from recent experiments in which telomerase was introduced into normal human cells. Ectopic expression of hTERT in foreskin fibroblasts and retinal epithelial cells, which are telomerase negative, resulted in the maintenance of telomere length, and the life span of the cells was extended by at least 200 population doublings beyond the point at which control cells senesced (95–98). As one would expect, the inhibition of telomerase has also been shown to restrict the life span of primary human fibroblasts (99) and to result in the decreased survival of tumor cells in vitro (92,93,100–102). These results indicate that telomerase may serve as a good target for novel therapies. In fact, the use of telomerase inhibitors as a therapy to treat malignancies is being actively investigated (103). The inhibitors being evaluated are dominant negative hTERT subunits (100,101), peptide nucleic acids and oligonucleotides (102,104,105), and chemical inhibitors (106–109). We anticipate that developing the means to restore mortality to tumor cells in vivo will be studied intensively and would lead to new, useful therapies in the future.

Sustained Angiogenesis The growth of new blood vessels, termed ‘‘angiogenesis,’’ is required for most tumor growth and metastasis. Without new blood vessel formation, tumor clones will be confined within 1 to 1.5 mm diameter (110). Experimental and clinical evidence underpins the notion that neovascularization of a tumor requires a critical number of its cells to have switched to the angiogenic phenotype (110,111). Evidence for this ‘‘angiogenic switch’’ has been derived from three transgenic mouse models that were analyzed throughout multistep tumorigenesis (112). In these animal models, the midstage lesions had developed an angiogenic phenotype prior to the appearance of invasive tumors. The mechanisms by which tumor cells become angiogenic can be categorized as either intrinsic or extrinsic, and both mechanisms result in a shift in the balance between the proangiogenic and antiangiogenic signals. An intrinsic proangiogenic switch implies that some activity within the tumor itself results in the induction of new blood vessel formation. The easiest explanation for how such a switch occurs is through the production of a proangiogenic molecule within the tumor, such as vascular endothelial growth factor (VEGF) (113). Alternatively, transcriptional changes within the tumor cells may result in downregulation of angiogenesis inhibitors such as thrombospondin-1 or b-interferon (113,114). Extrinsic angiogenic signals are derived from host cells recruited by the tumor, such as macrophages, or may be mobilized by the extracellular matrix (115). A variety of proteases can release a basic fibroblast growth factor that is stored in the extracellular matrix (116). Interestingly, essential components of the clotting system can be cleaved into angiogenic inhibitors (117,118). Tumor angiogenesis offers an attractive target for new therapeutics. Two general approaches have been used in the development of antiangiogenic agents: inhibition of proangiogenic factors and therapy with endogenous inhibitors of angiogenesis. More than 10 specific inhibitors of angiogenesis are under development for the treatment of cancer. The agents include antibodies to VEGF (bevacizumab), antibodies to the VEGF-receptor (IMC-IC11), proteins with antiangiogenic activity (angiostatin, endostatin, IL-12, etc.), and a several small molecules (111,119). Many of these small molecules act by blocking VEGF, by blocking its production

201

by a tumor cell, by blocking its receptor, or by neutralizing VEGF itself (120–122).

Tissue Invasion and Metastasis Metastasis entails the spread of a primary tumor throughout the body by entering either the blood or lymphatic system. Metastatic tumors arise as a combination of cancer cells and normal supporting cells from the primary tissue. To be successful in the process of metastasis and invasion, most tumor cells must have acquired the first five traits of a cancer cell— they must be self-sufficient in growth signals, be insensitive to growth-inhibitory signals, evade programmed cell death, have limitless replicative potential, and have the ability to sustain angiogenesis. Additional genetic traits that are required for the development of metastasis are at present unknown. Two general models of how metastases develop have been proposed. The prevailing model was proposed over 30 years ago and predicted that metastasis results from selection of a small fraction of cells within the primary tumor that has the ability to metastasize. In support of this hypothesis, murine malignant melanoma cells growing in culture have been found to be heterogeneous in their ability to produce metastatic colonies when injected into a susceptible animal (36). However, cells with greater metastatic potential can be selected for by removing a metastatic focus of tumor from an animal, culturing these cells in vitro, and reinjecting these cells into another animal (123–125). Data such as these are certainly consistent with the conclusion that metastasis is the result of a selection process, but much work still needs to be done in this area to fully understand the complex process of metastasis formation. The second model of metastasis postulates that the capacity to metastasize might be acquired relatively early during multistep tumorigenesis and is intrinsic to the tumor (126). In support of this model, researchers using DNA microarrays recently ascertained the gene expression profiles of a panel of 12 metastatic adenocarcinoma nodules of diverse origins (127). Rigorous data analysis helped in identifying 17 genes that have been described as the metastasis profile. Importantly, this same profile was found in a subset of primary tumors. Patients with primary tumors having this metastases-associated gene-expression program had significantly shorter survival times compared with individuals whose tumors lacked it (127). Others have also shown by genomic screens that gene profiles predictive of metastases can be found in both the metastatic and primary tumors of the same patient (128,129). Findings such as these have many implications. First, if the tendency of a tumor to metastasize is present early on in tumor development, then relatively small primary tumors may already have the ability to give rise to metastatic foci. Second, genetic and biochemical changes that are required for metastases are likely to be the same changes that are required for cells to become tumorigenic (126). A major problem with either of these models of metastasis is that they deal only with the tumor cells and ignore the microenvironment provided by the host. In fact, it has become clear that malignancy is the product of the tumor– host microenvironment (130). The stroma can play a significant role in invasion and metastasis through the production of growth factors or secretion of proteinases that play a role in the angiogenic switch. Therefore, it is quite likely that not only are genetic and biochemical properties of the tumor important for the development of metastases but perhaps equally important are those properties of the host that

medwedi.ru

202

Part One: General Considerations

regulate its susceptibility to metastasis formation. This is an exciting area of research that is in its infancy, but future findings could clearly have significant implications for treatment and prognosis.

BIOLOGIC RATIONALE FOR THERAPY Chemotherapy General Considerations The ability to identify antitumor agents has been enhanced by insight into the patterns of growth of normal and neoplastic cells. The most fully characterized portions of the normal cell cycle are the S phase and mitosis. Most of the active chemotherapeutic agents inhibit processes occurring during these two phases of the cell cycle, and these drugs are in general more effective against rapidly dividing cells. Although many classic anticancer treatments such as the alkylating agents are directed at nuclear targets, DNA is also the target for many new anticancer drugs. The synthesis of DNA is a multistep process using various enzyme pathways (131). Anticancer agents have been developed, which, when combined, can inhibit the process at several points simultaneously, thereby enhancing the cytocidal effect. A variety of general strategies can be used, including sequential blockade of different steps in the same biosynthetic pathway, concurrent blockade of different pathways for the synthesis of necessary compounds, complementary inhibition of biochemical processes that may circumvent chemotherapeutic damage, metabolic sensitization of intracellular constituents to chemotherapeutic effects, and the utilization of combined chemotherapy and radiotherapy. Examples of each of these approaches have been described (132,133). Other considerations in the use of chemotherapeutic drugs and the design of chemotherapy regimens include the emergence of drug-resistant cells either by selection of insensitive clones or by the induction of cellular changes that result in drug resistance. There have been many studies related to the origins of chemotherapeutic resistance. It is clear that drug resistance is one of the primary causes of suboptimal outcomes in cancer therapy. Drug resistance in cancer mimics that of antibiotic resistance (134). Limitations in drug delivery via poor absorption, excessive metabolism, environmental changes, or poor penetration to certain sites (organs and tissues) are recognized, and measures to counteract these have been explored. For example, the use of prodrugs or pegylated chemotherapy, organ-specific administration, such as hepatic arterial infusion or intrathecal therapy, hyperoxygenation, and hyperthermia are all strategies aimed at increasing drug-to-target ratio. Resistance at the molecular level may be more difficult to overcome. Certainly, mutation of specific drug targets will result in clinical resistance (135,136). Other molecular changes can also lead to cellular resistance, including alterations in the expression levels of proteins or enzymes responsible for the metabolism of the drug, overexpression of antiapoptotic proteins, and increased expression of DNA repair machinery (137–139). Cells can also develop intrinsic resistance to a broad spectrum of drugs through the action of a membrane protein termed ‘‘P-glycoprotein’’ (140,141). Expression of this protein in cells leads to a multidrug resistance (MDR) phenotype and has been identified to be the cause of resistance to a spectrum of drugs in a number of different cancer types (140). However, at least 48 related human genes have been identified, which encode for proteins that contribute to

the MDR-phenotype (142). Inhibitors of the MDR-genes have been developed and tested but clinical trials thus far have not been promising. In fact, at least two clinical trials have demonstrated no improvement in outcome by the addition of MDR-inhibitors (143,144). Progress in this area of research has been made recently with the advent of newer MDR-inhibitors that appear to be more efficient and less toxic (140). It is likely that these inhibitors will play a role in some specific cancers that clearly overexpress the MDR-inhibitors.

Combination Chemotherapy Optimal chemotherapy requires the use of combinations of drugs because single agents do not cure cancer, with rare exceptions. While the reason for this is not clear, simple mathematics may provide the answer. For example, if tumors are genetically heterogeneous such that 90% of cells are susceptible to one drug and 90% of cells are susceptible to a second drug, the exposure of the cells to both drugs would result in the death of more than 90% of the cells in the tumor. For this reason, combination chemotherapy is now the standard for treatment of many disseminated or metastatic cancers and is curative in some (145). A series of accepted guidelines for combination chemotherapy have been recognized for a number of years: 1. 2. 3. 4. 5.

Select drugs that have been proven effective. Select drugs that have different mechanisms of action. Select drugs that have different spectrums of toxicity. Each drug should be used at maximal dose. Agents with similar dose-limiting toxicities can only be combined safely by reducing doses, resulting in decreased effects. 6. Drug combinations should be administered in the shortest interval between therapy cycles to allow for recovery of normal tissue (146). If these guidelines are followed, dosages that are close to the maximally tolerable dosages for each drug can be used in an intermittent drug treatment schedule designed to optimize the cytotoxic effect of each drug. In the case of hematologic toxicity, especially neutropenia, it is often possible to maintain the dosing schedule and to shorten the period of granulocytopenia by the use of hematopoietic growth factors granulocyte-colony stimulating factor (G-CSF) and granulocyte monocyte-colony stimulating factor (GMCSF) (147). The use of dosage modifications or the use of growth factors should be considered with the therapeutic goals of therapy in mind. If the regimen has potential for cure, every effort should be made to maintain dose and schedule. If palliation is the goal, dose reductions and lengthening of the interval between doses should be considered.

Adjuvant and Neoadjuvant Chemotherapy The use of drugs as adjuvants to surgery or irradiation has led to significant advances in the chemotherapy of cancer (146,148–150). In many instances, the primary localized tumor mass can be removed by surgery or destroyed by irradiation; but even if the diagnosis has been made relatively early, with certain tumors it is quite probable that small, clinically undetectable metastases have already occurred. Even with the considerable advances made in diagnostic techniques, the most common solid tumors (breast, lung, and colon carcinomas) are usually not detectable until the tumor attains a mass of 1 cm in diameter.

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

By this time, approximately 5 108 to 109 cells are present, and the tumor has already doubled in mass about 30 times. Because the chance for cell shedding into the lymphatic system or the blood stream increases with each doubling in tumor mass, there is a significant chance that cells have already metastasized by the time a tumor can be detected. It is not usually practical to eliminate small metastatic foci by surgery or irradiation; thus chemotherapy is usually the treatment of choice in patients at risk for occult metastatic disease. The principles for the use of drugs with surgery or radiotherapy are similar to those for the use of drugs in combination regimens. In general, drugs without a demonstrable activity against advanced tumor when used alone should not be used in adjuvant trials. If combinations of drugs have been shown to be effective in patients with advanced disease, they may be used in the adjuvant setting. Another important consideration is that the drug or the drug combination must be relatively low in general toxicity. Because a significant number of patients may remain free of disease with surgery or radiotherapy alone, the added risk of drug toxicity (and in some cases the induction of secondary malignancies such as leukemia) must be carefully weighed against the potential benefit. The use of an effective drug following surgical or radiation therapy makes sense from a cell kinetic point of view. Experimental evidence derived from the study of murine melanoma cells in vitro led investigators to believe that tumor growth is constant and occurs logarithmically. Using the murine melanoma model, the same investigators demonstrated that cell death induced by a given dose of a chemotherapeutic was independent of the tumor burden, the so-called log-kill hypothesis. While the results of these elegant experiments are very compelling, the principles of murine tumor growth may not be directly applicable to the growth of human tumors. For example, if human tumors responded similarly, one would predict that solid tumors should be more sensitive to chemotherapeutics than has been experienced. In fact, most experimental data is consistent with the conclusion that growth of human solid tumors is not exponential but rather follows Gompertzian kinetics, in which the fraction of cells actively growing is inversely related to the tumor burden. Therefore, Gompertzian growth predicts that when tumor burden is large, the actual fraction of cells growing and being susceptible to a chemotherapy agent is small. Experimental data strongly support the notion that the rate and extent of tumor reduction are related to the growth rate in a population of cells just prior to therapy (151). The difficult problem that continues to confound the curative goal of cancer therapy is the heterogeneity of the tumor cell population. The available models that help gain an insight into the processes underlying this heterogeneity suggest that it exists at the biochemical and pharmacologic level, conferring absolute drug resistance, and at the cell cycle kinetic level, conferring relative drug resistance. All the available models favor the use of combination chemotherapy and the administration of doses of chemotherapy that are as intensive as possible. An important issue that remains is the optimal manner in which to treat a disease such as breast cancer, small cell lung cancer, or lymphoma, for which multiple agents that display some antitumor activity are available. The Goldie–Coldman hypothesis, which mathematically predicts the likelihood that drug-resistant cancer cells are present in a patient at diagnosis (152), favors the use of all active drugs to be

203

included in the treatment over the shortest time frame possible. This favors a strict alternating approach. The Norton–Simon approach, which utilizes the concept of Gompertzian growth to explain clinically observed phenomena (151,153), advocates a crossover approach in which each active regimen is used switching to the alternative regimen. Theoretically, this approach accomplishes two important goals. First, it maintains the most dose-intensive administration of each regimen by giving it every cycle, rather than on alternate cycles. Second, it addresses the heterogeneous populations of cells, killing the most sensitive, rapidly growing cells first and then treating the slower-growing, more resistant cells as efficiently as possible. Studies designed to test the various regimens have not been conclusive to date. However, such models provide a framework within which to test new drug regimens. Improvement of chemotherapeutics in the future will require strict attention to such models of tumor growth in addition to the empirical clinical data that have often characterized the approach in the past. A second strategy that is used to treat the micrometastatic disease at the time of diagnosis is neoadjuvant chemotherapy. Neoadjuvant therapy is chemotherapy implemented before surgery in patients with apparently localized disease. The approach has several advantages over the more conventional postoperative adjuvant chemotherapy. It exposes the potential micrometastases to chemotherapy at an earlier stage, it can be an indicator of tumor response (based on in vivo response of the tumor itself), and it may cause significant regression of the primary tumor and perhaps allow for a more conservative surgical procedure (organ/function sparing). Additionally, preoperative chemotherapy may reduce the hypothetical stimulation of tumor cell growth after surgical resection of the primary tumor. The dangers, of course, include ineffectiveness of chemotherapeutic regimens, which may in some cases obscure proper staging of disease or even render a primary tumor unresectable. Some tumors that have been effectively managed using neoadjuvant chemotherapy are soft tissue sarcoma, osteosarcoma, anal cancer, bladder cancer, larynx cancer, esophageal cancer, pancreatic cancer, and locally advanced breast cancer (148).

Radiation Therapy General Considerations Therapeutic radiation is ionizing; it ejects electrons from atoms or molecules with which it interacts. The energy transfer from radiation to tissue by this ionization is immediate. There is now a great deal of evidence that DNA is the target of this ionizing process and the cytotoxic effects of radiation (154–156). The specific lesion believed to be responsible for most radiation-induced cellular death is known as the ‘‘double-strand break.’’ Differences in cellular sensitivity to radiation may be a reflection of the cell’s ability to repair this type of lesion. Not all types of DNA are equally vulnerable to damage. DNA is associated with proteins in a complex threedimensional structure called chromatin. The influence of higher-order DNA structure on its sensitivity to radiationinduced damage is evidenced by the fact that deproteinized DNA is 70 times more susceptible to radiation-induced strand breakage than DNA found in the nucleus (157). Uncoiled DNA is also more susceptible to radiation damage, which means that cells in early S phase are more sensitive to radiation. Experimental data show that cells are more sensitive in early S phase and mitosis than in the late S phase and G2 (158).

medwedi.ru

204

Part One: General Considerations

Selection of an optimal time–dosage pattern for treating tumors is a complex problem. It is unlikely that one-time dosage prescription will be optimal for a wide variety of kinetically different tumors located in different anatomic areas. The determination of fraction size, overall treatment time, and total dosage that is best for the control of various tumors constitutes a major, continuing research effort. It is based on several factors such as the inherent radiosensitivity of the tumor and surrounding normal tissues, tumor blood supply, and use of concomitant adjuvant chemotherapy. Although tumor type has a limited effect on inherent radiosensitivity, oxygen has a profound influence on a tumor’s radiation response. It has been known for quite some time that radiation delivered in the presence of oxygen has a more potent biologic effect than in hypoxic conditions (159). Hypoxic cells are 2.5 to 3 times more resistant to radiation than are well-oxygenated cells. There have been many attempts to overcome the hypoxic cell problem, including the use of hyperbaric oxygen, electron affinity compounds that selectively sensitize hypoxic cells, densely ionizing, or high-energy transfer radiation such as neutrons or pi mesons, optimization of the time–dosage schedule to increase reoxygenation between radiation doses, and induction of hyperthermia (160,161). Although the exact mechanism of the effect of oxygen is still speculative, it was noted that other compounds capable of accepting an electron can substitute for oxygen and restore sensitivity to hypoxic cells. These drugs include two thymidine analogs, iododeoxyuridine and bromodeoxyuridine, which increase cellular sensitivity to radiation in direct proportion to their incorporation into DNA by increasing radiation-induced DNA damage and decreasing its repair (162).

eradicated foci of the disease in the CNS, which were not accessible to chemotherapy (163). Treatment of cancer of the anal canal is another excellent example of the clinical benefit of combined chemotherapy and radiotherapy. In fact, it was in the treatment of anal canal squamous cell carcinoma that the use of combined radiotherapy and chemotherapy was first shown to be effective. Standard surgical management of anal canal carcinoma historically involved an abdominoperineal resection, but when local control was achieved with chemoradiotherapy, a conservative local approach, with sphincter preservation, was adopted. With long-term follow-up it has been confirmed that chemoradiation is the preferred therapy for epidermoid carcinoma of the anal canal (164,165). The role of radiation therapy in the local control of cancer is well established (166–171). However, the impact of radiation therapy on survival is less well established. Recently several groups have investigated the role of radiation therapy in the long-term survival of premenopausal and postmenopausal patients with breast cancer (172–174). Trials such as these have established that the addition of radiation therapy to the treatment regimen in certain high-risk patients may improve both disease-free and overall survival. Radiotherapy, chemotherapy, and surgery should be viewed as complementary and not as competitive methods of cancer management. New investigative approaches in radiotherapeutic trials aimed at improving disease control have increased dramatically. It is to be hoped that intelligent integration of improved radiotherapy, along with chemotherapy and surgery, will prove beneficial in the treatment of cancer.

Radiation Oncology

Surgical Oncology

Radiotherapy has three major roles in cancer treatment. It may be used singly as the primary curative method. It may be used as an adjuvant therapy with surgery (either before or after operation) or with chemotherapy, or both. Finally, radiation serves to palliate the symptoms of locally advanced or metastatic disease. As a single method of treatment undertaken with curative intent, radiotherapy is a local or regional form of therapy that is often competitive with surgery. If the probability of cure is equivalent for the two methods, a choice between them is often made on the basis of which carries the lower risk of morbidity. In the case of large tumors, surgery usually has a higher likelihood of tumor cure. However, primary radiotherapy is often used in neoplasms that are technically unresectable or that require excessively mutilating surgery. The combination of radiation with chemotherapy has become the mainstay of treatment for many cancers. Combining these two modalities allows for more conservative management of disease with the supplementation of local therapy with systemic therapy. Radiotherapy may be used in conjunction with a surgery or as an alternative to surgery to treat the primary tumor bed, whereas chemotherapy is used to treat the patient systemically. Adjuvant radiotherapy is of value for the treatment of subclinical disease in ‘‘sanctuary’’ sites not usually accessible to systemic chemotherapy. The best example of this arose from the treatment of acute lymphoblastic leukemia in children. It was clear that, although the disease could be controlled in most parts of the body, relapse in the central nervous system (CNS) was a particular risk. This problem was largely overcome by the addition of prophylactic irradiation that

Surgery is generally recognized as the original cancer therapy and for many years offered the only opportunity for cure. During the past few decades, however, there has been a tremendous advancement in the development of effective nonsurgical methods of treating cancer, and this has greatly changed the role of surgery. Perhaps, one of the most important advances in cancer surgery has been related to an understanding of the biology of cancer growth and metastases. The original concept of a local tumor spreading contiguously to surrounding tissues and to regional lymph nodes led to more and more radical operations. It is now recognized that at the time of cancer diagnosis, some 70% of all solid tumors are already systemic. This understanding of the cancer process has helped the surgeon rethink the role of primary surgery and better define realistic therapeutic goals based on a multimodality approach to treatment. The surgeon is most often the primary physician conducting the evaluation of the patient suspected of having cancer. As the primary physician, the surgeon must assume the responsibility for identifying which patients can be potentially cured by local resection alone and which patients should have adjuvant multimodality treatment. The surgeon must also decide the extent of resectional therapy, balancing the potential for cure through local control with the morbidity of extensive tissue resection. Today, the use of surgery as the sole treatment for a given cancer is rare. Thus the surgeon has a critical role in coordinating a patient’s care and interacting with other specialists. In recent years, the placement of short-term and long-term indwelling central venous catheters has become a relatively common procedure performed on patients with

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

cancer. These catheters provide chronic vascular access for administration of chemotherapy, hematological support, and occasionally nutritional support. The implementation of chronic vascular access has allowed the use of more aggressive treatment involving multiple drugs given over complicated schedules. To meet this need, a number of new implantable catheter systems and drug delivery pumps have been developed. Important developments relating to implantation technique and design have decreased the operative time required to place these devices, and it can usually be done as an outpatient procedure. The surgeon is also called on to handle a variety of surgical emergencies related to the advancing cancer or the use of aggressive therapy. Hemorrhage, sepsis, perforation of viscera, and obstruction of the gastrointestinal tract are examples of problems requiring surgical intervention. These emergencies require a thoughtful and caring physician who understands not only the need to solve the problem at hand but also the delicate balance between helping and harming. The role of the surgical oncologist, or cancer specialist involved in cancer diagnosis and treatment, continues to expand and includes an understanding of the biology of the cancer process, the natural history of specific tumors, the current status of integrated treatment options for each tumor, and the investigative options that may be important to the patient. The role of the surgeon assuming these responsibilities is best defined as that of a member of a multidisciplinary oncology team skilled in various treatment modalities and dedicated to experimental research that can lead to new diagnostic and treatment options (175).

Biologic Therapy We have used the term ‘‘biologic therapy’’ to encompass several different areas. The therapies contained within this term are under investigation to some degree and are at different points in their clinical utility. We have broken this very broad topic into three major groups: immunotherapy, gene therapy, and molecularly directed therapy.

Immunotherapy The effective treatment of cancer through the specific activation of an affected patient’s immune system has been the holy grail of cancer therapy. Any agent that is capable of altering the host–tumor relationship in favor of the host can be considered an immunologic response modifier. Because of the vast information existing in the immunotherapy literature, it is only possible to discuss a few areas that are of exceptional interest. Cytokine Therapy In vivo studies have demonstrated the efficacy of inducing tumor rejection by using immunomodulatory cytokines. Several cytokines are in clinical use today. For example, interferon a-2b has been utilized in the therapy of nodepositive malignant melanoma. Randomized controlled trials of interferon a-2b have demonstrated small but significant improvements in survival of the patients treated with the drug (176). However, such small increases in survival have come at a significant cost, because the morbidity of this cytokine is substantial. In fact, three-quarters of the patients receiving interferon required a dose modification and one quarter of the patients had treatment discontinued due to toxicity. Additionally, there have been two treatmentrelated deaths due to hepatic toxicity. While the beneficial effect of interferon is statistically significant, the toxicity of

205

therapy precludes its widespread use in the treatment of malignant melanoma. ILs are hormone-like substances, produced mainly by leukocytes, which have diverse activities on both immunologic and nonimmunologic targets (177). There are at least 12 well-defined ILs, and ongoing research has detected several others (178). IL-2 is Food and Drug Administration approved and has played a critical role in the field of adoptive immunotherapy. IL-2 stimulates the growth and activities of a wide range of cells including natural killer cells, lymphokine-activated killer cells (LAKs), cytotoxic Tlymphocytes, and tumor-infiltrating lymphocytes (TILs). A large number of clinical trials have evaluated the administration of IL-2 alone or in combination with LAKs and TILs (133,179,180). Objective and long-lived responses have been documented in a large proportion of cases, particularly renal cell carcinoma, melanoma, and acute myeloid leukemia (181). Several toxicities associated with IL-2 are generally short lived and resolve within 24 hours of discontinuation of therapy. However, studies indicate that the rate of drugrelated acute mortality is 4% to 5% (177). Use of IL-2 should be restricted to those who are familiar with administration and toxicity. Adoptive Cell Transfer Therapies Adoptive cell transfer therapy is the transfer of cells with antitumor activity to a tumor-bearing host (182). Efforts to identify immune cells with reactivity toward various tumors are ongoing. Lymphocytes present within tumor infiltrates are presumably enriched for effector cells capable of killing the tumor cells (183). However, they appear to have developed a tolerance to the presence of the tumor. These TILs can be enriched by propagating single-cell suspensions from the tumor in IL-2. When isolated and tested in vitro for cytolytic activity against autologous tumor cells, these TILs were found to be 50 to 100 times more potent than IL-2– activated splenocytes (LAKs). A similar superiority to LAKs was also apparent in vivo (184). Adoptive cell transfer therapies provide the opportunity to overcome tolerogenic mechanisms by enabling the selection and activation of highly reactive T-cell subpopulations and by manipulation of the host environment into which the T-cells are introduced. Recently it was demonstrated that treatment with autologous T-cell transfer and high-dose IL-2 therapy after nonmyeloablative lymphodepleting chemotherapy resulted in the rapid growth in vivo of clonal populations of T-cells specific for the melanoma antigen recognized by T-cells (MART-1) melanocyte differentiation antigen, and resulted in the destruction of metastatic tumors and autoimmune attack on normal tissues that expressed the MART-1 antigen (185). Other results have demonstrated transient tumor shrinkage but have no significant objective response (186). While adoptive cell transfer therapy may eventually prove to be useful for the treatment of many different cancers, such a role has yet to be realized. Antibody Therapy The development of antibodies against various membranesignaling proteins, which block the extracellular ligand-binding region of the receptor, has proven to be an important contribution to the management of cancers. The human epidermal growth factor receptor (HER) [erythroblastic leukemia viral oncogene homolog, neuro/glioblastoma derived oncogene homology (avian) (erbB)] family of receptor tyrosine kinases is one of these targets. HERs are transmembrane

medwedi.ru

206

Part One: General Considerations

receptors that play a pivotal role in normal cell growth, lineage determination, repair, and functional differentiation (187). These receptors have been demonstrated to be overexpressed in several solid tumor types, including breast, colorectal, esophageal, ovarian, and pancreatic (188). AntiHER2 monoclonal antibodies, trastuzumab and 2C4, have been developed. Traztuzumab acts against HER2-overexpressing tumors, in part, by inducing receptor endocytosis (189). Clinical trials have shown that traztuzumab provides significant clinical benefits as monotherapy (190,191), and improves survival when used in combination with chemotherapy compared with chemotherapy alone in women with HER2-overexpressing metastatic breast tumors (192). 2C4 is a humanized anti-HER2 monoclonal antibody that binds to a different HER2 epitope than does traztuzumab. It functions by inhibiting the heterodimarization of HER2 with other HER family members (193). This results in the inhibition of signaling both in cells with low and high levels of expression of HER2. In vitro and in vivo antitumor activity has been reported in a number of breast and prostate models (193). Clinical trials with 2C4 are currently underway.

Gene Therapy The concept of gene therapy has been around for at least 10 years and remains a very active area of investigation. The idea of introducing genes into tumor cells or into cells that may affect the tumor phenotype and ultimately target a subset of cells for death is tantalizing. However, advancement in this field remains hindered by the problem of cell-specific targeting and effective delivery systems. Despite these major limitations of the technology, we will discuss two potential uses for gene therapy. In the third section we will discuss potential mechanisms of targeting genes to tumor cells. Introduction of Therapeutic Genes Transduction of tumor cells with gene-encoding enzymes that function to convert a nontoxic prodrug into a toxic drug in the vicinity of the tumor cells is under study. The high local concentration of the toxic drug would result in death of tumor cells while limiting general toxicity to the host. Two such strategies involve transduction of the herpes simplex virus thymidine-kinase gene (HSV-tk) or of the cytosine deaminase gene, neither of which occur naturally in mammalian cells. HSV-tk phosphorylates nucleoside analogs, such as acyclovir and ganciclovir, which are not toxic to cells in the unphosphorylated state, and incorporates them into the replicating DNA (194). Even though not all cells are transduced with the gene, several studies have demonstrated killing of nontransduced cells. This observation, referred to as the bystander effect (195,196), is likely due to intracellular transfer of phosphorylated nucleoside via gap junctions. Cytosine deaminase works by deaminating the prodrug 5-flourocytosine to the cytotoxic fluorouracil (197,198). Enzymes such as these, which convert nontoxic prodrugs into toxic agents may prove to be useful in the therapy of cancer. Functional Replacement of Tumor Suppressor Genes As discussed earlier in the chapter, many tumors have lost the function of a tumor suppressor gene, which provides the cells with an overall survival advantage. The replacement of such genes through the introduction of an exogenous genetic template remains very attractive. For example, the human p53 gene is mutated in many human tumors. Transduction of

the wild-type p53 gene can partly reverse the malignant phenotype of tumor cells lacking functional p53 in experimental systems in vitro and in vivo (199). The functional replacement of tumor suppressor genes remains a potentially useful approach to the treatment of cancer. Cell-Specific Targeting The treatment of cancer through the introduction of genes is a natural goal and may eventually prove to be successful. However, this practice is currently severely limited by the process of targeting these therapies to the cells of interest. For example, the introduction of tumor suppressor genes, as discussed above, is theoretically exciting but the overexpression of p53 in all cells would have potentially devastating consequences. Therefore, approaches such as these remain useful in theory until the time they can be targeted to specific groups of cells. One novel approach to this problem has been to use the avian leukosis virus (ALV). ALV cannot infect human cells because they do not express the ALV receptor. However, a soluble version of this receptor has been produced as a fusion with EGF subgroup A avian leukosis virus receptor-EGF (TVA-EGF) (200). Cells expressing the EGF receptor can then be preloaded with this fusion protein and infected with the ALV that has been genetically manipulated to express genes of interest. Similar bridge proteins using VEGF have been developed and have been shown to be effective at rendering VEGF-receptor–expressing cells susceptible to ALV infection (201). The use of these bridge proteins and ALV vectors represent one potential approach for targeting genes to specific groups of cells.

Molecularly Directed Therapy The specific inhibition of signaling pathways by therapeutics is a relatively new field. However, the literature has grown and it is our goal to review two areas we find particularly exciting and to discuss potential applications and limitations. We will first discuss small molecule therapy with emphasis on the highly successful inhibition of BCR-ABL gene by signal transduction inhibitor-571 (STI571). In the second section, we will discuss the inhibition of protein expression by a relatively new technique called RNA-interference or RNAi-571. Small Molecule Therapy The improved understanding of molecular signaling pathways has led to the development of several new targets for cancer therapeutics. Furthermore, improved crystallographic techniques have allowed us to develop small, chemical molecules with specific structures that target these signaling proteins by interacting with their functional domains. Examples of such molecules are accumulating rapidly in the literature but the first such molecule to prove effective was directed against the BCR-Abl protein expressed in most patients with chronic myelogenous leukemia (CML; Fig. 3) (202). This molecule has been shown to have activity in patients with CML and in patients with acute lymphocytic leukemia (ALL), in whom the Philadelphia chromosome is present (203). This type of molecular therapy appears to be very well tolerated with low side effects (204). However, the specific inhibition of proteins will certainly bring a new set of challenges. For example, resistance to these inhibitors has been identified and may involve selection of cells that have mutations in the active site of the breakpoint cluster region/Abelson murine leukemia viral oncogene homolog (BCR/ABL) kinase, which is targeted by the small

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment

207

Figure 3 Mechanism of action of STI-571. (A) Depicted is the bcr-abl protein, the expression of which is the result of a chromosomal translocation between chromosomes 9 (c-abl) and 22 (bcr). The abl portion of this protein serves as a protein tyrosine kinase–activating downstream proteins, which ultimately effect cell proliferation. (B) The tyrosinekinase inhibitor STI-571 binds in the ATP-binding pocket of the bcr-abl protein resulting in its displacement and the inhibition of the protein’s functions. STI-571 has demonstrated inhibitory activity against other protein tyrosine kinases. Abbreviation: ATP, adenosine triphosphate.

molecule (135). Despite the challenges likely to be faced, targeted therapy remains one of the most promising and exciting developments in cancer therapy in the last 10 years. RNA Interference RNAi uses short double-stranded RNA (dsRNA) whose sequence matches that of the gene of interest (Fig. 4). Once

in a cell, a dsRNA molecule is cleaved into segments approximately 22 nucleotides long, called short interfering RNAs (siRNAs) (205). siRNAs become bound to the RNAinduced silencing complex, which then also binds any matching mRNA sequence. Once this occurs, the mRNA is degraded, effectively silencing the gene from which it came (205). Until recently, this technology involved the introduction

Figure 4 mRNA degradation mediated by siRNAs. Once in a cell, double-stranded siRNA is bound by the RNA silencing complex and targets matching RNA sequences leading to their destruction. Once this occurs, gene expression is effectively silenced. Abbreviations: mRNA, messenger RNA; siRNA, short-interfering RNA.

medwedi.ru

208

Part One: General Considerations

of dsRNA directly into cells. Charged oligonucleotides will not pass through a lipid bilayer, severely limiting the usefulness of RNAi in the treatment of human disease. However, recently developed vector-based strategies that contain stem-loop constructs encoding hairpin RNAs have lead to the intracellular generation of siRNA-like species (206). These constructs have been used to express siRNA stably in cells, resulting in a significant decrease in targeted protein expression (206). They have also been delivered in the context of a retrovirus, making their potential much greater (207–209). Inhibition of protein expression mediated by siRNA has been shown to be an effective means to inhibit the activity of H-ras in ovarian cancer cells and has limited the proliferative capacity of these cells both in vitro and in vivo (209). The utility of RNAi in the therapy of cancer has yet to be demonstrated but this remains a very exciting field of research and will, at the minimum, provide us with a better understanding of the biology of cancer.

SUMMARY The last 30 years have witnessed powerful advances in cancer biology and molecular genetics. These developments in modern biomedical research have shed new light on the processes involved in transformation of normal cells into neoplastic cells, tumor cell proliferation, and the biology of tumor metastasis. Today’s surgeon must have a thorough understanding of these processes and their relationship to therapy to participate as a key member of an integrated, multidisciplinary, oncology research and treatment program. This chapter reviews and highlights the basic concepts of cancer biology and the rationale for the integration of treatment options on the basis of our current understanding of those mechanisms responsible for oncogenesis.

REFERENCES 1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1):57–70. 2. Evan G, Littlewood T. A matter of life and cell death. Science 1998; 281(5381):1317–1322. 3. Czernilofsky AP, Levinson AD, Varmus HE, et al. Nucleotide sequence of an avian sarcoma virus oncogene (src) and proposed amino acid sequence for gene product. Nature 1980; 287(5779):198–203. 4. Temin HM. Viral oncogenes. Cold Spring Harb Symp Quant Biol 1980; 44(Pt 1):1–7. 5. Chen IS, Wilhelmsen KC, Temin HM. Structure and expression of c-rel, the cellular homolog to the oncogene of reticuloendotheliosis virus strain T. J Virol 1983; 45(1):104–113. 6. Varmus HE. The molecular genetics of cellular oncogenes. Annu Rev Genet 1984; 18:553–612. 7. Lowy DR, Willumsen BM. Function and regulation of Ras. Annu Rev Biochem 1993; 62:851–891. 8. Rommel C, Hafen E. Ras—a versatile cellular switch. Curr Opin Genet Dev 1998; 8(4):412–418. 9. Chin L, Tam A, Pomerantz J, et al. Essential role for oncogenic Ras in tumour maintenance. Nature 1999; 400(6743): 468–472. 10. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003; 3(1):11–22. 11. Kohl NE, Omer CA, Conner MW, et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in Ras transgenic mice. Nat Med 1995; 1(8):792–797. 12. Boulougouris P, Elder JB. Epidermal growth factor receptor and transformation. Surg Today 2002; 32(8):667–671.

13. Cowley GP, Smith JA, Gusterson BA. Increased EGF receptors on human squamous carcinoma cell lines. Br J Cancer 1986; 53(2):223–229. 14. Gusterson B, Cowley G, McIlhinney J, et al. Evidence for increased epidermal growth factor receptors in human sarcomas. Int J Cancer 1985; 36(6):689–693. 15. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999; 59(8):1935–1940. 16. Lukashev ME, Werb Z. ECM signalling: orchestrating cell behaviour and misbehaviour. Trends Cell Biol 1998; 8(11): 437–441. 17. Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999; 285(5430):1028–1032. 18. Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK)—from inflammation to development. Curr Opin Cell Biol 1998; 10(2):205–219. 19. Zhang Z, Vuori K, Reed JC, Ruoslahti E. The alpha 5 beta 1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci USA 1995; 92(13): 6161–6165. 20. Stromblad S, Becker JC, Yebra M, et al. Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis. J Clin Invest 1996; 98(2):426–433. 21. Scatena M, Almeida M, Chaisson ML, et al. NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol 1998; 141(4):1083–1093. 22. Petitclerc E, Stromblad S, von Schalscha TL, et al. Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res 1999; 59(11):2724–2730. 23. Skobe M, Fusenig NE. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci USA 1998; 95(3):1050–1055. 24. Olumi AF, Grossfeld GD, Hayward SW, et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999; 59(19):5002–5011. 25. Kurose K, Gilley K, Matsumoto S, et al. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 2002; 32(3):355–357. 26. Norbury C, Nurse P. Animal cell cycles and their control. Annu Rev Biochem 1992; 61:441–470. 27. Dynlacht BD. Regulation of transcription by proteins that control the cell cycle. Nature 1997; 389(6647):149–152. 28. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81(3):323–330. 29. Yeung RS, Bell DW, Testa JR, et al. The retinoblastoma-related gene, RB2, maps to human chromosome 16 q 12 and rat chromosome 19. Oncogene 1993; 8(12):3465–3468. 30. Knudson AG Jr, Hethcote HW, Brown BW. Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc Natl Acad Sci USA 1975; 72(12): 5116–5120. 31. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16(4): 168–174. 32. Slansky JE, Farnham PJ. Introduction to the E2F family: protein structure and gene regulation. Curr Top Microbiol Immunol 1996; 208:1–30. 33. Farnham PJ, Slansky JE, Kollmar R. The role of E2F in the mammalian cell cycle. Biochim Biophys Acta 1993; 1155(2): 125–131. 34. Weissman IL. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 2000; 287(5457): 1442–1446. 35. Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell 1997; 88(3):287–298. 36. Fidler IJ, Kripke ML. Metastasis results from preexisting variant cells within a malignant tumor. Science 1977; 197(4306): 893–895.

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment 37. Fidler IJ, Hart IR. Biological diversity in metastatic neoplasms: origins and implications. Science 1982; 217(4564):998–1003. 38. Heppner GH. Tumor heterogeneity. Cancer Res 1984; 44(6): 2259–2265. 39. Nowell PC. Mechanisms of tumor progression. Cancer Res 1986; 46(5):2203–2207. 40. Nowell PC. The clonal evolution of tumor cell populations. Science 1976; 194(4260):23–28. 41. Fialkow PJ. Clonal origin of human tumors. Biochim Biophys Acta 1976; 458(3):283–321. 42. Fearon ER, Hamilton SR, Vogelstein B. Clonal analysis of human colorectal tumors. Science 1987; 238(4824):193–197. 43. Raab-Traub N, Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 1986; 47(6):883–889. 44. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100(7):3983–3988. 45. Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003; 22(47):7340–7358. 46. Alvi AJ, Clayton H, Joshi C, et al. Functional and molecular characterisation of mammary side population cells. Breast Cancer Res 2003; 5(1):R1–R8. 47. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26(4):239–257. 48. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980; 68:251–306. 49. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis 2000; 21(3):485–495. 50. Hengartner MO, Horvitz HR. Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Dev 1994; 4(4):581–586. 51. Hengartner MO, Horvitz HR. The ins and outs of programmed cell death during C. elegans development. Philos Trans R Soc Lond B Biol Sci 1994; 345(1313):243–246. 52. Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell 1986; 44(6):817–829. 53. Hengartner MO, Horvitz HR. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 1994; 76(4):665–676. 54. Yuan J, Shaham S, Ledoux S, et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993; 75(4): 641–652. 55. Xue D, Shaham S, Horvitz HR. The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. Genes Dev 1996; 10(9):1073–1083. 56. Ozoren N, El-Deiry WS. Cell surface death receptor signaling in normal and cancer cells. Semin Cancer Biol 2003; 13(2): 135–147. 57. Stennicke HR, Salvesen GS. Caspases—controlling intracellular signals by protease zymogen activation. Biochim Biophys Acta 2000; 1477(1–2):299–306. 58. Wajant H. The Fas signaling pathway: more than a paradigm. Science 2002; 296(5573):1635–1636. 59. Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999; 68:383–424. 60. Strasser A, O’Connor L, Dixit VM. Apoptosis signaling. Annu Rev Biochem 2000; 69:217–245. 61. Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997; 22(8):299–306. 62. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998; 281(5381):1312–1316. 63. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988; 335(6189):440–442. 64. McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature 1991; 349(6306):254–256.

209

65. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 2003; 21(6):1174–1179. 66. Livingstone LR, White A, Sprouse J, et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 1992; 70(6):923–935. 67. Guidos CJ, Williams CJ, Grandal I, et al. V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors. Genes Dev 1996; 10(16):2038–2054. 68. Gao Y, Ferguson DO, Xie W, et al. Interplay of p53 and DNArepair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 2000; 404(6780):897–900. 69. Park WS, Oh RR, Kim YS, et al. Somatic mutations in the death domain of the Fas (Apo-1/CD95) gene in gastric cancer. J Pathol 2001; 193(2):162–168. 70. Lee SH, Shin MS, Park WS, et al. Alterations of Fas (APO-1/ CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res 1999; 59(13):3068–3072. 71. Lee SH, Shin MS, Park WS, et al. Alterations of Fas (Apo-1/ CD95) gene in non-small cell lung cancer. Oncogene 1999; 18(25):3754–3760. 72. Landowski TH, Moscinski L, Burke R, et al. CD95 antigen mutations in hematopoietic malignancies. Leuk Lymphoma 2001; 42(5):835–846. 73. Shen L, Liang AC, Lu L, et al. Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma. Am J Pathol 2002; 161(6):2123–2131. 74. Shin MS, Kim HS, Lee SH, et al. Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAILR1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res 2001; 61(13):4942–4946. 75. Hakem R, Hakem A, Duncan GS, et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 1998; 94(3):339–352. 76. Woo M, Hakem R, Soengas MS, et al. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev 1998; 12(6):806–819. 77. Bertin J, Mendrysa SM, LaCount DJ, et al. Apoptotic suppression by baculovirus P35 involves cleavage by and inhibition of a virus-induced CED-3/ICE-like protease. J Virol 1996; 70(9):6251–6259. 78. Sugimoto A, Friesen PD, Rothman JH. Baculovirus p35 prevents developmentally programmed cell death and rescues a ced-9 mutant in the nematode Caenorhabditis elegans. EMBO J 1994; 13(9):2023–2028. 79. Beidler DR, Tewari M, Friesen PD, et al. The baculovirus p35 protein inhibits Fas- and tumor necrosis factor-induced apoptosis. J Biol Chem 1995; 270(28):16,526–16,528. 80. Munger K, Scheffner M, Huibregtse JM, Howley PM. Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. Cancer Surv 1992; 12:197–217. 81. Vousden K. Interactions of human papillomavirus transforming proteins with the products of tumor suppressor genes. Faseb J 1993; 7(10):872–879. 82. Huibregtse JM, Beaudenon SL. Mechanism of HPV E6 proteins in cellular transformation. Semin Cancer Biol 1996; 7(6):317–326. 83. Kennedy G, Komano J, Sugden B. Epstein-Barr virus provides a survival factor to Burkitt’s lymphomas. Proc Natl Acad Sci USA 2003; 100(24):14,269–14,274. 84. Huettner CS, Zhang P, Van Etten RA, Tenen DG. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 2000; 24(1):57–60. 85. Banchereau J, de Paoli P, Valle A, et al. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science 1991; 251(4989):70–72. 86. Spriggs MK, Armitage RJ, Strockbine L, et al. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med 1992; 176(6): 1543–1550. 87. Middleton T, Gahn TA, Martin JM, Sugden B. Immortalizing genes of Epstein-Barr virus. Adv Virus Res 1991; 40:19–55.

medwedi.ru

210

Part One: General Considerations

88. Hammerschmidt W, Sugden B. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature 1989; 340(6232):393–397. 89. Sugden B, Mark W. Clonal transformation of adult human leukocytes by Epstein-Barr virus. J Virol 1977; 23(3):503–508. 90. Counter CM, Botelho FM, Wang P, et al. Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes. J Virol 1994; 68(5):3410–3414. 91. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985; 43(2 Pt 1):405–413. 92. Wong SC, Yu H, Moochhala SM, So JB. Antisense telomerase induced cell growth inhibition, cell cycle arrest and telomerase activity down-regulation in gastric and colon cancer cells. Anticancer Res 2003; 23(1A):465–469. 93. Schindler A, Fiedler U, Meye A, et al. Human telomerase reverse transcriptase antisense treatment downregulates the viability of prostate cancer cells in vitro. Int J Oncol 2001; 19(1):25–30. 94. Maser RS, DePinho RA. Connecting chromosomes, crisis, and cancer. Science 2002; 297(5581):565–569. 95. Bodnar AG, Ouellette M, Frolkis M, et al. Extension of lifespan by introduction of telomerase into normal human cells. Science 1998; 279(5349):349–352. 96. Vaziri H, Benchimol S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol 1998; 8(5): 279–282. 97. Jiang XR, Jimenez G, Chang E, et al. Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Nat Genet 1999; 21(1):111–114. 98. Morales CP, Holt SE, Ouellette M, et al. Absence of cancerassociated changes in human fibroblasts immortalized with telomerase. Nat Genet 1999; 21(1):115–118. 99. Masutomi K, Yu EY, Khurts S, et al. Telomerase maintains telomere structure in normal human cells. Cell 2003; 114(2): 241–253. 100. Hahn WC, Stewart SA, Brooks MW, et al. Inhibition of telomerase limits the growth of human cancer cells. Nat Med 1999; 5(10):1164–1170. 101. Zhang X, Mar V, Zhou W, et al. Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev 1999; 13(18):2388–2399. 102. Herbert B, Pitts AE, Baker SI, et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci USA 1999; 96(25):14,276–14,281. 103. Shay JW, Wright WE. Telomerase: a target for cancer therapeutics. Cancer Cell 2002; 2(4):257–265. 104. Shammas MA, Simmons CG, Corey DR, Shmookler Reis RJ. Telomerase inhibition by peptide nucleic acids reverses ‘immortality’ of transformed human cells. Oncogene 1999; 18(46): 6191–6200. 105. Corey DR. Telomerase inhibition, oligonucleotides, and clinical trials. Oncogene 2002; 21(4):631–637. 106. Naasani I, Seimiya H, Yamori T, Tsuruo T. FJ5002: a potent telomerase inhibitor identified by exploiting the diseaseoriented screening program with COMPARE analysis. Cancer Res 1999; 59(16):4004–4011. 107. Seimiya H, Oh-hara T, Suzuki T, et al. Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991. Mol Cancer Ther 2002; 1(9):657–665. 108. Gowan SM, Heald R, Stevens MF, Kelland LR. Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. Mol Pharmacol 2001; 60(5):981–988. 109. Gowan SM, Harrison JR, Patterson L, et al. A G-quadruplexinteractive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol Pharmacol 2002; 61(5):1154–1162.

110. Tonini T, Rossi F, Claudio PP. Molecular basis of angiogenesis and cancer. Oncogene 2003; 22(42):6549–6556. 111. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29(6 suppl 16):15–18. 112. Bergers G, Hanahan D, Coussens LM. Angiogenesis and apoptosis are cellular parameters of neoplastic progression in transgenic mouse models of tumorigenesis. Int J Dev Biol 1998; 42(7 Spec No):995–1002. 113. Volpert OV, Dameron KM, Bouck N. Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity. Oncogene 1997; 14(12):1495–1502. 114. Singh RK, Gutman M, Bucana CD, et al. Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci USA 1995; 92(10):4562–4566. 115. O’Reilly MS, Wiederschain D, Stetler-Stevenson WG, et al. Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J Biol Chem 1999; 274(41):29,568–29,571. 116. Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem 1996; 271(17):10,079–10,086. 117. Gately S, Twardowski P, Stack MS, et al. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 1997; 94(20):10,868–10,872. 118. O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science 1999; 285(5435):1926–1928. 119. Rosen L. Antiangiogenic strategies and agents in clinical trials. Oncologist 2000; 5(suppl 1):20–27. 120. Stopeck A, Sheldon M, Vahedian M, et al. Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin Cancer Res 2002; 8(9):2798–2805. 121. Rosen LS. Angiogenesis inhibition in solid tumors. Cancer J 2001; 7(suppl 3):S120–S128. 122. Ning S, Laird D, Cherrington JM, Knox SJ. The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation. Radiat Res 2002; 157(1):45–51. 123. Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980; 283(5743):139–146. 124. Poste G, Doll J, Hart IR, Fidler IJ. In vitro selection of murine B16 melanoma variants with enhanced tissue-invasive properties. Cancer Res 1980; 40(5):1636–1644. 125. Clark EA, Golub TR, Lander ES, Hynes RO. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 2000; 406(6795):532–535. 126. Bernards R, Weinberg RA. A progression puzzle. Nature 2002; 418(6900):823. 127. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003; 33(1):49–54. 128. Weigelt B, Glas AM, Wessels LF, et al. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc Natl Acad Sci USA 2003; 100(26):15,901– 15,905. 129. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 415(6871):530–536. 130. Liotta LA, Kohn EC. The microenvironment of the tumourhost interface. Nature 2001; 411(6835):375–379. 131. Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem 2002; 71:333–374. 132. Carmichael J. Cancer chemotherapy: identifying novel anticancer drugs. BMJ 1994; 308(6939):1288–1290. 133. Vokes EE. The promise of biochemical modulation in combined modality therapy. Semin Oncol 1994; 21(6 suppl 14):29–33. 134. Mitscher LA, Pillai SP, Gentry EJ, Shankel DM. Multiple drug resistance. Med Res Rev 1999; 19(6):477–496.

Chapter 9: Neoplastic Disease: Pathophysiology and Rationale for Treatment 135. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293(5531):876–880. 136. Griffin JD. Resistance to targeted therapy in leukaemia. Lancet 2002; 359(9305):458–459. 137. Rosell R, Monzo M, Alberola V, et al. Determinants of response and resistance to cytotoxics. Semin Oncol 2002; 29(1 suppl 4):110–118. 138. Shen D, Pastan I, Gottesman MM. Cross-resistance to methotrexate and metals in human cisplatin-resistant cell lines results from a pleiotropic defect in accumulation of these compounds associated with reduced plasma membrane binding proteins. Cancer Res 1998; 58(2):268–275. 139. Nitiss JL, Beck WT. Antitopoisomerase drug action and resistance. Eur J Cancer 1996; 32A(6):958–966. 140. Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. Oncologist 2003; 8(5):411–424. 141. Childs S, Ling V. The MDR superfamily of genes and its biological implications. Important Adv Oncol 1994; 21–36. 142. Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 2001; 11(7):1156–1166. 143. Sonneveld P, Schoester M, de Leeuw K. Clinical modulation of multidrug resistance in multiple myeloma: effect of cyclosporine on resistant tumor cells. J Clin Oncol 1994; 12(8):1584–1591. 144. Sonneveld P, Suciu S, Weijermans P, et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol 2001; 115(4):895–902. 145. Friedland M. Combination Chemotherapy. Baltimore: Williams and Wilkins, 1992. 146. DeVita VT, Schein PS. The use of drugs in combination for the treatment of cancer: rationale and results. N Engl J Med 1973; 288(19):998–1006. 147. Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. Am Soc Clin Oncol J Clin Oncol 1996; 14(6): 1957–1960. 148. Perry MCAC, Donehower RC. Chemotherapy. 2nd ed. New York: Churchill Livingstone, 2000. 149. Frei E III, Miller D, Clark JR, et al. Clinical and scientific considerations in preoperative (neoadjuvant) chemotherapy. Recent Results Cancer Res 1986; 103:1–5. 150. Frei E III. What’s in a name—neoadjuvant. J Natl Cancer Inst 1988; 80(14):1088–1089. 151. Norton L, Simon R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 1977; 61(7): 1307–1317. 152. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979; 63(11–12):1727–1733. 153. Norton L, Simon R, Brereton HD, Bogden AE. Predicting the course of Gompertzian growth. Nature 1976; 264(5586): 542–545. 154. Elkind MM. DNA damage and cell killing. Cause and effect? Cancer 1985; 56(10):2351–2363. 155. Frankenberg D, Frankenberg-Schwager M, Blocher D, Harbich R. Evidence for DNA double-strand breaks as the critical lesions in yeast cells irradiated with sparsely or densely ionizing radiation under oxic or anoxic conditions. Radiat Res 1981; 88(3):524–532. 156. Iliakis G, Mehta R, Jackson M. Level of DNA double-strand break rejoining in Chinese hamster xrs-5 cells is dose-dependent: implications for the mechanism of radiosensitivity. Int J Radiat Biol 1992; 61(3):315–321. 157. Warters RL, Lyons BW. Variation in radiation-induced formation of DNA double-strand breaks as a function of chromatin structure. Radiat Res 1992; 130(3):309–318. 158. McMillan TJ. Residual DNA damage: what is left over and how does this determine cell fate? Eur J Cancer 1992; 28(1):267–269.

211

159. Harrison LB, Chadha M, Hill RJ, et al. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 2002; 7(6):492–508. 160. Castro JR. Particle radiation therapy: the first forty years. Semin Oncol 1981; 8(1):103–109. 161. Chapman JD. Hypoxic sensitizers—implications for radiation therapy. N Engl J Med 1979; 301(26):1429–1432. 162. McGinn CJ, Shewach DS, Lawrence TS. Radiosensitizing nucleosides. J Natl Cancer Inst 1996; 88(17):1193–1203. 163. Bleyer WA, Poplack DG. Prophylaxis and treatment of leukemia in the central nervous system and other sanctuaries. Semin Oncol 1985; 12(2):131–148. 164. Beck DE, Karulf RE. Combination therapy for epidermoid carcinoma of the anal canal. Dis Colon Rectum 1994; 37(11): 1118–1125. 165. Mason M. Basic principles of radiotherapy for surgical oncologists. 5—combined radiotherapy and chemotherapy: twice the benefit, or double the trouble? Eur J Surg Oncol 1994; 20(5):597–602. 166. Widmark A, Flodgren P, Damber JE, et al. A systematic overview of radiation therapy effects in urinary bladder cancer. Acta Oncol 2003; 42(5–6):567–581. 167. Einhorn N, Trope C, Ridderheim M, et al. A systematic overview of radiation therapy effects in cervical cancer (cervix uteri). Acta Oncol 2003; 42(5–6):546–556. 168. Rutqvist LE, Rose C, Cavallin-Stahl E. A systematic overview of radiation therapy effects in breast cancer. Acta Oncol 2003; 42(5–6):532–545. 169. Strander H, Turesson I, Cavallin-Stahl E. A systematic overview of radiation therapy effects in soft tissue sarcomas. Acta Oncol 2003; 42(5–6):516–531. 170. Glimelius B, Gronberg H, Jarhult J, et al. A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol 2003; 42(5–6):476–492. 171. Zackrisson B, Mercke C, Strander H, et al. A systematic overview of radiation therapy effects in head and neck cancer. Acta Oncol 2003; 42(5–6):443–461. 172. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c Randomised Trial. Lancet 1999; 353(9165):1641–1648. 173. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997; 337(14):949–955. 174. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997; 337(14):956–962. 175. Balch CM. Surgical oncology in the 21st century. Arch Surg 1992; 127(11):1272–1277. 176. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14(1):7–17. 177. Holcombe RF. Clinical applications of the interleukins: present and future. J La State Med Soc 1994; 146(11):479–483. 178. Bubenik J. Cytokine gene-modified vaccines in the therapy of cancer. Pharmacol Ther 1996; 69(1):1–14. 179. Sumiyoshi Y, Yokota K, Akiyama M, et al. Neoadjuvant intraarterial doxorubicin chemotherapy in combination with low dose radiotherapy for the treatment of locally advanced transitional cell carcinoma of the bladder. J Urol 1994; 152(2 Pt 1):362–366. 180. Vujanovic NL, Yasumura S, Hirabayashi H, et al. Antitumor activities of subsets of human IL-2-activated natural killer cells in solid tissues. J Immunol 1995; 154(1):281–289. 181. Foa R, Guarini A, Gansbacher B. IL2 treatment for cancer: from biology to gene therapy. Br J Cancer 1992; 66(6):992–998. 182. Rosenberg SA. Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer. J Clin Oncol 1992; 10(2):180–199.

medwedi.ru

212

Part One: General Considerations

183. Belldegrun A, Muul LM, Rosenberg SA. Interleukin-2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity. Cancer Res 1988; 48(1):206–214. 184. Spiess PJ, Yang JC, Rosenberg SA. In vivo antitumor activity of tumor-infiltrating lymphocytes expanded in recombinant interleukin-2. J Natl Cancer Inst 1987; 79(5):1067–1075. 185. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298(5594): 850–854. 186. Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother 2002; 25(3):243–251. 187. Kirschbaum MH, Yarden Y. The ErbB/HER family of receptor tyrosine kinases: a potential target for chemoprevention of epithelial neoplasms. J Cell Biochem Suppl 2000; 34:52–60. 188. Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol 2003; 30(3 suppl 7):3–14. 189. Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology 2001; 61(suppl 2):1–13. 190. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17(9):2639–2648. 191. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20(3):719–726. 192. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11):783–192. 193. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002; 2(2):127–137. 194. Moolten FL. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 1986; 46(10):5276–5281. 195. Ramesh R, Marrogi AJ, Munshi A, et al. In vivo analysis of the ‘bystander effect’: a cytokine cascade. Exp Hematol 1996; 24(7):829–838. 196. Freeman SM, Abboud CN, Whartenby KA, et al. The ‘‘bystander effect’’: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53(21):5274–5283.

197. Huber BE, Austin EA, Good SS, et al. In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. Cancer Res 1993; 53(19):4619–4626. 198. Huber BE, Austin EA, Richards CA, et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci USA 1994; 91(17):8302–8306. 199. Wills KN, Maneval DC, Menzel P, et al. Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. Hum Gene Ther 1994; 5(9):1079–1088. 200. Snitkovsky S, Young JA. Cell-specific viral targeting mediated by a soluble retroviral receptor-ligand fusion protein. Proc Natl Acad Sci USA 1998; 95(12):7063–7068. 201. Snitkovsky S, Niederman TM, Mulligan RC, Young JA. Targeting avian leukosis virus subgroup A vectors by using a TVA-VEGF bridge protein. J Virol 2001; 75(3):1571–1575. 202. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2(5):561–566. 203. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344(14):1038–1042. 204. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344(14):1031–1037. 205. McManus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 2002; 3(10) :737–747. 206. Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296(5567):550–553. 207. Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002; 2(3):243–247. 208. Stewart SA, Dykxhoorn DM, Palliser D, et al. Lentivirusdelivered stable gene silencing by RNAi in primary cells. RNA 2003; 9(4):493–501. 209. Yang G, Thompson JA, Fang B, Liu J. Silencing of H-ras gene expression by retrovirus-mediated siRNA decreases transformation efficiency and tumorgrowth in a model of human ovarian cancer. Oncogene 2003; 22(36):5694–5701.

10 The Physiology of Anesthesia and Pain Charles Williams and Denise Lester

INTRODUCTION Although the discipline of anesthesiology has traditionally been focused on delivering safe and effective surgical analgesia and amnesia, more recently it has broadened to include the management of critical care and pain issues. Accordingly, to encompass these extended responsibilities, this chapter is divided into two sections. The first section concerns the physiology of anesthesia and its application toward carrying out operative procedures. This includes the management of intraoperative critical care. The second section deals with surgical pain by discussing current concepts underlying the pathophysiology of pain and how they relate to perioperative care.

THE PHYSIOLOGY OF ANESTHESIA Perioperative changes in a patient’s physiology can be attributed to an interaction between the underlying disease state and coexisting illnesses, the type of anesthesia and the pharmacodynamics of the medications necessary to create acceptable surgical conditions, and the results of the surgical process itself. The choice of the anesthetic technique is unique to each patient and should take these changes into consideration. Lesser considerations include the anesthesiologist’s skill at performing various anesthetic techniques, the patient’s preferences, and cost. The final choice of anesthesia is then made by assessing the patient’s risks of morbidity or mortality associated with a particular anesthetic technique versus the benefits to be gained by the surgery. The risks must be understood and acceptable to the anesthesiologist, the surgeon, and the patient.

PREOPERATIVE DECISIONS An anesthesiologist begins to choose an anesthetic technique by assessing the patient’s health preoperatively. Almost every disease process has anesthetic implications that must be taken into consideration; while an unstable trauma patient has obvious physiologic perturbations, patients with stable, long-standing processes may have more obscure implications. For example, although chronic hypertension and its pharmacologic treatment may appear benign, it can be associated with end-organ damage, autonomic instability, or intravascular volume depletion. The anesthetic implications of other disease states are discussed below. Once all aspects of the patient’s preoperative health are evaluated, a broader categorization can be applied to their condition. The American Society of Anesthesiologists (ASA) hasdevelopedtheASAPhysicalStatusClassificationSystem(1) whereby patients are assigned a classification based upon a

six-step gradation in their preoperative health; P1 is a normal, healthy patient and P6 is a brain-dead patient whose organs are being removed for donor purposes (Table 1). While this system functions as a useful quick reference tool, it is also tied to aspects of billing for professional anesthesia services and is a tacit implication of perioperative risks. In general, higher ASA Physical Status classifications are associated with greater preoperative physiologic perturbations and higher perioperative risks of mortality and morbidity. Numerous large single-institution and multi-institution studies have examined anesthesia outcome, but generalizations have been difficult due to differences in inclusion criteria and end points. One study assessed almost one million cases over a one-year period and reported a mortality rate of 1 in 185,000 cases where anesthesia was considered the sole cause of death. Anesthesia was a contributory cause of death in 7 out of 10,000 cases (2). While other studies have reported higher mortality rates, most agree that mortality and morbidity is higher with extremes of age (old and young), higher ASA physical status, and emergent conditions. Underlying disease processes in virtually every organ system can affect anesthetic outcome to some degree, but diseases involving the cardiovascular system have arguably the single greatest impact. Several studies have considered the incidence of fatal and nonfatal cardiac arrests primarily associated with anesthesia and have reported occurrence rates ranging from 1 in 9620 cases (3) to 1 in 14,493 cases (4). Therefore, careful preoperative evaluation of cardiac performance and the identification of potential or active ischemia are warranted. It has been repeatedly shown that if a patient has had a myocardial infarction within the six months prior to undergoing noncardiac surgery, the perioperative reinfarction rate is 5% to 86% (a 1.5 to 10 times higher rate than when the infarction and surgery are separated by more than 6 months) and a mortality rate of 23% to 86% (5). In general, however, anesthesia-related risks have declined markedly over the last 20 years. This has largely been due to two factors. First, developmental advances in the equipment used for the delivery of anesthesia have been produced with the specific goals of eliminating failures, and Table 1 The American Society of Anesthesiologists Preoperative Physical Status Classification System P1 A normal, healthy patient P2 A patient with mild systemic disease P3 A patient with severe systemic disease P4 A patient with severe systemic disease that is a constant threat to life P5 A moribund patient who is not expected to survive without the operation P6 A declared brain-dead patient whose organs are being removed for donor purposes Source: From Ref. 1.

medwedi.ru 213

214

Part One: General Considerations

each successive generation of anesthetic drugs is designed to reduce the complications and side effects of its predecessors. It has been suggested, for example, that the use of pulse oximetry and end-tidal capnometry since 1985 has significantly reduced poor outcomes related to ventilatory failure (6,7). Second, anesthesiology, as a professional specialty, has been very effective at learning from its own undesired outcomes. In 1985, the ASA established the ASA Closed Claims Project with the intention of identifying the causes of loss and therefore improving patient safety. To date, thousands of cases have been reviewed and data from their analysis have contributed significantly to the establishment of safe practice standards (8). Regardless of the type of anesthesia chosen or the complexity of the surgical procedure, all patients are carefully monitored intraoperatively. The ASA maintains well-established physiologic monitoring standards for all general, regional, or monitored care anesthetics (Table 2), and require continual evaluation of the patient’s oxygenation, ventilation, circulation, and body temperature (9). Additional monitors can be added if the patient’s preexisting or anticipated surgical condition warrants, including urimetry and various neurophysiologic monitors. Many patients needing surgical intervention also have significant cardiac disease and in these cases, more precise monitoring of cardiopulmonary dynamics is required. In addition to continuous arterial transduction of blood pressure, more direct measurement of cardiac performance can be obtained by pulmonary artery catheterization (Swan–Ganz catheter), noninvasive bioimpedence cardiac output monitors, or transesophageal echocardiography. The latter technique is especially useful in visualizing left ventricular function. Proper intravenous access is critical to the delivery of anesthesia, and if peripheral access is either inadequate or unsatisfactory, central venous access may be required. Such central access can be obtained through the internal jugular or subclavian veins, although sometimes basilic (long-arm) or femoral vein approaches are used. Arterial access for

Table 2 The American Society of Anesthesiologists Standardsa for Basic Anesthetic Monitoring Standard I Qualified anesthesia personnel shall be present in the room throughout the conduct of all general anesthetics, regional anesthetics, and monitored anesthesia care Standard II Oxygenation (i) Oxygen analyzer with a low oxygen concentration limit alarm (ii) Pulse oximetry. Adequate illumination and exposure of the patient are necessary to assess color Ventilation (i) Continual CO2 monitoring. Quantitative monitoring of the volume of expired gas is strongly encouraged (ii) Verify endotracheal tube placement with capnometry. Continual end-tidal CO2 must be employed while intubated or LMA is in place (iii) Continual ventilator disconnection alarm Circulation (i) Electrocardiogram (ii) Arterial blood pressure and heart rate at least every 5 min Body temperature (i) Temperature shall be monitored when clinically significant changes in temperature are intended, anticipated, or suspected a

American Society of Anesthesiologists, last amended October 27, 2004. Abbreviation: LMA, laryngeal mask airway. Source: From Ref. 9.

continual blood pressure monitoring is typically obtained through the radial or dorsalis pedis arteries, but if inaccessible, femoral or brachial artery approaches are also available.

REGIONAL ANESTHESIA Regional anesthesia is based upon a localized blockade of neural conduction created by an appropriately placed injection or infusion of a local anesthetic. These blocks can be categorized into two broad groups: peripheral nerve or plexus blocks and major conduction (neuraxial) blocks. The latter group includes spinal and epidural anesthetics. An anesthesiologist’s choice between regional and general anesthesia relates to the risks of each to the patient and to the ability of a particular block to satisfy surgical requirements. The types of regional blocks most commonly employed are detailed in Tables 3, 4 and 5. A regional technique is often chosen specifically to avoid exposing a patient to the risks of general anesthesia, but regional anesthesia may still present significant risks to a vulnerable patient. This is especially true for neuraxial anesthesia and its accompanying sympathetic blockade. For example, hypotension may be profound in a hypovolemic patient, and patients with ischemic heart disease may experience regional myocardial dysfunction due to hypotension, vasodilatation, and decreased coronary perfusion (10). On the other hand, global systolic ventricular dysfunction or a dilated cardiomyopathy may improve from the reduction in afterload and preload. Despite this, there are few absolute contraindications for regional anesthesia—the strongest being patient refusal. Relative contraindications must be weighed against patient benefit, and include preexisting neurologic disease (medicolegal issues), local or systemic infection, and iatrogenic or induced coagulopathy. Unfortunately, the medications used to produce a regional anesthetic can also present risks. The elimination pharmacokinetics and potency of the local anesthetic influences the onset and duration of the block, and the relative concentration of the anesthetic influences the density of the block. Therefore, an anesthesiologist skilled at regional techniques has a variety of aminoamide (e.g., lidocaine, bupivacaine, prilocaine, and ropivacaine), and aminoester (e.g., cocaine, procaine, and tetracaine) local anesthetics available. Aminoester anesthetics are derivatives of p-aminobenzoic acid, which has a significant allergic potential, but true allergic reactions are extremely rare among the aminoamides. Aminoamides, however, may contain methylparaben, which is a preservative whose chemical structure is similar to p-aminobenzoic acid. Prilocaine produces a dose-dependent methemoglobinemia (11), and bupivacaine (and etidocaine to a lesser extent) may introduce severe cardiac dysrhythmias with intravenous injection (12) that resembles torsades de pointes. It has also been suggested that intrathecal local anesthetics may be neurotoxic. For example, lidocaine has been reported to cause persistent lumbosacral neuropathy after a single intrathecal injection in 1.4 patients out of 1000. Intrathecal lidocaine has also been found to cause transient neurologic symptoms (formerly known as transient radicular irritation, defined as pain or dysesthesia in the buttocks or legs after recovery from spinal anesthesia) in 16% to 33% of patients (13). Systemic toxicity from an accidental intravascular, intrathecal, or excessive dose of local anesthetic involves the cardiovascular system or the central nervous system

Chapter 10:

The Physiology of Anesthesia and Pain

215

Table 3 Types of Neuraxial Regional Anesthesia and Their Uses Type

Area injected

Major conduction (neuraxial) blocks Spinal anesthesia Subarachnoid space via lumbar puncture below termination of the spinal cord Epidural anesthesia Epidural space outside the ‘‘dura mater’’

Agent injected

Nerves blocked

Indication

Local anesthetic with/without Somatic and visceral sensory Procedures performed in the narcotic by fine needle injection afferent nerves, as well as dermatomes at or below the or catheter placement efferent motor and autonomic mid-abdomen (sympathetic) fibers Local anesthetic and/or narcotic Similar to spinal anesthesia, but Can be used for procedures by catheter placed anywhere more ‘‘segmental’’; less anywhere from the neck to from the cervical to the sacral intense block above and below the sacral area hiatus epidural space the site of injection

(CNS), and often is related to the relative potency of the drug used. While the direct cardiovascular effects of lidocaine are clinically useful in decreasing the rate of depolarization in the fast-conduction tissues of Purkinje fibers and ventricular muscle, dysrhythmias created by bupivacaine toxicity are notoriously difficult to correct. The local anesthetic blood levels required to produce CNS toxicity, however, are much lower than those required to produce cardiovascular collapse; the initial blockade of inhibitory pathways and the stimulation of glutamate release can trigger a progression of symptoms from simple dizziness and disorientation to generalized tonic-clonic convulsions. In experienced hands, regional anesthesia remains a relatively safe alternative to general anesthesia, because the few side effects and complications can usually be managed easily or avoided altogether with prudent patient and block selection. Regional anesthesia, however, may not entirely avoid the risks of general anesthesia. Despite the use of nerve stimulators and various techniques that aid in the confirmation of correct needle location, percutaneous placement of a regional block remains a blind technique and each type of block is associated with varying rates of failure. Any anesthetic plan must therefore also consider the risks of alternative forms of anesthesia should the block fail.

GENERAL ANESTHESIA Patient identification, informed consent, and intravenous access are obtained on all patients regardless of whether general or regional anesthesia is performed. If general anesthesia is chosen, appropriate premedication is then administered, the patient is taken to the operating room, physiologic monitoring is applied, and the patient is preoxygenated. Because the induction of deep anesthesia typically produces respiratory arrest, care must be taken to protect the airway. If the patient has followed fasting guidelines and is not at risk for aspiration (see below), the goal is

to induce general anesthesia quickly and deeply with a shortacting intravenous barbiturate or analog. A mask airway is then established as a fallback point before longer- acting paralytics are administered and maintenance anesthetics are turned on. Once mask ventilation is assured, the patient can be paralyzed and intubated. If the patient is at risk for the aspiration of gastric contents, however, positive pressure ventilation by mask must be avoided so as not to insufflate the stomach and encourage regurgitation. In this case, induction proceeds in rapid sequence with a quick, deep induction of both hypnosis and paralysis, followed by immediate intubation of the airway. To further impede any regurgitated matter from reaching the larynx, external pressure is applied to the cricoid cartilage throughout induction, compressing the more posterior esophagus between the anterior cervical vertebral bodies and the cricoid ring. The immediate administration of a paralytic adds obvious risk to the induction process, but the risk is minimized by sound airway management technique and is acceptable when compared to the mortality and morbidity of aspiration. Maintenance anesthesia is then initiated and a gastric sump (e.g., nasogastric tube) is typically placed to empty the stomach in preparation for emergence at the end of surgery. Maintaining general anesthesia in a surgical patient requires the satisfaction of four components: amnesia, analgesia, hypnosis, and frequently, paralysis. There is currently no single drug that can produce all of these effects, so each is usually addressed individually, and the accompanying changes in the patient’s physiologic state are related to the pharmacodynamics of the drugs used and the patient’s underlying pathologic state. A summary of commonly used amnestics, analgesics, hypnotics, and paralytics is found in Table 6. Patient amnesia and anxiolysis is desirable in the preoperative period, as well as during cases that require only sedation. Historically, central-acting alpha-2 agonists (e.g., clonidine, atropine, and scopolamine) have been used for

Table 4 Types of Peripheral Nerve and Plexus Blocks of the Upper Extremity and Their Uses Type Brachial plexus

Elbow

Wrist

Area injected

Agent injected

Nerves blocked

Indication

Interscalene, supraclavicular, Short-/long-acting local anesthetic Depends upon which branches Operations on shoulder and infraclavicular or axillary injections by fine needle injection or of plexus needed blocked for upper arm block plexus selectively, based catheter placement operation upon operation needs Medial to brachial artery (median Each nerve is blocked with local Both median and radial nerves Operations on forearm and nerve) and lateral to supracondylar anesthetic by fine needle hand ridge (radial nerve) proximal to injection elbow crease Block of median, ulnar, and radial Each nerve is blocked with local Median, ulnar, and radial Operations on hand nerves just proximal to where they anesthetic by fine needle nerves enter hand injection

medwedi.ru

216

Part One: General Considerations

Table 5 Types of Peripheral Nerve and Plexus Blocks of the Lower Extremity and Their Uses Type Lumbar plexus

Sciatic nerve

Ankle

Area injected

Agent injected

Nerves blocked

Posterior, translumbar, paravertebral needle is Local anesthetic by fine Femoral, lateral femoral placed adjacent to plexus, but anterior needle injection or catheter cutaneous and obturator approach places needle into the femoral placement nerves nerve sheath Several approaches, but classic approach is Local anesthetic by fine Sciatic nerve, as well as injection deep to the gluteal muscles at the needle injection or catheter branches of the lumbar same time as posterior lumbar plexus block placement plexus Depends upon level of anesthesia needed in Local anesthetic by fine Combinations of saphenous, foot: nerves requiring injection include the needle injection superficial peroneal, deep saphenous, superficial peroneal, deep peroneal, tibial, and sural peroneal, tibial, and sural nerves nerves; all if needed

this purpose, performing as antisialagogues as well. Unfortunately, the unwanted side effects of tachycardia, lower esophageal sphincter relaxation, and CNS toxicity have limited their usefulness, especially in the elderly; so benzodiazepines (e.g., midazolam, lorazepam, and diazepam) are currently preferred. The most popular benzodiazepine, midazolam, has a fast onset (2 to 3 minutes to peak effect), short duration, and reliable anterograde amnesia. Furthermore, amnesia and sedation with midazolam occur in low doses, whereas respiratory depression and hemodynamic instability appear with higher doses. An agonist of the gammaaminobutyric acid type A (GABAA) receptor, the drug’s effects can be reversed by the administration of flumazenil, a competitive, but nonactive binder at the same receptor. Oral diazepam is still occasionally given for adults, and an oral midazolam preparation is now available for pediatric patients. Positive pressure mask ventilation can insufflate the stomach, leading to regurgitation of its contents, and aspiration of this fluid can cause severe pulmonary damage that is directly proportional to its acidity and particulate content. It is therefore important that the stomach is as empty as possible prior to the induction of general anesthesia or the placement of a regional block where the failure of the block may result in general anesthesia. For adults, a fast of at least six hours should elapse for solid foods and two hours for clear liquids. These same guidelines apply for pediatric patients, but if breast milk is the sole means of nutrition, a fast of at least four hours should elapse prior to the conduction of surgery (Table 7) (14). Patients who are at risk for pulmonary aspiration despite following the established guidelines for preoperative fasting (Table 8) may be given antacids and H2 antagonists to raise their gastric pH. In addition, metaclopramide is sometimes used to enhance

Indication Operations on hip and upper leg

Operations on hip and leg

Operations on foot

gastric emptying and decrease gastric fluid volume, but just like nasogastric or orogastric sumps, it does not fully guarantee gastric emptying (15). Although very small doses of opiates are sometimes given immediately preoperatively, they are generally used more aggressively after the airway is protected. Administration during the induction of general anesthesia will establish analgesia prior to incision (preemptive analgesia) and potentially avoid the development of plastic neuronal changes that can lead to increased pain postoperatively (16). While their ability to produce analgesia comes from binding to specific opioid receptors that directly inhibit ascending transmission of nociceptive information from the spinal cord dorsal horn and activate pain control circuits that descend from the midbrain via the rostral ventromedial medulla, these receptors also mediate undesirable side effects. Unfortunately, the side effects increase in both frequency and severity with more potent formulations, and include muscle rigidity, pupil constriction, pruritus (both histamine and nonhistamine mediated), urinary retention, decreased gastric and intestinal motility, and CNS-mediated respiratory depression and bradycardia. With high doses of narcotics, however, deep CNS depression can produce useful general anesthesia; a continuous intravenous infusion of ultra–short-acting remifentanil is often used during neuroanesthesia, and inducing anesthesia with large doses of sufentanil is often preferred for physiologically unstable patients. More frequently, however, general anesthesia is induced and maintained with hypnotic agents. Intravenous boluses of short-acting barbiturates or their analogs (e.g., propofol or etomidate) are commonly used as induction agents and are typically followed by an inhaled vapor (e.g., sevoflorane or isofluorane) administered through a breathing circuit for maintenance. Although an incomplete

Table 6 Drugs Commonly Used in Anesthesia Hypnotics Benzodiazepines Midazolam Diazepam Lorazepam Barbiturates Sodium pentothal Methohexital Other agents Propofol Etomidate Ketamine

Paralytics

Narcotics

Short acting Succinylcholine Rocuronium Mivacurium Intermediate acting Atracurium Vecuronium Long acting Pancuronium Curare

Short acting Remifentanil

Intermediate acting Sufentanil Fentanyl Long acting Meperidine Morphine

Inhalation agents Vapors Isoflurane Sevoflurane Desflurane Halothane Gasses Nitrous oxide

Table 7 Recommended Preoperative Fasting Periods to Reduce the Risk of Pulmonary Aspiration of Gastric Contents Guidelines for preoperative fastinga Material ingested Light meal Nonhuman milk Clear liquids Infant formula Breast milk a

Minimum fasting time 6 hr 6 hr 2 hr 6 hr 4 hr

Applicable to regional and general anesthetics, applicable to all levels of sedation, applicable to all ages. Source: From Ref. 14.

Chapter 10:

Table 8 Factors Influencing the Risks for the Aspiration of Gastric Contents Obesity Pregnancy Gastroparesis (e.g., diabetes, uremia, drugs) Trauma Symptomatic esophageal reflux Failure to complete preoperative NPO recommendations Abbreviation: NPO, nil per os.

anesthetic by itself, nitrous oxide is often added to supplement the hypnotic vapors because of its relatively few side effects. Physiologically, two general rules prevail regarding hypnotic agents. First, with few exceptions, all depress respiratory drive to some degree. Second, all hypnotics, except ketamine and nitrous oxide, are vasodilators and many are additionally cardiac depressants. Propofol, for example, is one of the most destabilizing agents used: its narrow therapeutic index quickly progresses from sedation to apneic general anesthesia and the associated hypotension can be particularly severe in hypovolemic patients. Therefore, only clinicians trained in the use of hypnotics, paralytics, and powerful narcotics should administer these drugs. Paralytics fall into two classes, depolarizing and nondepolarizing agents, and work primarily at the neuromuscular junction. Currently, the only depolarizing agent is succinylcholine, which acts by depolarizing the muscle postjunctional acetylcholine receptors. This triggers muscle fasciculation, and paralysis occurs because the half-life of succinylcholine does not allow muscle repolarization for approximately three minutes. Although succinylcholine has been used successfully since 1952 (17), it can have considerable side effects; under specific circumstances, it can cause significant hyperkalemia, sinus bradycardia, increased intraoccular and intracranial pressures, myalgias, and masseter spasm. Nondepolarizing agents, on the other hand, have few side effects, although some can cause histamine release and others can cause tachycardia. They act as competitive antagonists of acetylcholine at postsynaptic neuromuscular receptors. Reversal of their paralytic effects can be achieved by using medications that block the effects of acetylcholine esterase, which allows junctional concentrations of acetylcholine to rise high enough for it to become the competitive antagonist of the nondepolarizer. The unused nondepolarizing agent can then diffuse away for metabolic removal. Unfortunately, the paralytic reversal process allows acetylcholine levels to rise throughout the body and acetylcholine also mediates the parasympathetic system. Because this can lead to significant bradycardia, the use of paralytic reversal agents typically necessitates the concurrent administration of atropine or glycopyrolate. The choice of depolarizing or nondepolarizing paralytic agents is based upon clinical need—succinylcholine produces a short-acting, fast-onset, dense paralysis, but has side effects that can limit its usefulness. Although they possess far fewer side effects, nondepolarizing agents have considerably slower onsets and longer durations, and are generally much slower to produce a dense motor blockade. Finally, it is important to remember that all paralytic agents work only at the neuromuscular junction, so direct stimulation of muscle tissue by electrocautery will still produce local muscle contraction in a pharmacologically paralyzed patient. From the above discussion, it should be clear that successful airway management is critical if paralytics,

The Physiology of Anesthesia and Pain

217

hypnotics, or potent opioids are administered. If a secure airway is desired, a cuffed and properly sized endotracheal tube provides the most airway protection. Facemasks, laryngeal masks, and jet catheters may be appropriate in certain circumstances, but because they do not seal the airway from the esophagus, the patient remains an aspiration risk. These devices therefore are not considered to provide definitive airways in most situations. On the other hand, pediatric endotracheal tubes seldom have inflatable cuffs, but are still considered definitive. Cuffs unacceptably decrease the available lumen size in small tracheas, promote barotrauma in sensitive lungs, and risk fracturing of the narrowest part of the pediatric airway, the cricoid ring. If sized appropriately, however, the lack of a complete seal between the tracheal wall and the endotracheal tube is acceptably minimized.

CONSCIOUS SEDATION Most hospitals now maintain specific policies regarding the use of anesthetic agents by nonanesthesia personnel for invasive procedures occurring outside of the operating room. This involves achieving a state of moderate sedation described as a drug-induced depression of consciousness during which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, spontaneous ventilation is adequate, and cardiovascular function is always maintained (18). Note that reflex withdrawal from a painful stimulus is not a purposeful response. Narcotics and hypnotics used to produce this level of sedation are typically specified in the policy, and paralytics and potent narcotics are not allowed. The most commonly used hypnotic for this purpose is methohexital. An ultra–short-acting barbiturate, its CNS effects are mediated through activation of GABAA receptors and side effects include a depression of respiratory drive, a reduction in cardiac output and blood pressure, and a reflexive tachycardia. With judicious administration, methohexital is capable of producing moderate sedation over a relatively wide range of doses. Propofol, on the other hand, is not recommended for moderate sedation due to its much narrower therapeutic window. The difference between a sedated, spontaneously breathing patient, and an unconscious, apneic patient is often determined by the smallest of propofol doses, and is therefore only recommended for use in intubated patients.

ANESTHETIC IMPLICATIONS OF SELECTED DISEASE STATES As stated above, almost every chronic, underlying disease process has anesthetic implications that must be taken into consideration when assessing patient risk and choosing an anesthetic plan. Two of the most commonly encountered are obesity and diabetes mellitus. In the United States, obesity among adults has risen significantly over the past 20 years. Results from the 1999–2002 National Health and Nutrition Examination Survey (NHANES), as reported by the National Center for Health Statistics, indicate that 30% of American adults 20 years of age or older are obese, and an estimated 65% of American adults are either overweight or obese (19). This prevalence is 16% higher than in a similar study performed

medwedi.ru

218

Part One: General Considerations

only eight years earlier, and this increase is not limited to adults. The percentage of young people who are overweight has more than tripled since 1980, and among children and teens, 6 to 19 years old, 16% are considered overweight. Being overweight or obese increases the risk of many secondary diseases such as hypertension, type 2 diabetes, coronary heart disease, stroke, and respiratory conditions, all of which directly impact upon anesthesia risks; a patient who is 30% overweight has a 40% increased chance of dying of heart disease and a 50% increased chance of dying of stroke. The greatest physiologic impact of obesity upon anesthesia revolves around underlying cardiopulmonary derangements. Redundant soft tissue in the upper airway causes obstruction upon the induction of anesthesia and contributes to a difficult tracheal intubation that is already complicated by the high risk of gastric aspiration and the need for rapid airway control. A decreased functional residual capacity that is smaller than closing volumes is worsened by mechanical ventilation and predisposes to hypercapnia and rapid oxygen desaturation from significant atelectasis. Chronic respiratory insufficiency leads to pulmonary hypertension, and combined with a noncompliant left ventricle that is hypertrophied from systemic hypertension, poor myocardial perfusion, and the demand for increased cardiac output, obese patients often require invasive cardiac monitoring intraoperatively and prolonged postoperative intubation. As a result, these patients require extensive preoperative cardiopulmonary evaluation and careful anesthetic planning. The number of documented diabetic patients is enormous and progressively increasing, largely due to the rise in type 2 diabetes that accompanies the weight gain among Americans. In the operating room, tight control of blood glucose level has been shown to be important for the outcome of diabetic patients undergoing cardiopulmonary bypass (20) and during CNS ischemia associated with head injury (21). There otherwise remains little evidence that tight glucose controls benefit any other group of diabetic patients undergoing anesthesia. Instead, the major risks diabetics face during anesthesia comes from the potential end-organ damage created by long-standing disease. Cardiovascular dysfunction and renal insufficiency must be assessed preoperatively, and flexion-extension radiographs are recommended if atlanto-occipital instability is anticipated during intubation. During regional anesthesia, diabetics are more prone to nerve injury, and the peripheral microvascular disease of diabetes may worsen ischemic nerve damage if epinephrine is included in the local anesthetic. Additionally, although rare, intraoperative physical stresses can trigger ketoacidosis or nonketotic hyperosmolar coma in brittle diabetics. There have been numerous regimens advanced for both the preoperative and intraoperative management of insulin and glucose, but as yet, no single method has proven to be superior. Regardless of which regimen is chosen, however, there are several key elements that are important in managing diabetic patients. Clear parameters must be established preoperatively, which define how tightly the patient’s serum glucose is to be managed. For example, type 1 diabetics who produce little or no endogenous insulin are more likely to be candidates for tight control than are type 2 diabetics. Pregnancy, the type of surgical operation, any expected CNS ischemia, or the personal bias of the patient’s primary care physician can all create a disire for tighter intraoperative glucose control. Finally, the frequency of intraoperative serum glucose monitoring must reflect the desired level of glucose control.

ANESTHESIA EMERGENCIES Despite modern equipment, drugs, and techniques, true anesthetic emergencies can occur but are fortunately rare. Often, they are preceded by a progression of warning signs that, if managed in a timely fashion, could have either prevented the emergency or lessened its impact. All anesthesia providers must therefore maintain a high level of vigilance for physiologic changes that may herald a deeper problem. Cardiac arrest, for example, rarely occurs as an isolated event and is caused by harmful dysrhythmias, ionotropic failure, insurmountable afterload, or inadequate filling pressures. These conditions can arise from a wide variety of detectable circumstances that include electrolyte and acid–base disturbances, intravascular volume depletion, myocardial infarction, hypoxemia, tamponade, aortic cross-clamping, pulmonary embolus, and drug effects. When a cardiac arrest does occur in the operating room, the treatment is similar to the steps outlined by the American Heart Association in its Advanced Cardiac Life Support guidelines: proper ventilation should be confirmed and 100% oxygen applied, the circulation should be supported with chest compressions or heart massage, a defibrillator should be applied and used as indicated, consideration should be given to the use of appropriate pharmacological supplementation, and a search should be initiated for any correctable causes of the arrest. Venous air embolism (VAE), on the other hand, typically occurs rapidly with little warning, although its risk of occurrence may be predicted by patient positioning. Any surgery or procedure where the operative site is elevated above the right atrium places the patient at risk for VAE, because veins in this region develop an intravascular pressure that is less than central venous pressure. While this can occur under a variety of circumstances, it is most commonly associated with central line placements, certain gynecologic procedures, and craniotomies. If veins in the elevated site are open to the atmosphere, air will be entrained into the bloodstream and once in the central circulation, air bubbles pass through the right side of the heart and lodge in the pulmonary capillary beds. Here, they interfere with oxygen and carbon dioxide exchange, obstruct pulmonary artery return to the left ventricle (preload), and if severe, cause right-sided heart pressures to rise. If rightsided heart pressures exceed left-sided heart pressures, a patent ‘‘foramen ovale’’ can open, causing a right-to-left cardiac shunt and the possibility that air can pass into the aorta and up the carotid arteries. Precordial Dopplers and transesophageal echocardiograms are sensitive early detectors of VAE, but in the absence of these devices, VAE typically presents with hypotension, oxygen desaturation, hypoxemia, and a falling end-tidal carbon dioxide despite rising arterial levels. There are now several single-lumen, multiple-orifice central venous catheters on the market, which are designed to aspirate air from the right atrium; however, their value is often more diagnostic than therapeutic because presenting symptoms are caused by air that has already passed through the right atrium and into the pulmonarycirculation.Nonetheless,VAEtreatmentisbasedupon preventing the further entrainment of air, minimizing the passage of air to the pulmonary capillary beds, supporting the circulation, and maximizing oxygenation and ventilation (Table 9) until the air is dissolved into the blood. Malignant hyperthermia (MH) is a catastrophic anesthesia emergency that can potentially result in the

Chapter 10:

The Physiology of Anesthesia and Pain

219

Table 9 The Treatment of Venous Air Embolism

Table 10 The Treatment of Acute Malignant Hyperthermia

Inform the surgeon Administer 100% oxygen Discontinue nitrous oxide Have surgeon flood field with saline or pack wound with saline-soaked sponges to prevent further entrainment Aspirate right atrial VAE catheter, if available Lower surgical site below level of right atrium Place patient in left lateral decubitus position to trap entrained air in right ventricle Support circulation as necessary

Do not administer volatile anesthetics or succinylcholine once MH has been diagnosed or considered Call for additional help Hyperventilate with 100% oxygen Give 2.5 mg/kg of dantrolene sodium for injection. Repeat as often as necessary, titrated to control clinical signs of MH. Continue intravenous dantrolene for at least 24 hr after control of the episode (1 mg/kg q 6 hr) Treat acidosis with bicarbonate—if not promptly reversed by dantrolene Avoid calcium channel blockers: Persistent arrhythmias may be treated with any other standard antiarrhythmics. Most arrhythmias respond to correction of hyperkalemia and acidosis by hyperventilation, dantrolene, and bicarbonate Monitor core temperature Treat hyperkalemia with glucose, insulin, and calcium If hyperthermic or core temperature rises rapidly, cool the subject. Cease cooling efforts when temperature has fallen to 38 C Watch for recrudescence by appropriate monitoring in an intensive care unit for at least 24 hr. Recrudescence occurs in about 25% of MH cases Avoid parenteral potassium, if possible, during ongoing rhabdomyolysis Ensure urine output of at least 2 mL/kg/hr by hydration and diuretics Follow coagulation profile—disseminated intravascular coagulation may occur Measure CKs every 6 hr until decreased. CK may remain elevated for 2 wk if event was severe. After the patient has improved and stabilized, CK should be measured on a declining time basis until it is normal (e.g., every 4 hr during the acute episode to every week during convalescence). This is important because it is elevated normally in some myopathies, and this should be recognized as a part of overall evaluation and treatment

Abbreviation: VAE, venous air embolism.

unexpected death of a healthy patient. It is a sudden dysregulation of skeletal muscle intracellular calcium, triggered by exposure to certain anesthetic agents. These triggering agents include the volatile inhalation anesthetics and succinylcholine. The increase in intracellular calcium levels causes an increased muscle metabolic rate, with accompanying heat production, increased cellular acid content, muscle rigidity, and a leakage of intracellular contents. This then leads to escalating serum potassium levels, cardiac dysrhythmias, and markedly increased serum myoglobin levels with severe rhabdomyolysis. The body temperature rise can be rapid and dramatic: the fever may quickly exceed 110 Fahrenheit.Leftuntreated,cardiacarrest,renalfailure,disseminated intravascular coagulation, internal hemorrhage, liver failure, brain injury, and death may quickly ensue. While MH susceptibility is inherited with an autosomal dominant inheritance pattern, it has also been associated with over 90 genetic mutations (22) and MH-related deaths have been reported even though patients have undergone multiple prior uneventful surgeries. The incidence may be as low as 1 in 65,000 general anesthetics, but may be as high as 1 in 5000 in areas where MH-susceptible families are concentrated, such as Wisconsin, Nebraska, West Virginia, and Michigan in the United States (23). At one time, mortality rates were as high 70%, but with early diagnosis and rapid treatment, the mortality rate is now less than 5%. Worldwide, a number of organizations have been established to provide MH research and support. For example, the Malignant Hyperthermia Association of the United States maintains an informative website, a patient registry, and a toll-free hotline (Box 1) to aid in the diagnosis and treatment of acute MH. Currently, dantrolene sodium is the only specific treatment of MH because it decreases the release of calcium from the storage sites in muscle (the sarcoplasmic reticulum) by binding to calcium channels, but significant physiologic support must also be Box 1 In the United States, Malignant Hyperthermia Association of the United States (MHAUS) Is the Best Source of Information for Health Care Professionals on Malignant Hyperthermia MHAUS 11 East State Street PO Box 1069 Sherburne, New York United States 13460-1069 (607) 674-7901 or (800) 98 MHAUS Web site: www.mhaus.org Hot Line: (800) MH-HYPER or 1-315-464-7079 outside of the U.S.

Abbreviations: CK, creatine kinase; MH, malignant hyperthermia. Source: From Ref. 24.

maintained (Table 10) (24). It is vital that all hospitals, ambulatory care centers, and offices where general anesthesia is administered have a full supply of dantrolene sodium immediately available (Table 11), as well as the facilities to rapidly lower body temperature, test for muscle breakdown, and measure serum acid–base changes, electrolytes, and coagulation (25).

THE PHYSIOLOGY OF PAIN AND ANALGESIA Pain is the perception of an unpleasant sensation that originates from a specific region of the body and is associated with actual or potential tissue damage. In humans, this perception is not simply the afferent conduction of nociception, but includes the highly individual influences of behavioral, cognitive, and sociocultural experiences (26) that can either suppress or intensify pain. While it is this subjective nature to pain that often complicates successful clinical treatment, most approaches to analgesia are nonetheless based upon interruption of nociceptive conduction. Althoughtheanatomic,pharmacologic,andpsychological pathways that conduct and interpret pain are complex, a basic understanding of neurophysiology is essential to pain management. This can be characterized in four parts: transduction, transmission, modulation, and perception.

THE PHYSIOLOGY OF NOCICEPTION Transduction Nociceptors (pain receptors) exist in the skin and deep tissues as the free nerve endings of primary sensory neurons

medwedi.ru

220

Part One: General Considerations

Table 11 Contents of a Malignant Hyperthermia Carta 1. Dantrolene sodium for injection—36 vials (each able to be diluted at the time of use with 60 mL sterile water) 2.Sterile water for injection USP (without a bacteriostatic agent) to reconstitute dantrolene—1000 mL 2 3. Sodium bicarbonate (8.4%)—50 mL 5 4. Furosemide 40 mg/amp 4 ampules 5. Dextrose 50%—50 mL vials 2 6. Calcium chloride (10%) 10 mL vial 2 7. Regular insulin 100 units/mL 1 (refrigerated) 8. Lidocaine for injection, 100 mg/5 mL, or 100 mg/10 mL in preloaded syringes (3). Amiodarone is also acceptable 9. Syringes (60 mL 5) to dilute dantrolene 10. Mini-spike1 IV additive pins 2 and Multi-Ad fluid transfer sets 2 (to reconstitute dantrolene) 11. Angiocaths: 16 G, 18 G, 20 G, 2-inch; 22 G, 1-inch; 24 G, 0.75-inch (4 each) (for IV access and arterial line) 12. NG tubes 13. Irrigation tray with piston syringe (1) for NG irrigation 14. Toomy irrigation syringes (60 mL 2) for NG irrigation 15. Microdrip IV set (1) 16. CVP kits 17. Transducer kits for arterial and central venous cannulation 18. A minimum of 3000 mL of refrigerated cold saline solution 19. Large sterile Steri–Drape (for rapid drape of wound) 20. Three-way irrigating foley catheters 21. Urine meter (1) 22. Irrigation tray with piston syringe 23. Large clear plastic bags for ice (4) 24. Small plastic bags for ice (4) 25. Bucket for ice 26. ABG kits (6) 27. Blood specimen tubes for CK, myoglobin, SMA 19, LDH, electrolytes, thyroid studies, PT/PTT, fibrinogen, fibrin split products. CBC, platelets, lactic acid level 28. Urine collection container for myoglobin level 29. Urine hemoglobin dipstick a

All hospitals, ambulatory centers, and offices where general anesthesia is administered must have an malignant hyperthermia cart immediately available. Abbreviations: ABG, arterial blood gas; CBC, complete blood count; CK, creatine kinase; CVP, central venous pressure; IV, intravenous; LDH, lactate dehydrogenase; NG, nasogastric; PT, prothrombin time; PTT, partial thromboplastin time; SMA, serum metabolic assay; USP, United States Pharmacopeia. Source: From Ref. 25.

whose cell bodies are located in the dorsal root and trigeminal ganglia. Mechanical or heat injury results in the release of chemical mediators (autocoids) that trigger a repeated response from local nociceptors in the form of membrane depolarization and a subsequent propagation of afferent signals. There are two major types of nociceptors, codified by conduction rates and their response to specific stimuli. Smalldiameter, thinly myelinated Ad fibers conduct at about 5 to 30 m/s and are activated by thermal or mechanical stimuli. Polymodal C fibers are small-diameter, unmyelinated fibers that conduct at 0.5 to 2 m/s and respond to a wide variety of high-intensity mechanical, chemical, hot (> 45 C), and cold stimuli (27). Stimulation of Ad fibers generally results in sharply localized pricking pain of short duration, and stimulation of C fibers generally produces a poorly localized burning sensation of longer duration (28). Autocoids can arise directly from injured cells (potassium, adenosine triphosphate, acetylcholine, bradykinin, serotonin, prostaglandin E2, and arachidonic acid), released

platelets (serotonin), inflammatory mast cells (histamine), or primary afferent nerve endings (substance P). The release of some mediators also triggers the creation of other chemical mediators. For example, while strongly activating both Ad and C fibers, bradykinin increases the synthesis and release of prostaglandins from nearby cells utilizing the cyclooxygenase metabolism of arachidonic acid. The prostaglandins then sensitize nearby nociceptors that were previously nonresponsive to mechanical stimuli (a phenomenon known as hyperalgesia), probably by lowering nociceptive thresholds. Cyclooxygenase inhibitors such as aspirin and nonsteroidal anti-inflammatory analgesics are effective pain relievers because they block this prostaglandin synthesis and release.

Transmission Nociception is carried by Ad (myelinated) and C (unmyelinated) fibers to the spinal cord via the dorsal roots. Upon entering the cord, axon branches ascend and descend several levels in the tract of Lissauer while collaterals synapse with neurons in the dorsal horns. Nociceptive fibers generally end in the superficial dorsal horn, the marginal zone (Rexed lamina I), and substantia gelatinosa (lamina II), while some Ad fibers penetrate as deep as lamina V. Here, nociceptive afferents connect with either projection neurons that relay signals to the brain or with interneurons that regulate the flow of information to the projection neurons through excitation or inhibition. This convergence of nociception into the dorsal horns is thought to be responsible for referred pain from deep visceral sources that are perceived at the body surface; because a single projection neuron receives input from both sources, higher brain centers cannot distinguish the source. Pain can also arise in the absence of nociceptor activity, often due to peripheral nerve injury and probably related to the hyperactivity of dorsal horn neurons. The burning pain of brachial plexus avulsions or phantom limb pain is such an example. Furthermore, because about 20% of C fibers are sympathetic postganglionic efferents, damaged local nociceptors may be directly activated by sympathetic nonsynaptic electrical cross talk (ephaptic transmission) that produces a severely burning, painful condition called causalgia or reflex sympathetic dystrophy. Nociception is projected to the brain along five ascending spinal pathways: the spinothalamic, spinoreticular, spinocervical, and spinomesencephalic tracts, and the dorsal columns. The spinothalamic tract is the most prominent and has been studied in the most detail; it originates from cord neurons in laminae V-VII and I, crosses the midline, ascends in the anterolateral white matter on the contralateral side, and terminates in the thalamus. The spinoreticular tract is also in the anterolateral white matter of the cord, is both lateral and contralateral, and projects indirectly to the reticular network, thalamus, basal ganglia, and prefrontal and visual cortex. Two major areas of the thalamus receive afferent nociceptive input from spinal projection neurons, the medial and lateral nuclear groups. While many of the neurons in the medial nuclear group (the central lateral nucleus and the intralaminar complex) are exclusively nociceptive, they project widely and suggest a nonspecific role. The lateral nuclear group (the ventrobasal nucleus and the posterior nuclei) also contains neurons that respond exclusively to nociception, but they project to the somatosensory cortex. It is unclear how the cortex processes pain; nociceptive input does not follow any logical topical mapping as does tactile, auditory, or visual information, and clinical studies

Chapter 10:

Table 12 Perioperative Physiologic Dysfunction Resulting from Uncontrolled Pain Endocrine system Sympathetic activation Hyperglycemia (elevated glucagon) Accelerated protein breakdown Accelerated nitrogen loss Increased aldosterone secretion Increased cortisol secretion Increased antidiuretic hormone Pulmonary system Decreased functional residual capacity Decreased tidal volume (splinting) Cardiovascular system Increased heart rate Increased blood pressure Increased contractility Increased systemic vascular resistance Renal system Activated rennin-angiotensin system Coagulation Activated coagulation cascade Increased platelet activity Decreased fibrinolysis Immune system Suppressed humoral/cellular immune response Delayed wound healing Gastrointestinal system Inhibited intestinal motility

The Physiology of Anesthesia and Pain

221

been completely proven, it may explain the effectiveness of several clinical modalities. Conceptually, therapeutic pharmacology is directed at blocking these ‘‘gates,’’ and transcutaneous electrical nerve stimulation (TENS) (see below) is thought to relieve pain by stimulating the myelinated dorsal column and peripheral nerve fibers that suppress pain transmission. Price (33) advanced a sequential processing theory as a modification of the Gate Control Theory in which cognitive and contextual appraisal of sensory input have direct causal relationships to affective reactions to pain. Such psychological influences may contribute to cortical modulation of distant nociception.

Perception Human pain perception and pain response are influenced by emotional (affective) components, but the exact nature of this relationship is unclear. For example, does depression in a cancer patient exacerbate pain or does pain exacerbate depression? Pain can induce reflexive or deliberate behavioral changes such as facial grimacing and splinting, and cognition is often altered, notably with chronic and terminal cancer pain, affecting the patient’s ability to cope with their pain. While widely researched in surgical, burn, and cancer pain patients, such psychosocial aspects of pain remain poorly understood, but may represent yet another avenue for therapeutic pain intervention.

PAIN MEASUREMENT have shown that damage to large areas of the cortex does not impair pain detection. Transmission of nociception through the CNS produces a neuroendocrine stress response that involves hypothalamic, pituitary, and adrenal pathways, and results in increased production of cortisol, antidiuretic hormone, glucagon, aldosterone, renin, and angiotension II. The effects include sodium and free water retention, increased blood glucose levels, and a hypermetabolic state that elevates oxygen and substrate consumption (29). In turn, a hypercoagulable state is induced, which may contribute to such postoperative complications as venous graft failure and deep venous thrombosis, and sympathomimetic activation may increase myocardial oxygen consumption, which can precipitate myocardial ischemia in susceptible individuals. Therefore, attenuation of this pathophysiologic neuroendocrine stress response through appropriate pain control may improve related perioperative mortality and morbidity (30,31). A brief summary of perioperative physiologic dysfunction during uncontrolled pain can be found in Table 12.

Modulation The variable nature of the response to pain suggests the existence of a modulatory system within the anatomic pain pathways. Neurophysiological studies have shown that stimulation of low-threshold, myelinated, non-nociceptive spinal cord afferent fibers decreases the response of dorsal horn neurons to afferent unmyelinated nociceptors, and a conduction blockade of these myelinated afferents enhances the response of dorsal horn neurons. Such observations have led Melzack and Wall (32) to propose that reception of nociception at the dorsal horn level is subject to ‘‘gated’’ control (Gate Control Theory) from higher centers via myelinated afferent pathways. Although this theory has not

The subjective nature of pain precludes accurate assessment of a patient’s pain by simple observation; patient reporting is essential. While a number of different methods have been proposed, a visual bar graph with an analog scale is often employed, by which a patient identifies their pain intensity. Typically, the scale is from 0 to 10, where 0 is the absence of pain and 10 is the worst pain the patient can imagine. Frequent and consistently obtained analog pain scores can then be used to quantitatively follow the effectiveness of treatment. The Joint Commission on Accreditation of Healthcare Organizations has recently established standards related to pain management (Table 13). They include recognition of the right of patients to appropriate assessment and management of pain, and a mechanism for screening the presence, nature, and intensity of pain in all patients (34). A visual/ analog scale is a quick and effective means of screening and treating pain in patients, which has been adopted by many hospitals meeting these standards, and is rapidly seeing widespread use in surgical wards.

THE MANAGEMENT OF ACUTE POSTOPERATIVE PAIN In 1992, the U.S. Department of Health and Human Services Agency for Health Care Policy and Research, now known as the Agency for Healthcare Research and Quality (AHRQ), published the Acute Pain Management Clinical Practice Guideline to help surgeons effectively manage acute postoperative pain (35). Over 2.4 million copies of the guideline were printed and distributed, and since then, over 30 additional pain management guidelines have been published by governmental agencies and professional organizations (Table 14). It has been estimated that approximately 23 million patients undergo surgery each year in the United

medwedi.ru

222

Part One: General Considerations

Table 13 The Joint Commission on Accreditation of Healthcare Organizations Standards Related to Pain Management Recognize the right of patients to appropriate assessment and management of pain Assess the existence and, if so, the nature and intensity of pain in all patients Record the results of the assessment in a way that facilitates regular reassessment and follow-up Determine and assure staff competency in pain assessment and management, and address pain assessment and management in the orientation of all new staff Establish policies and procedures that support the appropriate prescription or ordering of effective pain medications Educate patients and their families about effective pain management Address patient needs for symptom management in the discharge planning process Ensure that pain does not interfere with a patient’s participation in rehabilitation Incorporate pain management into performance activities (i.e., establish a means of collecting data to monitor the appropriateness and effectiveness of pain management) Source: From Ref. 34.

States alone, and after reviewing over 7000 published reports, the AHRQ concluded that most of these patients still do not get adequate pain relief; these patients continue to feel moderate to severe pain (37). As such, the AHRQ views untreated pain as a patient safety problem (38), and Congress has declared the decade beginning on January 1, 2001 as the Decade of Pain Control and Research. Many of the physiologic responses typically ascribed to perioperative stress, injury, and pain can be reduced or eliminated with appropriate analgesia, and typically, a multimodal approach must be used to fully maximize pain management. For example, while infiltration of incisions with long-acting local anesthetics can produce incisional analgesia intraoperatively, it alone is rarely sufficient for effective overall perioperative pain control. A broad understanding of pain management is therefore necessary, because it allows the surgeon and anesthesiologist to develop pain control plans before surgery and informs the patient what to expect in terms of pain during and after surgery.

Preoperative Assessment Perioperative pain management begins with preoperative planning. A careful assessment of the patient’s medical

history should be obtained, because information about the presence of underlying chronic pain syndromes, medication allergies, or a history of undesirable side effects from narcotics will influence treatment plans. Furthermore, the chronic use of preoperative narcotics or a history of substance abuse may introduce medication tolerances that impact heavily upon intraoperative and postoperative narcotic dosages. Once all information is gathered, postoperative pain control options should be discussed with the patient. It is important to establish a collaborative approach for pain management based upon the patient’s understanding about, and acceptance of, available treatment options (39); patient refusal is a contraindication to any treatment option.

Preemptive Analgesia An intense nociceptive stimulation such as a surgical incision can lead to plastic changes in the CNS (windup), which cause the patient to perceive postoperative pain as more painful than it would have been had the patient not perceived the incision as painful first (40). Numerous clinical studies have shown that if regional anesthesia, epidural opioid analgesia, or, more recently, a nonsteroidal cyclooxygenase-2 inhibitor is administered prior to surgery, postsurgical pain hypersensitivity can be minimized with a subsequent reduction in the requirement for postoperative pain intervention (16,41–44). Such preemptive action may offer prophylaxis from developing certain chronic pain syndromes as well; amputees, for example, are less likely to develop phantom limb pain postoperatively if they receive adequate analgesia prior to surgery. Unfortunately, successful preemptive analgesia remains controversial. Variability in the type and density of analgesia, surgical site, and the timing of administration prior to surgery seem to affect outcome, and because most studies focus only on postoperative pain requirements, there is little evidence that recuperation or long-term outcome is improved (45). Despite this, the concept of preemptive analgesia continues to hold promise for improving postoperative patient comfort.

Systemic Opioids Opioids produce analgesia through direct interaction with opioid receptors in the central, and to a lesser extent, peripheral nervous systems. Most commonly used opioids bind to mu receptor types; activation at the mu1 receptor produces

Table 14 Selected Guidelines for Perioperative Pain Management Guideline title Acute pain management: operative or medical procedures and trauma. AHCPR Publication No. 92-0032 Acute pain management in infants, children, and adolescents: operative and medical procedures. Quick reference guide for clinicians. AHCPR Publication No. 92-0020 (also in 36) Acute pain management in adults: operative procedures. Quick reference guide for clinicians. AHCPR Publication No. 92-0019 Practice guidelines for acute pain management in the perioperative setting Guidelines for the pediatric perioperative anesthesia environment

Release date

Available from

1992

AHRQ Clearinghouse, 1201 East Jefferson Street, Suite 501 Rockville, Maryland 20852 800-368-9295, www.ahrp.gov AHRQ Clearinghouse, 1201 East Jefferson Street, Suite 501 Rockville, Maryland 20852 800-368-9295, www.ahrp.gov

1992

1993

AHRQ Clearinghouse, 1201 East Jefferson Street, Suite 501 Rockville, Maryland 20852 800-368-9295, www.ahrp.gov

April, 1995

American Society of Anesthesiologists, 520 North Northwest Highway Park Ridge, Illinois 60068-2573, www.asahq.org American Academy of Pediatrics, P.O. Box 747 Elk Grove, Illinois 60009-0747, www.aap.org

February, 1999

Abbreviations: AHRQ, Agency for Healthcare Research and Quality; AHCPR, Agency for Health Care Policy and Research.

Chapter 10:

supraspinal analgesia, whereas mu2 receptor activation leads to the undesired effects of respiratory depression, bradycardia, nausea, and decreased gastrointestinal motility. Traditionally, until a postoperative patient could tolerate oral narcotics, opioids were largely administered intramuscularly due to the widespread perception that it was the safest way to give narcotics, but apnea and severe oxygen desaturation can still occur with this route of delivery. Also, the pharmacokinetics and pharmacodynamics of opioids administered intramuscularly display a four- to fivefold variation between individual patients, and inadequate analgesia is often the result. Now, intravenous opioids are more commonly employed, typically utilizing a patientcontrolled analgesia (PCA) pump that is triggered when the patient depresses a remote handheld button. These pumps operate on the theory that patients in pain receive analgesic medications in small increments, but only upon demand: if the patient is not in pain, no medication is administered. An internal timer provides a specified lockout interval during which an additional bolus cannot be obtained so that a safe and effective analgesia is provided without the risks of overdose. For patients who require a more constant narcotic serum level, most PCA pumps can be set to additionally deliver a continuous background infusion (basal rate), although this option can introduce more opportunities for overdose and programming error. Agents that are most commonly used for PCA analgesia include morphine (1 mg/mL) given in 0.5 to 2.5 mg increments, meperidine (10 mg/mL) given in 5 to 25 mg increments, and hydromorphone (0.2 mg/mL) given in 0.05 to 0.25 mg increments. Lockout intervals for these drugs should be between 5 and 10 minutes. A more potent but shorter-acting narcotic, fentanyl (10 mcg/mL), can also be used, and is generally given in 10 to 20 mcg increments with a lockout interval of between 3 and 10 minutes. Both the quality and the safety of PCA analgesia have been extensively studied. Although there have been reports of respiratory depression during PCA use, mechanical parameters such as forced expiratory volume in one second, functional residual capacity, and peak flow rates are not different when compared to intramuscular narcotic administration (46). Factors that seem to increase PCA complication risk are advanced age, hypovolemia, large incremental doses, and the use of a basal rate. The quality of PCA analgesia, however, has consistently been shown to be equal or superior to intramuscular narcotic administration: compared with intramuscular narcotic regimens, postoperative pain management with PCA pumps generally uses less total narcotics and produces higher patient and nurse satisfaction levels (47). Sudden cessation of opioid medications after continued therapy may lead to the development of abstinence syndromes. Physiologic dependence (tolerance) can develop after only five days of therapy, and opioid withdrawal can result in tachycardia, lacrimation, yawning, nausea, hypertension, restlessness, and insomnia.

Intra- and Postoperative Intraspinal and Epidural Analgesia Local anesthetics infused through a properly placed epidural or intrathecal catheter produce satisfactory intraoperative regional anesthesia for a variety of conditions, and although long-term use of intrathecal catheters pose unacceptable infection risks, epidural catheters are often left in place for extended postoperative periods to maintain analgesia.

The Physiology of Anesthesia and Pain

223

Surgical doses of local anesthetics, however, are impractical postoperatively because of the unwanted side effects of hypotension, dense sensory and motor blocks, nausea, and urinary retention; so epidural opioids are commonly employed. When comparing epidural versus intramuscular analgesic regimens, patients utilizing the epidural route have been shown to use up to seven times less narcotic, have superior analgesia, ambulate sooner, have fewer pulmonary complications, have earlier return of bowel function, and be discharged from the hospital earlier (48). Furthermore, highrisk surgical patients receiving combined epidural/general anesthesia and postoperative epidural opioids have lower overall complication and infection rates, shorter times to extubation, and significantly lower hospital costs than those receiving postoperative intramuscular or intravenous opioids (49). Despite these advantages, however, there are risks associated with the use of intraspinal and epidural opioids. As with the intramuscular and intravenous route, severe respiratory depression and CO2 narcosis can develop, as well as pruritus, urinary retention, and nausea. These side effects can be effectively managed, but treatment begins with vigilant monitoring of the patient. While intensive care facilities are well suited for this, step-down units or conventional surgical wards where the nursing staff has been specially educated in the care of patients with epidural catheters can also be effectively employed. In many institutions, the use of neuraxial techniques such as epidural and spinal anesthesia has been declining with the increasing use of low-molecular-weight heparin for thromboprophylaxis. Spinal hematoma is relatively rare; although it defies study by a prospective randomized study or laboratory model, there are multiple case reports and clinical series documenting its occurrence. As a result, in 2002, a Consensus Conference of the American Society of Regional Anesthesia and Pain Medicine formally recognized spinal hematoma as a definite risk during spinal and epidural anesthesia in patients receiving antithrombotic therapy (44). The patient’s coagulation status must be optimized at the time of needle placement, and anticoagulation must be carefully monitored during any epidural catheterization. Furthermore, indwelling catheters should not be removed in the presence of therapeutic anticoagulation, because this appears to significantly increase the risk of potentially devastating spinal hematoma (50).

Other Regional Techniques A variety of surgical neural blockades can be continued postoperatively for pain management. For example, while single injections of long-acting local anesthetics into the axillary sheath, femoral sheath, lumbar plexus, or sciatic nerve produce blocks that are dense enough to allow surgery, they can also provide postoperative analgesia for up to 24 hours. Insertion of catheters into these sites for continuous analgesia and sympathetic blockade may be particularly advantageous after implantation surgery or for maintaining a normal range of motion following joint surgery. In addition, interpleural catheters, correctly placed following thoracic surgery provide unilateral analgesia without apparent sensory block, presumably from multiple intercostal nerve blocks (51).

Nonpharmacologic Modalities Cognitive modalities such as distraction, relaxation, and hypnosis have been successfully utilized as adjuncts to other analgesic interventions in the perioperative period. While

medwedi.ru

224

Part One: General Considerations

having the ability to improve overall patient satisfaction without producing limiting side effects, it should be noted that randomized controlled trials have produced conflicting results on efficacy; further study is needed to clarify their exact role in the management of postoperative pain. Physical modalities such as TENS may be beneficial adjuncts in the treatment of postoperative pain or in relieving discomfort associated with positioning during surgery and immobilization. TENS produces electroanalgesia through the spinal cord–gating mechanism (see above), and has been shown to be effective over incision sites and for thoracotomy, post–cesarean section, total hip replacement, knee replacement, shoulder pain, lumbar spine surgery, and cholecystectomy (52,53). Unfortunately, it is contraindicated in patients with cognitive impairment and should not be used near demand-type cardiac pacemakers, over a pregnant uterus, carotid sinuses, and laryngeal or pharyngeal muscles, or around the eye. There are few random controlled trials of needle acupuncture in the management of postoperative pain, but a recent Consensus Statement from the National Institutes of Health suggests that it may be considered a treatment option (54). For example, acupuncture has been shown to provide effective pain relief and improved range of motion following ablation and axillary lymphadenectomy in patients with breast cancer (55). While there can be unfortunate side effects, most complications can be avoided by the use of licensed, certified practitioners and Food and Drug Administration–approved single-use needles.

Acute Pain Services Acute Pain Services began to appear in 1988. Today, although few small hospitals have them, approximately 34% to 44% of hospitals in Europe (56,57) and most major institutions in the United States (58) have organized Acute Pain Services. Typically anesthesiology based, they are often multidisciplinary and are designed to create a framework in which postoperative pain can be managed more effectively. To date, there have been no high-quality, systematic review of the benefits, costs, and comparative outcomes, but large-scale observational studies of Acute Pain Services indicate that they can improve postoperative pain without endangering patient safety (59).

SUMMARY The major advances that have occurred in surgery over the past 50 years would not have been possible without similar advances in the field of anesthesiology. The ability to regionally anesthetize various parts of the body without necessarily having to induce general anesthesia has broadened the scope of operative surgery and enabled even high-risk patients to undergo needed procedures with an acceptable morbidity and mortality. Thus, choosing the anesthetic technique and the corresponding pharmacologic agents needed to achieve the best anesthetic result can now be individualized for the patient’s specific needs. Factors contributing to these selections include the part of the body requiring surgery, the patient’s health status, the patient’s particular preferences, and the skill of the anesthesiologist. Working together, the patient, surgeon, and anesthesiologist can tailor the approach to anesthesia so that it optimizes the patient’s desires and safety while allowing the surgeon to successfully complete the operation.

Equal advances have occurred in our understanding of the physiology of pain. Although the complexity of nociception continues to present unique challenges, much of the process has now been deciphered, and innovative strategies are continually being developed to interrupt the transduction, transmission, modulation, and perception of pain. These strategies, both pharmacologically and nonpharmacologically mediated, can now be combined to effectively manage the cause and severity of pain, even in the most difficult of circumstances.

REFERENCES 1. American Society of Anesthesiologists. The ASA Physical Status Classification System. www.asahq.org/clinicalinfo.htm. 2. Buck N, Devlin HB, Lunn JL. Report of a confidential enquiry into perioperative deaths. Nuffield Provincial Hospitals Trust, London: The King’s Fund Publishing House, 1987. 3. Keenan RL, Boyan CP. Cardiac arrest due to anesthesia. JAMA 1985; 253:2373. 4. Newland MC, Ellis SJ, Lydiatt CA, et al. Anesthetic-related cardiac arrest and its mortality: a report covering 72,959 anesthetics over 10 years from a US teaching hospital. Anesthesiology 2002; 97:108. 5. Shah KB, Kleinman BS, Sami H, et al. Reevaluation of perioperative myocardial infarction in patients with prior myocardial infarction undergoing noncardiac operations. Anesth Analg 1990; 71:231. 6. Keenan RL, Boyan CP. Decreasing frequency of anesthetic cardiac arrests. J Clin Anesth 1991; 3:354–357. 7. Eichhorn JH. Effect of monitoring standards on anesthesia outcome. Int Anesth Clin 1993; 31(3):181–190. 8. American Society of Anesthesiologists. The ASA Closed Claims Project. www.asaclosedclaims.org. 9. American Society of Anesthesiologists. Standards for Basic Anesthetic Monitoring. Last amended on October 27, 2004. www.asahq.org/clinicalinfo.htm. 10. Saada M, Duval AM, Bounet F, et al. Abnormalities in myocardial segmented wall motion during lumbar epidural anesthesia. Anesthesiology 1989; 71:26–32. 11. Lund PC, Cwik JC. Propitocaine (citanest) and methemoglobinemia. Anesthesiology 1965; 26:569–571. 12. Reiz S, Nath S. Cardiotoxicity of local anaesthetic agents. Br J Anaesth 1986; 58:736–746. 13. Auroy Y, Benhamou D, Bargues L, et al. Major complications of regional anesthesia in France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97:1274–1280. 14. American Society of Anesthesiologists. Task Force on preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures. Last modified October 7, 2002. www.asahq.org/clinicalinfo.htm. 15. White PF. Pharmacologic and clinical aspects of preoperative medication. Anesth and Anal 1986; 65:963–974. 16. Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief. Anesthesiology 2002; 96(3):725–741. 17. Foldes FF, McNall PG, Borrego-Hinojosa JM. Succinylcholine, a new approach to muscular relaxation in anesthesiology. N Engl J Med 1952; 247:596–600. 18. American Society of Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. An updated report by the American Society of Anesthesiologists Task Force on sedation and analgesia by non-anesthesiologists. Approved by the House of Delegates on October 25, 1995. Last amended on October 17, 2001. www.asahq.org/clinicalinfo.htm. 19. National Center for Health Statistics, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services.

Chapter 10:

20.

21. 22.

23.

24.

25.

26.

27.

28. 29.

30.

31. 32. 33. 34.

35.

36.

37.

38.

Prevalence of overweight and obesity among adults: United States, 1999–2002. Results from the 1999–2002 National Health and Nutrition Examination Survey (NHANES). http://www.cdc.gov/ nchs/products/pubs/pubd/hestats/obese/obse99.htm. Lanier WL. Glucose management during cardiopulmonary bypass: cardiovascular and neurologic implications. Anesth Analg 1991; 72:423. Lam AM, et al. Hyperglycemia and neurological outcome in patients with head injury. J Neruosurg 1991; 75:545. Jurkatt-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23:4–17. Malignant Hyperthermia Association of the United States. What is malignant hyperthermia? An MHAUS online brochure. Last updated August 31, 2004. http://www.mhaus.org/index.cfm/fuseaction/OnlineBrochures.List.cfm. Malignant Hyperthermia Association of the United States. Clinical update—managing MH. An MHAUS online brochure. Last updated July 1, 2005. http://www.mhaus.org/index.cfm/ fuseaction/OnlineBrochures.List.cfm. Malignant Hyperthermia Association of the United States. Drugs, equipment, and dantrolene—managing MH. An MHAUS online brochure. Last updated October 1, 2004. http://www.mhaus. org/index.cfm/fuseaction/OnlineBrochures.List.cfm. McGuire DB. The multidimensional phenomenon of cancer pain. In: McGuire DB, Yarbro CH, eds. Cancer Pain Management. Philadelphia: Saunders, 1987:1–20. Jessell TM, Kelly DD. Pain and analgesia. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science. 3rd ed. East Norwalk, Connecticut: Appleton & Lange, 1991:386. Sorkin LS. Pain pathways and spinal modulation. Anesthes Clinic North Amer 1989; 7:17. Kehlet H. Modification of responses to surgery by neural blockade. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia Management of Pain. 3rd ed. Philadelphia: Lippincott-Raven Publishers, 1998. Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in postoperative outcome. Anesthesiology 1995; 82:1474. Wu CL, Fleisher LA. Outcomes research in regional anesthesia and analgesia. Anesth Analg 2000; 91:1232. Melzak R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150:971–979. Price DD. Psychological and Neural Mechanisms of Pain. New York: Raven, 1988. Joint Commission of Accreditation of Healthcare Organizations. Comprehensive Accreditation Manual for Hospitals. Oakbrook Terrace, Illinois: Joint Commission of Accreditation of Healthcare Organizations, 2001. Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical Practice Guideline. Publication No. AHCPR 92-0032. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, 1992. Acute pain management in infants, children, and adolescents: operative and medical procedures. Quick reference guide for clinicians. J Pain Symptom Manage 1992; 7:229–242. Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical Practice Guideline. Panel findings. Carr DB, Jacox A, co-chairs. Agency for Healthcare Research and Quality, Public Health Service, U.S. Department of Health and Human Services, released 1994. Brownfield E. Pain management. In: Evidence Report/Technology Assessment, No. 42. Making Health Care Safer: A Critical Analysis of Patient Safety Practices. Contract No. 290-97-0013, Publication No. 01-E058. Agency for Healthcare Research and Quality, Public Health Service, U.S. Department of Health and Human Services, 1997.

The Physiology of Anesthesia and Pain

225

39. Owen H, McMillan V, Rogowski D. Post-operative pain therapy: a survey of patients’ expectations and their experiences. Pain 1990; 41(3):303–307. 40. Woolf CJ. Evidence for a central component of postinjury pain hypersensitivity. Nature 1983; 308:386–388. 41. Bekker A, Cooper PR, Frempong-Boadu A, Errico T, Lebovits A. Evaluation of preoperative administration of the cyclooxygenase-2 inhibitor rofecoxib for the treatment of postoperative pain after lumbar disc surgery. Neurosurgery 2002; 50(50): 1053–1057. 42. Carr DB, Sternlicht A, Carabuena JM, Wurm WH, Robelen G. Efficacy and safety of pre-emptive levobupivicaine in elective shoulder surgery. Reg Anesth Pain Med 2000; 25(suppl):20. 43. Katz J, Clairoux M. Kavangh BP, et al. Pre-emptive lumbar anesthesia reduces postoperative pain and patient-controlled morphine consumption after lower abdominal surgery. Pain 1994; 59:395–403. 44. Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural analgesia and recovery from radical prostatectomy. JAMA 1998; 279:1076–1082. 45. Hogan QH. No preemptive analgesia: is that so bad? Anesthesiology 2002; 96:526–527. 46. Welchew EA. On-demand analgesia. A double-blind comparison of on-demand intravenous fentanyl with regular intramuscular morphine. Anaesthesia 1983; 38:19. 47. White PF, Parker RK. Use of patient-controlled analgesia for management of acute pain. JAMA 1988; 259:243. 48. Rawal N, Sjostrand U, Christoffersson E, et al. Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese: influence on postoperative ambulation and pulmonary function. Anesth Analg 1984; 63:583. 49. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 1988; 68:925. 50. American Society of Regional Anesthesia and Pain Medicine. Regional anesthesia in the anticoagulated patient—defining the risks. Developed from American Society of Regional Anesthesia and Pain Medicine Consensus Conference during the Annual Spring Meeting on Regional Anesthesia, 2002. http://www. asra.com/items_of_interest/consensus_statements. 51. Baxter AD, Jennings FO, Harris RS, Flynn JF. Continuous intercostals blockade after cardiac surgery. Br J Anaesth 1987; 59:162. 52. Hamza MA, White PF, Ahmen HE, Ghoname EA. Effect of the frequency of transcutaneous electrical nerve stimulation on the postoperative opioid analgesic requirement and recovery profile. Anesthesiology 1999; 91(5):1232–1238. 53. Bruzga R, Speer K. Challenges of rehabilitation after shoulder surgery. Clin Sports Med 1999; 18(4):769–793. 54. National Institutes of Health. Acupuncture, NIH consensus statement, Nov 3–5, 1997. 55. He JP, Friedrich M, Ertan AK, Muller K, Schmidt W. Pain-relief and movement improvement by acupuncture after ablation and axillary lymphadenectomy in patients with mammary cancer. Clin Exp Obstet Gynecol 1999; 26(2):81–84. 56. Bardiau FM, Braeckman MM, Seidel L, Albert A, Boogaerts JG. Effectiveness of an acute pain service inception in a general hospital. J Clin Anesth 1999; 11:583–589. 57. Hall PA, Bowden MI. Introducing an acute pain service. Br J Hosp Med 1996; 55:15–17. 58. Ready LB. How many acute pain services are there in the US and who is managing patient-controlled analgesia? Anesth 1995; 82:322. 59. Acute pain services. In: Markowitz AJ, ed. Evidence Report/ Technology Assessment, No. 43, Making Health Care Safer: A Critical Analysis of Patient Safety Practices. Contract No. 29097-0013, Publication No. 01-E058. Agency for Healthcare Research and Quality, Public Health Service, U.S. Department of Health and Human Services, 1997.

medwedi.ru

11 Sepsis and the Syndrome of Multiple Organ Failure Lena M. Napolitano

INTRODUCTION Sepsis is the leading cause of morbidity and mortality in critically ill patients in most intensive care units. Sepsis is recognized as the systemic response to infection, and connotes a clinical syndrome that may occur in any age group, in markedly different patient populations, and in response to a multitude of microbial pathogens from multiple different anatomical sites within the human body. It may range in severity from mild systemic inflammation without significant chemical consequences to multisystem organ failure and septic shock with an exceedingly high mortality rate. This chapter is an update of the understanding of the relationship between sepsis and multiple organ dysfunction and failure, the underlying pathophysiology and outcomes of both, and contemporary strategies for the prevention and treatment of sepsis and multiple organ dysfunction syndrome.

SEPSIS: DEFINITIONS In 1991, the American College of Chest Physicians and the Society of Critical Care Medicine convened a consensus conference to more accurately define sepsis (1,2). The term ‘‘systemic inflammatory response syndrome’’ (SIRS) was defined as a clinical response arising from a nonspecific insult such as infection, trauma, thermal injury, or sterile inflammatory processes such as pancreatitis. This clinical response included fever or hypothermia, tachycardia, tachypnea, and leukocytosis or leukopenia (Table 1). SIRS is characterized by two or more of these clinical manifestations. ‘‘Sepsis’’ was defined as SIRS with a presumed or confirmed infectious process. Sepsis can progress to ‘‘severe sepsis,’’ which was defined as sepsis with organ dysfunction or evidence of hypoperfusion or hypotension. ‘‘Septic shock’’ was defined as sepsis-induced hypotension, persisting despite adequate fluid resuscitation, along with the presence of hypoperfusion abnormalities or organ dysfunction. While consensus definitions of sepsis have proven to be of great value, the lack of uniformity in interpretation of these definitions continues to be problematic for clinicians and basic researchers alike (3). A recent European Society of Intensive Care Medicine and Society of Critical Care Medicine physician attitudinal survey revealed that 71% of responders cited no common definition of sepsis (4), despite the previously published consensus conference criteria for sepsis, severe sepsis, and septic shock. In 2001, an International Sepsis Definitions Conference was convened to review the strengths and weaknesses of the current definitions of sepsis and related conditions, identify ways to improve the current definitions, and identify methodologies for increasing the accuracy, reliability,

and/or clinical utility of the diagnosis of sepsis (5). The primary consensus points of this conference were as follows: &

&

&

&

&

The current concepts of sepsis, severe sepsis, and septic shock seem to be robust definitions and should remain as described 10 years ago. Current definitions do not allow for precise staging of the host response to infection. Signs and symptoms of sepsis are more varied than the initial criteria established in 1991. A list of these signs and symptoms, for the diagnosis of sepsis is presented. The future lies in developing a staging system that will characterize progression of sepsis. A new system, predisposition, infection, response, and organ dysfunction (PIRO), is proposed for characterizing and staging the host response to infection.

This new conceptual framework for understanding sepsis, which was developed, called the PIRO concept, is a classification scheme that could stratify patients on the basis of their predisposing conditions, the nature and extent of the insult (in the case of sepsis and infection), the nature and magnitude of the host response, and the degree of concomitant organ dysfunction (Table 2). This has been conceptually modeled from the TNM classification (tumor size, nodal spread, and metastases) that has been successfully

Table 1 Definitions of SIRS, Sepsis, and Severe Sepsis Term

Definition

SIRS

A clinical response arising from a nonspecific insult, including 2 of the following: Temperature 38 C or 36 C Heart rate 90 beats/min Respirations 20/min White blood cell count 12,000/mm3 or 4000/mm3 or > 10% neutrophils SIRS with a presumed or confirmed infectious process Sepsis with 1 sign of organ failure: Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic Central nervous system Metabolic acidosis Sepsis-induced hypotension, despite adequate fluid resuscitation, with presence of perfusion abnormalities

Sepsis Severe sepsis

Septic shock

Abbreviation: SIRS, systemic inflammatory response syndrome. Source: From Ref. 1.

medwedi.ru 227

228

Part One: General Considerations

Table 2 The PIRO System for Staging Sepsis Domain

Present

Predisposition

Premorbid illness with reduced probability of short-term survival. Cultural or religious beliefs, age, sex

Insult, infection

Culture and sensitivity of infecting pathogens; detection of disease amenable to source control SIRS, other signs of sepsis, shock, CRP

Response

Organ dysfunction

Organ dysfunction as number of failing organs or composite score (e.g., MODS, SOFA, LODS, PEMOD, PELOD)

Future Genetic polymorphisms in components of inflammatory response (e.g., TLR, TNF, IL-1, CD 14); enhanced understanding of specific interactions between pathogens and host diseases Assay of microbial products (LPS, mannan, bacterial DNA); gene transcript profiles Nonspecific markers of activated inflammation (e.g., PCT or IL-6) or impaired host responsiveness (e.g., HLA-DR); specific detection of target of therapy (e.g., protein C, TNF, PAF) Dynamic measures of cellular response to insult—apoptosis, cytopathic hypoxia, cell stress

Rationale In the present, premorbid factors impact on the potential attributable morbidity and mortality of an acute insult; deleterious consequences of insult heavily dependent on genetic predisposition (future) Specific therapies directed against inciting insult require demonstration and characterization of that insult Both mortality risk and potential to respond to therapy vary with nonspecific measures of disease severity (e.g., shock); specific mediator-targeted therapy is predicated on the presence and activity of mediator Response to preemptive therapy (e.g., targeting microorganism or early mediator) not possible if damage already present; therapies targeting the injurious cellular process require that it be present

Abbreviations: TLR, Toll-like receptor; TNF, tumor necrosis factor; IL, interleukin; LPS, lipopolysaccharide; SIRS, systemic inflammatory response syndrome; CRP, C-reactive protein; PCT, procalcitonin; HLA-DR, human leukocyte: antigen-DR; PAF, platelet-activating factor; MODS, multiple organ dysfunction syndrome; SOFA, sepsis-related organ failure assessment; LODS, logistic organ dysfunction system; PEMOD, pediatric multiple organ dysfunction; PELOD, pediatric logistic organ dysfunction; PIRO, predisposition, infection, response, and organ dysfunction. Source: From Ref. 5.

used in defining treatment and prognostic indicators in clinical oncology. PIRO was introduced as a hypothesisgenerating model for future research, and extensive testing will be necessary before it can be considered ready for routine application in clinical practice. Advances in sepsis research will require better markers to delineate more homogenous subsets of patients within a highly heterogenous group of critically ill patients. A roundtable meeting on biomarkers in sepsis was held in 2000 to develop a taxonomy of markers relevant to clinical research in sepsis (6). A ‘‘marker’’ is a measure that identifies a biological state or that predicts the presence or severity of a pathologic process or disease. More than 80 putative markers of sepsis have been described (Table 3). Virtually all of the putative sepsis markers can be classified as prognostic markers, because they identify patient groups at increased risk for mortality. None of these markers has yet shown utility in stratifying patients with respect to therapy (i.e., diagnostic markers) or in titrating that therapy (i.e., response markers). For instance, elevation in the serum concentration of procalcitonin (PCT) has been associated with systemic infection and sepsis in a number of human studies. This association has led to the proposed use of PCT as a novel biomarker of bacterial sepsis. A recent systematic health technology assessment of PCT as a diagnostic test for sepsis was performed (7) to answer a specific and important question—can PCT accurately distinguish sepsis in patients with SIRS who have a suspected infection? Likelihood ratios were calculated from published data. The published evidence did not support a general claim that PCT is a useful decision support tool for diagnosing sepsis in patients who have SIRS. PCT had a slightly better ability to exclude the diagnosis of sepsis. The role for using PCT testing in the intensive care unit (ICU) will likely continue to evolve along with our understanding and definition of sepsis. Similarly, C-reactive protein (CRP), an acute-phase protein released by the liver after the onset of inflammation or tissue damage, has been evaluated as a marker of

infection and sepsis in critically ill patients (8). Blood concentrations of CRP have been documented to increase rapidly in response to infection, trauma, ischemia, burns, and other inflammatory conditions. Serum CRP concentrations are increased in patients with sepsis, and a recent study documented that the combination of CRP > 50 mg/L with clinical criteria for SIRS was an independent predictor of infection in critically ill patients. Elevated CRP concentrations on ICU admission have also been documented to correlate with mortality and organ failure in critically ill patients (9). A new method to help assess the presence or absence of infection in critically ill patients was recently developed (10). The infection probability score (IPS) was developed using routinely available variables in a cohort of 353 critically ill patients at risk for infection and sepsis, and was validated in another set of patients (n ¼ 140). The resulting IPS consists of six different variables and ranged from 0 to 26 points (0–2 for temperature, 0–12 for heart rate, 0–1 for respiratory rate, 0–3 for white blood cell count, 0–6 for CRP, and 0–2 for sequential organ failure assessment score). The best predictors for infection were heart rate and CRP, whereas respiratory rate was found to have the poorest predictive value. The cutoff value for the IPS was 14 points, with a positive predictive value of 53.6% and a negative predictive value of 89.5%. Model performance was very good (Hosmer–Lemeshow statistic, P ¼ 0.918), and the areas under receiver operating characteristic curves were 0.820 for the developmental set and 0.873 for the validation set. Patients with a score <14 points had only a 10% risk of infection. The IPS is a simple score that can help assess the probability of infection in critically ill patients, because the variables used are simple, routinely available, and familiar to clinicians. This score must, however, be further validated in other critically ill patient populations. It is clear that further refinements in the definitions and predisposing factors of severe sepsis should improve the understanding and management of severe sepsis and septic shock in the near future.

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

Table 3 Putative Markers of Sepsis Increased

Table 3

Putative Markers of Sepsis (Continued )

Decreased

Increased

Endotoxin Enterobacterial common antigen Candida antigen Bacterial DNA Physiologic Temperature Temperature parameters Heart rate Blood pressure Cardiac index Systemic vascular Respiratory rate resistance Urine output Level of consciousness Hematopoietic cells Neutrophils Neutrophils Monocytes Monocytes Platelets Cell surface markers PMN, monocyte CD11b Monocyte HLA-DR Monocyte CD40 Monocyte TNFr Monocyte CD63 Monocyte CD64 E-selectin Soluble receptors SCD25 (IL-2R) sE-selectin sELAM-1 sTNF-RI sTNF-RII sCD14 sICAM-1 Cytokines IL-1 IL-1ra IL-6 IL-8 IL-10 IL-18 TNF TGF MIP-1 HMGB-1 Hepatocyte growth factor Leptin MSH Acute phase CRP Albumin reactants LPS-binding Prealbumin protein Fibrinogen 1 antitrypsin Mediators of Fibrin degradation Antithrombin III coagulation products Activated protein C von Willebrand’s TPA activity factor Fibrinopeptide A PAI-1 TPA F 1þ2 Thrombin–antithrombin complexes D-dimers Thrombomodulin Platelet thrombospondin Procoagulant activity Cellular processes Lymphocyte apoptosis Neutrophil apoptosis Whole blood synthesis of TNF Miscellaneous Procalcitonin, Nitric ACTH Red cell GSH oxide, NO2/NO3 Ceramide

Microbial products

(Continued)

229

Decreased

Lactate Cardiac troponin 1 Neopterin Carbohydrate-deficient transferrin Intestinal fatty acid binding protein Myeloperoxidase Elastase Lactoferrin Lipid peroxidation products Hydrogen peroxide Conjugated dienes Abbreviations: CRP, C-reactive protein; LPS, lipopolysaccharide; TNF, tumor necrosis factor; IL, interleukin; HLA-DR, human leukocyte: antigen-DR; TGF, transforming growth factor; PAI-1, plasminogen-activator inhibitor 1; sTNF, soluble tumor necrosis factor; sELAM-1, endothelial leukocyte adhesion molecule-1 (also E-selectin, CD62E); MIP, macrophage inflammatory protein; HMGB-1, high mobility group box-1 protein; MSH, melanocyte stimulating hormone; TPA, tissue plasminogen activator; Red cell GSH, red cell glutathione. Source: From Ref. 6.

INCIDENCE AND OUTCOMES OF SEPSIS Severe sepsis is a significant healthcare challenge. The incidence of severe sepsis is approximately 300 cases per 100,000 population, which is higher than population-based rates of AIDS, colon and breast cancer, and congestive heart failure. The incidence of severe sepsis is projected to increase by 1.5% per year in the future. Sepsis is a complex syndrome that can lead to multiple organ failure and death. Severe sepsis has been associated with high mortality rates ranging from 28% to 50% (11–13). More than 750,000 cases of severe sepsis occur in the United States annually with 215,000 deaths. In the United States, more than 500 patients die of severe sepsis daily. The mortality rate associated with severe sepsis is greater than the mortality rates for AIDS and breast cancer, and similar to mortality rates for patients with acute myocardial infarction. Sepsis is a major cause of morbidity and mortality worldwide, and is the leading cause of death in noncoronary ICUs in the United States (12). Severe sepsis is the 11th leading cause of death overall in the United States. Septicemia was the 10th cause of death overall in the United States in 2001 (14). Angus et al. (11) recently examined the incidence, cost, and outcome of severe sepsis in the United States. All patients (n ¼ 192,980) met criteria for severe sepsis (defined as documented infection and acute organ dysfunction) based on the International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification were included. All 1995 state hospital discharge records (n ¼ 6,621,559) from seven large states with population and hospital (n ¼ 847) data from the U.S. Census, the Centers for Disease Control, the Health Care Financing Administration, and the American Hospital Association were linked. National age- and gender-adjusted estimates of incidence, cost, and outcome were generated. They identified 192,980 cases of severe sepsis, yielding national estimates of 751,000 cases (3.0 cases per 1000 population and 2.26 cases per 100 hospital discharges), of whom 383,000 (51.1%) received intensive care, and an additional 130,000 (17.3%) were ventilated in an intermediate care unit

medwedi.ru

230

Part One: General Considerations

Figure 1 Variability in the mortality rate (%) of control arms of clinical trials classified according to type of mediator-specific anti-inflammatory agent. Abbreviations: PAF, platelet-activating factor; IL, interleukin; TNF, tumor necrosis factor; TFPI, tissue factor pathway inhibitor; NOS, nitric oxide synthase.

or cared for in a coronary care unit. Incidence increased greater than 100-fold with age (0.2/1000 in children to 26.2/1000 in those >85 years old). Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 years old. Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection. The average costs per case were $22,100, with annual total costs of $16.7 billion nationally. Costs were higher in infants, nonsurvivors, ICU patients, surgical patients, and patients with more organ failure. This study documented that severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction. It is especially common in the elderly and is likely to increase substantially as the U.S. population ages. European studies have also examined the incidence, risk factors, and outcomes of severe sepsis and septic shock. The French ICU Group for Severe Sepsis conducted a large inception cohort study from a two-month prospective survey of 11,828 consecutive admissions to 170 adult ICUs of public hospitals in France (15). This study documented that 742 patients had documented infection and severe sepsis, confirming severe sepsis rates of 6.3 per 100 ICU admissions. The 28-day mortality rate was 56% in patients with severe sepsis. Major determinants of both early (< 3 days) and secondary deaths in the whole cohort were the Simplified Acute Physiology Score (SAPS) II and the number of acute organ system failures. Other risk factors for early death included a low arterial blood pH (< 7.33, P < 0.001) and shock (P ¼ 0.03), whereas secondary deaths were associated with the admission category (P < 0.001), a rapidly or ultimately fatal underlying disease (P < 0.001), a preexisting liver (P ¼ 0.01) or cardiovascular (P ¼ 0.002) insufficiency, hypothermia (P ¼ 0.02), thrombocytopenia (P ¼ 0.01), and multiple sources of infection (P ¼ 0.02). In patients with documented sepsis, bacteremia was associated with early mortality (P ¼ 0.03). This study was important, in that it determined that only three of four patients presenting with clinically suspected severe sepsis in France had documented infection. Review of the control arms of recent sepsis trials also documents a variable mortality rate of sepsis, dependent on the number of patients enrolled with SIRS and presumed infection, severe sepsis, and septic shock in each trial

(Fig. 1). Variability in sepsis mortality rates in the control arm of these trials is also likely related to variability in treatment of sepsis in the individual institutions (16,17). A recent retrospective cohort study (18) examined long-term mortality among patients with severe sepsis. All persons with bacterial or fungal infections and acute organ dysfunction (severe sepsis) who were hospitalized between January 1, 1991, and August 31, 2000 (n ¼ 16,019) were studied using a large, integrated, geographically diverse, U.S. health-insurance claims database covering three million lives annually. All patients were followed from the date of hospitalization with severe sepsis (index admission) to August 31, 2000, disenrollment from the health plan, or death, whichever occurred first. Most patients (81.2%) were >65 years of age; 53.4% were men. Mortality was 21.2% for the index admission, and increased to 51.4% at one year, and 74.2% at five years. This study demonstrated that mortality rates are high in patients with severe sepsis, during the period of acute illness as well as long-term mortality rates up to five years post-hospitalization. In October 2002, the Centers for Medicare and Medicaid Services established new ICD-9 codes for sepsis (Table 4) (19). Prior to this, the only ICD-9 code for sepsis was ‘‘septicemia.’’ As medical practitioners caring for SIRS and sepsis patients utilize these new codes, additional information will be captured regarding the accurate incidence and outcome of patients with sepsis and severe sepsis in the United States.

PATHOPHYSIOLOGY OF SEPSIS Despite advances in both antibiotic therapy and supportive care, the mortality rate due to severe sepsis has only slightly improved in the past several decades. The pathophysiology of organ failure and death in patients with sepsis remains elusive. With increased understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation, novel therapeutic agents that may improve clinical outcomes are being researched and developed. The pathophysiology and current treatment of severe sepsis are reviewed. The prevailing theory has been that sepsis represents an uncontrolled inflammatory response or hyperinflammation manifest as the SIRS. But more recent data document a subsequent state of severe immunosuppression or hypoimmune state in sepsis (20). We have come to realize that,

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

Table 4 New ICD-9 Codes for Sepsis ICD-9 code 995.90 995.91 995.92 995.93 995.94

Diagnosis SIRS, unspecified SIRS due to infectious process without organ dysfunction SIRS due to infectious process with organ dysfunction (severe sepsis) SIRS due to noninfectious process without organ dysfunction SIRS due to noninfectious process with organ dysfunction

Abbreviations: ICD, International Classification of Diseases; SIRS, systemic inflammatory response syndrome.

Immune Status Hypoimmune Normal Hyperimmune

initially, sepsis may be characterized by increases in inflammatory mediators; but as sepsis persists, there is a shift toward an anti-inflammatory immunosuppressive state (Fig. 2). The term ‘‘compensatory anti-inflammatory response syndrome (CARS)’’ has been used to define immunologically those patients with sepsis syndromes, who are manifesting predominantly a pattern of macrophage deactivation, reduced antigen presentation, and T-cell anergy. Intact innate and acquired immune responses are essential for defeating systemic microbial infections in sepsis (17).

Healthy person with meningococcemia Elderly patient with malnutrition and diverticulitis Patient with diabetes, chronic renal failure, and pneumonia

Recovery

Death 1

2

3

4 Days

5

6

7

8

Figure 2 Immunologic response of three hypothetical patients with sepsis. The individual response is determined by many factors, including the virulence of the organism, the size of the inoculum, and the patient’s coexisting conditions, age, and polymorphisms in genes for cytokines. The initial immune response is hyperinflammatory, but the response rapidly progresses to hypoinflammatory. A secondary bump in the hyperimmune state can occur during the hospital course with secondary infections. In the hypothetical healthy person who has contracted a serious meningococcal infection, there is an initial robust hyperinflammatory response. This patient would have extremely high plasma concentrations of TNF-a and other inflammatory cytokines. Death may occur due to a hyperinflammatory state, and antiinflammatory treatments may improve the likelihood of survival. If infection resolves rapidly, there is only a minimal hypoimmune state. In the hypothetical elderly malnourished person with diverticulitis, the initial response is limited, and, if infection persists, a prolonged hypoinflammatory response develops, followed by either recovery or death. In the hypothetical patient with diabetes, chronic renal failure, and pneumonia, the initial response is blunted, and there is prolonged depression of immune function, culminating in death. Abbreviation: TNF, tumor necrosis factor. Source: From Ref. 14.

231

The orchestration of diverse cell types, including macrophages, monocytes, dendritic cells, and lymphocytes, is critical in the physiologic response to infection and sepsis (Fig. 3). One mechanism of immune suppression in sepsis is related to the activation of CD4 T-cells to secrete cytokines with anti-inflammatory (type 2 helper T-cell, Th2) properties, including interleukin-4 (IL-4) and IL-10. Activated CD4 T-cells can also secrete cytokines with inflammatory (type 1 helper T-cell, Thl) properties, including tumor necrosis factor-a (TNF-a), interferon-g, and IL-2. Reversal of the Th2 response has been documented in some studies to improve survival in sepsis (21,22). Additional studies have demonstrated that the level of IL-10 is increased in patients with sepsis, and that this level predicts mortality (23,24). Sepsis caused by gram-negative bacteria and that caused by gram-positive bacteria often manifest similar clinical features. A recent study (25) investigated plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria and studied the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide (LPS) or heat-killed Staphylococcus aureus. Concentrations of TNF-a, IL-1 receptor antagonist (IL-IRa), IL-8, IL-10, IL-18-binding protein, PCT, and protein C in plasma did not differ between patients with sepsis due to gram-negative and gram-positive bacteria. However, plasma IL-lb, IL-6, and IL-18 concentrations were significantly higher in patients with sepsis due to gram-positive bacteria. Ex vivo stimulation of whole blood with heat-killed S. aureus markedly increased IL-lb and IL-18 levels more than E. coli LPS stimulation. Microarray analysis revealed at least 359 cross-validated probe sets (genes) significant at the P < 0.001 level whose expression discriminated among gram-negative organism–stimulated, gram-positive organism– stimulated, and unstimulated whole-blood leukocytes. The host inflammatory responses to gram-negative and grampositive stimuli not only share some common response elements, but also exhibit distinct patterns of cytokine appearance and leukocyte gene expression. The role of apoptotic cell death in sepsis is of great interest. Apoptosis is a programmed form of cell suicide in which executioner proteins known as caspases initiate enzymatic pathways that culminate in disruption of mitochondrial function, cleavage of DNA, cell shrinkage, and membrane changes that mark the cell for phagocytosis. Three recent reviews (26–28) focused on advances in our understanding of the mechanisms of cell death in sepsis, the types of cells that are dying, and the consequences on immunity. Extensive apoptotic death results in immune cell depletion and may compromise the ability of the patient to eradicate the primary infection and predispose to secondary nosocomial infections. Peripheral circulating lymphocyte apoptosis is also increased in patients with sepsis and correlates with the severity of the disease (29). In addition, recent evidence indicates that uptake of apoptotic cells impairs the immune function of surviving cells and contributes to immunosuppression. Furthermore, significantly increased apoptosis of splenic dendritic cells was identified in an animal model of sepsis (30). Dendritic cells are a phenotypically diverse group of antigen-presenting cells that have unique capabilities to regulate the activity and survival and B- and T-lymphocytes. Proper functioning of dendritic cells is essential to the host’s control of invading pathogens (Fig. 3). This profound loss of dendritic cells by caspase 3–mediated apoptosis may significantly compromise B- and T-cell function and impair the ability

medwedi.ru

232

Part One: General Considerations

Figure 3 The response to pathogens in sepsis, involving ‘‘cross talk’’ among many immune cells, including macrophages, dendritic cells, and CD4 T-cells. Macrophages and dendritic cells are activated by the ingestion of bacteria and by stimulation through cytokines (e.g., interferon) secreted by CD4 T-cells. Alternatively, CD4 T-cells that have an anti-inflammatory profile (Th2) secrete IL-10 that suppresses macrophage activation. CD4 T-cells become activated by stimulation through macrophages or dendritic cells. For example, macrophages and dendritic cells secrete IL-12, which activates CD4 T-cells to secrete inflammatory (Th1) cytokines. Depending on numerous factors (e.g., the type of organism and the site of infection), macrophages and dendritic cells will respond by inducing either inflammatory or anti-inflammatory cytokines or causing a global reduction in cytokine production (anergy). Macrophages or dendritic cells that have previously ingested necrotic cells will induce an inflammatory cytokine profile (Th1). Ingestion of apoptotic cells can induce either an anti-inflammatory cytokine profile or anergy. A plus sign indicates upregulation, and a minus sign indicates downregulation; in cases where both a plus sign and a minus sign appear, either upregulation or downregulation may occur, depending on a variety of factors. Abbreviations: IL, interleukin; Th1, type 1 helper T-cells; Th2, type 2 helper T-cells. Source: From Ref. 20.

of the host to survive sepsis. This new understanding of the complex pathophysiology of sepsis may lead to novel therapeutic approaches, including pharmacological agents that block apoptosis. Recent studies in animal models of sepsis with increased lymphocyte apoptosis have shown that inhibition of apoptosis increases survival. Transgenic mice overexpressing Bcl-2 were protected from lethality secondary to generalized peritonitis (31). Similarly, treatment of mice with a broadacting caspase inhibitor protected mice from sepsis-induced mortality (32). These studies provide strong evidence that

lymphocyte apopotosis plays a critical role in sepsis, indicating a potentially new therapeutic approach for the treatment of sepsis.

GENETIC VARIABILITY IN SEPSIS It has recently been identified that genetic differences may be important markers or determinants of clinical outcomes, including nosocomial infection and severe sepsis (33). This is a complex area of investigation in humans, and relies on identification of particular genetic markers (DNA

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

sequences) and the association with risk for sepsis and ultimate outcome in sepsis. The genetic risk for pneumonia, sepsis, and other serious infections is generally unrecognized or underestimated. Sepsis is caused by the immune response to infection and is manifest by pain, fever, and edema as the result of the activation of coagulation and inflammatory responses. In severe cases, sepsis leads to organ dysfunction and failure and ultimately death. Most patients with infection do not develop severe sepsis and septic shock, and yet those that do have a significantly increased risk of death. Genetic and environmental variables may influence why one patient with infection gets sicker than the other. For example, people may be programmed to respond to infection in different ways; some with aggressive immune responses that may be able to eradicate infection before it manifests itself in physical symptoms, while others may have less aggressive immune systems that allow them to get sick more often. The discovery of various common genetic polymorphisms in genes that control the inflammatory response (e.g., TNF) has lent credence to this hypothesis (34). Yet discovery of the actual relationship between risks of infection or severe sepsis and individual genotypes will require larger, more rigorously designed studies. Genetic epidemiologic studies suggest a strong genetic influence on the outcome from sepsis, and genetics may explain the wide variation in the individual response to infection that has long puzzled clinicians. Several candidate genes have been identified as important in the inflammatory response and investigated in case-controlled studies, including the TNF-a and TNF-b genes, positioned next to each other within the cluster of human leukocyte antigen class III genes on chromosome 6. Other candidate genes for sepsis and septic shock include the IL-1 receptor antagonist gene, the heat shock protein gene, the IL-6 gene, the IL-10 gene, the CD14 gene, the Toll-like receptor (TLR)-4 gene, and the TLR-2 gene, to name a few. A recent comprehensive review (35) summarized the evidence for a genetic susceptibility to development of sepsis and death from sepsis, discussed the candidate genes likely to be involved in the pathogenesis of sepsis, and reviewed the potential for targeted therapy of sepsis and septic shock based on genetic variability. Although the strongest evidence for a genetic risk comes from an adoptee study, most evidence for a genetic role in infection involves association studies that compare the incidence of specific mutations in a population with infection to a control population (36). Investigators have studied polymorphisms in or near genes that code for proteins that participate in the inflammatory response. Most positive association studies have examined genes for important inflammatory molecules such as TNF, the IL-1 family, IL-10, and angiotensin-converting enzyme as well as molecules important in antigen recognition, such as the mannose-binding lectin, CD14, and TLRs. Single nucleotide polymorphisms in regulatory regions may affect trans cription of inflammation-related genes such as TNF-a, ILs, and cell surface receptors, in ways that contribute to an increased risk for sepsis. Naturally occurring genetic differences in the TNF-a promotor have been documented as markers for the development of severe sepsis in trauma. A recent study (37) examined the risk for severe sepsis and for death associated with polymorphism in the TNF-a promoter by multivariate analysis. One hundred fifty-two patients had a 24% incidence of severe sepsis and a 13% case fatality rate.

233

The A-allele was most common at the 308 position (n ¼ 35). A-allele carriage at this location was associated with an adjusted odds ratio of 4.6 (95% confidence interval, 1.9–10.9) for severe sepsis and of 2.1 (95% confidence interval, 0.6–7.3) for death. This study documented a clear association between the A-allele at the 308 position in the TNF-a promoter and increased risk for severe sepsis and possibly for death after trauma. Gender differences in TNF-b polymorphisms were prospectively examined in 201 patients (68 women and 133 men) with severe sepsis (38). The genotype distribution of patients homozygous for TNFB1 and heterozygous or homozygous for TNFB2 was comparable between men and women with severe sepsis. In women, no difference in survival rate was found between the different genotypes, while mortality rate was significantly increased in men homozygous for TNFB2 compared with the other genotypes (P < 0.05; P < 0.01). Overall, survival rate was higher for women (P < 0.05), but was not significantly different between men and women with respect to genotypes (P ¼ 0.07 for TNFB2/B2). Poor prognosis of surgical sepsis was associated with male gender and the genomic marker TNF-b Ncol polymorphism in this study. Genomic polymorphism within the IL-1 family cytokines is also associated with outcome in sepsis. The allele frequencies and genotype distribution of IL-la, IL-lb, and IL-1Ra gene polymorphism have also been examined in septic patients (39). The allele frequencies of IL-1 receptor antagonist RN2 and genotype RN2/2 were increased in 60 septic patients compared with normal controls (P < 0.01 and 0.05, respectively). Allele frequencies or genotype distribution of interleukin-1-alpha and interleukin-1-beta gene polymorphism did not differ between septic patients and normal controls. In addition, genotypes A2/2, B2/2, and KN2/2 were associated with a significantly higher mortality rate (70–80%) in septic patients. Patients with any two of the three alleles (i.e., A2, B2, and RN2) suffered from much more severe sepsis (as measured by the acute physiology and chronic health evaluation II (APACHE II) and multiple organ dysfunction syndrome score) and a higher mortality rate (55–65%), whereas septic patients with genotypes A1/1, B1/1, or RN1/1 showed a much lower mortality rate (0–13%). Allele IL-1RN2, but not IL-1A or IL-1B gene polymorphism, was associated with susceptibility to sepsis. Alleles A2, B2, and RN2 might be important high-risk genetic markers for sepsis. A recent study (40) determined the functionality of identified polymorphisms in the promoter and upstream regions of the IL-10 gene in terms of release of IL-10 from LPS-stimulated whole blood from healthy volunteers, and evaluated the relationship of IL-10 polymorphisms to IL-10 release, development of sepsis, and mortality in critically ill patients. A total of 132 healthy volunteers plus 67 consecutive critically ill patients were recruited within 24 hours of admission to the ICU, regardless of diagnosis. Stimulated IL-10 release in critically ill patients was significantly lower than in healthy subjects (P < 0.0001). In addition, in the patients who developed sepsis, IL-10 release at admission to the ICU was significantly lower than in patients who did not subsequently develop sepsis [median (range) 1.47 (0.13– 6.90) ng/mL compared with 4.93 (0.03–16.80) ng/mL, P ¼ 0.001]. The A allele of the single nucleotide polymorphism at 592 base pairs was associated with lower IL-10 release and higher mortality in critically ill patients. Other polymorphisms were not linked to IL-10 release, sepsis, or mortality.

medwedi.ru

234

Part One: General Considerations

Contrasting findings regarding IL-10 were reported in a recent study of patients (n ¼ 61) with pneumococcal infection (41). IL-10 allele G homozygous patients (for the biallelic IL-10–1082 promoter) had the highest risk for septic shock (odds ratio of 6.1; 95% confidence interval, 1.4–27.2; corrected P ¼ 0.024). The whole blood LPS-stimulated IL-10 release was highest in IL-10 G homozygous patients (P ¼ 0.04). In contrast to the prior study, this IL-10 polymorphism, associated with high IL-10 inducibility, was associated with worse outcome of pneumococcal infection, possibly via induced immunosuppression and impaired bacterial clearance. A genetic component to risk of sepsis and resultant complications clearly exists. Confirmation of these findings and associations with other genetic polymorphisms await large-scale population studies and further validation of the physiologic significance of the variant alleles.

TREATMENT STRATEGIES IN SEPSIS Standard therapy for sepsis and severe sepsis includes source control, antibiotics, aggressive resuscitation and hemodynamic support, and nutrition and supportive therapy for other organ dysfunctions.

Source Control Optimal management of infection and sepsis encompasses the important concept of ‘‘source control,’’ i.e., control of the source of the infection. Decisive implementation of optimal source control measures includes the drainage of abscesses and collections of infected fluid, the debridement of necrotic infected tissue, and the use of definitive measures to prevent further contamination. Source control in pneumonia, for example, may require endotracheal intubation for adequate clearance of purulent tracheal secretions. In complicated pneumonia, source control may require tube thoracostomy for a parapneumonic empyema. Source control is a particularly important concept in the treatment of abdominal sepsis (42) and surgical sepsis (43). The current clinical management of surgical patients with sepsis is governed by two principles: control of the source of infection and supportive management of the patient until recovery. Intra-abdominal infections are a common source of sepsis, and are an important cause of morbidity and mortality in the ICU. Outcome in abdominal sepsis is dependent on timely and accurate diagnosis, early adequate source control, and vigorous resuscitation and antibiotic support. In May 1997, a panel of surgeon-investigators met to discuss the clinical importance and research implications of controlling the source of abdominal infections (44). It was concluded that source control is critical to therapeutic success, and that antimicrobial therapy and other adjunctive interventions will fail if the source of infection is not controlled by drainage resection, exteriorization, or other means. The definitions of drainage source control varied dependent on the type and location of infection. All participants agreed that failure to consider the adequacy of source control of infection has limited the value of most clinical trials of therapeutic anti-infective agents. Besides recognizing source control as an essential goal of patient care, there is considerable need for further investigative work to define, record, and stratify the adequacy of source control in clinical trials of therapeutic agents for abdominal infections.

Evaluation of the adequacy of source control in the critically ill patient can be difficult (45). As with other modes of anti-infective therapy, effective source control measures are expected to result in clinical improvement, reflected in the resolution of clinical signs of sepsis or systemic inflammation, bacteriological resolution, and resolution of organ dysfunction and ultimately survival. Adequacy of source control can be determined by radiographic evidence (i.e., drainage of an abscess and resolution of pneumonia infiltrate), repeated surgical evaluation (i.e., adequacy of debridement of necrotizing soft-tissue infections until there is evidence of healthy granulation tissue throughout the wound), and microbiologic eradication of infection (i.e., blood cultures negative after an episode of bacteremia). The appropriate interventions to determine the adequacy of source control are dictated by the clinical circumstances and the site and source of infection. The general principles that guide the use of source control techniques in the management of the patient with severe sepsis or septic shock are fundamental to effective sepsis treatment.

Systemic Antibiotics Systemic antibiotic therapy is a fundamental component of the standard therapy of sepsis. Antibiotics are essential to the treatment of bacterial sepsis, because they reduce the bacterial burden. The adequacy of initial empirical antimicrobial treatment, therefore, is crucial in terms of successful outcome. Unfortunately, many studies have documented high rates of inadequate initial antibiotic therapy in infection and sepsis, ranging from 20% to 70% (46–50). These studies have also confirmed increased mortality associated with inadequate antimicrobial therapy in the treatment of nosocomial infections, including pneumonia and bacteremia. Inadequate antimicrobial therapy has also been associated with increased mortality in sepsis. The incidence and outcome associated with inadequate antibiotic therapy was recently examined in the Monoclonal Anti-TNF: A Randomized Controlled Sepsis (MONARCS) trial, which enrolled patients with suspected sepsis (51). The study enrolled 2634 patients, 91% of whom received adequate antibiotic therapy. The mortality rate among patients given adequate antibiotic treatment was 33% versus 43% among patients given inadequate treatment (P < 0.001). This study concluded that adequate antibiotic therapy resulted in a significant decrease in the crude mortality rate among patients suspected of sepsis. Similarly, a prospective observational study of 107 septic shock patients documented that 89% of patients received adequate antimicrobial therapy, but 11% did not (52). Inadequate antimicrobial therapy was associated with a 39% excess of mortality. A de-escalation (removal of a nonpivotal antibiotic that was not necessary based on microbiologic cultures) of the empiric antimicrobial therapy was possible in 64% of patients. A recent study (53) evaluated the impact of adequate empirical antibiotic therapy on in-hospital mortality rate, after controlling for confounding variables, in a cohort of patients (n ¼ 406) admitted to the ICU with sepsis. The impact of adequate empirical antibiotic therapy on early (less than three days), 28-day, and 60-day mortality rates also was assessed. Microbiological documentation of sepsis was obtained in 67% of the patients. At ICU admission, sepsis was present in 105 patients (25.9%), severe sepsis in 116 (28.6%), and septic shock in 185 (45.6%). By multivariate analysis, predictors of in-hospital mortality were sepsisrelated organ failure assessment (SOFA) score at ICU

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

admission [odds ratio (OR), 1.29], the increase in SOFA score over the first three days in the ICU (OR, 1.40), respiratory failure within the first 24 hours in the ICU (OR, 3.12), and inadequate empirical antimicrobial therapy in patients with ‘‘nonsurgical sepsis’’ (OR, 8.14). Adequate empirical antimicrobial therapy in ‘‘surgical sepsis’’ (OR, 0.37) and urologic sepsis (OR, 0.14) was a protective factor. Regarding early mortality (less than three days), factors associated with fatality were immunosuppression (OR, 4.57), chronic cardiac failure (OR, 9.83) renal failure within the first 24 hours in the unit (OR, 8.63), and respiratory failure within the first 24 hours in the ICU (OR, 12.35). Fungal infection (OR, 47.32) and previous antibiotic therapy within the last month (OR, 2.23) were independent variables related to administration of inadequate antibiotic therapy. This study clearly determined that in patients admitted to the ICU for sepsis, the adequacy of initial empirical antimicrobial treatment was an independent predictor of in-hospital mortality. The incidence and effect of inappropriate initial antimicrobial therapy on the prognosis of patients with sepsis who were enrolled in a clinical trial of an immunomodulating agent conducted in 108 hospitals in North America and Europe was recently examined (54). Initial antimicrobial choice and results of microbiologic cultures were studied in 904 patients who had microbiologically confirmed severe sepsis or early, septic shock. If a patient did not receive at least one antimicrobial agent to which the causative microorganisms were susceptible within 24 hours from the diagnosis of severe sepsis, then the initial antimicrobial treatment was considered to be inappropriate. A propensity score that adjusted for factors associated with inappropriate antimicrobial treatment was calculated and included in multivariable models to adjust for confounding. A total of 468 patients (52%) had documented bloodstream infection, and 211 patients (23%) received inappropriate initial antimicrobial therapy. Characteristics associated with inappropriate treatment were study enrollment in Europe, admission to surgery, nosocomial infection, infection with multiresistant microorganisms, and fungal or polymicrobial infection (all P< 0.05). The 28-day mortality was 24% (168/693) for patients in the adequately treated group versus 39% (82/211) for patients receiving inappropriate initial antimicrobial therapy (P< 0.001). After adjusting for comorbid conditions, severity of illness, site of infection, and the propensity score, inappropriate antimicrobial therapy was independently associated with increased mortality (OR, 1.8; 95% confidence interval: 1.2–2.6). In this large cohort of patients with microbiologically confirmed severe sepsis, appropriate initial antimicrobial therapy was an important determinant of survival. One important factor contributing to the high incidence of inadequate initial antimicrobial therapy in sepsis is the increasing incidence of antibiotic-resistant organisms as the etiology of infection and sepsis. In critical care, particularly problematic pathogens include methicillinresistant S. aureus and multidrug-resistant Pseudomonas species. A number of studies in sepsis have documented that, for most pathogens, resistance contributes to significant increases in mortality (55). This has been clearly demonstrated in bacteremia, including community- and hospital-acquired infection, and with bacteremia caused by vancomycin-resistant enterococci, methicillin-resistant staphylococci, and extended-spectrum–producing gramnegative bacteria. Significant mortality increases have also been documented with antibiotic-resistant pathogens as the

235

etiology of ventilator-associated pneumonia and serious infections requiring admission to intensive care. There is now convincing evidence and consensus that initiation of broad-spectrum antimicrobial therapy to cover the likely pathogens including multi-drug resistant pathogens pending culture results is mandatory in sepsis to minimize adverse outcomes. De-escalation of this therapy from broad-spectrum initial coverage to targeted antimicrobial therapy after results of cultures and susceptibility tests become available is a necessary component of this strategy, in order to minimize unnecessary use of broad-spectrum antibiotics and possibly promote further bacterial resistance.

Resuscitation and Hemodynamic Support Early aggressive fluid resuscitation is a standard component of sepsis therapy and should be the initial step in hemodynamic support of patients with septic shock (56). The goal of fluid resuscitation in sepsis is restoration of tissue perfusion and normalization of oxidative metabolism. Increasing cardiac output and oxygen delivery is dependent on expansion of blood and plasma volume. Intravascular volume can be repleted through the use of packed red cells, crystalloid solutions, and colloid solutions. Fluid infusion is best initiated with boluses titrated to clinical endpoints of heart rate, urine output, and blood pressure. If a central venous pressure is available, levels of 8–12 mmHg should be maintained. Patients who do not respond rapidly to initial fluid boluses or those with poor physiologic reserve should be considered for invasive hemodynamic monitoring. If fluid therapy alone fails to restore adequate arterial pressure and organ perfusion, therapy with vasopressor agents should be initiated. Potential vasopressor agents include dopamine, norepinephrine, epinephrine, or phenylephrine. Dopamine and norepinephrine are both effective for increasing arterial blood pressure, although norepinephrine may be a more effective vasopressor in some patients. An important study (prospective, double-blind, randomized) compared dopamine and norepinephrine for the treatment of hyperdynamic septic shock (57). At the doses tested, norepinephrine was found to be more effective and reliable than dopamine to reverse the abnormalities of hyperdynamic septic shock. In the great majority of the study patients, norepinephrine was able to increase mean perfusion pressure without apparent adverse effect on peripheral blood flow or on renal blood flow, and at the same time, resulted in increased oxygen uptake. Furthermore, it has been documented that the use of epinephrine in sepsis may be associated with increased tachyarrhythmias and potential vasoconstriction of the splanchnic circulation resulting in gut hypoperfusion. A study in 20 patients with septic shock (58) examined the effects of dopamine, norepinephrine, and epinephrine on the splanchnic perfusion in septic shock by measurement of changes in splanchnic circulation (indocyanine green dilution and hepatic vein catheter) and gastric mucosal pCO2 (gas tonometry). This study documented that dopamine and norepinephrine had similar systemic hemodynamic effects, but epinephrine resulted in impaired splanchnic circulation in severe septic shock. When adequately fluid resuscitated, most septic patients are hyperdynamic, but myocardial contractility, as assessed by ejection fraction, is impaired (59). Serial radionuclide cine angiographic and hemodynamic evaluations were done on 20 patients with documented septic shock. Although all patients had a normal or elevated cardiac index, 10 patients (50% of the study cohort) had moderate

medwedi.ru

236

Part One: General Considerations

to severe depression of their ejection fraction with values below 0.40. The mean initial ejection fraction for the survivors was 0.32 0.04, and their mean end-systolic and end-diastolic ventricular volumes were substantially increased with a normal stroke volume. The survivors’ serial scans showed a gradual return to normal ejection fraction and ventricular volume by 10 days after the onset of shock. Some patients, especially those with preexisting cardiac dysfunction, may have decreased cardiac output and may require inotropic agents such as dobutamine, dopamine, and epinephrine. Dobutamine is the first choice for patients with low cardiac index and/or low mixed venous oxygen saturation and an adequate mean arterial blood pressure, following fluid resuscitation. Based on the principles outlined above, a simple clinical strategy for resuscitation and hemodynamic stabilization in sepsis and septic shock has been established (Fig. 4). A more aggressive approach to resuscitation in sepsis and septic shock has recently been evaluated. Goal-directed therapy has been used for severe sepsis and septic shock in the ICU. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. A recent study (61) evaluated the efficacy of early goal-directed therapy (EGDT) (Fig. 5) before admission to the ICU. Patients who arrived at an urban emergency department with severe sepsis or septic shock (n ¼ 263) were randomized to receive either six hours of

Central venous and arterial catheterization

CVP or FTc

CVP < 8 mm Hg or FTc < 330 msec

500-mL bolus of NS or LR every 30 min prn

CVP 8–12 mm Hg or FTc 330–360 msec

MAP

< 65 mm Hg Norepinephrine (adjustable dosage) ± vasopressin 0.04 U/min (fixed dosage)

EGDT or standard therapy (as a control) before admission to the ICU. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and APACHE II scores were obtained serially for 72 hours and compared between the study groups. There were no significant differences between the groups with respect to base-line characteristics. Inhospital mortality was 30.5% in the group assigned to EGDT, as compared with 46.5% in the group assigned to standard therapy (P ¼ 0.009). During the interval from 7 to 72 hours, the patients assigned to EGDT had a significantly higher mean central venous oxygen saturation, a lower lactate concentration, a lower base deficit, and a higher pH than the patients assigned to standard therapy (P < 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to EGDT than in those assigned to standard therapy (13.0 6.3 vs. 15.9 6.4, P<0.001). EGDT provided significantly improved outcome in patients with severe sepsis and septic shock. An important commentary by Natanson and Banner (62) regarding this study documented that the control group received significantly less fluid in the first six hours during unblinded treatment in the emergency department, and both central venous pressure and mean arterial pressure were lower in the control group at six hours. Later in the ICU, the control group received more fluid resuscitation than the EGDT group, but the adverse effect on survival based on the early differences in fluid resuscitation could not be overcome. Death attributable to sudden cardiovascular collapse but not to multiple organ failure occurred less frequently in the EGDT group. Because of several treatment differences between study groups, it cannot be determined which aspect of the protocol was most crucial in producing this observed effect on survival. Moreover, large beneficial effects of some interventions, such as better fluid resuscitation, could have obscured harmful effects of others. A point not addressed but of equal importance to rapid resuscitation is the need to start antibiotics within 60 minutes of diagnosing severe sepsis. Approximately six hours after randomization for severe sepsis or septic shock, 1 in 10 patients in this study had not received antibiotics. Clearly, septic patients are best served by promptly initiating antimicrobial therapy and rapid life-saving resuscitation based on frequent physiologic measurements.

MAP > 65

New Strategies for the Treatment of Sepsis CI and ScvO2 or SvO2

CI < 2.0 and ScvO2 or SvO2 < 70% Dobutamine 5 µg/kg/min (adjustable dosage)

CI > 2.0 and ScvO2 or SvO2 < 70%

Goals achieved

Figure 4 Resuscitiation and hemodynamic stabilization strategy in sepsis and septic shock. Abbreviations: CVP, central venous pressure; FTc, flow time corrected; NS, normal saline or 0.9% sodium chloride; LR, lactated Ringer’s solution; MAP, mean arterial pressure; CI, cardiac index; SCVO2, central venous oxygen saturation; SVO2, mixed venous oxygen saturation. Source: From Ref. 60.

Considerable progress has been made in the past few years in the development of therapeutic interventions that can reduce mortality in sepsis. However, encouraging physicians to put the results of new studies into practice is not always simple. A report from a recent roundtable convened to provide guidance for clinicians on the integration and implementation of new interventions for treatment of sepsis was recently published (63). Five topics were selected that have been shown in randomized, controlled trials to reduce mortality in sepsis: limiting the tidal volume in acute lung injury or acute respiratory distress syndrome, EGDT, use of drotrecogin alfa (activated), use of moderate doses of steroids, and tight control of blood sugar. Each new intervention has a place in the management of patients with sepsis. Furthermore, and importantly, the therapies are not mutually exclusive; many patients will need a combination of several treatment strategies. Optimal patient selection and timing

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

237

Supplemental oxygen ± endotracheal intubation and mechanical ventilation

Central venous and arterial catheterization

Sedation, paralysis (if intubated), or both

<8 mm Hg

CVP

Crystalloid Colloid

8_12 mm Hg

MAP

<65 mm Hg >90 mm Hg

Vasoactive agents

≥ 65 and ≤ 90 mm Hg

ScvO2

<70%

Transfusion of red cells unit hematocrit ≥ 30%

≥70% <70%

≥70% Inotropic agents No

Goals achieved

Figure 5 Protocol for EGDT. Abbreviations: CVP, central venous pressure; EGDT, early goal-directed therapy; MAP, mean arterial pressure; SCVO2, central venous oxygen saturation. Source: From Ref. 53.

Yes Hospital admission

for each intervention are both important. Furthermore, integration of these new therapies into ICU practice, including protocol development, is imperative so that mortality rates related to sepsis can be significantly reduced. The supportive evidence regarding a number of new strategies for treatment of sepsis will be reviewed.

Adrenal Insufficiency and Peripheral Glucocorticoid Resistance Syndrome The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. During sepsis or acute respiratory distress syndrome, the hypothalamic-pituitaryadrenal axis is rapidly activated through a systemic pathway, i.e., by circulating proinflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone that will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic-pituitary-adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Adrenal insufficiency has been documented in a significant portion of patients with severe sepsis and septic shock (64), and recent small studies have documented the efficacy of low-dose hydrocortisone therapy in septic shock. Subnormal adrenal corticosteroid production during acute severe illness has been termed ‘‘functional adrenal insufficiency,’’ to reflect the notion that hypoadrenalism can

occur without obvious structural defects in the hypothalamicpituitary-adrenal axis (65). A related concept is that of ‘‘relative adrenal insufficiency,’’ in which cortisol levels, although high in absolute terms, are insufficient to control the inflammatory response. Inability to mount an adequate cortisol response, as seen in patients with structural disease of the hypothalamic-pituitary-adrenal axis, adrenal suppression by corticosteroids or prolonged treatment with offending drugs increases the risk of death during acute illness. Thus, if functional adrenal insufficiency can be identified, treatment with supplemental corticosteroids may be of significant benefit. The correct method to diagnosis of adrenal insufficiency in a septic shock patient remains controversial. Traditionally, an adrenocorticotropic hormone (ACTH) (corticotropin)-stimulation test is utilized to make the diagnosis of adrenal insufficiency, with a baseline cortisol measurement, followed by the administration of 250 mcg of synthetic ACTH, and then repeat plasma cortisol concentrations obtained at 30 and 60 minutes after ACTH administration. An incremental increase of < 9 mcg/dL is interpreted as adrenal insufficiency. Recent studies have also investigated the use of a 1 mcg ACTH stimulation test for the diagnosis of adrenal insufficiency in critically ill patients. One recent study (64) evaluated whether a baseline (random) cortisol concentration < 25 mcg/dL in patients with septic shock was a better discriminator of adrenal insufficiency than the standard (250 mcg) and the low-dose (1 mcg) corticotropin stimulation tests as assessed by the

medwedi.ru

238

Part One: General Considerations

hemodynamic response to steroid replacement in 59 patients with septic shock. Mortality was 47%, and 22% of patients met the diagnostic criteria of adrenal insufficiency by the low-dose test and 8% by the high-dose test. However, 61% of patients met the criteria of adrenal insufficiency when a baseline cortisol concentration of < 25 mcg/dL was used. Twenty-two patients (37%) were steroid responsive; the baseline serum cortisol was 14.1 5.2 mcg/dL in the steroid-responsive patients compared with 33.318 mcg/dL in the steroid-nonresponsive patients (P < 0.0001). Ninetyfive percent of steroid-responsive patients had a baseline cortisol concentration < 25 mcg/dL. Fifty-four percent of steroid responders had a diagnostic low-dose test and 22% a diagnostic high-dose test. Receiver operating characteristic curve analysis revealed that a stress cortisol concentration of 23.7 mcg/dL was the most accurate diagnostic threshold for determination of the hemodynamic response to glucocorticoid therapy. This study confirmed that adrenal insufficiency is common in patients with septic shock, the incidence depending largely on the diagnostic test and criteria used to make the diagnosis. There is clearly no absolute serum cortisol concentration that distinguishes as efficient from an insufficient adrenal response. However, the authors believe that a random cortisol concentration of < 25 mcg/dL in a highly stressed patient is a useful diagnostic threshold for the diagnosis of adrenal insufficiency. The prognostic value of basal and ACTH-stimulated cortisol concentration in patients with sepsis remains a controversial issue. In a retrospective cohort study (66), 82 consecutive patients with septic shock underwent a short ACTH test performed more than 24 hours after the onset of vasopressor therapy. Forty-one (50%) patients died within 28 days after the onset of septic shock. The mean (SD) basal cortisol level was 22.7 (10.6) mcg/dL. With threshold values of 7 and 9 mcg/dL maximal increases in cortisol level, 28 (34%) and 31 (38%) patients were, respectively, classified as nonresponders to the short ACTH stimulation test. On multivariate analysis, a cortisol level > 20 mcg/dL (P ¼ 0.0002), a maximal response to ACTH < 9 mcg/dL (P ¼ 0.044), abnormal lactate values (P ¼ 0.0098), and positive blood cultures (P ¼ 0.004) were independent predictors of 28-day mortality. This study documented that high basal cortisol and low increase on corticotropin stimulation are independent predictors of a poor outcome in late septic shock. The underlying mechanisms of these prognostic patterns remain to be elucidated. Relative adrenal insufficiency and ‘‘peripheral glucocorticoid resistance syndrome’’ are the two main features of the inappropriate hormonal response, and provide the grounds for cortisol replacement in these diseases (67). In practice, prior studies using high-dose corticosteroids (i.e., one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomized controlled trials reporting the benefits and risks of low-dose corticosteroids (i.e., 200–300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low-dose corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival, and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e., 150–300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.

The largest study to date, a placebo-controlled, randomized, double-blind, parallel-group trial, was performed in 19 ICUs in France and included 299 patients with septic shock (68). A short ACTH stimulation test was performed to determine adrenal insufficiency (defined as response of 9 mcg/dL or less) and 229 patients (76.5%) were nonresponders. In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47–0.95; P ¼ 0.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29–2.84; P ¼ 0.001). Adverse events rates were similar in the two groups. A seven-day treatment with low doses of hydrocortisone (50 mg q6h IV) and fludrocortisone (50 mg tablet via nasogastric tube) significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events. Other studies have documented that the administration of modest doses of hydrocortisone in the setting of pressor-dependent septic shock resulted in a significant improvement of hemodynamics and a beneficial effect on survival, unrelated to adrenal insufficiency (69,70). It is presumed that these patients have ‘‘peripheral glucocorticoid resistance syndrome.’’ Increased cytokines induce glucocorticoid resistance in targeted tissues by altering steroid receptor function. Cytokines also reduce steroid-binding affinity for cortisol. Exogenous administration of pharmacologic low-dose steroids may be sufficient for treatment in this steroid-resistant state. Glucocorticoids display a wide spectrum of anti-inflammatory properties (71) that have been identified in in vitro and in vivo experimental models (e.g., inhibition of production of proinflammatory cytokines, free radicals, and prostaglandins, inhibition of chemotaxis, and adhesion molecule expressions). In addition, glucocorticoids have profound effects on the cardiovascular system (e.g., increasing mean blood pressure, increasing pressor sensitivity, and therefore decreasing the duration of the use of catecholamines during septic shock). Through these anti-inflammatory and cardiovascular effects, low doses of glucocorticoids may improve septic shock survival.

Insulin and Glycemic Control Hyperglycemia and insulin resistance are common in critically ill patients, even without a prior history of diabetes. A recent study showed that mortality is significantly reduced by the maintenance of normoglycemia using intensive insulin therapy. This prospective study (72) randomized 1548 patients admitted to the surgical ICU requiring mechanical ventilation to intensive insulin therapy (maintenance of blood glucose between 80 and 110 mg/dL) or conventional treatment (insulin infusion only if blood glucose greater than 215 mg/dL and maintenance of glucose between 180 and 200 mg/dL). Intensive insulin therapy reduced mortality from 8.0% to 4.6% (P < 0.04). The benefit of intensive insulin therapy was attributable to its effect on reducing mortality among patients with ICU length of stay of greater than five days (mortality 20.2% in conventional group vs. 10.6% with intensive insulin therapy, P ¼ 0.005). The greatest reduction in mortality involved deaths due to multiple organ dysfunction syndrome (MODS) with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34%, bloodstream infections by 46%, and acute renal failure requiring dialysis or hemofiltration by 50%. The majority of patients included in this surgical study were

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

cardiac surgical patients (63%). A subsequent analysis of this study cohort (73), using multivariate logistic regression analysis, determined that the lowered blood glucose level rather than the insulin dose was related to reduced mortality (P < 0.0001), critical illness polyneuropathy (P < 0.0001), bacteremia (P ¼ 0.02), and inflammation (P ¼ 0.0006) but not to the prevention of acute renal failure, for which the insulin dose was an independent determinant (P ¼ 0.03). As compared with normoglycemia, an intermediate blood glucose level (110–150 mg/dL) was associated with worse outcome. Metabolic control, as reflected by normoglycemia, rather than the infused insulin dose, was related to the beneficial effects of intensive insulin therapy in these surgical critical care patients. Glycemic control is therefore emerging as a strategy for prevention of septic complications in critically ill patients. Another large clinical study evaluated whether blood glucose level or quantity of insulin administered was associated with reduced mortality in critically ill patients. This was a single-center, prospective, observational study of 531 ICU patients (cardiothoracic surgery and medicine, median age, 64 years) performed in the United Kingdom (74). Multivariate logistic regression analysis demonstrated that increased administration of insulin was positively and significantly associated with ICU mortality [odds ratio, 1.02 (95% confidence interval, 1.01–1.04) at a prevailing glucose level of 111–144 mg/dL (6.1–8.0 mmol/L) for a 1-IU/d increase], suggesting that mortality benefits are attributable to glycemic control rather than increased administration of insulin. Also, the regression models suggested that a mortality benefit accrues below a predicted threshold glucose level of 144 to 200 mg/dL (8.0–11.1 mmol/L), with a speculative upper limit of 145 mg/dL (8.0 mmol/L) for the target blood glucose level. Increased insulin administration was positively associated with death in the ICU regardless of the prevailing blood glucose level. Thus, control of glucose levels rather than of absolute levels of exogenous insulin appeared to account for the mortality benefit associated with intensive insulin therapy demonstrated by others. Other studies have documented an association between hyperglycemia and worse outcome in trauma and burn victims (75,76). These findings suggest that aggressive normalization of plasma glucose in critically ill and injured patients may be beneficial, and future trials in patients with sepsis, severe sepsis, and septic shock are warranted. Hyperglycemia is a risk marker of morbidity and mortality in acute, critical illness, and insulin therapy seems to be beneficial in this patient group. Whether this is true for a population of sepsis patients, as such, has not been investigated in clinical trials, but evidence from in vitro studies and experimental sepsis suggests that this may be the case (77). The endocrinology of septic patients is characterized by a shift in the balance between insulin and its counterregulatory hormones favoring the latter. This leads to prominent metabolic derangements composed of high release and low use of glucose, amino acids, and free fatty acids (FFA), resulting in increased blood levels of these substrates. Circulating, proinflammatory mediators further enhance this state of global catabolism. Increased levels of glucose and FFA have distinct effects on inflammatory signaling, leading to additional release of proinflammatory mediators and endothelial and neutrophil dysfunction. Insulin has the inherent capability to counteract the metabolic changes observed in septic patients. Concomitantly, insulin therapy may act as a modulator of inflammatory pathways inhibiting the unspecific, inflammatory activation

239

caused by metabolic substrates. Given these properties, insulin could conceivably be serving a dual purpose for the benefit of septic patients. The mechanisms underlying the beneficial effects of aggressive glycemic control in critical illness are myriad. Intensive insulin therapy is associated with increased serum levels of low-density lipoprotein and high-density lipoprotein, whereas it suppressed the elevated serum triglyceride concentrations (78). Multivariate logistic regression analysis, corrected for baseline univariate risk factors and the effect on inflammation, indicated that lipid rather than glucose control independently determined the beneficial effects of intensive insulin therapy on morbidity and mortality. In postmortem biopsies obtained from 74 patients who died in the ICU, intensive insulin therapy increased mRNA levels of skeletal muscle glucose transporter 4 and hexokinase. These data suggest that intensive insulin therapy normalizes blood glucose levels through stimulation of peripheral glucose uptake and concomitantly partially restores the abnormalities in the serum lipid profile, which may contribute significantly to the improved outcome of protracted critical illness. Recent studies suggest that intensive insulin therapy may also exert anti-inflammatory effects and result in decreased apoptosis, a mechanism associated with organ failure in severe sepsis. Acute hyperglycemia induces hyperinsulinemia and increases circulating cytokine concentrations, and these effects are more pronounced in sepsis (79). This suggests a potential modulation of immunoinflammatory responses in human sepsis by hyperglycemia. A prospective study (80) in 451 patients requiring greater than five days of intensive care, and randomized to either conventional treatment or intensive insulin therapy, had serial CRP concentrations measured on admission, day 5, day 15, and on the last day in the ICU. Decrease in the concentrations of CRP was significantly more pronounced in the intensive insulin-treated patients compared with the conventionally treated patients (P < 0.02). Multivariate logistic regression analysis, corrected for all other determinants of outcome, revealed that the anti-inflammatory action of intensive insulin therapy on CRP largely explained the beneficial effects of intensive insulin therapy on morbidity and mortality. In human sepsis, a prominent component of the hypermetabolism is impaired glucose tolerance and hyperglycemia. Elevations in plasma glucose concentration impair immune function, in part, by altering cytokine production from macrophages. The finding that high insulin serum concentrations induce a more prolonged increase in the anti-inflammatory cytokine IL-6 and suppress the levels of FFA in normal volunteers receiving intravenous endotoxin suggests that insulin treatment of patients with sepsis may exert beneficial effects by inducing anti-inflammation and protection against FFA toxicity and inhibit FFA-induced insulin resistance (81). The protective mechanism of insulin in sepsis is not fully known. The phagocytic function of neutrophils is impaired in patients with hyperglycemia, and correcting hyperglycemia may improve bacterial phagocytosis. Another potential mechanism involves the antiapoptotic effect of insulin. Insulin prevents apoptotic cell death from numerous stimuli by activating the phosphatidylinositol 3-kinase (PI3-kinase)-Akt pathway (82). It has been documented that insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible antiapoptotic mechanism (83), and insulin is a potent survival factor in

medwedi.ru

240

Part One: General Considerations

mesangial cells (84). Moreover, the cardioprotective and antiapoptotic effects of insulin are mediated via tyrosine kinase and PI3-kinase signalling pathways. Regardless of mechanism, it seems reasonable to control blood glucose more tightly in critically ill patients. Frequent monitoring of blood glucose is imperative, and studies are needed to determine whether less tight control of blood glucose—for example, a blood glucose level of 120 to 160 mg/dL—provides similar benefits. Additional studies to determine whether tight glycemic control results in improved outcomes in septic patients are necessary.

Vasopressin Therapy for Septic Shock Vasopressin is emerging as a rational therapy for the hemodynamic support of septic shock and vasodilatory shock due to SIRS (85). Both hemorrhagic and septic shock are associated with a biphasic response in vasopressin levels. In early shock, appropriately high levels of vasopressin are produced to support organ perfusion. As the shock state progresses, plasma vasopressin levels fall for reasons that are not entirely clear. Importantly, vasopressin levels in established septic and vasodilatory shock are low. Several mechanisms for this vasopressin deficiency have been proposed. The potential mechanisms of vasopressin deficiency include (i) depletion of pituitary stores of vasopressin due to excessive baroreceptor firing or exhaustive release in early septic shock, (ii) autonomic dysfunction and citing lack of baroreflex-mediated bradycardia after vasopressin infusion as evidence, (iii) elevated norepinephrine levels (endogenous or exogenous) that have a central inhibitory effect on vasopressin release, and (iv) increased nitric oxide release by vascular endothelium within the posterior pituitary during sepsis that may inhibit vasopressin production. In addition to the deficiency of vasopressin identified in septic shock patients, these patients are exquisitely sensitive to low-dose vasopressin (86–88). A recent study of 62 septic shock patients confirmed that plasma vasopressin levels are almost always increased at the initial phase of septic shock and decrease significantly thereafter. Relative vasopressin deficiency was documented in approximately one-third of late septic shock patients. Vasopressin deficiency may contribute to the refractory hypotension of late septic shock, resulting in the continued requirement of vasopressor therapy. In physiologic doses (0.01–0.04 U/min), low-dose vasopressin infusion causes a pressor response in septic shock and a sparing of conventional exogenous catecholamines and no evidence of organ hypoperfusion. There has been only one randomized controlled trial (89) to date that studied vasopressin continuous infusion at 0.04 U/min in septic shock trauma patients (n ¼ 10). Patients receiving vasopressin had a significant increase in blood pressure and were able to have all other catecholamines withdrawn, whereas the control patients had no change in blood pressure and none were able to have pressor therapy withdrawn. Vasopressin mediates vasoconstriction via VI-receptors, coupled to phospholipase C, and increases intracellular calcium concentration. This action is not impaired during sepsis, and thus vasopressin has been shown effective in reversal of catecholamine-resistant hypotension in septic shock patients (90–92). The use of higher doses of vasopressin in septic shock may be associated with potentially deleterious vasoconstriction of mesenteric, renal, pulmonary, and coronary vasculature. A recent study (93) examined the effects of vasopressin, when substituted for norepinephrine as a

vasopressor in septic shock, on global and hepatosplanchnic hemodynamic and oxygen transport variables in 12 septic shock patients. Vasopressin, in doses sufficient to replace norepinephrine, had mixed effects in septic shock patients. Hepatosplanchnic blood flow was preserved during substantial reduction in cardiac output. An increased gastric pCO2 gap suggests that the gut blood flow could have been redistributed to the disadvantage of the mucosa. Based on these limited data, it does not appear beneficial, and may be potentially harmful, to use high-dose vasopressin in septic shock. Based on the results of studies to date, clinicians should consider the addition of low-dose (up to 0.04 U/min) continuous infusion vasopressin in individual septic shock patients who are adequately resuscitated and still requiring high doses of vasopressors. Whether the use of low-dose vasopressin in septic shock, with the goal of restoring vasopressin levels to a physiologic level, will translate to improved clinical outcomes (i.e., improved organ dysfunction or improved survival) awaits the conduct of future large prospective randomized clinical trials.

Activated Protein C for Severe Sepsis Dysregulation of coagulation and inflammation is common in sepsis and is thought to be fundamental to the pathogenesis of MODS (94,95). Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. Systemic inflammation results in activation of coagulation, due to tissue factor–mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis (96). Proinflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. The relevance of the cross talk between inflammation and coagulation is underlined by the promising results in the treatment of severe systemic infection with modulators of coagulation and inflammation. Increased D-dimers and decreased protein C blood concentrations are common in patients with sepsis and organ dysfunction. Decreased protein C concentrations play an active role in the development of the hypercoagulable state in patients with severe sepsis, and are linked to the development of organ dysfunction and increased mortality. Activated protein C, an endogenous protein that promotes fibrinolysis and inhibits thrombosis and inflammation, is an important modulator of the coagulation and inflammation associated with severe sepsis (Fig. 6). The properties of activated protein C include: (i) antithrombotic activity, by inhibition of thrombin formation and inhibition of factors V and VIII; (ii) profibrinolytic activity, enhancing the body’s ability to lyse fibrin, via inhibition of plasminogen activator inhibitor (PAI)-1; and (iii) anti-inflammatory activity, indirectly through reduced thrombin resulting in less TNF and IL-1 production, and via a direct effect on monocytes and endothelial cells through a nuclear factor kappaB (NF-kB) mechanism. The conversion of protein C to activated protein C may be impaired during sepsis as a result of the downregulation of thrombomodulin by inflammatory cytokines (97). Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death (98–100). In fact, protein C deficiency was documented in approximately 80% of all severe sepsis patients studied (101).

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

241

Figure 6 Proposed actions of activated protein C in modulating the systemic inflammatory, procoagulant, and fibrinolytic host responses to infection. The inflammatory and procoagulant host responses to infection are intricately linked. Infectious agents and inflammatory cytokines such as TNF-a and IL-1 activate coagulation by stimulating the release of tissue factor from monocytes and the endotheliurn. The presentation of tissue factor leads to the formation of thrombin and a fibrin clot. Inflammatory cytokines and thrombin can both impair the endogenous fibrinolytic potential by stimulating the release of PAI-1 from platelets and the endothelium. PAI-1 is a potent inhibitor of tissue plasminogen activator, the endogenous pathway for lysing a fibrin clot. In addition, the procoagulant thrombin is capable of stimulating multiple inflammatory pathways and further suppressing the endogenous fibrinolytic system by activating TAFI. The conversion of protein C, by thrombin bound to thrombomodulin, to the serine protease–activated protein C is impaired by the inflammatory response. Endothelial injury results in decreased thrombomodulin levels. The end result of the host response to infection may be the development of diffuse endovascular injury, microvascular thrombosis, organ ischemia, multiorgan dysfunction, and death. Activated protein C can intervene at multiple points during the systemic response to infection. It exerts an antithrombotic effect by inactivating factors Va and VIIIa, limiting the generation of thrombin. As a result of decreased thrombin levels, the inflammatory, procoagulant, and antifibrinolytic response induced by thrombin is reduced. In vitro data indicate that activated protein C exerts an anti-inflammatory effect by inhibiting the production of inflammatory cytokines (TNF-a, IL-1, and IL-6) by monocytes and limiting the rolling of monocytes and neutrophils on injured endothelium. By binding selectins, activated protein C indirectly increases the fibrinolytic response by inhibiting PAI-1. Abbreviations: IL, interleukin; TNF-a, tumor necrosis factor a; PAI-1, plasminogen-activator inhibitor 1; TAFI, thrombin-activatable fibrinolysis inhibitor. Source: From Ref. 101.

The administration of a 96-hour continuous infusion of drotrecogin alfa (activated) or recombinant humanactivated protein C in the Recombinant Human Activated protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial (101) was associated with a significant reduction in 28-day mortality in patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (assessed by APACHE II score). Eligible patients were randomly assigned to receive a 96-hour intravenous infusion of drotrecogin alfa (activated) at 24 mg/kg/hr (n ¼ 850) or placebo (n ¼ 840). Patients with an APACHE II score 25 who received activated protein C had reduced mortality (31%, RR 0.71, constant interval 0.59–0.85) compared to 44% mortality in the placebo patients, reflecting a 13% absolute mortality difference. This survival advantage in septic patients who were randomized to activated protein C treatment was confirmed to persist for 2.5 years after conclusion of the PROWESS trial. Data from the FDA document an important difference regarding mortality in this study based on whether patients received heparin during their ICU stay. Patients who received heparin (n ¼ 1271) demonstrated only a 3% absolute difference in mortality, whereas nonheparinized patients had a 15% absolute difference in mortality. This

confounding variable will require additional study in all future trials with activated protein C in severe sepsis, and septic shock. PROWESS is the first successful trial of a biological modifying agent in the treatment of severe sepsis, and bleeding is the only notable side effect. A recent study (102) evaluated all available data on the safety of treatment with drotrecogin alfa (activated) in 2786 adult patients with severe sepsis enrolled in all phase II and III clinical trials, and in an estimated 3991 patients receiving the drug in commercial use. Serious bleeding events during the infusion period and 28-day study period occurred in 2.8% (79/2786) and 5.3% (148/2786) of patients, respectively. Of bleeding events during the infusion period, 43% (34/79) were procedure related. Fatal serious bleeding events during the infusion period occurred in 0.4% (12/2786) of cases. Intracranial hemorrhage (ICH) events during the infusion period and 28-day study period occurred in 0.6% (16/2786) and 1.1% (32/2786) of patients, respectively. Ten out of the 16 ICH events occurring during the study drug infusion period were associated with severe thrombocytopenia (< 30,000/ mm3) and/or meningitis. Serious bleeding and ICH events spontaneously reported from commercial use (n ¼ 3991) occurred in 0.9% and 0.2% of patients, respectively. In

medwedi.ru

242

Part One: General Considerations

surgical patients, a careful assessment of risk for bleeding must be completed when considering the use of activated protein C in the treatment of severe sepsis and septic shock. Furthermore, the conduct of invasive procedures in patients receiving activated protein C treatment requires transient discontinuation of the drug infusion. Because of its anticoagulant properties, caution must be exercised with the use of activated protein C in those patients who meet the contraindications for its use or who have risk factors for increased bleeding complications. Two additional analyses of the PROWESS trial (103,104) documented significant improvements in organ function measured by SOFA scores for 28 days, and significantly faster resolution of cardiovascular (P ¼ 0.009) and respiratory (P ¼ 0.009) dysfunction and significantly slower onset of hematologic organ dysfunction (P ¼ 0.041) compared with placebo patients for days 1 to 7. Treatment with activated protein C represents an important advance in the care of selected patients with sepsis, and was associated with more prompt resolution of MODS. However, given the evidence of a variable effect on survival rates in patient subgroups and its acquisition cost, controversy has arisen concerning the appropriate use of activated protein C (105). A recent cost–efficacy analysis (106) documented that drotrecogin alfa (activated) costs $27,400 per quality-adjusted life-year when limited to patients with an APACHE II score >25 and was cost-ineffective when limited to patients with a score < 25. Drotrecogin alfa has a cost-effectiveness profile similar to that of many wellaccepted healthcare strategies, and below commonly quoted thresholds. Therefore the use of activated protein C should be considered early in appropriate patients (APACHE II score >25 and minimal risk for bleeding) with severe sepsis and septic shock.

Hemofiltration in Sepsis Hemofiltration, especially early hemofiltration, has emerged as a therapeutic modality for early renal dysfunction and renal failure in sepsis, acute respiratory distress syndrome (ARDS), multiple organ failure, and patients with severe metabolic abnormalities (107). Newer devices for hemofiltration have made continuous renal replacement therapy very easy. Extracorporeal therapies designed to remove substances from the circulation now include hemodialysis, hemofiltration, hemoadsorption, plasma filtration, cell-based therapies, and combinations of any of the above. In recent years, there have been considerable advances in our understanding and technical capabilities, but consensus over the optimal way and under what conditions to use these therapies does not exist. There is significant controversy regarding whether hemofiltration in septic patients without renal dysfunction or renal failure is associated with any improvement in ultimate outcome (108). One potential mechanism for the efficacy of hemofiltration may be improved hemostatic changes, similar to the mechanism for activated protein C treatment in sepsis. One study in 40 patients with SIRS-associated renal failure documented a significant reduction in PAI type 1 activity in patients receiving continuous renal replacement therapy (109). Hemofiltration induces fibrinolysis, allows clot breakdown, and prevents microthrombosis, similar to the underlying mechanism for activated protein C. Proapoptotic molecules are generated during sepsis, which may be responsible for alteration of organ function in sepsis, and removal of systemic apoptotic activity may

affect recovery from sepsis. These proapoptotic factors can be eliminated by dialytic membranes with the removal rate maximized by using super high-flux dialysers that may represent a compromise between hemofiltration and plasmafiltration membranes (110). Another potential mechanism is related to clearance of inflammatory mediators. Continuous veno-venous hemofiltration with high permeability hemofilters is a novel approach in the adjuvant therapy of septic patients. High-permeability hemofilters are characterized by an increased pore size that facilitates the filtration of inflammatory mediators. A recent study (111) documented that high-permeability hemofiltration restores peripheral blood mononuclear cell proliferation in septic patients probably by eliminating immunomodulatory mediators. This may represent a new renal replacement therapy able to modulate monocyte function in sepsis. Some studies show that hemofiltration may have some beneficial effects in sepsis, such as shortened length of stay (112–114). Yet, the prospective clinical studies investigating hemofiltration in sepsis have been so small that translating them into overall improved survival has been difficult. The ‘‘Acute Dialysis Quality Initiative’’ (115) was established to perform an evidence-based appraisal and set of consensus recommendations to standardize care and direct further research in this area. The results of previous consensus conferences are available online (www.ADQI.net). Three prospective randomized controlled trials of extracorporeal blood therapy for SIRS/Sepsis and not for renal replacement therapy have been conducted. The first was a small multicenter trial of 30 patients randomized to plasmafiltration or conventional treatment (112). Plasmafiltration was performed by hollow fiber plasma filter continuously for 34 hours. This study showed no difference in mortality or organ failure. The concentration of several mediators was decreased. This study was not sufficiently powered to detect clinically important differences. The second study was a small single-center trial of 24 septic patients without renal failure randomized to continuous venovenous hemofiltration (CVVH) (2 L/hr of ultrafiltrate) or conventional treatment. This study showed no effects of CVVH on organ failure, survival, or concentration of several immune mediators (113). This study was not sufficiently powered to detect clinically meaningful differences in survival. Finally, the third trial was a larger single-center trial of 106 patients with severe sepsis/septic shock randomized to conventional treatment or plasmapheresis. In this study, plasmapheresis was performed by intermittent continuous flow centrifugation. This study showed that patients treated with plasmapheresis had a 33.3% mortality, while the control group had a 53.8% mortality (P ¼ 0.049 Fisher’s exact test) (114). Together with the existing literature, these three studies suggest that CVVH at 2 L/hr may not be useful in SIRS/Sepsis in the absence of acute renal failure, but the studies had insufficient sample size. The studies of plasmapheresis in SIRS/Sepsis have so far been inconsistent in their findings, making evaluation difficult. However, it remains possible that plasmapheresis might offer a clinical benefit, and larger multicenter studies of this modality of extracorporeal blood treatment in SIRS/Sepsis should be considered. The consensus recommendation of the ADQI group was that in SIRS/Sepsis without acute renal failure, standard-dose continuous renal replacement therapy is unlikely to provide benefit over standard therapy and is a poor candidate for future studies. Other methods of

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

extracorporeal blood treatment including high-volume hemofiltration, plasma therapies, and hemoadsorption are perhaps more promising but relatively untested, and they should undergo further study. Plasma therapies should be further explored to determine the importance of such technical aspects as plasmafiltration versus centrifugation, continuous versus intermittent therapy, timing, intensity, and type of replacement fluid. The existing preliminary data are sufficiently strong to recommend further investigation in the treatment of SIRS/Sepsis in appropriately designed and powered prospective randomized clinical trials.

Failed Strategies for the Treatment of Sepsis There is no question that excessive production of inflammatory mediators during invasive infection plays a key role in the pathogenesis of septic shock. However, novel therapies directed at modifying the inflammatory response in severe sepsis and septic shock have, up to now, not proven beneficial (17,116,117). Drotrecogin alfa (activated), activated protein C, is the first biological modifier that has been shown, in a phase III randomized controlled trial, to be of benefit in the treatment of severe sepsis. However, novel treatments have so far failed to live up to the expectations following extensive and promising in vitro and in vivo

243

animal studies, and following promising phase I and II clinical trials. Natanson et al. (17) carefully scrutinized the results of 21 nonglucocorticoid mediator-specific anti-inflammatory agents in sepsis and septic shock (Fig. 7). The combined results of all 21 of these sepsis trials demonstrated consistent, small, statistically significant beneficial effect (OR, 1.11, 95% constant interval, 1.02–1.20, P ¼ 0.02). Further examination of only the double-blind trials (n ¼ 16), which theoretically have less potential for bias than single-blind studies (n ¼ 5), documented the same small but significant beneficial effect (OR, 1.11; 95% constant interval, 1.01–1.21, P ¼ 0.02). Also important to realize, however, is that significant differences in mortality rates were identified in the control arms of these sepsis trials (Fig. 1). The reasons for these significant differences in 28-day all-cause mortality rates of septic patients must be carefully scrutinized. A recent metaregression analysis (118,119) of these preclinical and clinical trials in combination with prospective confirmatory studies demonstrated that risk of death as assessed by control group mortality rate significantly altered the treatment effect of these agents in both humans and animals. While anti-inflammatory agents were very beneficial in groups with high control mortality rates, they were ineffective or harmful in groups with low control

Number of Patients Enrolled 500 1000 1500 2000 Control

Therapy/Type of agent

Treated

Odds Ratio

BAY x 1351/TNF-MAb

P-55/sTNFr BAY x 1351/TNF-MAb Antril/IL-1ra Antril/IL-1ra Odds Ratio BN52021/PAFra

Clinical Trial

BAY x 1351/TNF-MAb CPO-127/Anti-Bradykinin

95% Confidence Interval

P-55/s TNFr Ibuprofen/Anti-Prostaglandin MAK 195FTNF-MAb BN 52021/PAFra CPO-127/Anti-Bradykinin P-80/s TNFr MAK 195F/TNF-MAb Antril/IL-1ra CB0006/TNF-MAb CDP571/TNF-MAb MAK 195F/TNF-MAb Ibuproten/Anti-Prostaglandin Ibuprofen/ Anti-Prostaglandin

0.125 0.25 0.5 0.67 1 0.5 2.0 4.0 8.0 Increasing Harm Increasing Benefit No Effect Odds Ratio

medwedi.ru

Figure 7 Survival odds ratios and 95% confidence intervals for 21 clinical trials of nonglucocorticoid mediator– specific anti-inflammatory agents. The 21 trials are ranked in order by the total number of patients enrolled. The larger clinical trials enrolling >250 patients had similar small beneficial effects. The smaller trials enrolling 250 patients were equally likely to show beneficial or harmful trends. The results of these smaller trials are not inconsistent with the larger trials, as can be seen by the overlap of the 95% confidence intervals. Rather, the estimate of the drug’s treated effect in smaller trials is less accurate because of sampling error. Two of these trials had treatment effects at specific doses of the agents used that were significant outliers (P ¼ 0.016, data not shown). The p-80 sTNFr in high and medium doses and the P-55 sTNF in very low doses produced harmful effects (combined, P ¼ 0.009). Excluding patients treated with the high and medium doses of the P-80 sTNFr and very low doses of the P-55 sTNFr (the groups that constitute significant outliers) results in a small, but even more significant, increase in the odds of surviving for patients treated with mediator–specific anti-inflammatory therapies. Abbreviations: IL-1ra, interleukin-1 receptor antagonist; PAFra, platelet-activating factor receptor antagonist; sTNFr, soluble tumor necrosis factor receptor. Source: From Ref. 17.

244

Part One: General Considerations

mortality rates. Thus, variation in the risk of death due to sepsis provides a basis for the marked difference in the efficacy of these anti-inflammatory agents in preclinical and clinical trials over the last decade. In contrast to mediatorspecific anti-inflammatory agents, glucocorticoids and activated protein C have recently demonstrated significant beneficial effects in individual clinical trials. However, glucocorticoids were studied only in patients with vasopressor-dependent septic shock, which is associated with a high control mortality rate (i.e., 61%) similar to the level at which mediator-specific agents would have been expected to be markedly beneficial. Furthermore, consistent with earlier findings for mediator-specific anti-inflammatory agents, analysis of the activated protein C study also demonstrated a relationship between risk of death and effect of treatment. Developing better methods to define high-risk septic populations for treatment with anti-inflammatory agents will increase the efficacy of this therapeutic approach and minimize its potential for harm. Similar to the anti-inflammatory studies in sepsis, anticoagulant therapies have produced mixed results regarding efficacy (improved survival) in sepsis. Once again, it is clear that coagulation abnormalities are in part responsible for the physiologic derangements of the sepsis syndrome. A metaanalysis (120) of clinical trials of anticoagulants in sepsis was recently performed and included 11 studies that satisfied the inclusion criteria. Collectively, these studies enrolled 4690 patients (range of 29–2314) and examined three agents: antithrombin III (2659 patients), tissue factor pathway inhibitor (210 patients), and activated protein C (1821 patients). The OR (with 95% CI) for effect on mortality for these agents, relative to control treatment, was 0.8692 (0.7519–1.006). Weighted linear regression analysis was consistent with a control group mortality–dependent effect for these agents (P ¼ 0.02). Only five of the studies reported bleeding complications. Pooling the results of these five studies (4376 patients) resulted in an OR (with 95% CI) of 1.70 (1.40–2.07) relative to control treatment for bleeding risk. This meta-analysis concluded that anticoagulants as adjuvant therapy do not appear to improve outcome in sepsis and are associated with a significant risk of bleeding complications. As stated above for anti-inflammatory strategies, treatment effect of the anticoagulant therapies was dependent upon disease severity, suggesting that the safety and efficacy of these agents may be enhanced by refinement in techniques of clinical stratification. Another confounding variable in the design of sepsis trials is lack of control of basic treatment strategies in sepsis, such as adequate source control, adequate early aggressive fluid resuscitation, and adequate systemic antibiotic therapy. It is common knowledge that in many of the sepsis trials, patients were treated with inappropriate antibiotics with initial empiric therapy based on subsequent culture results, and these patients had worse outcome. These uncontrolled variables may have obscured the potential efficacy of the numerous immunomodulatory strategies tested in severe sepsis and septic shock. By standardizing protocols and reducing these uncontrolled variables, research in septic shock can be more precisely targeted and evaluated in improving patient outcomes (121). Additional recent prospective randomized controlled studies in severe sepsis and septic shock have documented the lack of efficacy of tissue factor pathway inhibitor (122) and antienterobacteriaceae monoclonal antibody (123). The use of the nonselective nitric oxide inhibitor (NG-methylL-arginine hydrochloride) in septic shock was associated

with increased 28-day mortality (59% vs. 49%, P < 0.001), due to a higher portion of cardiovascular deaths, despite a lower incidence of deaths caused by multiple organ failure (124). A number of different strategies are currently being investigated in preclinical and early clinical trials for the treatment of patients with sepsis and septic shock. These can be broadly divided into three groups: strategies aimed at bacterial targets, strategies aimed at disorders of immune regulation in the host, and, finally, other novel strategies based on modifying host response (125). Which, if any, of these will prove successful in large clinical trials is unknown. Nevertheless, changes in trial design and improved methodology to focus on septic patients at high risk of death, and control of the many confounding variables identified in prior studies should result in more meaningful and positive results for the future.

MULTIPLE ORGAN DYSFUNCTION AND FAILURE: DEFINITIONS Advances in intensive care have allowed many critically ill patients to survive their initial insult. These patients may later demonstrate multiple organ dysfunction and failure, the genesis of which appears to be the body’s reaction to critical illness, manifested by an imbalance and failure of inflammatory and immune system homeostasis. The manifestation of multiple organ dysfunction syndrome in the critically ill has been termed MODS. MODS mortality is high and remains a leading cause of death in ICUs. The understanding of the pathophysiology of severe sepsis and MODS has moved from a focus on inflammation to include an understanding of the associated anti-inflammatory responses. Loss of homeostasis can manifest as malignant inflammation or immune paralysis. Increased emphasis is emerging on the role of loss of immune homeostasis and disordered coagulation as a cause of organ injury and dysfunction. MODS is a common but poorly understood complication of critical illness (126–128). MODS is associated with significant morbidity and mortality in critical illness and trauma and is commonly associated with nosocomial infectious complications. About half of the patients who succumb to septic shock die of multiple organ system failure (129). A MODS severity score is useful to standardize reports in order to improve the understanding of the course of disease. Furthermore, the MODS scoring systems allow scientific evaluation of the impact of new treatments on outcome, including organ failure. Two severity scores are commonly utilized for MODS, including the Marshall MODS score (Table 5) (128), and the Sequential Organ Failure Assessment (SOFA) score (Table 6) (130).

INCIDENCE AND OUTCOME OF MODS Critically ill patients who develop MODS (one or more organ system failures) have increased mortality compared to critically ill patients without MODS. This has been documented for medical, surgical, and trauma critically ill patients. A number of studies have identified, however, that there has been a significant improvement in survival in patients with MODS over the last three decades (131,132). An early, large prospective, multicenter inception cohort study of 60 ICUs in the United States, including over 20,000 ICU patients, compared the outcomes for patients with one or more organ system failures treated in 1988 to 1990 with those outcomes from 1979 to 1982, documented

245

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

Table 5 The MODS Score (Marshall MODS Score) MODS score Variables Respiratory: PaO2/FiO2 ratio Renal: Serum creatinine Hepatic: Serum bilirubin Cardiovascular: Pulse-adjusted HR Hematologic: Platelet count Neurologic: Glasgow coma score

0

1

2

3

4

>300 100 20 10.0

226–300 101–200 21–60 10.1–15.0

151–225 210–350 61–120 15.1–20.0

76–150 351–500 121–240 20.1–30.0

75 >500 >240 >30.0

>120 15

81–120 13–14

51–80 10–12

21–50 7–9

20 6

PaO2/FiO2 ratio is calculated with reference to the use or mode of mechanical ventilation, and without reference to the use or level of positive end-expiratory pressure. The serum creatinine concentration is measured in mmol/L, without reference to the use of dialysis. The serum bilirubin concentration is measured in mmol/L. The PAR is calculated as the product of the HR multiplied by the ratio of the RAP to the MAP: PAR ¼ HR RAP/MAP. The platelet count is measured in platelets/mL 10-3. The Glasgow Coma Score is preferably calculated by the patient’s nurse, and is scored conservatively (for the patient receiving sedation or muscle relaxants, normal function is assumed, unless there is evidence of intrinsically altered mentation). Abbreviations: PAR, pressure-adjusted heart rate; HR, heart rate; RAP, right atrial (central venous) pressure; MAP, mean arterial pressure; MODS, multiple organ dysfunction syndrome. Source: From Ref. 128.

patients in ICUs. The incidence and overall outcome did not significantly change over the eight-year study period, but there was a significant improvement in survival for patients with persistent severe organ system failure. A recent study (132) examined the current incidence and mortality of organ failure in a homogenous population of critically ill trauma patients (n ¼ 869). All trauma patients admitted to the ICU at an urban Level I trauma center were prospectively studied. Patients were evaluated for the presence of organ failure using initial definitions proposed by Knaus and co-workers (131) and by Fry et al. (133). Newer definitions of organ failure incorporating organ dysfunction and severity-of-illness scores were also obtained in all patients in an attempt to predict outcome. These included lung injury scores (acute respiratory distress syndrome scores), APACHE II and III scores, injury severity score (ISS), and multiple organ dysfunction scores. Single organ failure occurred in 163 patients (18.7%) and multiple organ failure occurred in 44 patients (5.1%). All single organ failure was caused by respiratory failure. Respiratory failure

risk factors for developing organ system failure, and investigated the relationship of these factors to hospital survival (131). The incidence of organ system failure (48%) among patients treated in 1988 to 1990 was similar (44%) to the occurrence rate in patients in 1979 to 1982; and an identical proportion (14%) developed multiple organ system failure. There was a significant (P< 0.0003) improvement in hospital mortality for patients with three or more organ system failures on day 4 or later of organ system failure. However, overall hospital mortality rates from multiple organ system failure were not different over this eight-year period. The most important predictor of hospital mortality was the severity of physiologic disturbance on the initial day of failure. Discrimination of patients by risk of hospital mortality was better using the prognostic scoring system on day 1 of organ system failure (receiver operating characteristic curve ¼ 0.88) than using a model based on the number of organ system failures (receiver operating characteristic curve ¼ 0.68). This pivotal study documented that organ system failure remains a major contributor to death in

Table 6 The SOFA Score SOFA score Variables Respiration: PaO2/FiO2 Coagulation: Platelets, 103/mL Liver: Bilirubin mg/dL mmol/L Cardiovascular: Hypotension

CNS: Glasgow coma score Renal: Creatinine Mg/dL mmol

1

2

3

4 a

<100a <20

<400 <150

300 <100

<200 <50

1.2–1.9 20–32 MAP < 70b

2.0–5.9 33–101 Dopamine 5, or doubtamine any dosec

13–14

10–12

6.0–11.9 102–204 Dopamine >5, or epinephrine 0.1, or norepinephrine 0.1c 6–9

>12.0 >204 Dopamine >15, or epinephrine >0.1, or norepinephrine >0.1c <6

1.2–1.9 110–170

2.0–3.4 171–299

3.5–4.9 300–440

>5 >440

a

With respiratory support. MAP. c Adrenergic agents administered for at least 1 hr (dosages are in mg/kg/min). Abbreviations: SOFA, Sequential Organ Failure Assessment; CNS, central nervous system; MAP, mean arterial pressure. b

medwedi.ru

246

Part One: General Considerations

occurred first in the majority of patients with multiple organ failure. Mortality was 4.3% with one organ system failure, 32% with two, 67% with three, and 90% when four organ systems failed. None of the patients with single organ failure died secondary to respiratory failure. Multiple stepwise regression analysis confirmed that APACHE III, lactate at 24 hours, and total blood products transfused in 24 hours were associated with the occurrence of organ failure. The overall incidence of organ failure in a homogeneous trauma population appears to be lower than that reported in studies performed in heterogeneous patient populations in the 1980s. Mortality for single organ failure is low and appears to be related primarily to the patient’s underlying injuries and not to organ failure. Mortality for two or three organ system failures is lower than reported 15 to 20 years ago. Mortality for patients with four or more organ system failures remains high, approaching 100%. The incidence and outcome of acute respiratory failure (ARF), the most common early organ failure, is dependent on dysfunction in other organs. This was confirmed in a recent study of 832 patients, of which 529 (63%) had ARF (134). The ICU, hospital, and three-month mortality rates were lowest in single organ acute respiratory failure (3.2, 14.7, and 21.8%, respectively), with increasing mortality with each additional organ failure. When ARF occurred with four or five additional organ failures, the three-month mortality rate was 75%. This study clearly documented that the prognosis for ICU patients with single organ ARF is good, both in the short and long term, but the high overall mortality rate observed is caused by dysfunction in other organs. Another study documented that organ dysfunction was an independent risk factor for increased mortality related to acute lung injury or acute respiratory distress syndrome (135). A recent longitudinal analysis of MODS in surgical ICU patients (n ¼ 938) documented that 54% of patients developed some degree of MODS during their ICU stay (136). The most common risk factor for the development of MODS was hypoperfusion/ischemia without shock, although sepsis and shock were also notable risk factors. The Marshall MODS score was utilized to assess risk for mortality in this cohort of patients, and the area under the receiver operating characteristic curve was 0.95, reflecting nearly perfect discrimination. MODS is also associated with increased ICU length of stay, and thus has an important impact on resource utilization.

PATHOPHYSIOLOGY OF MODS MODS is thought to be caused by an overwhelming, uncontrolled systemic inflammatory response that is activated by a number of hostile stimuli including infection, sepsis, shock, and trauma (137). The indiscriminate activation of the inflammatory response due to these insults causes loss of the host’s ability to localize the inflammation to the focus of the problem, leading to systemic inflammation and severe host tissue damage. Neutrophils, macrophages, endotoxin, cytokines, and oxidants can all play a role in this inflammatory response. Cellular dysfunction in MODS is the final outcome of a process with multiple stimuli. Prominent mechanisms include cellular ischemia, disruption of cellular metabolism by the effects of inflammatory mediators, and toxic effects of free radicals. Additionally, as discussed earlier in the pathophysiology of sepsis, apoptosis (programmed cell death) may play a major role in MODS. Organs from patients who died from

sepsis-induced MODS had extensive evidence of apoptosis (29). Furthermore, apoptosis of lymphocytes and intestinal epithelial cells was detected more often in septic patients that in nonseptic controls. Activation of caspases and induction of heat shock proteins may lead to apoptotic cell death in patients with MODS. This accelerated cell death was associated with marked depletion of lymphocyte populations in spleens and samples of peripheral blood. Likewise, trauma complicated by shock also increased apoptosis in intestinal epithelial cells and lymphocytes (138). It has also been suggested that the gut plays a significant role in the development of MODS (139). The role of the gut may be an indirect one. It may be that the oxidants generated during gut ischemia-reperfusion injury rather than the bacteria actually serve as priming molecules for the subsequent inflammatory response. It has been documented that oxidants generated in the gut are able to induce translocation of the transcription factor NF-kB into the nucleus in distant organs initiating cytokine expression and subsequent neutrophil chemotaxis and damage to those organs. Furthermore, proinflammatory molecules from the gastrointestinal tract may reach the circulation through the mesenteric lymph. Resuscitation strategies to maintain the gastrointestinal mucosal barrier and minimize the effects of gut-derived mediator injury (such as early enteral nutritional support and antioxidant administration) may be critically important for the reduction of MODS. Mechanisms by which sepsis induces organ dysfunction have not been fully elucidated. The coexisting findings of metabolic acidosis, yet increased tissue oxygen tensions that are unique to sepsis, suggest cellular availability but decreased use of oxygen, i.e., tissue dysoxia. Because mitochondria use more than 90% of total body oxygen consumption for adenosine triphosphate (ATP) generation, a bioenergetic abnormality is implied. Cell and animal data have shown that nitric oxide (and its metabolites), produced in considerable excess in patients with sepsis, can affect oxidative phosphorylation by inhibiting several of its component respiratory enzymes. Human data are scarce. However, in skeletal muscle biopsies taken from patients with sepsis, a relationship between increased nitric oxide production, antioxidant depletion, reduced respiratory chain complex I activity, and low ATP levels was recently demonstrated (140). These findings correlated with severity of disease and outcome and support the notion that mitochondrial dysfunction resulting in bioenergetic failure may be an important factor in the pathophysiology of sepsisassociated multiorgan failure. However, a reasonable argument can be made that the reduction in energy supply could represent a last-ditch adaptive response to ongoing inflammation, resulting in a cellular shutdown analogous to hibernation that allows eventual restoration of organ function and long-term survival in patients fit enough to survive the acute phase.

POTENTIAL TREATMENT STRATEGIES FOR REDUCTION OF MODS A number of the treatment strategies, focused on reducing septic complications, will also be effective in reducing MODS. For instance, intensive glycemic control (discussed above) was associated with a significant reduction in MODS related to a septic etiology. Additional specific treatment strategies that can be considered for risk reduction in MODS in trauma and sepsis include the following.

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure

Early Enteral Nutrition and Immunonutrition Multiple studies have confirmed that the administration of early enteral nutrition in trauma is associated with improved outcome (141,142). Furthermore, clinical evidence suggests that enteral feeding supplemented with specific immunonutrients (glutamine, arginine, omega-3 polyunsaturated fatty acids, or nucleotides) further improves clinical outcome in trauma (143,144). Several clinical studies in trauma patients with significant injury (ISS >20, abdominal trauma index >25) show reduced septic complications, significant reduction in MODS, and reduced resource utilization in patients randomized to the immune-enhancing diets. One comprehensive review of clinical studies of immune-enhancing diets concluded that immune-enhancing enteral formulas should be used in all patients sustaining major torso trauma. Future studies need to determine potential differences among the commercially available specialized immunonutrient enteral formulas and the optimal duration of these immuneenhancing diets in trauma patients. The efficacy of these specialized formulas in reducing MODS in other critically ill patients will require additional investigation.

Antioxidant Supplementation (a-Tocopherol and Ascorbate) A recent prospective randomized study compared outcomes in patients receiving early antioxidant supplementation versus those receiving standard care, with a cohort of 595 patients, 91% of whom were trauma victims (145). The treatment regimen included a-tocopherol [Aquasol-E 1000IU q8h via nasogastric tube (NGT)] and ascorbate (1000 mg IV in 100 mL D5W q8h) for the shorter duration of ICU stay or 28 days. Patients randomized to antioxidant supplementation had significantly decreased risk for pulmonary morbidity, including ARDS and pneumonia (RR 0.81, CI 0.60–1.1) and multiple organ failure (RR 0.43, CI 0.19–0.96). Patients randomized to antioxidant supplementation also had a shorter duration of mechanical ventilation and length of ICU stay. This important study documented that the early administration of antioxidant supplementation reduced the incidence of organ failure and shortened ICU length of stay in a cohort of critically ill surgical patients. Significant limitations of this study included lack of a placebo and lack of investigator blinding. Additional studies in this important area of investigation are warranted.

Reduction in Allogeneic Blood Transfusion Numerous studies have documented an association between blood transfusion and risk for infection, SIRS, MODS, and worse outcome after traumatic injury and in critical illness (146–149). Furthermore, two recent large prospective studies have documented the high use of blood transfusion in critically ill patients, including the Anemia and Blood Transfusion in Critical Care (ABC) trial in Western Europe (150) and the Anemia and Blood Transfusion in the Critically III (CRIT) study in the United States (151). The ABC Trial included 3534 patients from 146 western European ICUs. The mean hemoglobin concentration at ICU admission was 11.3 2.3 g/dL, with 29% of patients having a concentration of less than 10 g/dL. The transfusion rate during the ICU period for the entire cohort was 37.0% (1307/3534). Patients admitted for emergency surgery were transfused more frequently (57.5%), followed by those admitted for trauma (48%), elective surgery (42.1%), and medical reasons (32%). Older patients and those with a longer ICU length of stay were more commonly transfused.

247

In patients with an ICU length of stay of >7 days, 73% received a blood transfusion. The overall mean pretransfusion hemoglobin was 8.4 þ 1.3 g/dL in this European study. Both ICU and overall mortality rates were significantly higher in patients who were transfused. This large epidemiologic study provided evidence of an association between blood transfusions and diminished organ function as well as between transfusions and mortality. A similar prospective, multicenter, observational, cohort study in the United States, the CRIT Study, enrolled 4892 patients from 284 ICUs (151). The goal of the CRIT Study was to quantify the incidence of anemia and RBC transfusion practice in critically ill patients and to examine the relationship of anemia and RBC transfusion to clinical outcomes. Mean baseline hemoglobin concentration on admission to the ICU was 11.0 2.4 g/dL, and mean hemoglobin decreased to 9.8þ1.4 g/dL by the end of the study (P< 0.0045). A large percentage (44%) of patients were transfused (mean 4.6 þ 4.9 units) during their ICU stay. Patients with an ICU length of stay of > 7 days were more commonly transfused (63.0%) compared with patients with ICU length of stay < 7 days (33.4%, P< 0.0001). Mean pretransfusion hemoglobin was 8.6 þ 1.7 g/dL in this U.S. study. The number of RBC transfusions a patient received during the study was independently associated with longer ICU and hospital lengths of stay and an increase in mortality. A large prospective, multicenter trial (Transfusion Requirements in Critical Care Trial, TRICC) by the Canadian Critical Care Trials Group (152) documented that a restrictive transfusion strategy (hemoglobin maintained between 7 and 9 g/dL) was as effective as a liberal transfusion strategy (hemoglobin maintained between 10 and 12 g/dL). In this trial, 838 critically ill patients were randomized to a restrictive or liberal transfusion strategy. Although the 30-day mortality rates were similar in the two groups, the hospital mortality rate was significantly lower in the restrictive-strategy group (22.3% vs. 28.1%, P ¼ 0.05). Mortality rates were also significantly lower with the restrictive transfusion strategy among patients who were less acutely ill (APACHE II score of < 20, 8.7% in restrictive group vs. 16.1% in liberal group; P ¼ 0.03) and among patients who were less than 55 years of age (5.7% vs. 13.0%, respectively; P ¼ 0.02). This study documented that a restrictive strategy of RBC transfusion in critically ill patients was at least as effective as and possibly superior to a liberal transfusion strategy, with the possible exception of patients with acute myocardial infarction and unstable angina. Efforts to reduce blood transfusion rates in the ICU are warranted, and blood transfusion should be reserved for physiologic indications. Alternatives to allogeneic blood transfusion are currently under preclinical and clinical investigation. These include the use of the new generation of hemoglobin-based oxygen carriers (153) from both human and bovine source and recombinant human hemoglobin expressed in E. coli for treatment of acute blood loss and the use of recombinant human erythropoietin for the treatment of ICU-acquired anemia (154).

SUMMARY Sepsis and the multiple organ failure that often results there from is frequently the cause of death in critically ill and severely injured patients. With increasing understanding of the linkage between these two events and the pathogens and mediators responsible for this relationship, strategies have evolved that have favorly impacted the lethal outcome as commonly observed in the past in patients developing

medwedi.ru

248

Part One: General Considerations

sepsis. The foregoing chapter has attempted to provide stateof-the-art knowledge concerning the evolution of sepsis into organ failure and contemporary management to decrease the associated morbidity and all too frequent mortality.

REFERENCES 1. Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians-Society of Critical Care Medicine consensus conference: definitions for sepsis and organ failure and guidelines for use of innovative therapies in sepsis. Chest 1992; 101: 1644–1655. 2. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864–874. 3. Opal SM. Severe sepsis and septic shock: defining the clinical problem. Scand J Infect Dis 2003; 35(9):529–534. 4. Ramsay G, Gerlach H, Levy MM, et al. An International Sepsis Survey: a study of doctors’ knowledge and perception about sepsis. Crit Care Med 2003; 31. 5. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250–1256. 6. Marshall JC, Vincent JL, Fink MP, et al. Measures, markers and mediators: toward a staging system for clinical sepsis. A report of the fifth Toronto sepsis roundtable, Toronto, Ontario, Canada, October 25–26, 2000. Crit Care Med 2003; 31(5):1560–1567. 7. Gattas DJ, Cook DJ. Procalcitonin as a diagnostic test for sepsis: health technology assessment in the ICU. J Crit Care 2003; 18(1):52–58. 8. Reny JL, Vuagnat A, Ract C, Benoit MO, Safar M, Fagon JY. Diagnosis and follow-up of infections in intensive care patients: value of C-reactive protein compared with other clinical and biological variables. Crit Care Med 2002; 30(3): 529–535. 9. Lobo SM, Lobo FR, Bota DP, et al. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 2003; 123(6):2043–2049. 10. Peres Bota D, Melot C, Lopes Ferreira F, Vincent JL. Infection Probability Score (IPS): a method to help assess the probability of infection in critically ill patients. Crit Care Med 2003; 31(11):2579–2584. 11. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29(7):1303–1310. 12. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. Academic Medical Center Consortium Sepsis Project Working Group. JAMA 1997; 278(3):234–240. 13. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997; 25(7):1095–1100. 14. Anderson RN, Smith BL. Deaths: leading causes for 2001. Natl Vital Stat Rep 2003; 52(9):1–85. 15. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995; 274(12): 968–974. 16. Natanson C. Re-evaluation of anti-inflammatory trials in sepsis: a meta-analysis. In: Cytokines and Pulmonary Infection: Part II: The Role of Cytokines in Systemic and Pulmonary Medicine. Continuing Education Monograph Series. Chicago: American Thoracic Society, 1997:7–18. 17. Natanson C, Esposito CJ, Banks SM. The sirens’ song of confirmatory sepsis trials: selection bias and sampling error editorial. Crit Care Med 1998; 26:1927–1931.

18. Weycker D, Akhras KS, Edelsberg J, Angus DC, Oster G. Long-term mortality and medical care charges in patients with severe sepsis. Crit Care Med 2003; 31(9):2316–2323. 19. http://www.cms.hhs.gov/manuals/pm_trans/AB02085.pdf. 20. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348(2):138–150. 21. Lederer JA, Rodrick ML, Mannick JA. The effects of injury on the adaptive immune response. Shock 1999; 11:153–159. 22. O’Sullivan ST, Lederer JA, Horgan AF, Chin DHL, Mannick JA, Rodrick ML. Major injury leads to predominance of the T-helper-2 lymphocyte phenotype and diminished interleukin-12 production associated with decreased resistance to infection. Ann Surg 1995; 222:482–492. 23. Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndrome: understanding the role of innate and acquired immunity. Shock 2001; 16(2):83–96. 24. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest 2000; 117:1162–1172. 25. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro-versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 2000; 181:176–180. 26. Feezor RJ, Oberholzer C, Baker HV, et al. Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. Infect Immun 2003; 71(10):5803–5813. 27. Hotchkiss RS, Tinsley KW, Karl IE. Role of apoptotic cell death in sepsis. Scand J Infect Dis 2003; 35(9):585–592. 28. Power C, Fanning N, Redmond HP. Cellular apoptosis and organ injury in sepsis: a review. Shock 2002; 18(3):197–211. 29. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock and multiple organ dysfunction. Crit Care Med 1999; 27:1230–1251. 30. Tinsley KW, Grayson MH, Swanson PE, et al. Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. J Immunol 2003; 171(2):909–914. 31. Hotchkiss RS, Swanson PE, Knudson CM, et al. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 1999; 162:4148–4156. 32. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci USA 1999; 96:14,541–14,546. 33. Tabrizi AR, Zehnbauer BA, Freeman BD, Buchman TG. Genetic markers in sepsis. J Am Coll Surg 2001; 192(1): 106–117. 34. Kellum JA, Angus DC. Genetic variation and risk of sepsis. Minerva Anestesiol 2003; 69(4):245–253. 35. Holmes CL, Russell JA, Walley KR. Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. Chest 2003; 124(3):1103–1115. 36. Wuhderink RG, Waterer GW. Genetics of sepsis and pneumonia. Curr Opin Crit Care 2003; 9(5):384–389. 37. O’Keefe GE, Hybki DL, Munford RS. The G – > A single nucleotide polymorphism at the 308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after trauma. J Trauma 2002; 52(5):817–825; discussion 825–826. 38. Schroder J, Kahlke V, Book M, Stuber F. Gender differences in sepsis: genetically determined? Shock 2000; 14(3):307–310; discussion 310–313. 39. Ma P, Chen D, Pan J, Du B. Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients. Crit Care Med 2002; 30(5):1046–1050. 40. Lowe PR, Galley HF, Abdel-Fattah A, Webster NR. Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients. Crit Care Med 2003; 31(1):34–38. 41. Schaaf BM, Boehmke F, Esnaashari H, et al. Pneumococcal septic shock is associated with the interleukin-10–1082 gene promoter polymorphism. Am J Respir Crit Care Med 2003; 168(4):476–480 (Epub 2003 May 13).

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure 42. Marshall JC, Innes M. Intensive care unit management of intraabdominal infection. Crit Care Med 2003; 31(8):2228–2237. 43. Danielson D, West MA. Recent developments in clinical management of surgical sepsis. Curr Opin Crit Care 2001; 7(5): 367–370. 44. Bohnen JM, Marshall JC, Fry DE, Johnson SB, Solomkin JS. Clinical and scientific importance of source control in abdominal infections: summary of a symposium. Can J Surg 1999; 42(2):122–126. 45. Jimenez MF, Marshall JC. International Sepsis Forum. Source control in the management of sepsis. Intensive Care Med 2001; 27(suppl 1):S49–S62. 46. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000; 118:146–155. 47. Leibovici L, Shraga I, Driucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infections. J Intern Med 1998; 244:379–386. 48. Kollef MH. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999; 115:462–474. 49. Dupont H, Mentec H, Sollet JP, Bleichner G. Impact of appropriateness of initial antibiotic therapy on the outcome of ventilator-associated pneumonia. Intensive Care Med 2001; 27:355–362. 50. Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis 2000; 31(suppl 4):S131–S138. 51. MacArthur RD, Miller M, Albertson T, et al. Adequacy of early empiric antibiotic treatment and survival in severe sepsis: experience from the MONARCS Trial. Clin Infect Dis 2004; 38(2):284–288 (Epub 2003 Dec 22). 52. Leone M, Bourgoin A, Cambon S, Dubuc M, Albanese J, Martin C. Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome. Crit Care Med 2003; 31(2):462–467. 53. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31(12):2742–2751. 54. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 2003; 115(7):529–535. 55. Turnidge J. Impact of antibiotic resistance on the treatment of sepsis. Scand J Infect Dis 2003; 35(9):677–682. 56. Hollenberg SM, Ahrens TS, Astiz ME, et al. ACCM-SCCM practice parameters for hemodynamic support of sepsis in adult patients. Crit Care Med 1999; 27:639–660. 57. Martin C, Papazian L, Perrin G, Saux P, Gouin F. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103(6):1826–1831. 58. De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Crit Care Med 2003; 31(6):1659–1667. 59. Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984; 100(4):483–490. 60. Micek ST, Shah RA, Kollef MH. Management of severe sepsis: integration of multiple pharmacolotic interventions. Pharmacotherapy 23(11):1486–1496, 2003. 61. Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345(19):1368–1377. 62. Natanson C, Banner RL. Early goal-directed therapy reduced mortality and multiorgan dysfunction in severe sepsis or septic shock. ACP J Club 2002; 136(3):90.

249

63. Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den Berghe G. Reducing mortality in sepsis: new directions. Crit Care 2002; 6(suppl 3):S1–S18 (Epub 2002 Dec 05). 64. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003; 31(1):141–145. 65. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003; 348(8):727–734. 66. Bollaert PE, Fieux F, Charpentier C, Levy B. Baseline cortisol levels, cortisol response to corticotropin, and prognosis in late septic shock. Shock 2003; 19(1):13–15. 67. Chadda K, Annane D. The use of corticosteroids in severe sepsis and acute respiratory distress syndrome. Ann Med 2002; 34(7–8):582–589. 68. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862–971. 69. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998; 26(4):645–650. 70. Annane D. Sepsis clinical knowledge: a role of steroid treatment. Minerva Anestesiol 2003; 69(4):254–257. 71. Annane D, Cavaillon JM. Corticosteroids in sepsis: from bench to bedside? Shock 2003; 20(3):197–207. 72. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Eng J Med 2001; 345:1359–1367. 73. Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003; 31:359–366. 74. Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA 2003; 290(15):2041–2047. 75. Gore DC, Chinkes D, Heggers J, Herndon DN, Wolf SE, Desai M. Association of hyperglycemia with increased mortality after severe burn injury. J Trauma 2001; 51(3):540–544. 76. Walia S, Sutcliffe AJ. The relationship between blood glucose, mean arterial pressure and outcome after severe head injury: an observational study. Injury 2002; 33(4):339–344. 77. Andersen SK, Gjedsted J, Christiansen C, Tonnesen E. The roles of insulin and hyperglycemia in sepsis pathogenesis. J Leukoc Biol 2003 (Epub ahead of print). 78. Mesotten D, Swinnen JV, Vanderhoydonc F, Wouters PJ, Van den Berghe G. Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy. J Clin Endocrinol Metab 2004; 89(1):219–226. 79. Yu WK, Li WQ, Li N, Li JS. Influence of acute hyperglycemia in human sepsis on inflammatory cytokine and counterregulatory hormone concentrations. World J Gastroenterol 2003; 9(8):1824–1827. 80. Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 2003; 88(3):1082–1088. 81. Krogh-Madsen R, Moller K, Dela F, Kronborg G, Jauffred S, Pedersen BK. Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-alpha and free fatty acids to low-dose endotoxemia in humans. Am J Physiol Endocrinol Metab 2004 (Epub ahead of print). 82. Gao F, Gao E, Yue TL, et al. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemiareperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 2002; 105: 1497–1502. 83. Jonassen AK, Brar BK, Mjos OD, Sack MN, Latchman DS, Yellon DM. Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism. J Mol Cell Cardiol 2000; 32(5):757–764. 84. Hiromura K, Monkawa T, Petennann AT, Durvasula RV, Shankland SJ. Insulin is a potent survival factor in mesangial cells: role of the PB-kinase/Akt pathway. Kidney Int 2002; 61(4):1312–1321.

medwedi.ru

250

Part One: General Considerations

85. Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Crit Care Rev Chest 2001; 120:989–1002. 86. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122–1125. 87. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997; 25:1279–1282. 88. Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31(6):1752–1758. 89. Malay MB, Ashton RC Jr, Landry DW, et al. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999; 47:699–703. 90. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 2001; 27:1416–1421. 91. Dunser M, Luckner G, Mayr A, et al. The effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: a retrospective analysis. Anesth Analg 2001; 93:7–13. 92. Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002; 96: 576–582. 93. Klinzing S, Simon M, Reinhart K, Bredle DL, Meier-Hellmann A. High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med 2003; 31(11):2646–2650. 94. Gando S, Nanzaki S, Kemmotsu O. Disseminated intravascular coagulation and sustained SIRS predicts organ dysfunction after trauma: application of clinical decision analysis. Ann Surg 1999; 229(1):121–127. 95. Gando S, Kameue T, Matsuda N, et al. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromb Haemost 2002; 88(6):943–949. 96. Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res 2003; 60(1):26–39. 97. Boehme MW, Deng Y, Raeth U, et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology 1996; 87:134–140. 98. Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation: compared patterns of antithrombin HI, protein C, and protein S deficiencies. Chest 1992; 101:816–823. 99. Lorente JA, Garcia-Frade LJ, Landin L, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103:1536–1542. 100. Boldt J, Papsdorf M, Rothe A, Kumie B, Piper S. Changes of the hemostatic network in critically ill patients—is there a difference between sepsis, trauma, and neurosurgery patients? Crit Care Med 2000; 28:445–450. 101. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699–709. 102. Bernard GR, Macias WL, Joyce DE, Williams MD, Bailey J, Vincent JL. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis. Crit Care 2003; 7(2):155–163 (Epub 2003, Feb 28). 103. Vincent JL, Angus DC, Artigas A, et al. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003; 31(3):834–840. 104. Dhainaut JF, Laterre PF, Janes JM, et al. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003 (Epub ahead of print). 105. Doig CJ, Laupland KB, Zygun DA, Manns BJ. The epidemiology of severe sepsis syndrome and its treatment with recombinant human activated protein C. Expert Opin Pharmacother 2003; 4(10):1789–1799.

106. Angus DC, Linde-Zwirble WT, Clermont G, et al. PROWESS Investigators. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003; 31(1):1–11. 107. Napolitano LM. Hemofiltration in sepsis: additional supportive evidence. Crit Care Med 2001; 29(7):1485–1487. 108. Honore PM, Matson JR. Hemofiltration, adsorption, sieving and the challenge of sepsis therapy design. Crit Care 2002; 6(5):394–396 (Epub 2002 Sep 04). 109. Garcia-Fernandez N, Lavilla FJ, Rocha E, Purroy A. Haemostatic changes in systemic inflammatory response syndrome during continuous renal replacement therapy. J Nephrol 2000; 13(4):282–289. 110. Bordoni V, Bolgan I, Brendolan A, et al. Caspase-3 and -8 activation and cytokine removal with a novel cellulose triacetate super-permeable membrane in an in vitro sepsis model. Int J Artif Organs 2003; 26(10):897–905. 111. Morgera S, Haase M, Rocktaschei J, et al. High permeability haemofiltration improves peripheral blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol Dial Transplant 2003; 18(12):2570–2576. 112. Reeves J, Butt W, Shann F, et al. Continuous plasmafiltration in sepsis syndrome. Crit Care Med 1999; 27:2096–2104. 113. Cole L, Bellomo R, Hart G, et al. A phase II randomized, controlled trial of continuous hemofiltration in sepsis. Crit Care Med 2002; 30:100–106. 114. Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomized, controlled trial. Intensive Care Med 2002; 28: 1434–1439. 115. Kellum JA, Bellomo R, Mehta R, Ronco C. Blood purification in non-renal critical illness. Blood Purif 2003; 21(1):6–13. 116. Napolitano LM, Faist E, Wichmann MW, Coimbra R. Immune dysfunction in trauma. Trauma Care in the New Millennium. Surg Clin N Am 1999; 79(6):1385–1416. 117. Dellinger RP, Parrillo JE. Mediator modulation therapy of severe sepsis and septic shock: does it work? Crit Care Med 2004; 32(1):282–286 [Editorial]. 118. Eichacker PQ, Parent C, Kalil A, et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002; 166(9): 1197–1205. 119. Minneci P, Deans K, Natanson C, Eichacker PQ. Increasing the efficacy of anti-inflammatory agents used in the treatment of sepsis. Eur J Clin Microbiol Infect Dis 2003; 22(1):1–9 (Epub 2003 Jan 28). 120. Freeman BD, Zehnbauer BA, Buchman TG. A meta-analysis of controlled trials of anticoagulant therapies in patients with sepsis. Shock 2003; 20(1):5–9. 121. Nasraway SA. The problems and challenges of immunotherapy in sepsis. Chest 2003; 123(suppl 5):451S–459S. 122. Abraham E, Reinhart K, Opal S, et al. OPTIMIST Trial Study Group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003; 290(2):238–247. 123. Albertson TE, Panacek EA, MacArthur RD, et al. MAB-T88 Sepsis Study Group. Multicenter evaluation of a human monoclonal antibody to Enterobacteriaceae common antigen in patients with Gram-negative sepsis. Crit Care Med 2003; 31(2):419–427. 124. Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 2004; 32:21–30. 125. Cohen J. Recent developments in the identification of novel therapeutic targets for the treatment of patients with sepsis and septic shock. Scand J Infect Dis 2003; 35(9):690–696. 126. Khadaroo RG, Marshall JC. ARDS and the multiple organ dysfunction syndrome. Common mechanisms of a common systemic process. Crit Care Clin 2002; 18(1):127–141. 127. Marshall JC. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 2001; 29(suppl 7):S99–S106.

Chapter 11: Sepsis and the Syndrome of Multiple Organ Failure 128. Marshall JC. Multiple organ dysfunction score: reliable descriptor of a complex clinical outcome. Crit Care Med 1995; 23(10):1638–1652. 129. Parrillo JE, Parker MM, Natanson C, et al. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy. Ann Intern Med 1990; 113:227–242. 130. Vincent JL, Moreno R, Takala J, et al. The SOFA score to describe organ dysfunction/failure: on behalf of the Working Group on Sepsis-related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22:707–710. 131. Zimmerman JE, Knaus WA, Wagner DP, Sun X, Hakim RB, Nystrom PO. A comparison of risks and outcomes for patients with organ system failure: 1982–1990. Crit Care Med 1996; 24(10):1633–1641. 132. Durham RM, Moran JJ, Mazuski JE, Shapiro MJ, Baue AE, Flint LM. Multiple organ failure in trauma patients. J Trauma 2003; 55(4):608–616. 133. Fry DE, Pearlstein L, Fulton RL, Polk HC Jr. Multiple system organ failure. The role of uncontrolled infection. Arch Surg 1980; 115(2):136–140. 134. Flaatten H, Gjerde S, Guttormsen AB, et al. Outcome after acute respiratory failure is more dependent on dysfunction in other vital organs than on the severity of the respiratory failure. Crit Care 2003; 7(4):R72 (Epub 2003 Jul 09). 135. Brun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute lung injury in European intensive care units results from the ALIVE study. Intensive Care Med 2003 (Epub ahead of print). 136. Barie PS, Hydo LJ. Epidemiology of multiple organ dysfunction syndrome in critical surgical illness. Surg Infect 2000; 1(3):173–186. 137. Maier R. Pathogenesis of MODS–Endotoxin, inflammatory cells and their mediators: cytokines and reactive oxygen species. Surg Infect 2000; 1(3):197–205. 138. Cobb JP, Buchman TG, Karl IE, Hotchkiss RS. Molecular biology of MODS: injury, adaptation and apoptosis. Surg Infect 2000; 1(3):207–213. 139. Rotstein OD. Pathogenesis of MODS: gut origin, protection and decontamination. Surg Infect 2000; 1(3):217–225. 140. Brealey D, Singer M. Mitochondrial dysfunction in sepsis. Curr Infect Dis Rep 2003; 5(5):365–371. 141. Biffl WL, Moore EE, Haenel JB. Nutrition support of the trauma patient. Nutrition 2002; 18(11–;12):960–965.

251

142. Yanagawa T, Bunn F, Roberts I, Wentz R, Pierro A. Nutritional support for head-injured patients. Cochrane Database Syst Rev 2002; 3:CD001530. 143. Bastian L, Weimann A. Immunonutrition in patients after multiple trauma. Br J Nutr 2002; 87(suppl 1):S133–S134. 144. Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 2001; 286(8):944–953. 145. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002; 236(6):814–822. 146. Moore FA, Moore EE, Sauaia A. Blood transfusion: an independent risk factor for postinjury multiple organ failure. Arch Surg 1997; 132(6):620–625. 147. Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 2003; 54(5):898–907. 148. Claridge JA, Sawyer RG, Schulman AM, McLemore EC, Young JS. Blood transfusions correlate with infections in trauma patients in a dose-dependent manner. Am Surg 2002; 68(7):566–572. 149. Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis. J Trauma 2003; 54: 908–914. 150. Vincent JL, Baron JF, Reinhart K, et al. ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288(12):1499–1507. 151. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill-current clinical practice in the United States. Crit Care Med 2004; 32(1): 39–52. 152. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340(6):409–417. 153. Moore EE. Blood substitutes: the future is now. J Am Coll Surg 2003; 196(1):1–17. 154. Corwin HL, Gettinger A, Pearl RG, et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002; 288:2827–2835.

medwedi.ru

12 Application of Cellular and Molecular Biology in Modern Surgical Practice Huiping Zhou and Jian-Ying Wang

INTRODUCTION During the last two decades, there has been a great explosion in new knowledge and technology regarding cellular and molecular biology. One of the most important achievements in this field is the successful completion of the Human Genome Project in 2003. The identification and sequencing of the entire human genome is revolutionizing our surgical practice. These advances will rapidly transform our traditional surgical care to modern surgical practice that is based on cellular and molecular approaches for prevention, diagnosis, and treatment of human surgical diseases. There are several excellent textbooks available (1–5), in which the information about core knowledge of advanced cellular and molecular biology is presented in detail. The goal of this chapter is to present an overview of basic concepts and common techniques of cellular and molecular biology and also to highlight its potential application in the modern surgical practice.

BASIC GENETIC MECHANISMS Cells and Human Genome There are millions of living species on earth today. Each species possesses a genome that contains all of the biological information required to reproduce itself faithfully. The structural and functional units of all living organisms are cells. The human body contains more than 1014 cells with different types and functions (1). As the smallest irreducible units of life, cells share the same machinery for their functions. Two important functions of living cells are (i) to store, reproduce, and transmit information, and (ii) to enhance the rate of chemical reactions, a property referred to as catalysis (2). Although there are significant differences among various cell types, all of the living cells share common structural features. They all have a nucleus or nucleoid, in which the genome is stored and replicated, the plasma membrane, which is composed of enormous lipids and proteins, and the cytoplasm, which contains an aqueous solution, suspended particles, and organelles. Cells with a nuclear membrane (or nuclear envelope) are named eukaryotes, while cells without a nuclear envelope are called prokaryotes (Fig. 1). Eukaryotic cells also have a number of other membrane-bound compartments, which are absent in prokaryotes, such as endoplasmic reticulum, mitochondrion, lysosomes, and Golgi apparatus (3). Cells are very small, but chemically very sophisticated in general. The simplest cells contain more than 2500 different molecules. There are two large classes of molecules in every cell. One is the ‘‘small molecule class’’ such as sugars, amino acids, fatty acids, and nucleotides;

the other is the ‘‘macromolecule class’’ such as proteins and nucleic acids (4). All living cells, without any known exception, store their hereditary information in DNA molecules. The genome is the entire DNA content of a cell. The eukaryotic genome is made up of two distinct components: nuclear genome and mitochondrial genome. The nuclear genomes are divided into two or more linear DNA molecules. The basic structures of all eukaryotic nuclear genomes are similar, but the size is very different in various organisms. The human nuclear genome is divided into 24 linear DNA molecules, which comprises approximately 3 109 base pairs (bp). The mitochondrial genome is a circular DNA molecule of 16,569 bp (1,5). A gene is a segment of DNA (or, in a few cases, RNA such as in viruses) that encodes the information required to produce a functional RNA. A messenger RNA (mRNA) is a transcript of a protein-coding gene and can be translated into protein. Each protein-coding gene encodes one specific protein. The noncoding genes are transcribed into structural RNA molecules such as ribosomal RNA (rRNA) or transfer RNA (tRNA). The eukaryotic genes are not precisely colinear with their proteins. The length of human genes is usually much longer than that of mRNA sequences. The expressed (or coding) sequences of most genes are named exons and are usually interrupted by intervening introns or other sequences that do not encode any amino acid sequences for the polypeptide products and must be spliced out during transcription (5). The existence of splicing makes it possible that some eukaryotic genes can be spliced in different ways and transcribed into different mature mRNA molecules. This process is called ‘‘differential splicing.’’ Therefore, organisms can use differential splicing to produce different forms of a given protein, depending on various cell types or different stages of development. In general, one gene makes one protein, but it has been realized that some eukaryotic genes are able to produce several different versions of the protein (1). The human genome was originally predicted as having 50,000 to over 140,000 genes. However, recent completion of the human genome sequence has clearly revealed that the human genome only contains approximately 26,000 to 38,000 genes, which are far fewer than the earlier molecular predictions (5,6). The coding regions of these genes take up only 3% of the genome (1,3). All of the cells in the adult human body have their own copy or copies of the genome except a few cell types that lack nuclei in their fully differentiated state, such as red blood cells. It is clear that the diversity of cell types and functions reflects patterns of different gene expression.

medwedi.ru 253

254

Part One: General Considerations

Figure 1 Cells of eukaryotes (A) and prokaryotes (B). Eukaryotic cells are characterized by their membrane-bound organelles such as nucleus, endoplasmic reticulum, mitochondrion, and Golgi. The nuclear body of the eukaryotic cell is bounded by a nuclear membrane and is called a nucleus. The prokaryotic cells are much smaller and simpler than eukaryotic cells and lack characteristics of subcellular membrane-enclosed organelles. The prokaryotic cells do not have a nucleus and the nuclear body is called a nucleoid. Some prokaryotic cells have external whiplike flagella for locomotion.

DNA and Chromosomes DNA is the most important substance of life. It carries the hereditary information that determines the structures of RNAs and proteins. The only known functions of DNA are the storage and transmission of biological information. The DNA molecules consist of two antiparallel nucleotide strands with complementary nucleotide sequences that are held together principally by hydrogen bonds and basestacking interactions to form a right-hand double helix (7). Each nucleotide contains a phosphate group, a sugar moiety, and a base (either purine or pyrimidine) (Fig. 2). These two nucleotide strands are composed of four different nucleotides that are linked together by phosphodiester bonds

Figure 2 The chemical structures of DNA nucleotide (A) and the bases of nucleic acids (B). A DNA nucleotide consists of a nitrogencontaining base, five-carbon sugar, and one or more phosphate groups. The base is attached to a ribose ring, which is in turn bonded to a phosphate group. Principal bases of nucleic acids include adenine (A), guanine (G), thymine (T), cytosine (C), and uracil (U).

between the base and the phosphate group. These linkages are always the same, with the phosphate group connecting the 50 -carbon atom of one deoxyribose residue to the 30 -carbon atom of the deoxyribose in the adjacent nucleotide. Each nucleotide strand has a 50 -end with a free hydroxyl or phosphate group at the 50 -carbon of a sugar and a 30 -end with a free hydroxyl group at the 30 -carbon of a sugar (Fig. 3). The sugar–phosphate backbones are on the outside of the double helix, and the bases project inward toward each other. The complementary strands have opposite polarity and their bases must be paired. The adenine (A) must be paired with thymine (T) by two

Figure 3 Phosphodiester linkage of DNA backbone. The regular phosphodiester bonds between sugar and phosphate groups form the backbone of DNA. The phosphate group is always connecting the 50 -carbon atom of one deoxyribose residue to the 30 -carbon atom of the deoxyribose in the adjacent nucleotide.

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

Figure 4 The base paring of two DNA strands. In the double helix, two polynucleotides, running in antiparallel directions, are wound around one another and held together by hydrogen bonds between base pairs. Sequence of four bases, including adenine (A), guanine (G), thymine (T), cytosine (C), determines the specificity of genetic information. The bases face inward from the sugar–phosphate backbone and form pairs with complementary bases on the opposing strand.

hydrogen bonds, while the cytosine (C) must be paired with guanine (G) by three hydrogen bonds (Fig. 4). Each of these base pairs possesses a symmetry that permits it to be inserted into the double helix in two ways (A ¼ T and T ¼ A; G ¼ C and C ¼ G). DNA molecules are the largest macromolecules in the cell and are normally packaged into structures known as chromosomes. Most prokaryotic cells have a single chromosome, but eukaryotic cells usually contain multiple chromosomes. Each chromosome contains one linear DNA molecule. Human beings are diploid organisms and carry 46 chromosomes in total, including two copies of 22 different autosomes and two sex chromosomes, XX for females or XY for males. One copy of chromosomes is inherited from the mother and one is inherited from the father (1–5). The total length of chromosomal DNA in the nucleus of a human cell is about 105 times the diameter of a typical cell. The chromosomal DNA is folded and compacted with a number of specific proteins called histones to form chromatin. Histones are small basic proteins, which bind to DNA primarily through ionic bonds between the negatively charged phosphate groups of DNA and the positively charged side groups of arginine and lysine. There are two types of chromatin: euchromatin and heterochromatin. Euchromatin is compacted during the division but decondenses at the interphase, and it is genetically active. Heterochromatin is highly compacted and remains condensed throughout the cell cycle, which is genetically inactive. The DNA folding is essential for packaging the long DNA molecules in an orderly way in the nucleus. The packaging of chromosome DNA not only facilitates DNA replication and segregation but also affects the activity of genes (1,2).

DNA Replication, Repair, and Recombination With the discovery of the DNA double helical structure by James Watson and Francis Crick in 1953, it was possible to

255

understand how genes could be faithfully duplicated prior to cell division. Fundamental properties of the DNA replication process are essentially identical in all organisms. The DNA replication is semiconservative. Each DNA strand serves as a template for the synthesis of a new strand by DNA polymerases and results in the production of two identical daughter DNA molecules, each containing one original and one newly replicated strand (4). DNA replication begins at a large number of sites in the genome, which are called the origins of replication, and usually precedes bidirectionally along the DNA molecule. A new strand of DNA is always synthesized in the 50 to 30 direction. Because the two strands are antiparallel, the template strand is read from 30 end to 50 end. The leading strand is continuously synthesized in the same direction as the replication fork movement. The other strand (called ‘‘lagging strand’’) is synthesized discontinuously in short pieces, which are called Okazaki fragments, in the direction opposite to the direction of fork movement (Fig. 5). The nick is sealed by DNA ligase. The fidelity of DNA replication is extremely important, and any mistake results in the change of DNA sequences in a daughter strand, which is named mutation. The mutation rate of DNA replication is extremely low, about 1 nucleotide change per 109 nucleotide replication. The DNA polymerases not only have base selection activity but also have 30 ! 50 exonuclease (or proofreading) activity. Both activities account for the high degree of fidelity in replication. The additional accuracy accounts for the repair systems after replication. The DNA molecules in a cell are irreplaceable. Many processes can damage the DNA structures and result in mutations. The most frequent chemical reactions to induce DNA damages in cells are depurination and deamination. Ultraviolet radiation also damages the DNA by covalently linking two adjacent pyrimidine bases (C or T). The gene mutations represent changes in the sequence of bases, through either the replacement of one base pair with another (substitution mutation) or the addition and/or deletion of one or more base pairs (insertion or deletion mutation).

Figure 5 The structure of a DNA replication fork. The DNA replication is semiconservative, and a new DNA strand is always synthesized in the 50 !30 direction. Only the leading strand can begin at the 30 end of the template DNA and grow continuously as the replication fork moves along the template DNA. The other strand must grow discontinuously by synthesizing a series of short DNA molecules, called Okazaki fragments, in the opposite direction. These Okazaki fragments are ligated together by the action of an enzyme called DNA ligase.

medwedi.ru

256

Part One: General Considerations

The mutations that result in incorrect substitutions of amino acids are termed ‘‘missense mutation.’’ The missense mutation may affect the structure and function of a protein. If the mutations result in the replacement of an amino acid codon with a stop codon, they are called nonsense mutation. Nonsense mutation usually leads to the early termination of protein synthesis. If the addition or deletion of one or multiple base pairs leads to the open reading frame shift, it is called frameshift mutation. The frameshift mutation will lead to the introduction of different amino acids or a stop codon. Both the amino acid sequence and the length will be different from the original protein (Fig. 6). If the mutation occurs in the nonessential DNA or has no effect on the gene function, it is called silent mutation. However, most mutations are deleterious. If these damages are uncorrected when DNA is replicated, most of them will lead to deletion or substitution of one or more base pairs in the newly synthesized DNA strand (1,5,8). The human genome is constantly injured by many endogenous and exogenous agents. It is estimated that a human cell accumulates thousands of injuries every day. Maintenance of genetic stability requires not only the accuracy of DNA replication but also the presence of repair systems, which are essential to DNA integrity. Correction of the mutations in DNA sequences is called DNA repair (1–5). The double helical structure of DNA molecule is critical to the safe storage of genetic information and ideally suited for DNA repair. Because both strands contain the same genetic information, the damage in one strand can be readily removed and correctly replaced by using the complementary strand as template. There are multiple repair systems in the cell; most of them use the undamaged strand as a template to repair the damaged strand. The five major repair systems in most cells are (i) direct repair systems—fill in nicks and

correct some types of nucleotide modification without excision of nucleotides; (ii) base excision repair systems—repair many types of damaged nucleotides by removal of a damaged nucleotide followed by resynthesis of DNA to fill the gap; (iii) nucleotide excision repair systems—similar to base excision repair and are used to correct more extensive types of damages; (iv) mismatch repair systems—correct errors of DNA replication; and (v) recombinant repair systems—mend double-strand breaks. All of the repair systems require a number of specific enzymes to correct or excise the damaged sequences and replace them. Recent studies have shown that the gene mutations and deficiency of DNA repair systems are strongly related to a variety of serious human diseases such as cancers (1–5,9). Although genetic stability is very important for survival, there must be a balance between genetic stability and genetic variation for evolution to proceed in response to environmental change. The chromosomal DNA sequences can be occasionally rearranged. The rearrangements of DNA sequences are carried out by genetic recombinations, which include general recombination, site-specific recombination, and DNA transposition (1,4). The general recombination is also called homologous recombination. The genetic exchanges occur between any two chromosomes (or segments of the same chromosome) that have homologous DNA sequences. These rearrangements usually do not change the order of the genes on the chromosomes. The general recombination is essential for the repair of several types of DNA damages and accurate chromosome segregation during meiosis, and also provides genetic diversity in a population. The site-specific recombination only occurs at the specific DNA sequences. Specialized nucleotide sequences can move between two different positions in a single chromosome or between two different chromosomes, which alters gene order and adds new information into the genome. The DNA transposition is distinct from both the general recombination and the site-specific recombination. This process involves a small segment of DNA (called transposon), which is able to move or hop from one location on a chromosome to another on the same or different chromosome. The movement of a transposon does not require sequence homology. The most studied example of transposition is the generation of complete immunoglobulin genes (1). In general, genetic recombination plays an important role in the evolution of cells and organisms, which includes DNA repair, regulation of gene expression, and maintenance of genetic diversity.

How Cells Read the Genome: From DNA to Protein

Figure 6 Different types of mutations. (A) Missense mutation: a single base change results in the incorporation of a different amino acid. (B) Nonsense mutation: a single base change results in the incoporation of a stop codon. (C) Frameshift mutation: a single base deletion results in the incorporation of different amino acids.

Most of the biological activities of the cell are carried out by proteins. The structure and the biological function of a protein are determined by the order and number of amino acids of the polypeptide, while the amino acid sequence of the polypeptide is determined by the DNA sequence of the corresponding gene. Most of the genes in eukaryotic cells are located in the nucleus, while protein synthesis occurs in the ribosomes, which are located in the cytoplasm. Therefore, the DNA itself does not directly guide the protein synthesis. To transfer the genetic information from nucleus to ribosomes, the nucleotide sequence of the gene is first copied to an intermediate molecule, RNA, which is also a linear polymer of nucleotides. The primary structures of RNA and DNA molecules are very similar and thus make it possible such that DNA can transfer its genetic information to

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

RNA. The major differences between DNA and RNA are that the sugar molecule in the backbone of RNA molecules is ribose instead of deoxyribose, and uracil (U) is used to pair with adenine (A) instead of thymine (T). RNA is the only macromolecule known to store and transmit genetic information from the nucleus to the cytoplasm. The RNA is synthesized from DNA with a base sequence complementary to one of the DNA strands by a process called transcription. There are three major kinds of RNA transcripts including rRNA, mRNA, and tRNA. rRNAs are the most abundant in the cell, and more than 80% of total cellular RNA is found in ribosomes. rRNAs function as a framework to which ribosomal proteins are bound. mRNA only constitutes 4% of the total cellular RNA and is used as a template to direct the synthesis of the protein through a process called translation. Most of the mRNA molecules have a short half-life and are immediately destroyed after directing the synthesis of a protein (5). As shown in Figure 7, a mature eukaryotic mRNA molecule contains a 50 -end leader sequence capped with a 7-methyl-guanosine during transcription, a coding sequence and a 30 -end poly (A) tail added after transcription. The 50 -cap structure is critical for initiation of protein synthesis and protects the pre-mRNA from being degraded by enzymes, while the 30 -poly (A) tail is important for the stability of mature mRNA. tRNAs function as an interpreter and read the information in the mRNA and transfer the appropriate amino acid to the growing polypeptide during the protein synthesis. All tRNAs have the same cloverleaf structure with an amino acid attachment site. There is at least one tRNA molecule for each amino acid, although many amino acids have more than one tRNA molecule (10).

257

It has been well established that every three nucleotide residues of mRNA encode one amino acid. The groups of nucleotides that code for an amino acid are called codons. Each codon can specify only one amino acid. There are four different nucleotides, which constitute 64 different types of codons. Because there are only 20 different types of amino acids, many amino acids must be specified by more than one codon. The rules by which the nucleotide sequence of the mRNA is translated to amino acid sequence of a protein are called the genetic code, which was completely deciphered in 1966 (5). Among the 64 codons, 61 codons are used to code for specific amino acids. The other three codons do not specify the incorporation of any amino acid but code for the termination of polypeptide synthesis, and are named stop codons. Another special codon is AUG. In addition to coding for methionine, AUG also functions as a start codon to signal the beginning of the polypeptide synthesis in all cells (Table 1). The sequence of nucleotides that runs from a start codon to a termination codon is referred as a reading frame. Most RNAs can only be read in one frame (4). The synthesis of protein is the most complex biosynthetic process, which requires the mRNA as template and hundreds of different macromolecules to cooperate together. To form a functional protein, the newly synthesized polypeptide chain must fold up into its unique three-dimensional confirmation, modified by other enzymes, and conjugated with any small-molecule cofactors required for its activity. Thus, the flow of genetic information in cells is DNA ! mRNA ! protein (Fig. 8).

Control of Gene Expression

Figure 7 mRNA processing in eukaryotic cells. The transcription of DNA into mRNA begins by the binding of the RNA polymerase to a site upstream of the gene called promoter. Once the polymerase is bond to the promoter, it moves along the DNA, making a single mRNA copy from only one strand of the DNA double helix. During transcription, methyl caps are added at the 50 -end of the pre-mRNA. After transcription, the introns are excised and a poly(A) tail is added at the 30 end to produce a mature mRNA molecule. Abbreviation: mRNA, messenger RNA.

Basically, all the cells in a human body contain exactly the same genetic information. However, the structure and function of different cell types are totally unrelated. Not all genes are expressed in every type of cell. Instead, each cell type only expresses a certain subset of its genes to make the proteins that are necessary for its specific functions. For example, the hemoglobins are only expressed in red blood cells. This does not mean that other types of cells do not have the gene for hemoglobin. The generation of cellular diversity is known as differentiation. The cells have the ability to change the pattern of gene expression by activating or repressing certain genes, and regulating the levels of their proteins based on both their needs during development and various physiological responses. The cell-type specific gene expression is precisely regulated and controlled by numerous factors at different levels (11). There are two major ways through which cells control the differential expression of various genes. The first mechanism is transcriptional control, which regulates the rates in which specific mRNA molecules are transcribed off their DNA templates via various molecular signals. The second mechanism is translational control, which determines the rates in which mRNAs are translated into polypeptides. For most cells, the primary control of gene expression is at the level of transcription. Transcription is initiated by the binding of the RNA polymerase to the promoter, which is located at the upstream of the gene, and followed by the moving of RNA polymerase along the DNA and synthesizing single-strand mRNA. The newly synthesized mRNA molecule is further modified before it is exported from the nucleus to the cytoplasm where it is translated into protein (Fig. 8). The gene expression is controlled by either regulating the ability of the RNA polymerase to bind to

medwedi.ru

258

Part One: General Considerations

Table 1 The Genetic Code 2nd base in codon

U

A

G

C

A

G

Phe UUU Phe UUC Leu UUA Leu UUG Leu CUU Leu CUC Leu CUA Leu CUG Ile AUU Ile AUC Ile AUA Met AUG Val GUU Val GUC Val GUA Val GUG

Ser UCU Ser UCC Ser UCA Ser UCG Pro CCU Pro CCC Pro CCA Pro CCG Thr ACU Thr ACC Thr ACA Thr ACG Ala GCU Ala GCC Ala GCA Ala GCG

Tyr UAU Tyr UAC Stop UAA Stop UGG His CAU His CAC Gln CAA Gln CAG Asn AAU Asn AAC Lys AAA Lys AAG Asp GAU Asp GAC Glu GAA Glu GAG

Cys UGU Cys UGC Stop UGA Trp UGG Arg CGU Arg CGC Arg CGA Arg CGG Ser AGU Ser AGC Arg AGA Arg AGG Gly GGU Gly GGC Gly GGA Gly GGG

U C A G U C A G U C A G U C A G

3rd base in codon

1st base in codon

C

U

The RNA is constructed from four types of nucleotides, there are 64 possible triplet codons (4 4 4). Three of these possible codons specify the termination of the polypeptide chain. They are called ‘‘stop codons.’’ The rest of 61 codons specify only 20 different amino acids. Most of the amino acids are represented by more than one codon. In addition to specifying for methionine, AUG also serves as a ‘‘start’’ signal for protein synthesis. Abbreviations: A, adenine; G, guanine; C, cytosine; U, uracil.

the promoter or regulating the ability of the RNA polymerase to transcribe the gene. In eukaryotic cells, regulation of the transcription initiation is the most widespread form of gene control. There are many regulatory proteins (called transcription factors), which are assembled in a particular order and bind to very specific DNA sequences (called regulatory elements) located upstream or downstream of the gene to regulate the process of transcription (Fig. 9). These regulatory elements are cell-type specific or tissue-type specific, and they only activate the genes in certain cells or tissues at a given time and determine which gene is

Figure 8 From DNA to protein. The genetic information in DNA is read out by transcription into mRNA in the nucleus. After processing, the mature mRNA is exported to the cytosol, where it is used to guide the protein synthesis. Abbreviation: mRNA, messenger RNA.

transcribed into RNA molecules. For example, MyoD is a muscle-specific transcription activator that is essential to myogenesis and is only found in muscle tissue. Many transcriptional factors are able to form dimers, either homodimers or heterodimers, and then bind to specific DNA sequences. Under most circumstances, the homodimers and heterodimers bind to distinct DNA sequences. For example, c-Jun/c-Jun homodimers bind to the well-known AP-1 regulatory site and c-Fos/c-Fos homodimers do not recognize this AP-1 site, whereas the c-Jun/c-Fos heterodimers bind to the AP-1 with much higher affinity than the c-Jun/c-Jun homodimers. These regulatory proteins function in various combinations to control gene expression and generate many different cell types during development. It has been clear that eukaryotic genes are interrupted by introns that must be spliced out during RNA processing. The processing of mature RNA molecules determines how many proteins are generated from the same primary RNA transcript, and also are regulated by many different factors in different cells (4). There are many steps for the synthesis of protein from DNA. In general, every step required for gene expression could be controlled. Although gene transcription is the predominant step of regulation for most genes, posttranscriptional regulations are also crucial for many genes under various physiological and pathological conditions. The stability of mRNA determines the rate of degradation, and is regulated by proteins that bind to the 50 - or 30 -untranslated regions of mRNA. The mature mRNA molecules are synthesized in the nucleus and must be transported into the cytoplasm for translation by ribosome complex. The RNA transport determines which mRNA is exported and when it is exported, and this process is also tightly regulated. In addition to the transcriptional and posttranscriptional regulations, control of the translation and the post-translation also regulates the activity of gene expression by determining the frequency of translation, and modulates the protein activity through various modifications.

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

259

Figure 9 The structure of a gene. The entire functional unit of the gene includes a regulatory region and a transcription region. The regulatory region contains promoter, response element, and enhancer, while the transcription region consists of coding DNA sequences (exon) and noncoding DNA sequences (intron).

Genetic Polymorphism Genetic polymorphism is the difference in DNA sequence among individuals, groups, and populations, which include single nucleotide polymorphism (SNP), sequence repeats, insertions, deletions, and recombinations (1–5). Genomic variation is responsible for diversity in the human species. A genetic polymorphism is related to the different phenotypes such as different colors of eyes, skin, and hair. Genetic polymorphisms result from chance processes, or are induced by external agents such as viruses and radiation. The disease-associated or external agents inducing DNA sequence changes are called genetic mutations, which are a kind of genetic polymorphism. An SNP is a single base mutation in DNA, which is the simplest form and most common source of genetic polymorphism in the human genome (approximately 90% of all human DNA polymorphisms). Most of the SNPs (approximately 66%) result from a ‘‘transition’’ substitution between purines or pyrimidines. The rest of the SNPs are from a ‘‘transversion’’ substitution between purine and pyrimidine. The distribution of SNPs is not uniform in the human genome. If the SNP occurs in a coding region of a gene, it may have two different effects on the corresponding proteins. The mutation may or may not cause any change in the amino acid sequence. If the SNP occurs in regulatory regions of the gene, it affects the expression of the gene. The observable properties of the individual are called phenotype, which is developed under the combined influences of the individual’s genotype and the effects of environmental factors. Genotype is the genetic constitution of an individual, with respect to a single trait or a larger set of traits. The particular pattern of sequential SNPs (or alleles) on a single chromosome is called haplotype. Several studies have indicated that SNP haplotypes are more useful than genotypes in association-based studies for the analysis of candidate genes and gene regions. There are also cases in which disease susceptibility is related to the presence or absence of a known haplotype. The haplotype patterns are usually specific to populations; the haplotype mapping will reveal the association of certain diseases with the specific populations. The most important applications of the SNP-related research are gene–disease association studies and drug– target validation. Even though most diseases are influenced by multiple genes and various environmental factors, the SNP mapping identifies the individual genes responsible for a number of diseases such as Huntington’s disease and cystic fibrosis. Some recent studies have demonstrated that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type-I diabetes mellitus. Pharmacogenetics mostly relies on the associations between the specific genetic marker such as SNPs, either alone or arranged in a specific linear order on a certain chromosomal region (haplotypes), and a particular

response to drugs. Numerous associations have been reported between selected genotypes and specific responses to cardiovascular drugs. Studies of the correlation between patients’ genotype and their sensitivity to different drugs have greatly advanced drug design and development. Analysis of an individual haplotype also provides valuable information for genetic predisposition to a particular health condition, determining the risk to certain diseases and confirmation of genetic disease diagnosis (12).

CELLULAR AND MOLECULAR BIOLOGICAL TECHNOLOGY: FROM RECOMBINANT DNA TO TRANSGENIC ANIMALS Cell Isolation and Growth in Culture Most of the tissues in human bodies contain a mixture of cell types. To study the structures and functions of an individual type of cell, it is necessary to obtain a pure population of one type of cells. The initial step is to rupture the extracellular matrix that holds the cells together and obtain a mixture of cell suspension. The most typical way is through digestion of the tissue sample with proteolytic enzymes such as collagenase and trypsin. Several techniques have been developed to isolate a single type of cells from a mixture of cell suspension (1–5). The ‘‘first’’ basic technique is based on the different physical properties such as densities and sizes of different types of cells. For example, white blood cells and red blood cells have very different densities and can easily be separated by centrifugation; and coronary endothelial cells and smooth muscle cells can be isolated by mesh sizing and centrifugation (13). Some cells adhere strongly to a glass or plastic surface and can be separated from those cells having low tendency to adhere. Another approach is based on the specific binding of the surface molecules of a single cell type in a tissue to immobilized antibodies. The bound cells can be recovered by enzyme digestion or gentle shaking. The ‘‘second’’ technique is laser capture microdissection. Selected cells are carefully dissected from thin tissue slices using a laser beam. This method can be used to isolate a single cell from a tissue sample. The third and most advanced technique is using a fluorescence-activated cell sorter (FACS), an instrument based on flow cytometry, to select different cells. The cells are sorted out from thousands of other cells by measuring the light they scatter or the fluorescence they emit as they pass single-file through a laser beam both by the fluorescent tagging of cell surface molecules and by the insertion of fluorescent genetic markers. Single cell sorting as a refinement of flow cytometric or FACS has been used for the selection and isolation of individual cells, for microscopy, for culture, and, more recently, for genetic analysis by single cell polymerase chain reaction (PCR; see discussion below) (14,15).

medwedi.ru

260

Part One: General Considerations

Most of the cells isolated from animal tissues are grown in a tissue-culture dish using appropriate culture medium. The requirements for different cells to grow in vitro are distinct. Usually, the cultures prepared directly from tissues are called primary cultures, which can be further subcultured and made to proliferate. Isolation and in vitro culture of single type of cells make it possible to study their specific functions. Most vertebrate cells will stop dividing after a limited number of divisions in culture. It is difficult to construct the stable cell line from normal human cells. Most of the stable human cell lines are generated from tumor cells, which proliferate indefinitely and express at least some of the special characteristics of the original normal cells (1). The most important breakthrough in cell culture is the establishment of human embryonic stem (ES) cell lines. There are four essential processes during the development of an embryo, which are controlled by selective gene expression: cell proliferation, cell specialization, cell interactions, and cell movement. Human ES cells can proliferate indefinitely. Because ES cells retain the ability to control gene expression, they have the ability to develop into any kind of tissue of the body, which can then be potentially used to replace or repair damaged tissues in the human (16). Additionally, two different cells can be fused together to form hybrid cells in culture. The most important application of a hybrid cell line is the production of monoclonal antibodies (7). The procedure was established through the pioneering efforts of Kohler and Milstein in the 1970s (17). The antibody-producing B lymphocytes are fused with a specialized myeloma cell line that no longer produces its own antibody, but continuously reproduces. The fused cells are called hybridomas and have the properties of both parent cells. They propagate rapidly in culture like myeloma cells, and simultaneously produce antibodies specified by the B lymphocyte. They provide a permanent and stable source of monoclonal antibodies that have been widely used for biomedical research, clinical diagnosis, and therapy.

Fractionation of Cells A typical mammalian cell is made of several functional organelles. Cell biology provides the means required for the analysis of the composition and properties of purified cellular elements. Subcellular fractionation is an approach universal across all cell types and tissues. The intracellular organelles and proteins can be purified and analyzed by various biochemical techniques. The initial step in subcellular fractionation is to break the cell membrane, which is done by osmotic shock, sonication, grinding in a high-speed blender, or homogenization. The components of the cell homogenate, which differ greatly in size and density, are simply separated by centrifugation. Most fractionation procedures start with differential centrifugation (also called differential-velocity centrifugation) at increasingly higher speeds. The cellular components are partially separated by their different sedimentation rates. Each pellet fraction of differential centrifugation is further purified by equilibrium density-gradient centrifugation, which separates cellular components according to their density. The partially purified organelle fraction is layered on top of a dense nonionic substance with increasing gradient (sucrose or glycerol) and centrifuged at high speed for several hours. This method can be used to separate lysosomes, mitochondria, and peroxisomes. Some cell fractions still contain more

than one type of organelle even after differential and equilibrium density-gradient centrifugation. These fractions are further purified by immunological methods using specific antibodies for organelle-specific proteins. This method is particularly useful for separating organelles that have a similar size and density (1–5).

DNA Isolation, Cloning, and Sequencing Recombinant DNA techniques have brought about a revolution in our understanding of fundamental biological processes, provided new tools for studying the structures and functions of proteins, and dramatically advanced the methods for diagnosis and treatment of various human genetic diseases, and along with the development of genetically engineered pharmaceutical products. The first specific restriction nuclease, HindII, was discovered by Hamilton Smith in 1970. Since that time, it has been greatly successful for molecular biologists to manipulate large DNA molecules (7). To date, several hundred restriction nucleases have been isolated from various bacterial strains, and more than 150 different specific cleavage sites have been identified. These enzymes recognize the specific sequences of four to eight nucleotides in DNA, and cut the DNA molecule into various fragments, either with the blunt end or with the cohesive end, which are easily rejoined together with other DNA fragments which have blunt ends or the same cohesive ends. These restriction nucleases opened a new direction to develop extremely useful methods of DNA sequencing and recombinant techniques (7,18). DNA cloning refers to isolation and amplification of a specific gene sequence. To isolate the specific gene, the first step is to construct a DNA library, which includes, at least, one fragment of DNA that contains the gene of interest. The most common vectors used to construct the DNA library are plasmids and phages, which replicate rapidly in bacterial cells. There are two types of DNA libraries, which have different usages, namely genomic DNA library and complementary DNA (cDNA) library. Genomic DNA library is constructed by the digestion of the entire genome with the specific restriction nuclease and cloning each fragment into a cosmid vector, which is derived from plasmids and l-phages. A cosmid is able to carry a much larger segment of foreign DNA than that of plasmid and phage vector, and facilitates the genomic cloning. The cDNA library is constructed by reverse transcription of mRNA isolated from the cell or tissue into the cDNA and cloning of the entire collection of cDNA into the vector, plasmid, or phage (7). Both the genomic DNA and the cDNA library are screened to isolate the clones carrying the desired DNA sequence by using specific nucleic acid probes. Many genes of receptors and enzymes are cloned by using this method. It has been shown that the nucleotide sequence is not always available for screening libraries. The alternative method to identify specific cDNA is to look for its gene product in bacteria or assay for the function of the protein after cloning the cDNA into appropriate expression vectors. More recently, the eukaryotic expression cloning is also used to isolate genes by functional assay in mammalian cells. For example, the receptor for erythropoietin (EPO) was cloned by assaying the high-affinity EPO-binding site on the cell surface (19). Once an individual vector containing the cDNA of interest is obtained, the next step is to determine the nucleotide sequence that encodes the protein of interest. Based on the DNA sequence, the amino acid sequence of the protein can be predicted. The modern history of DNA sequencing began in 1977, when Sanger reported his method for

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

determining the nucleotide sequence by chain-terminating nucleotide analogs (20). Since then, many improvements have been made. By using fluorescent dye–labeled nucleotides, the DNA sequence is read by a computer (21). DNA sequencing is now completely automated. In contrast to only being able to sequence 1000 bp a day in the bestequipped laboratory in the mid-1980s, the sequence centers of the Human Genome Project sequence 1000 bp a second presently. The success of the Human Genome Project is largely due to the development of high-throughput DNA sequencing methods (6). In the early 1980s, the major problem in studying and analyzing genes was the low copy numbers of the target genes in a complex genome. The invention of the PCR technique revolutionized molecular genetics and enables us to easily produce enormous numbers of copies of the specified DNA sequence being studied, to directly clone the specific gene from genomic DNA or mRNA isolated from cells or tissues without the construction of cDNA libraries, and manipulate the gene sequence. The principle of PCR technique is illustrated in Figure 10. The PCR method is extremely sensitive and able to detect a single DNA molecule in the sample. It has been used to diagnose genetic diseases, to detect very low levels of viral infection such as HIV infection, and to identify the genetic ‘‘fingerprint.’’

261

Advances in the field of recombinant DNA have dramatically accelerated the pace of basic biomedical research and biopharmaceutical development (22). Gene manipulation has become one of the important basic approaches to new drug design since the early 1990s. The isolation, cloning, and expression of genes in vitro make it possible to manufacture biological agents with therapeutic value on a large scale. This technology is especially attractive when the sources for the isolation of biopharmaceutical agents are scarce, the isolation and purification are difficult, or the only available source is likely to be contaminated with infectious or immunogenic agents. The first recombinant DNA-produced therapeutic protein on the market was human insulin, which is now approved for treatment of insulin-dependent diabetes. Presently, there are more than 50 FDA-approved biopharmaceutical agents and/or indications for use in United States.

Analyses of Protein Structure and Function Most of the biological functions of living cells are performed by proteins. Understanding how proteins function helps us define how cells work under physiological and pathological conditions. The functions of the specific protein are determined by its structure. Based on the amino acid sequence, the secondary structure is predicted in regard to a-helices

Figure 10 Amplification of DNA using the PCR. The DNA from a selected region of a gene is amplified by using two specific synthetic DNA oligonucleotides (called primers). The primers are complementary to the sequences that flank the target region on each strand. The standard cycle of PCR includes three steps: denature of template DNA, annealing of primers, and extension of new strands. This process is repeated for as many as 30 to 60 cycles to produce a large numbers of identical DNA fragments of interest. Abbreviation: PCR, polymerase chain reaction.

medwedi.ru

262

Part One: General Considerations

and b-sheets. However, the three-dimensional structure is difficult to predict. The major technique used to determine the three-dimensional structure of macromolecules such as proteins, at atomic resolution, is X-ray crystallography (1). In order for the object to be seen, its size needs to be at least half the wavelength of the light being used to see it. Using visible light, it is never possible to see atoms even under the most powerful of microscopes, because visible light has a wavelength much longer than the distance between atoms. X-rays are the form of electromagnetic radiation with a wavelength on the order of bond lengths. When X-rays pass through a crystal sample of the protein, the diffraction pattern is created by the atoms of the sample, which is interpreted mathematically into the actual location of atoms in the crystal sample by a computer. Therefore, the threedimensional structure of the protein can be deduced. To perform X-ray crystallography, it is necessary to grow crystals with appropriate size. If the protein has difficultly forming crystals, such as membrane proteins, an alternative method is Nuclear Magnetic Resonance (NMR) spectroscopy (23). NMR is the phenomenon that occurs when the nuclei of certain atoms are immersed in a static magnetic field and exposed to a second oscillating magnetic field. Some nuclei experience this phenomenon, and others do not, depending upon whether they possess a property called magnetic moment or spin. NMR spectroscopy employs the use of the NMR phenomenon to study physical, chemical, and biological properties of matter. It is routinely used by chemists to study chemical structure using simple one-dimensional techniques. Two-dimensional techniques are used to determine the structure of more complicated molecules. These techniques are replacing X-ray crystallography for the determination of protein structure. NMR spectroscopy only requires a small volume of concentrated protein. Because this study is performed in solution, it provides the dynamic information of the protein. During the last decade, the databases of protein and nucleic acid sequences have dramatically proliferated. Based on sequence similarity, the function of the gene is predicted by the available information of other characterized genes. Proteins having similar amino acid sequences or structures usually have similar biological functions. To identify the function of the new protein, the first step is to search the databases such as BLAST and FASTA for similar sequences, which usually provide valuable information for predicting the structure and function of the protein. Recombinant DNA techniques are able to replace or add the DNA fragment in a gene. Two different genes can be ligated together to express fusion proteins, which is a useful method in studying protein function and tracking proteins in living cells. The common strategy is to tag the protein with an epitope such as six-histidine, HA, FLAG, and Myc or with the well-characterized marker proteins including glutathione S-transferase, which are recognized by commercially available antibodies. These tagged proteins are easily purified by immunoprecipitation or affinity chromatography, and monitored by using the fluorescence- or dye-labeled secondary antibody. For tracking the proteins in living cells, the most useful tool is the green fluorescent protein (GFP). Once the target protein is fused with GFP, the movement of the protein is simply monitored by fluorescence microscopy. There are several GFP derivatives of different colors, which are used together with GFP to monitor the protein–protein interactions. Most proteins must form a complex with other proteins or molecules to perform their biological functions.

Identification of their partners facilitates the characterization of their biological roles. There are several methods available to study the protein–protein interactions. Protein affinity chromatography is used to isolate the interacting proteins. However, the simplest method for identifying the interacting proteins is the coimmunoprecipitation in which a specific antibody is used to bind the target protein; the immunocomplex is precipitated by using an affinity reagent attached to a solid matrix such as protein A/G-conjugated agarose. The proteins that physically interact with the target protein are also precipitated out of the solution, and their identity is further determined by western blot analysis or other suitable method. Recently, two powerful techniques, the two-hybrid system and phage display system, have been developed to simultaneously isolate the interacting proteins and the genes that encode them (24,25). To understand how the protein interacts with its partners, it is necessary to study the dynamics of protein association. The interactions between proteins can be monitored in real time using surface plasmon resonance, which has been used to characterize ligand–receptor coupling, DNA–protein binding, and antibody–antigen binding (26).

Studying Gene Expression and Function Structure and function of the protein is determined by its gene. When and/or where the gene is expressed reflects its biological functions in the cell or organism. Expression of the specific gene is tightly regulated and controlled by regulatory sequences in the noncoding region of the gene. The easiest way to examine how the gene expression is regulated is to replace the coding sequence of the specific gene with a reporter gene such as b-galactosidase or GFP. Once the recombinant DNA is transfected into cells, expression of the reporter gene is easy to detect by measuring enzyme activity or fluorescence. Regulation of the reporter gene expression is controlled by the same regulatory sequences that regulate original gene expression (1–3). Expression of the gene is the process by which the DNA sequence of the gene is transcribed and the mRNA is further translated into the protein. Expression pattern of the specific gene in different tissues and cells can be determined by hybridization techniques such as northern blotting analysis and in situ hybridization. Invention of DNA microarrays has revolutionized the way to monitor the gene expression. In contrast to monitoring a single gene at a time, DNA microarrays are able to simultaneously monitor the expression of thousands of genes and provide a powerful tool to potentially identify and quantify levels of gene expression for all genes at the same time (27). As mentioned earlier, searching the databases for the homologous genes is used to predict the gene function based on the information from other identified genes. However, we still need specific tools to confirm what exactly the gene does in cells. To understand how the gene is expressed and what biological function it has in the cell or organism, the most effective way is to interrupt expression of the gene and to monitor the changes in cellular functions. This can be done by replacing the normal gene with a mutant gene or inactivating the target gene. During last decade, the ‘‘antisense’’ approach has been widely used to block the synthesis of the protein by artificially providing complementary single-strand antisense nucleic acid corresponding to the target gene. However, the antisense molecules are not stable and difficult to deliver effectively to target tissues (28,29). To avoid the degradation of the antisense RNA, a stable

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

synthetic RNA analogue, morpholino-RNA, is used (30). More recently, the RNA interference (RNAi) technique has been rapidly advanced. RNAi is the process of sequencespecific and post-transcriptional gene silencing in the cells initiated by double-stranded RNA that is homologous in the sequence to the silenced gene. The RNAi was originally observed in plants, fungi, and C. elegans (31). Elbashir et al. have demonstrated that chemically synthesized 21-nt small interfering RNA (siRNA) duplexes specifically suppress the expression of endogenous and heterologous genes in different mammalian cell lines, including human 293 and Hela cells (32–34). The discoveries of siRNA-mediated RNAi in different eukaryotic species and plants suggest a highly conserved mechanism in nature. The specific pathways and mechanisms of RNAi in mammalian cells are currently under intense investigation (35). The basic mechanism of siRNA-mediated RNAi is illustrated in Figure 11. The siRNA approach provides a new effective tool for studying gene function in mammalian cells, and it has a great potential to develop the gene-specific therapeutics.

263

Transgenic Animals The development and application of transgenic technologies have made a serious impact on our understanding of complex biological mechanisms during the last decade. Application of transgenic animals in various in vivo studies has increased dramatically, and has greatly advanced our knowledge regarding biological functions of various novel proteins under physiological and pathological conditions (36). A transgenic animal is one in which its genome has been permanently modified by gene insertion, gene deletion, or gene replacement. There are two methods that are widely used to produce transgenic mice. The first method is the employment of transforming ES cells with the desired DNA in tissue culture. ES cells are harvested from the inner cell mass of mouse blastocysts. They are grown in culture and retain their full potential to produce all the cells of mature animals when they are reintroduced into a mouse blastocyst, and then the blastocyst is introduced into the uterus of a pseudopregnant female. The target gene is modified in ES cells by using homologous recombination. The second method involves injecting the desired gene into the pronucleus of a fertilized mouse egg. The transgenic animals that carry foreign genes provide the important information for regulation and function of the specific genes being studied. If the replacement gene is nonfunctional or the functional gene is deleted, the transgenic animals with a deleted or inactivated gene are called ‘‘knockout’’ animals. By using knockout mice, the biological functions of many mammalian genes have been dissected. Under various biological circumstances, knockout mice are not affected by their deficiency, because the mouse genome has sufficient redundancy to compensate for a single missing pair of alleles. Most genes are also pleiotropic; they are expressed in different tissues in different ways and at different times during development (1,11,36). The past decade has witnessed a spectacular explosion in both the development and the use of transgenic technologies. Transgenic animals are used not only to aid our fundamental understanding of biological mechanisms, but also to facilitate the development of a range of various disease models. Information obtained from transgenic approaches is now truly beginning to impact our knowledge regarding human diseases. Some of the most exciting model systems relevant to neurodegenerative disease and cancer are allowing the radical development of new therapies in vivo. Transgenic sheep and chickens are produced that express foreign proteins in their milk or in the ‘‘white’’ of eggs. These animals provide a valuable source for producing therapeutic proteins (1–5).

THE MOLECULAR ORGANIZATION OF THE CELLS Cell Signaling

Figure 11 The mechanism of siRNA-mediated RNAi in mammalian cells. The synthetic dsRNA is transfected into the cells. These siRNAs are assembled into endoribonuclease-containing complexes known as RISCs. After unwinding, the antisense strands of the siRNAs base pair with a short region of the target mRNA and result in degradation of the target mRNA. Abbreviations: dsRNA, double stranded RNA; siRNA, small interfering RNA; RNAi, RNA interference; RISC, RNA-induced silencing complex.

There are more than 200 different types of cells in the human body. Each cell is constantly exposed to hundreds of different signals from its environment. The intercellular communication network coordinates the growth, differentiation, and metabolism of various cells. Cells communicate with each other by either direct interactions or various extracellular signaling molecules. Normal functions of different cellular signaling pathways are essential to the health of the human body. The process by which various signals alter the physiology of a cell is called transduction. Many diseases such as cancer result from dysfunctions or imbalance of cell-signaling transduction (2).

medwedi.ru

264

Part One: General Considerations

Cell-signaling occurs via the initial interaction of two or more molecules. There are a variety of signaling molecules such as amino acids, peptides, proteins, nucleotides, and lipids, which are involved in the cell-to-cell communication. These molecules are synthesized and released from the signaling cells and then act on the specific target cells. Binding of the signaling molecule (ligand) to the specific protein (receptor) on the target cells triggers a cascade of intracellular signals that affect behavior of the target cells. Based on the distance between signaling molecules and their targets, intracellular signaling molecules are classified into four types: endocrine, paracrine, autocrine, and contactdependent signaling (Fig. 12). In endocrine signaling, the signaling molecules secreted from endocrine cells, known as hormones, enter the systemic circulation and then bind to the specific receptors on the target cells at remote sites. In paracrine signaling, the transmitters released from paracrine cells bind to receptors on adjacent cells to exert their biologic functions such as neurotransmitters. The action of paracrine transmitters is rapid and short compared to endocrine signaling. In autocrine signaling, the signaling molecules are released and act on the other cells of the same type as well as themselves. Many cells secrete growth factors that stimulate their own growth and proliferation. This is the major signaling mechanism of cancer cells. Another form of signaling is the contact-dependent signaling. Many signaling molecules remain bound to the cell surface of the signaling cells and interact directly with the receptors on the adjacent cells. Some signaling molecules are produced by different types of cells and act in more than one type of cell-to-cell signaling. For example, cholecystokinin (CCK) is secreted into the bloodstream by endocrine cells of the upper small intestine. However, CCK is also present in the nerves of the gastrointestinal tract and brain. Epidermal growth factor (EGF) is a membrane-bound protein hormone, which directly binds to the receptors on the adjacent cells. The EGF molecule is also released from the membrane by protease cleavage. The secreted EGF acts on distant cells as an endocrine-signaling molecule (4,37).

The cellular response to a particular signaling molecule depends on its binding to the specific receptors, which are the cell surface receptors, nucleus receptors, or cytosolic receptors. Different cell types have different receptors for the same ligand, and even the same receptor triggers different biological responses to the same ligand in different types of cells. On the other hand, different receptors induce the same cellular response in certain cell types. For example, activation of glucagon or epinephrine receptors in liver cells induces degradation of glucagon and increases the level of blood glucose. Some extracellular hydrophobic hormones such as steroids, thyroxine, and retinoic acid interact with intracellular receptors by diffusing across the plasma membrane, while some small signaling molecules such as nitric oxide and carbon monoxide directly regulate the activities of the intracellular enzymes. However, most of the extracellular signaling molecules are hydrophilic and bind to the cell surface receptors of the target cells to modulate cellular responses. The three major classes of cell surface receptors are G protein–coupled receptors (GPCRs), enzyme-linked receptors, and ion-channel receptors (2,4,11). GPCRs represent a major class of signal transduction proteins that transduce extracellular signals to the cell interior through the activation of heterotrimeric guanine nucleotide–binding proteins (G proteins). G proteins contain three subunits—a, b, and g. When G protein is activated, the Ga subunit binds guanosine triphosphate (GTP) and dissociates from bg subunits. The Ga subunit has intrinsic GTPase activity, which hydrolyzes GTP to guanosine diphosphate (GDP). Once the GTP is hydrolyzed to GDP, the GDP-bound Ga subunit will reassociate with bg subunits. It has been demonstrated that the GTPase activity of the a subunit is regulated by regulator of G protein signaling proteins, which function as a-subunit–specific GTPase-activating proteins and play an important role in shutting-off G protein–mediated responses. Receptor occupation promotes interaction between the receptor and the G protein on the interior surface of the membrane. This induces the exchange of GDP for GTP on the G protein a subunit and dissociation of

Figure 12 General pathways of cell communication. (A) Endocrine signaling. It depends on endocrine cells, which secrete hormones into the bloodstream that are then distributed widely throughout the body. (B) Paracrine signaling. It depends on signals that are released into the extracellular space and act locally on neighboring cells. (C) Autocrine signaling. A group of identical cells produces a higher concentration of a secreted signal than does a signal cell. When this signal binds back to a receptor on the same cell type, it encourages the cells to respond coordinately as a group. (D) Contact-dependent signaling. This signaling pathway requires cells to be in direct membrane–membrane contact. Many of the same types of signaling molecules are used in all of four signaling pathways and critical differences lie in the speed and selectivity with which the signals are delivered to their targets.

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

265

Figure 13 The structure of seven transmembrane G protein– coupled receptors. Most of the GPCRs belong to the seven transmembrane superfamily of transmenbrane receptors. A typical GPCR possesses seven transmembrane helices, which contain roughly 20 to 25 amino acids. Upon binding of the specific ligands on one side of the membrane, these receptors activate G proteins on the other side. Activated GPCRs further initiate a cascade of events regulating cell proliferation, cell survival, and cell migration.

the a subunit from the bg heterodimer. Depending on its isoform, the GTP-a subunit complex mediates intracellular signaling either indirectly by acting on effector molecules such as adenylyl cyclase and phospholipase C (PLC) or directly by regulating the activity of ion channels or kinases (38). More than 2000 GPCRs have been reported since bovine opsin was cloned in 1983 and the b-adrenergic receptor in 1986. They are classified into over 100 subfamilies according to the sequence homology, ligand structures, and receptor functions. The ligands for the GPCRs include ions, organic odorants, amines, peptides, proteins, lipids, nucleotides, and photons. The GPCRs can be single- or multitransmembrane proteins. Most of the GPCRs are seven transmembrane proteins, which have a similar structure (Fig. 13). The GPCRs contain an extracellular N-terminal segment, seven transmembrane segments (TMs), three extracellular loops, three intracellular loops, and a C-terminal segment. Each of the seven TMs is generally composed of 20–35 amino acids. However, the lengths of N-terminal segments, loops, and C-terminal segments at different receptors are substantially variable. Although the majority of GPCRs mediate signal transduction via G proteins, some of these receptors are also capable of sending signals via a number of other signal molecules, including Jak2 kinase, PLCg, or protein kinase C. Differences in agonists and effectors provide an early hint of the remarkable diversity of situations in which GPCRs are employed to select, amplify, and transmit signals from the external environment to elicit cellular responses and modify functions (39–42). These receptors play an important physiological role, and their dysfunctions are involved in the pathogenesis of various diseases. GPCRs are also the most common targets for drug development at present. It has been estimated that more than half of all modern drugs target the GPCR-signaling pathway, and the effects of more than 30% of the top 100 marketed drugs are mediated directly or indirectly through an activation or blockade of GPCR-mediated receptors (43). Enzyme-linked receptors are the second major type of cell-surface receptors, which are activated by extracellular signaling proteins and promote cell proliferation, differentiation, and survival. Similar to GPCRs, enzyme-linked receptors also are transmembrane proteins, but only span the plasma membrane once. The ligand-binding domain is located on the outer surface of the plasma membrane. The intracellular domain has the intrinsic enzyme activity or is coupled to intracellular enzymes. Based on the type of enzymatic activity during signal transduction, they are classified into five subtypes: (i) tyrosine kinase receptors such as insulin-like growth factor, platelet-derived growth factor,

EGF, and fibroblast growth factor receptors, which phosphorylate the specific tyrosine residues on the intracellular signaling proteins; (ii) tyrosine kinase–associated receptors, which are associated with tyrosine kinase proteins; (iii) receptor-like tyrosine phosphatases, which remove phosphate groups from tyrosine of specific signaling proteins; (iv) receptor serine/threonine kinases such as transforming growth factor beta and bone morphogenetic proteins, which phosphorylate the specific serine or threonine to transduce the intracellular signals; and (v) receptor guanylate cyclases such as natriuretic peptide receptors, which catalyze the production of cyclic GMP in the cytosol. The activation of enzyme-linked receptors is essential for a variety of biological functions (2). Ion-channel receptors are the simplest signal transducers and form holes or pores in the plasma membrane and open or close in response to the ligand binding or changes in transmembrane potential. The ion channels are selective for the ions that pass through and generally allow passage of either anions or cations, but not both. The way through which the ion passes through channels is passive in general. There are three types of ion-channels: (i) ligand-gated ion channels, which transfer the chemical signal to electrical signal, such as nicotinic acetylcholine receptor; (ii) voltagegated ion channels such as voltage-gated Naþ channels, voltage-gated Kþ channels, and voltage-gated Ca2þ channels, which are responsible for the generation of action potentials in electrically excitable cells; and (iii) mechanically gated channels. The ion channels transduce a signal by either changing the cytosolic concentration of an ion such as Ca2þ or altering transmembrane electrical potential (2).

Cell Proliferation and the Cell Cycle The ability of cells to grow and divide underlies the propagation of life. The cell cycle is the ‘‘program’’ for cell growth and cell division (proliferation). There are four phases of the cell cycle: G1 (and G0), S, G2, and M (Fig. 14). The G1 phase is characterized by gene expression and protein synthesis, which enables the cell to produce all the necessary proteins for DNA synthesis, and primes the cell to enter the S phase. This is the only phase of the cell cycle that is regulated primarily by extracellular stimuli. The length of G1 phase depends on the extracellular conditions and signals. During the S phase, the cell replicates its DNA once, which allows the cell to divide into two daughter cells, each with a complete copy of DNA. Before the cells do this, they need to enter the third phase of the cell cycle: the G2 phase. The G2 phase provides additional time for cells to synthesize

medwedi.ru

266

Part One: General Considerations

Figure 14 The phases of the cell cycle in mammalian cells. The cell grows continuously and the cell cycle consists of four phases: G1 (first gap) phase, S (DNA synthesis) phase, G2 (second gap) phase, and M (mitosis) phase. Progression through the cell cycle is highly regulated by a conserved family of serine/threonine protein kinases that are composed of a regulatory subunit (the cyclins) and a catalytic subunit (the cyclindependent kinases). During the cell cycle progression, both G1 to S phase transition and G2 to M phase transition are critical checkpoints.

proteins and primes them to be able to divide. During the G2 phase, the cell monitors the faithful completion of S phase. Once this is complete, the cell finally enters the fourth and final phase of the cell cycle: the M phase. At the M phase, the cell divides (called cytokinesis) into two daughter cells. The newly divided cells can either start the cycle again by entering G1 phase or become quiescent by entering G0 (2). The cell cycle is primarily regulated at two checkpoints, the G1/S and the G2/M transitions, which are tightly controlled by heterodimeric proteins composed of the catalytic subunit and the regulatory subunit that determine substrate specificity (44). The protein kinase activity of the catalytic subunits depends on the formation of heterodimeric complex with various cyclins, which are called cyclin-dependent kinases (CDKs). The cyclin–CDK complexes phosphorylate many other proteins, which regulate DNA replication and mitosis. Different cyclin–CDK complexes choreograph the passage of cells through the different phases. There are four classes of cyclins that bind to CDKs at different stages of the cell cycle: G1/S-cyclins, S-cyclins, M-cyclins, and G-cyclins. The activities of CDKs are regulated by extracellular stimuli through cyclin binding, phosphorylation, dephosphorylation, and the binding to CDK inhibitors (45). The rate of cell proliferation is mainly determined by the relative proportion of cycling cells versus quiescent cells. Uncontrolled or inappropriate cell growth and proliferation contribute to the development of cancers (46,47).

Cell Migration Cell migration is an important process that is involved in a variety of normal and pathological events, including embryo development, wound healing, and the abnormal and life-threatening movement of cancer cells. The ability of cells to adapt a variety of shapes and to carry out coordinated and directed movements is a complex process that is regulated through multiple signaling pathways. Cell migration is the result of a series of coordinated cellular events, including lamellipodial extension and retraction, cortical transport of myosin and actin, contraction of transverse fibers, and tail retraction (26). Understanding the signals that start, direct, and stop cell migration is one of the central questions of modern biology, and the current knowledge regarding the regulation and control of cell

motility is reviewed and presented in detail in several textbooks (1–5).

Apoptosis All cells have a limited lifespan. There are two forms of cell death. Cell death caused by external factors such as mechanical damage and injurious agents is called necrosis, which is characterized by swelling, leaking of cell contents, and inflammation of surrounding tissues. Cells are also induced to commit suicide, which is called programmed cell death or apoptosis. Apoptosis is a genetically regulated form of programmed cell death defined by distinct morphological and biochemical features. These features include membrane blebbing, chromatin condensation, cell shrinkage, DNA fragmentation, release of cytochrome c, and apoptotic body formation (48). Apoptosis is an important physiologic process and regulates tissue homeostasis by balance in cell number between newly divided and surviving cells. Defects of apoptosis are implicated in many diseases such as hyperplasia and cancers (49). Two major classes of proteins involved in regulation of apoptosis are the Bcl-2 family and the caspase family (50,51). The Bcl-2 proteins were initially isolated from human follicular lymphoma cells and comprising both proapoptotic and antiapoptotic members, which are the major intracellular regulators of apoptosis. There are more than a dozen kinds of proteins that have been identified as the members of Bcl-2 family such as Bcl-2, BclXL, Bax, Bak, and Bad. All members possess at least one of four conserved motifs known as Bcl-2 homology domains (BH1 to BH4), which control the ability of these proteins to dimerize and act as a checkpoint upstream of caspases and mitochondrial dysfunction (48,52). Caspases as essential mediators of apoptosis are highly specific proteases that cleave proteins exclusively at aspartic acid residues and regulate proteolysis during the apoptotic cell death. The substrate specificity of these proteins is determined by the sequence of three amino acids before the aspartate residue (53). There are three different pathways by which cells commit suicide through apoptosis. The first is the intrinsic or mitochondrial pathway, which is triggered by internal signals. In healthy cells, the internal damage results in the release of cytochrome c and Apaf-1 protein, which are normally bound to Bcl-2 on the outer membranes of mitochondria. The released cytochrome c and Apaf-1 bind to molecules of caspase-9, which sequentially activate other caspases and results in the degradation of chromosomal DNA, digestion of structural proteins in the cytoplasm, and phagocytosis of the cell. The second pathway is known as the death receptor pathway that is triggered by external signals. This pathway is particularly important in the immune system. The death receptors such as Fas/CD95 and tumor necrosis factor receptor are integral membrane proteins with their receptor domains exposed on the surface of the cell and a conserved protein–protein interaction module (called death domain) in the cytoplasm. Binding of the complementary death activators transmits the signal to the cytoplasm that leads to activation of caspase-8, which initiates a cascade of other caspase activation and results in the phagocytosis of the cell. The third pathway is mediated by apoptosis-inducing factor (AIF), which is the protein normally located in the intermembrane space of mitochondria. This pathway is usually triggered by dangerous reactive oxygen species such as hydrogen peroxide, hypochlorite ion, and hydroxyl radical and superoxide anion. The released

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

AIF binds to the DNA in the nucleus and results in the destruction of DNA, leading to cell death (2). In summary, apoptosis is a central regulator of tissue homeostasis in multicellular organisms. Cells that are no longer needed or are a threat to the body are destroyed by apoptosis. Apoptosis is mediated by proteolytic enzymes called caspases that cause cell death by cleaving specific proteins in the cytoplasm and nucleus. The activation of caspases is initiated by either extracellular or intracellular death signals, and is regulated by members of the Bcl-2 and IAP protein families. Disruption of apoptosis is responsible for a variety of diseases such as autoimmune diseases and cancers.

Gut Mucosal Wounds and Healing Gastrointestinal mucosal wounds and injury occur in circumstances commonly encountered in daily life, from mild physical trauma during digestion to localized damage from the ingestion of alcohol, aspirin, and/or nonsteroidal anti-inflammatory compounds, or from Helicobacter pylori infection. Acute mucosal injury also occurs in critical illnesses including various surgical conditions such as trauma, thermal injury, shock, and sepsis. After injury, the mucosal tissue exhibits a spectrum of responses. In an acute response to injury, damaged cells are sloughed, and remaining viable cells from areas adjacent to or just beneath the injured surface migrate to cover the denuded area. This early restitution is independent of cell proliferation and appears to be an initial host response to prevent noxious agents from causing deeper tissue damage (54). In contrast to this rapid repair process, deeper damage and chronic ulcers manifest long-term complex responses that require de novo mRNA and protein synthesis and cell replication. Altered gene regulation in response to wounding or ulceration results in an increase in cell proliferation to replace lost cells (52). Over the last decade, considerable progress has been made in understanding the roles of early primary response genes in events responsible for the process of cell renewal during ulcer and wound healing in the gastrointestinal mucosa and other tissues. Most of these early primary response genes belong to the family of proto-oncogenes and are responsible for control of the cell cycle. Because the expression of these early primary response genes is rapid and transient following injury or when normal quiescent cells are exposed to mitogenic substances, they have been thought to act as mediators linking short-term signals, immediately after cell surface stimulation, to proliferation by regulating the activation of specific genes. These early primary response genes such as proto-oncogenes code for sequence-specific DNA binding nuclear proteins with a potential to influence directly the expression of specific genes at the transcriptional level. Therefore, activation of early primary response gene expression plays important roles in healing following the wounding of the gastrointestinal mucosa and other tissues. Normal cells respond to wounding by altering rapidly the expression of various genes whose products are central to cell migration and proliferation. In the early response following injury, the increased synthesis of transcription factors is critical to the modulation of expression of cell-type specific or developmentally regulated genes (55,56). This provides a pathway for controlling the expression of a gene whose product is infrequently required under physiological conditions. The process of transcription is a fundamental element in gene expression and is an attractive control point for the regulation of gene activation. The region immediately upstream of the transcribed sequence contains two

267

types of elements: (i) sequences involved in the process of transcription itself and (ii) sequences found in genes transcribed in a particular tissue or in response to a specific signal. These tissue- and stimulus-specific sequences are implicated in selective cellular responses to wounding and to growth factors or cytokines. Transcription factors are regulated to become active only in the appropriate cell type or in response to the appropriate stimulus. One of the mechanisms responsible for the control of transcription factor activity is the regulation of the synthesis and degradation of the factor itself. The other is the regulation of the activity of the pre-existing factor. Although low basal expression of the nuclear protooncogenes c-fos, c-jun, and c-myc is observed in most cells, their expression is rapidly and transiently induced following wounding in vivo as well as in vitro (55,56). The products of these proto-oncogenes are nuclear transcription factors that bind to specific DNA sequences in the vicinity of target genes, leading to the activation of ‘‘second responsive genes’’ in generative tissues following injury. Recently, CDK4 and p21 were identified as target genes of c-myc. This is significant because c-myc activation stimulates expression of the CDK4 gene, but represses the p21 promoter activity, providing a direct link between c-myc and cell-cycle regulation. In addition to AP-1 and c-myc, there are additional cis-acting elements, including the serum responsive element of SP1/SP2, the NF-kB binding site, and the AP-2 activation site, which also may be involved in the process of wound healing. These elements are recognized by transcription factors distinct from AP-1 and c-myc, but their activity is modulated by exposure to phorbol esters or other protein kinase C activators.

NOVEL TREATMENT STRATEGIES IN MODERN SURGICAL CARE Gene Therapy Gene therapy is an exciting and powerful tool that offers new opportunities for potential treatment and prevention of a wide array of diseases (57–59). Instead of giving a patient a traditional chemical drug to treat or control the symptoms of a genetic disorder, gene therapy is directed at actually treating the basic problem by altering the genetic makeup of the patient’s cells through the use of targeted and relatively nontoxic therapy, which can identify, disable, and destroy sick cells. For example, the gene therapy for cancers involves the manipulation of intracellular DNA to control or kill malignant cells. Cancer gene therapy has the potential to provide highly selective and curative cancer treatment without systemic toxicity, depending on our understanding of tumor biology, methods for gene delivery to specific cell types, and strategies to regulate the levels and duration of gene expression. In order for the transgene to work in patients, the gene of interest must be inserted into a vector adjacent to a promoter that induces transcription. Then the construct is packaged and delivered to a specific target cell, transcribed, and expressed in a concentration high enough to have an effect. Typically, the transfer of transgene constructs into living cells is accomplished by using viral or nonviral vectors. Viral vectors are used in the majority of gene therapy studies because of their higher efficiency of gene transfer compared to nonviral techniques. Viral vectors for gene therapy may be RNA- or DNA- virus based. To date, the RNA viruses include the retroviruses such as murine leukemia virus and mouse

medwedi.ru

268

Part One: General Considerations

mammary tumor virus, the lentiviruses derived from human immunodeficiency virus, and the spumaviruses. The DNA viruses include adenovirus, adeno-associated viruses, vaccinia virus, and herpes simplex virus. Because viral vectors are designed to be replication deficient, they cannot spread outside the transfected target cells. However, some viral vectors are replication competent or replication attenuated, permitting viral replication in permissive cells.The selection of the viral vectors for the gene therapy of particular tissues or diseases is based on (i) their maximum permissible transgene size, (ii) transfection efficiency and maximum viral titer attainable, (iii) tendency to provoke inflammatory and immune response, (iv) persistence of gene expression and ability to transduce nondividing cells, and (v) target cell specificity and impact on the host genome. Several nonviral gene transfer systems are currently available to introduce a new genetic material into mammalian cells (60). These methods include the direct tissue injection of DNA, the transfection across the cell membrane using liposomes, peptide delivery systems, and polymer vectors. Although various nonviral gene transfer approaches are nontoxic and nonimmunogenic, their efficiency of gene transfer is lower than that achieved by using viral vectors. ‘‘Naked’’ DNA vectors (plasmids) are unsuitable for systemic administration because they are rapidly degraded by serum nucleases. However, direct injection of DNA vectors into specific tissues such as muscle and the gut mucosa can produce transient low levels of gene expression. Cationic liposomes are positively charged lipid bilayers that form vesicles with negatively charged DNA vectors on the external surface and are also able to package large transgenes, but the efficiency gene transfer is low. DNA–protein complexes are developed by using naturally occurring or synthetic peptides as gene delivery systems. The DNA-binding peptides coupled to cell-specific ligands allow receptor-mediated targeting of the peptide/DNA complexes to specific cells types. Hybrid vectors that combined both viral and synthetic approaches have also been devised and are currently under extensive investigation. It has been shown that DNA complexed to polylysine or DEAE-dextran–conjugated adenovirus improves gene transfer efficiency dramatically. The current in vivo trials for gene therapy face several challenging questions, although a number of in vitro experiments have shown great promise. These difficult issues include patient safety, vector design, improvement of in vivo gene delivery, transfer efficiency, and gene regulation after cellular transduction.

Cell Therapy Cell therapy provides an alternative approach that overcomes some of the shortcomings of gene therapy. Cell therapy is a new concept to repair diseased organs by using genetically modified cell grafts that are initially transfected ex vivo with excellent long-term efficiency, and then transplanted to the targeted organs (57,61–63). Cell therapy is subdivided into two principally different approaches: (i) implantation of isolated cells and (ii) implantation of in vitro engineered tissue constructs. Generally, cell therapy is applied for the treatment of a variety of diseases at three different levels: (i) to replace absent or malfunctioning cells, (ii) to modify the biological functions of targeted organs by using cell grafts genetically engineered to express specific proteins, and (iii) to modify the targeted organ environment by local secretion of specific recombinant proteins.

During the past two decades, several attempts have been made in order to find a new strategy to treat diseased organs such as injured spinal cords, heart failure, cancers, and diabetes in experimental animals, which provide a novel therapeutic approach for some critical illnesses in humans. Cell therapy is one of these new therapeutic strategies to restore the normal functions of injured organs by transplantation of the appropriate cell populations. To do so, cell therapy requires the following steps: (i) establish the proper cell sources for transplantation, (ii) in vitro assessment of the phenotypic structural and functional properties of the cell grafts, (iii) establish transplantation strategies to deliver the cells to the desired locations, and (iv) achieve the desired in vivo effect by assuring the survival of the cell grafts, their integration and interactions with host tissue, and their proper function. A critical limitation for the development of cell replacement strategies is the limitation of cell sources for humans. One solution to this cell-sourcing problem is to use the recently described human ES cell lines (57). These unique cell lines are able to be propagated in vitro in the undifferentiated state in large quantities and to be coaxed to differentiate to a plurality of cell lineages. It has been shown, for example, that ES cells cultured in the specific differentiating system are not limited to the generation of isolated cardiac cells, but rather a functional cardiac syncytium is generated with a stable pacemaker activity and electrical propagation that also respond to adrenergic and cholinergic stimuli. There is no doubt that application of ES cells is of great value for future cell therapy strategies, although a number of ethical, psychological, and legal implications are envisioned and will need to be addressed.

Oncologic Surgery The significant advances in cellular and molecular biology, especially the Human Genome Project, will have farreaching effects on diagnostic studies, treatment, and counseling of cancer patients and their family members. Microarray technology using DNA ‘‘chips’’ provides one of the most promising approaches to large-scale studies of genetic variations and detection of gene mutations and gene expression for cancer patients and high-risk populations (64). DNA chips generally consist of a thin slice of glass or silicone about the size of a postage stamp on which threads of synthetic nucleic acids are arrayed, and thousands of gene expression can be determined on a single DNA chip. For example, microarray technology has been applied to detect HIV sequence variation, p53 gene mutation in breast tissue, and expression of cytochrome P-450. This new technology is also used to make genomic comparisons across species, genetic recombination, large-scale analysis of gene copy number and expression, and protein expression in cancers. Based on cellular and molecular evidence for potential development of various cancers in high-risk groups, surgeons are going to play a critical role in both genetic assessment and ultimate therapy. There are several successful applications in this new area. For example, the new finding regarding the association between mutations of the ret proto-oncogene and hereditary medulary thyroid carcinoma allows surgeons to identify patients in whom medulary thyroid cancer will eventually develop. In addition, clinical molecular evidence by genetic screening for mutations of the ret proto-oncogene in patients with the multiple endocrine neoplasia type-II syndrome allows prophylactic thyroidectomy to be performed at an earlier stage of the disease process than does traditional biochemical screening. Other

Chapter 12: Application of Cellular and Molecular Biology in Modern Surgical Practice

application of cellular and molecular biology in modern surgical practice is to test patients with familial adenomatous polyposis in which the timing and extent of therapy are dependent on exact location of the adenomatous polyposis coli mutations. Furthermore, although it is still controversial, some patients will receive early surgical treatment based on identification of the mutations of the breast cancer susceptibility genes such as BRCA-1 and BRCA-2. There is no doubt that surgical cancer treatment protocols will be improved significantly because more information becomes known regarding mutations of these genes and the clinical implications of these mutations.

Tissue Engineering and Transplantation Although remarkable advances have been made in organ transplantation over the past two decades, the most significant limitation is the availability of suitable organs. There is an increasing concern that the level of organ and tissue demand cannot be met by organ donation alone. It has been proposed for many years that xenotransplantation is a possible solution to the problem of organ availability and suitability. Although several critical studies have been carried out to elucidate the possibility of using xenotransplanted organs and short-term successes have been reported, there have been no long-term survivors using these techniques. Based on information from the fields of genomics and structural biology, it is possible that scientists will be able to genetically engineer tissues and animals to potentially have more specific combinations of human antigens. Animals can be developed whose immune systems are engineered to more closely resemble that of humans, thus decreasing the dependence on organ donors. The current progress of cellular and molecular biology, especially the successful cloning of sheep and cattle, also offers another possibility to address the organ donation problem by the potential for organ cloning. Recently, this concept and possibility has received a considerable amount of attention. Although the issue of whole animal cloning is fascinating, the growing field of stem cell biology is the greatest hope for transplant patients. Based on the characterization of human stem cells and the information gathered from the Human Genome Project, scientists are already able to develop organ-cloning techniques that will most assuredly revolutionize the field of transplantation in the future. Human ES cells have the ability to divide without limitation and give rise to many types of differentiated and specialized tissues with a specific purpose. It is anticipated that scientists will genetically engineer tissues for the purpose of human organ transplantation by the identification of human ES cells and the potential modification of these cells via gene therapy.

SUMMARY This chapter provides an overview of the tremendous advances that have been made in cellular and molecular biology over the past two decades and the impact this knowledge has had and which will continue to have on the management of surgical disease. It is which anticipated that application of this information will become even more extensive during the next decade and that many of the diseases currently treated by surgical manipulation will lend themselves either partially or completely to alteration of fundamental molecular processes within cells. As such, it is mandatory that the modern surgeon be aware of this knowledge explosion and how advances in

269

molecular biology can be employed to more effectively treat surgical disease.

REFERENCES 1. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 4th ed. New York: Garland Science, 2002. 2. Pollard TD, Earnshaw WC. Cell Biology. 1st ed. Philadelphia: Saunders, 2002. 3. Brown TA. Genomes. New York: John Wiley & Sons Inc, 1999. 4. Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J. Molecular Cell Biology. 4th ed. New York: W.H. Freeman and Company, 1999. 5. Hawley RS, Mori CA. Human Genome-A User’s Guide. Academic Press, 1999. 6. Collins FS, Morgan M, Patrinos A. The human genome project: lessons from large-scale biology. Science 2003; 300:286–290. 7. Watson JD, Gilman M, Witkowski J, Zoller M. Recombinant DNA. 2d ed. New York: Scientific American Books, 1992. 8. Hawkins J. Deoxyribonucleic acid (DNA). In: Gene Structure and Expression. 3rd ed. New York: Cambridge University Press, 1996:1–18. 9. Bogenhagen DF. Repair of mtDNA in vertebrates. Am J Hum Genet 1999; 64:1276–1281. 10. Belson DL, Cox MM. Lehninger Principles of Biochemistry. 3rd ed. New York: Worth Publishers, 2000. 11. Ko TC, Evers M. Molecular and Cell Biology. In: Townsend CMJ, ed. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 16th ed. W.B. Saunders Company, 2001:13–27. 12. Macarthur M, Hold GL, El-Omar EM. Inflammation and Cancer II: role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol Gastrointest Liver Physiol 2004; 286: G515–G520. 13. Zhou H, Das S, Murthy KS. Erk1/2- and p38 MAP kinasedependent phosphorylation and activation of cPLA2 by m3 and m2 receptors. Am J Physiol Gastrointest Liver Physiol 2003; 284:G472–G480. 14. Battye FL, Light A, Tarlinton DM. Single cell sorting and cloning. J Immunol Methods 2000; 243:25–32. 15. Battye FL, Shortman K. Flow cytometry and cell-separation procedures. Curr Opin Immunol 1991; 3:238–241. 16. Hirai H. Stem cells and regenerative medicine. Hum Cell 2002; 15:190–198. 17. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495–497. 18. Smith HO, Marley GM. Purification and properties of HindII and HindIII endonucleases from Haemophilus influenzae Rd. Methods Enzymol 1980; 65:104–108. 19. Jones SS, D’Andrea AD, Haines LL, Wong GG. Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood 1990; 76:31–35. 20. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chainterminating inhibitors. Proc Natl Acad Sci USA 1977; 74: 5463–5467. 21. Gillaspy AF. Sequencing using fluorescent-labeled nucleotides. Methods Mol Biol 2003; 235:195–202. 22. Collins FS. Shattuck Lecture–Medical and social consequence of the Human Genome Project. N Engl J Med 1999; 341: 28–37. 23. Machius M. Structural biology: a high-tech tool for biomedical research. Curr Opin Nephrol Hypertens 2003; 12:431–438. 24. Liao M, Fang F. Yeast one-hybrid system—one effective method studying DNA-protein interaction. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2000; 22:388–391. 25. Westerlund-Wikstrom B. Peptide display on bacterial flagella: principles and applications. Int J Med Microbiol 2000; 290: 223–230.

medwedi.ru

270

Part One: General Considerations

26. Morrill PR, Millington RB, Lowe CR. Imaging surface plasmon resonance system for screening affinity ligands. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 793:229–251. 27. Linn SC, van de RM, Giaccone G. Novel approaches; improved diagnostics and therapeutics with DNA microarrays. II. Applications. Ned Tijdschr Geneeskd 2003; 147:800–804. 28. Fire A. RNA-triggered gene silencing. Trends Genet 1999; 15: 358–363. 29. Matzke M, Matzke AJM, Kooter JM. RNA: guiding gene silencing. Science 2001; 293:1080–1083. 30. Heasman J. Morpholino oligos: making sense of antisense? Dev Biol 2002; 243:209–214. 31. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by doublestranded RNA in Caenorhabditis elegans. Nature 1998; 391: 806–811. 32. Elbashir SM, Harborth J, Weber K, Tuschl T. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods 2002; 26:199–213. 33. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001; 411: 494–498. 34. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21-and 22-nucleotide RNAs. Genes Dev 2001; 15: 188–200. 35. Pickford AS, Cogoni C. RNA-mediated gene silencing. Cell Mol Life Sci 2003; 60:871–882. 36. Grosveld F, Kollias G. Transgenic Animals. San Diego: Academic Press Inc., 1992. 37. Shetzline MA, Liddle RA. Gastrointestinal hormones and neurotransmitters. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Diseases: Pathophysiology, Diagnosis, and Management. 7th ed. Philadelphia: Saunders, 2002:3–20. 38. Marinissen MJ, Gutkind JS. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 2001; 22:368–376. 39. Ji TH, Grossmann M, Ji I. G Protein-coupled Receptors–I: diversity of receptor-ligand interactions. J Biol Chem 1998; 273: 17299–17302. 40. Lefkowitz RJ. G Protein-coupled Receptors–III: new roles for receptor kinases and beta-arrestins in receptor signaling and desensitization. J Biol Chem 1998; 273:18677–18680. 41. Gether U, Kobilka BK. G Protein-coupled Receptors–II: mechanism of agonist activation. J Biol Chem 1998; 273: 17979–17982. 42. Vaughan M. G Protein-coupled Receptors. J Biol Chem 1998; 273:17297. 43. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 2003; 63:1256–1272.

44. Woo RA, Poon RY. Cyclin-dependent kinases and S phase control in mammalian cells. Cell Cycle 2003; 2:316–324. 45. Fischer PM. Recent advances and new directions in the discovery and development of cyclin-dependent kinase inhibitors. Curr Opin Drug Discov Devel 2001; 4:623–634. 46. Vermeulen K, Berneman ZN, Van Bockstaele DR. Cell cycle and apoptosis. Cell Prolif 2003; 36:165–175. 47. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 2003; 36:131–149. 48. Otsuki Y, Li Z, Shibata MA. Apoptotic detection methods— from morphology to gene. Prog Histochem Cytochem 2003; 38: 275–339. 49. Nicholson DW, Thornberry NA. Apoptosis–life and death decisions. Science 2003; 299:214–215. 50. Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 1999; 274:20049–20052. 51. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281:1322–1326. 52. Wang JY. Expression of early primary response genes in healing of gastrointestinal mucosal injury. In: Cho CH, Wang JY, eds. Gastrointestinal Mucosal Repair and Experimental Therapeutics. Switzerland: S Karger AG, 2002:82–100. 53. Thornberry NA. Caspases: key mediators of apoptosis. Chem Biol 1998; 5:R97–R103. 54. Silen W, Ito S. Mechanisms for rapid-epithelialization of the gastric mucosal surface. Annu Rev Physiol 1985; 47:217–229. 55. Wang JY, Johnson LR. Expression of proto-oncogenes c-fos and c-myc in healing of gastric mucosal stress ulcers. Am J Physiol Gastrointest Liver Physiol 1994; 266:G878–G886. 56. Makino R, Hagashi K, Sugimura T. c-myc transcript is induced in rat liver at very early stage of regeneration or by cycloheximide treatment. Nature 1984; 310:697–698. 57. Hochedlinger K, Jaenisch R. Nuclear transplantation, embryonic stem cells, and the potential for cell therapy. N Engl J Med 2003; 349:275–286. 58. Fink D, Mata M, Glorioso JC. Cell and gene therapy in the treatment of pain. Ad Drug Deliv Rev 2003; 55:1055–1064. 59. Hughes RM. Strategies for cancer gene therapy. J Surg Oncol 2004; 85:28–35. 60. Baltzer A, Lieberman JR. Regional gene therapy to enhance bone repair. Gene Ther 2004; 11:344–360. 61. Menasche P. Cell therapy of heart failure. C R Biol 2002; 325: 731–738. 62. Gepstein L, Feld Y, Yankelson L. Somatic gene and cell therapy strategies for the treatment of cardiac arrhythmias. Am J Physiol Heart Circ Physiol 2004; 286:H815–H822. 63. Ramon-Cuete A, Santos-Benito FF. Cell therapy to repair injured spinal cords: olfactory ensheathing glia transplantation. Restor Neurol Neurosci 2001; 19:149–156. 64. Khan J, Bittner ML, Chen Y. DNA microarray technology: the anticipated impact on the study of human disease. Biochim Biophys Acta 1999; 1423:M17–M28.

13 Physiologic Principles in Preparing Patients for Surgery Henry J. Schiller, Kara C. Kort, and Lelan F. Sillin

INTRODUCTION Surgery can be considered ‘‘controlled trauma’’ that predictably alters the patient’s normal physiology. These physiologic derangements may be more severe, and less well tolerated, in patients with concurrent illnesses such as coronary artery disease or chronic obstructive pulmonary disease (COPD). The potential benefits of an operative procedure must be balanced against the potential risks of the procedure and the risks and benefits of management alternatives. It is imperative that the surgeon be able to recognize those features that may increase a patient’s expected morbidity or mortality and to modify the perioperative management and operative plan accordingly. Just as ‘‘an ounce of prevention is better than a pound of cure,’’ anticipating the patient’s expected clinical course provides a better outcome than reacting to what may have been a preventable complication. An optimal outcome in surgery requires a thoughtful diagnostic workup, careful perioperative care, appropriate surgical procedure, and conscientious follow-up. Preoperative care remains an integral part of surgical care and is the ultimate responsibility of the surgeon. While preparing a patient for surgery may become routine, it is better to understand the physiologic principles involved rather than simply issuing ‘‘standard orders’’ by rote. A thoughtful evaluation based on a thorough knowledge of the natural history of the disease process involved, associated medical conditions, and the physiologic changes produced by them are essential for assessing the risk of treatment options and engaging in appropriate management of the patient’s problems.

GENERAL ASPECTS OF PREOPERATIVE PREPARATION A thorough history and physical examination should be performed along with a pertinent review of systems. All preoperative medications should be known, and allergies should be especially noted. Operative notes and pathology reports from prior surgical procedures frequently prove enlightening. One may obtain a general impression of the patient’s physical condition by physical examination. Often a patient may pass or fail the ‘‘look test.’’ Important features to note are the patient’s apparent nutritional status and body habitus. Simple observations may give clues to clinically important conditions; for example, breathlessness, a barrel chest, clubbing, and cyanosis may indicate COPD. Patients in distress generally display an easily recognizable picture of vigilant anxiety. A patient’s functional status should also be assessed, because this may provide an important indication of underlying cardiac disease. Age greater

than 70 has been implicated as a risk factor for postoperative cardiac complications (1). Ideally, patients should be kept nil per os (NPO) for eight hours prior to an anesthetic to minimize the risk of aspiration. They should be well hydrated, and electrolytes should be within normal limits. Any active infection should be identified and treated preoperatively.

Surgical Consent The surgeon must speak with the patient candidly about the proposed surgery. The patient should be given an explanation of the disease process, its expected course, and the indications for surgery. This should include a clear discussion of therapeutic alternatives. In discussing the specifics of the procedure, the patient should be informed of the expected rates of mortality and morbidity. Although it is unnecessary and counterproductive to intentionally frighten the patient, the surgeon has the medical, legal, and moral responsibility to inform the patient of potential complications or adverse outcomes. This is best done in the presence of a family member or another witness to prevent later misunderstandings. The risk of bleeding should be specifically discussed with the patient, and specific consent for the transfusion of blood products must be obtained. It is also desirable to obtain advance directives from the patient, in the event the patient is unable to participate in medical decisionmaking later in the course of the disease. Finally, the patient should be told what to expect postoperatively, including the tubes and lines one is likely to have in place, the amount of pain one is likely to experience despite analgesia, and regimens one is likely to undergo. Clear and honest communication increases the patient’s confidence in the care he or she is receiving and will serve to strengthen the patient–physician relationship.

Nutrition A patient’s nutritional stores may be rapidly depleted by perioperative fasting and dietary restrictions. Moreover, the patient who is poorly nourished at the outset has fewer reserves and tolerates fasting poorly. Although fluid and electrolyte losses from recent emesis or diarrhea are easily documented, there is no specific laboratory measure for malnutrition. A serum albumin of less than 3.5 mg/dL may give a crude indication of malnutrition, but its long serum half-life (18 days) makes it relatively insensitive to acute perturbations in nutrition. Serum proteins with shorter circulating half-lives, such as retinol-binding protein, prealbumin, and fibrinogen, are also acute phase proteins and therefore may be artifactually elevated by recent infection or inflammation. Ultimately, history (weight loss, dietary habits, etc.), physical examination, and

medwedi.ru 271

272

Part One: General Considerations

anthropometrics (e.g., triceps skinfold) should be used in concert with serum protein levels to determine a patient’s nutritional reserve. In general, patients weighing 80% or less of ideal body weight or patients with recent, profound weight loss (greater than 10% ideal body weight) should be considered for preoperative hyperalimentation (2,3). Enteral nutrition should be used in patients with a functioning gastrointestinal tract. Preoperative total parenteral nutrition should be given for at least 10 days preoperatively in malnourished patients. Consideration should be given for perioperative total parenteral nutrition even in wellnourished patients who will require bowel rest for more than five to seven days (3).

Obesity Obesity, an all too common disorder in industrialized nations, provides additional physiologic stress including increased work of breathing and a requirement for a higher cardiac output. Comorbidities often seen in obese patients include respiratory insufficiency, coronary artery disease, hypertension, and diabetes mellitus (4). Although the precise definitions of obesity and morbid obesity vary, in general, a patient weighing more than 130% of his or her ideal body weight is at increased risk for perioperative complications such as atelectasis, pneumonia, respiratory failure, deep venous thrombosis (DVT), or wound complications (5). In patients undergoing bariatric surgery, hypertension and sleep apnea have been identified as independent risk factors for postoperative complications (6). There is usually little that can be done preoperatively to remedy obesity. Attention must therefore be directed toward the prevention of expected postoperative complications. Preoperative incentive spirometry, DVT prophylaxis, skin care, and early mobilization postoperatively may help decrease the risk of complications.

Integument The integument is the largest organ of the body. The skin plays an invaluable role both as a barrier to conserve body heat and water and as a barrier to prevent infection from potential environmental pathogens. Trauma, or burns, that lead to major skin loss may predispose to hypovolemia from fluid loss and hypothermia from heat loss. Such patients must receive fluid resuscitation and must be kept warm. Percent skin loss may be determined by the ‘‘rule of nines’’ (7) so that an estimate of the patient’s fluid requirements may be calculated by the Parkland formula (8). Relatively minor skin trauma may predispose to infection by providing a portal of entry for resident skin flora. Skin harbors a resident microbial flora and therefore represents not only a barrier to infection, which will be compromised by a surgical incision, but also a source of microbes with which to contaminate the surgical wound. For this reason, the skin ought to be scrubbed for surgery with povidone-iodine, hexachlorophene, or chlorhexidine (9). This provides both mechanical cleansing to remove contaminants and debris and topical antiseptics to further decrease bacterial counts in the surgical field. Shaving the patient the night before surgery increases the incidence of wound infection compared to shaving just prior to the surgical incision (9). This is doubtlessly due to compromise of the skin’s microbial barrier function by microabrasions and nicks. Depilatory agents may be used in place of shaving, although risk of hypersensitivity reactions to these agents remains. Ideally, abrasions, rashes, eruptions, and furuncles are treated prior to operation, particularly in

situations in which prosthetics are to be implanted. In the event this is not possible, incisions should be planned to avoid these areas. Preoperative antibiotics possessing grampositive coverage may be given for prophylaxis.

Antibiotic Prophylaxis The incidence of postsurgical infection ranges from 2.8% to 7.6%, making it the second most common nosocomial infection, after catheter-related urinary tract infection (10). These range from simple skin infections to major sepsis, and they may have a profound impact on patient outcome and cost of care. Preexisting infections should be treated prior to elective operation to minimize the risk of postoperative infection. Prophylactic antibiotics administered perioperatively are clearly beneficial (10,11). Conversely, prophylactic antibiotics administered after the skin incision is made do not achieve the desired effect and may be detrimental to both the patient and the institution by promoting the overgrowth of antibiotic-resistant bacteria. Surgical procedures are classified as clean, clean contaminated, contaminated, or dirty. Clean cases involve no entry into the respiratory, gastrointestinal, or genitourinary tract and have no break in sterile technique. The incidence of postsurgical infection is only 2% to 5%, which decreases to 0.8% with perioperative antibiotic prophylaxis (12). Because clean surgical cases comprise approximately 75% of all procedures, unless the patient has additional risk factors for infection (Box 1), antibiotics are withheld because of the low incidence of infection. The benefit of prophylactic antibiotics is difficult to demonstrate. Clean contaminated cases involve entry into the respiratory, gastrointestinal, or genitourinary tract without gross contamination of the surgical field. The incidence of postsurgical infection is 8% to 10%, which decreases to 1.3% with antibiotic prophylaxis. Contaminated wounds include open traumatic wounds, major breaks in sterile technique, or significant spillage from the gastrointestinal tract. In these wounds, the incidence of postsurgical infection is 20%, which decreases to 10.2% with antibiotic prophylaxis. Dirty cases involve fields with established infection and carry a 40% incidence of wound infection. Therapeutic, rather than prophylactic, antibiotic coverage is indicated for these cases (12,13). Prophylactic antibiotic coverage should be chosen according to the organisms most likely to cause infection. In general, first-generation cephalosporins (i.e., cefazolin) have been used because of their broad gram-positive and Box 1 Factors Increasing the Risk of Postoperative Infection Duration of operation greater than 2 hours Emergency surgery Advanced age Placement of prosthetic material Medical conditions Preexisting infection Malignancy Diabetes mellitus Obesity Malnutrition Steroid usage Immunoincompetence Local vascular disease Source: From Ref. 13.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

273

Table 1 Bowel Preparation for Elective Colonic Surgery Preoperative day 3 2

1

0

Traditional preparation

Polyethylene glycol

Clear liquid diet Bisacodyl capsule orally at 6 P.M. Clear liquid diet Magnesium citrate 6% sodium, 296 mL orally at 10 A.M., 2 P.M., and 6 P.M. Cleansing enemas until clear rectal effluent Clear liquid diet Magnesium citrate 6% sodium, 296 mL orally at 10 A.M. and 2 P.M. Neomycin sulfate and erythromycin base, 1 g each orally at 1 P.M., 2 P.M., and 11 P.M. NPO after midnight Rectal evacuation at 7 A.M. Cefoxitin or cefotetan, intravenous perioperative administration

Regular diet as desired Regular diet as desired

Light breakfast as desired before 8 A.M. Polyethylene glycol 1 L hr orally 5 hr or until clear rectal effluent Neomycin sulfate and erythromycin base, 1 g each orally at 1 P.M., 2 P.M., and 11 P.M. NPO after midnight Rectal evacuation at 7 A.M. Cefoxitin or cefotetan, intravenous perioperative administration

Abbreviation: NPO, nil per os. Source: From Ref. 16.

gram-negative coverage, their long half-life, low cost, and low toxicity. It is important to obtain adequate tissue levels prior to operation. Repeated doses should be administered during lengthy procedures (14). Providing prophylactic antibiotic coverage beyond 24 to 48 hours is of no benefit and increases the risk of colonization or infection by antibiotic-resistant bacterial strains (15). Colonic surgery usually requires more significant preoperative regimens (Table 1). The colon contains the highest bacterial concentrations of any location in the body. The flora includes both aerobes and anaerobes. Although the latter predominate, some of the aerobes are particularly virulent (i.e., Escherichia coli). Consequently, postoperative infections are the major source of morbidity in colonic surgery. Although it is not possible to actually sterilize the colon, significant reduction in colonic flora can be achieved. A combination of mechanical colonic lavage preparation and oral nonabsorbable antibiotics prior to surgery is required to decrease infection rates (17). The standard prophylactic regimen still remains a combination of oral neomycin and oral erythromycin. Mechanical cleansing is achieved either with the traditional three-day preparation using bisacodyl, magnesium citrate, and cleansing enemas or a one-day preparation using a large volume of orally administered polyethylene glycolelectrolyte lavage solution. One-day preparations have been found to be efficacious, safe, and relatively well tolerated preoperatively, in addition to minimizing dietary alterations and reducing preoperative hospitalization (16). Systemic intravenous antibiotics are often added to this regimen (i.e., cefoxitin or cefotetan); however, it remains controversial as to whether this provides any benefit over mechanical preparation with oral antibiotics (10,17,18).

SPECIFIC ASPECTS OF PREOPERATIVE PREPARATION Risks of Pulmonary Disease Patients should be questioned regarding smoking history, chronic cough or sputum production, wheezing, or shortness of breath. Any history of chronic lung disease, pneumonia, chest injury, occupational exposures, or requirement for intubation should be obtained. Current exercise tolerance and medication use, particularly use of bronchodilators and corticosteroids, give an indication as

to the severity of pulmonary disease. The physical examination should document body habitus, respiratory rate and effort, the presence and quality of breath sounds, the anteroposterior diameter of the chest, cyanosis, and clubbing. Patients over the age of 40 or patients with a history of cigarette smoking or pulmonary disease should receive a preoperative chest X-ray examination. Patients undergoing pulmonary resection should have formal pulmonary function testing, including spirometry, room air arterial blood gas determination, and split-lung perfusion testing. ‘‘Formal pulmonary function testing has not been shown to be superior to history and physical examination in predicting postoperative pulmonary complications in abdominal and nonresective thoracic surgery (19–21). While forced vital capacity (FVC) of less than 1.5 L/min, preoperative hypercapnea of 45 mmHg or more and a forced expiratory time of nine seconds or more predict postoperative pulmonary complications, so do age of 65 years or greater, smoking of 40 pack years or more and a body mass index of 30 or more (22).’’ General anesthesia leads to depression of respiratory drive, particularly in response to hypercarbia and hypoxia. Tidal volume (TV), functional residual capacity (FRC), and thoracic volume decrease as the diaphragm loses tone and moves cephalad. The resulting atelectasis and preferential ventilation of the nondependent regions of the lungs leads to ventilation-perfusion mismatch, thereby increasing shunt fraction (21). High abdominal incisions, thoracotomy incisions, and median sternotomy predispose toward postoperative pulmonary complications. Pain and muscular splinting lead to inhibition of coughing, and a decrease in TV high abdominal incisions result in ‘‘diaphragmatic dysfunction’’ such that ventilation is more dependent on chest excursion (23). Forced expiratory volume in one second (FEV1) and vital capacity decrease from 25% to 50%, and the FRC decreases (24). Cardiac surgery may result in dysfunction of the left hemidiaphragm, probably from left phrenic nerve injury incurred either during dissection of the left internal mammary artery at the thoracic inlet or by cold injury during slush cooling of the heart (25). These predispose the patient to mucous plugging, atelectasis, and ultimately pneumonia. Although laparoscopic surgery largely avoids the muscle splinting seen with high abdominal incisions, absorption of carbon dioxide from the pneumoperitoneum

medwedi.ru

274

Part One: General Considerations

occurs, predisposing to intraoperative hypercarbia and acidosis (23,26). Smokers and patients with chronic lung disease are at increased risk for these postoperative pulmonary complications. Smoking eventually leads to COPD, but even smokers with normal pulmonary function tests (PFTs) face an increased risk of pulmonary complication. Smoking both stimulates mucous secretion and impairs the mucociliary apparatus necessary to efficiently clear these secretions. Carbon monoxide found in cigarette smoke binds hemoglobin in preference to oxygen, thereby decreasing oxygen-carrying capacity. Moreover, cigarette smoking increases airway irritability, which may lead to perioperative bronchospasm and small airway dysfunction. Current smokers undergoing surgery can expect up to a 33% rate of pulmonary complications (mucus plugging, atelectasis, pneumonia, pleural effusion, or pneumothorax). Cessation of smoking for at least two months preoperatively decreases this rate to 14.5%, and cessation of smoking for more than six months decreases the rate of pulmonary complications to that of patients who have never smoked. ‘‘Paradoxically, cessation of smoking within a month of a planned surgery may increase the risk of pulmonary complications by 14-fold (27,28). Smoking has also been noted to increase wound-healing complications in surgical patients (29,30).’’ Patients with chronic pulmonary disease either have a restrictive or an obstructive pattern. Restrictive diseases are generally characterized by a decreased FVC and total lung capacity (TLC), whereas obstructive diseases are characterized by a decrease in the ratio of FEVI/FVC. Patients with COPD such as emphysema and chronic bronchitis have an increased FRC and TLC but may have a decreased TV. Consequently, a greater respiratory rate is required to maintain an adequate minute ventilation. Carbon dioxide retention indicates severe disease. The presence of these chronic pulmonary diseases can be determined by history and physical examination. Subtle decrements in pulmonary function and the severity of overt pulmonary disease may be measured objectively by formal PFTs, including clinical spirometry and arterial blood gas determination. In abdominal and nonresective thoracic surgery, PFTs are used to assess risk for postoperative pulmonary complications and to identify those patients likely to require specialized postoperative respiratory therapy or even postoperative mechanical ventilation. ‘‘In general, formal PFTs are not superior to a detailed history and physical examination for this purpose, although an FVC of less than 1.5 L/min, an FEVI of less than 1 L/min, and a PCO2 of 45 mmHg or more do predict postoperative pulmonary complications (19–22).’’ Clinical spirometry, split perfusion lung scanning, and preoperative arterial blood gas determinations do correlate with postoperative respiratory insufficiency and mortality in patients undergoing pulmonary resection. In general, the predicted FEVI postresection should exceed 800 mL (31). ‘‘Patients preparing for general anesthesia should cease smoking at least two months beforehand (32).’’ Moreover, they should be educated preoperatively regarding the importance of deep breathing and coughing. Those with preexisting pulmonary disease should receive preoperative bronchodilator therapy with either beta-adrenergic agonists or ipratroprium bromide (an atropine derivative) (24). Patients already receiving theophylline preparations should continue them. Aminophylline should not be administered prophylactically because the toxic-to-therapeutic index is small (24). Patients with steroid-dependent COPD should receive stress-dose steroids perioperatively. Elective

operation should be avoided in patients with active pulmonary infections, and prophylactic antibiotics with activity against Haemophilus influenzae and Streptococcus pneumoniae may be administered in those with chronic lung disease to suppress endogenous bronchial flora (24). High-risk patients should additionally receive postural drainage and chest physiotherapy. Epidural analgesia may improve the diaphragmatic dysfunction seen with high abdominal incisions (23), while pleural catheter analgesia may improve the respiratory mechanics after thoracotomy (33).

Risks of Cardiovascular Disease The cardiac history should detail exercise tolerance and symptoms of angina, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, palpitations, and syncope. Any history of myocardial infarction, congestive heart failure, valvular heart disease, or arrhythmia should be elicited. Examiners should listen for murmurs, clicks, extra heart sounds (S3 and S4), rales, and bruits. Blood pressure, heart rate, and pulses should be noted, as should the presence of jugulovenous distension, peripheral edema, and hepatomegaly. The results of previous cardiac testing should be reviewed. During operation, the cardiovascular system is stressed both by anesthetic agents and by fluid shifts. The inhalation agents are generally myocardial depressants (32). Loss of vascular tone during general, spinal, or epidural anesthesia may provoke hypotension, particularly in the hypovolemic patient. Postanesthetic recovery of vascular tone may result in fluid overload. Hypothermia results in vasoconstriction, and rewarming is associated with vasodilation and consequent hypotension. Longer procedures have greater evaporative fluid and heat losses, and more extensive procedures promote greater fluid loss into the ‘‘third space.’’ The hypotension seen with induction of anesthesia can be minimized by adequate preoperative hydration. Patients requiring preoperative bowel preparation or those receiving chronic diuretic therapy may require additional fluids because of baseline volume contraction.

Hemodynamic Monitoring Basic hemodynamic monitoring is performed noninvasively with pulse and blood pressure determinations. Urine output is followed as a crude indicator of visceral perfusion. Invasive monitoring is reserved for the hemodynamically unstable patient or those with underlying cardiac disease such as congestive heart failure, recent myocardial infarction, or significant coronary artery disease. It is also useful when urine output cannot be used as an indicator of visceral perfusion, such as in patients with end-stage renal disease (ESRD) or with diabetes insipidus. The benefits derived from invasive monitoring must always be weighed against the complications, which generally include infection, thrombosis, and hemorrhage. Percutaneous arterial catheters are used in patients requiring instantaneous, continuous blood pressure monitoring or for those requiring repeated arterial blood sampling. The catheters are usually placed in the radial artery after ensuring adequate ulnar artery collateral flow to the palmar arch by the modified Allen’s test. Central venous catheters measure pressure in the superior vena cava. This equals right ventricular pressure at the end of diastole and therefore gives an approximation of right ventricular end-diastolic volume (right ventricular preload) in the normal, compliant heart. This is useful in patients with preserved myocardial function, who may

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

275

experience large fluid shifts during operation. Central venous catheters are generally inserted into either the internal jugular or the subclavian vein, although insertion into the femoral vein is also acceptable. Percutaneous insertion into the left internal jugular vein places the patient at risk for thoracic duct injury. Inadvertent arterial cannulation is risked at all insertion sites but is particularly worrisome in the subclavian position, where direct arterial compression for hemostasis is not generally possible. The subclavian approach also places the patient at risk for pneumothorax. The Swan–Ganz, or pulmonary artery, catheter provides a better indication of left-sided cardiac function. The proximal port provides a central venous pressure. The distal port provides pulmonary artery pressures and the pulmonary capillary wedge pressure, which, in the absence of severe mitral stenosis, equals left ventricular end-diastolic pressure, giving an indication of left ventricular preload. Cardiac output may also be measured by thermodilution. These values, along with blood pressure, hemoglobin concentration, and saturation may be used to calculate systemic vascular resistance, pulmonary vascular resistance, stroke work, oxygen delivery, and oxygen consumption. Complications of pulmonary artery catheter insertion are the same as those seen in central venous catheter insertion. In addition, the patient is at risk for ventricular arrhythmias, right bundle branch block, valvular injury, cardiac perforation, and pulmonary artery rupture. Moreover, catheter sepsis, endocarditis, venous thrombosis, and pulmonary infarction may develop over time. Therefore pulmonary artery catheterization should be performed only for specific indications. Specific indications for preoperative pulmonary artery catheterization include the following (34–36). 1. 2. 3.

High risk for myocardial ischemia Refractory congestive heart failure Symptomatic valvular heart disease

A prospective randomized study by Berlauk et al. (35) examined the utility of preoperative pulmonary artery catheterization in patients undergoing peripheral vascular surgery, who lacked the above indications. Patients receiving pulmonary artery catheters were optimized to the following end points: pulmonary capillary wedge pressure 8 mmHg, < 15 mmHg; cardiac index 2.8 L/min/m2; and systemic vascular resistance 1100 dyne sec cm5 (Fig. 1). The death rate was decreased from 9.5% in the control group to 1.5% in the pulmonary artery catheter group, and the overall rate of complications (intraoperative arrhythmia, tachycardia or hypotension, postoperative cardiac morbidity, or early graft thrombosis) decreased from 42.9% to 16.2%. Pulmonary artery catheterization more than 12 hours preoperatively offered no advantage to that performed immediately preoperatively. Although these patients lacked specific indications for pulmonary artery catheter insertion, patients with peripheral vascular disease are known to be at high risk for cardiac complications (37,38).

Coronary Artery Disease The cardiovascular effects of anesthesia, along with fluid shifts, may stress those patients with coronary artery disease beyond their ability to respond appropriately. Perioperative myocardial infarction and/or death may result. Myocardial ischemia will, and infarction may, occur when the myocardial oxygen demand exceeds the myocardial oxygen supply. Patients with fixed coronary artery stenoses depend on maintaining coronary artery perfusion pressure above a

Figure 1 Algorithm for preoperative cardiovascular tune-up. CV measurements were repeated after each intervention. Inotropes: dobutamine or dopamine. Vasodilators: nitroglycerin or nitroprusside. Measurement units are mmHg for pressure, dyne sec cm5 for resistance, and L/min/m2 for CI. Abbreviations: CI, cardiac index; CV, cardiovascular; PAWP, pulmonary artery wedge pressure; SVR, systemic vascular resistance. Source: From Ref. 35.

critical level to prevent ischemia. In these patients, hypotension decreases coronary artery perfusion pressure. A reduction in mean arterial pressure of just 6% may provoke myocardial ischemia (39). Coronary artery blood flow is dependent both on wall tension and diastolic filling time. In the failing ventricle, increasing preload (end-diastolic pressure) increases wall tension, thereby decreasing coronary perfusion. Tachycardia decreases diastolic filling time, also decreasing coronary perfusion (40). In hypertensive patients, myocardial oxygen demand is increased, which may provoke ischemia and infarction (40). Recent myocardial infarction increases the risk of reinfarction and death in the noncardiac surgery patient. In one study, a general anesthetic administered within three months of myocardial infarction resulted in a reinfarction rate of 37%. The rate decreased to 16% from three to six months after infarction to just 6% after six months, with an overall mortality of 50% in the reinfarcted patients (41). In the emergent setting, aggressive cardiac management with invasive hemodynamic monitoring can reduce the risk of reinfarction to approximately 6% in patients suffering myocardial infarction

medwedi.ru

276

Part One: General Considerations

within the previous six months (42). While it was previously recommended that a patient not undergo elective surgery within six months of suffering myocardial infarction, more recent recommendations from the American Heart Association allow stratification of risk during convalescence. In the absence of residual myocardium at risk by stress testing, the risk of reinfarction is low, and the patient should be able to undergo elective surgery after waiting four to six weeks (36). In 1996, the American College of Cardiology and the American Heart Association first published guidelines for perioperative cardiovascular evaluation of patients undergoing noncardiac surgery, which were subsequently updated in 2002 (36). These recommendations provide clinical markers of increased perioperative cardiovascular risk (Table 2) and estimates of functional capacity (Table 3) and stratify the cardiac risk of various noncardiac surgical procedures (Table 4). These factors are then incorporated into an algorithm to determine which patients require further cardiac evaluation prior to undergoing surgery (Fig. 2). Moreover, the use of beta-blockers for patients at risk for coronary artery disease has been shown to reduce perioperative cardiovascular complications and mortality for up to two years after surgery and should be administered preoperatively and continued postoperatively (44).

Congestive Heart Failure Left ventricular dysfunction eventually leads to cardiac pump failure. Compensatory mechanisms include ventricular dilation and hypertrophy. As the ejection fraction Table 2 Clinical Predictors of Increased Perioperative Cardiovascular Risk (Myocardial Infarction, Heart Failure, Death) Major Unstable coronary syndromes Acute or recent MI with evidence of important ischemic risk by clinical symptoms or noninvasive study Unstable or severe angina (Canadian class III or IV) Decompensated heart failure Significant arrhythmias High-grade atrioventricular block Symptomatic ventricular arrthythmias in the presence of underlying heart disease Suptaventricular arrhythmias with uncontrolled ventricular rate Severe valvular disease Intermediate Mild angina pectoris (Candian class I or II) Previous MI by history or pathological Q waves Compensated or prior heart failure Diabetes mellitus (particularly insulin-dependent) Renal insufficiency Minor Advanced age Abnormal ECG (left ventricular hypertrophy, left bundle branch block, ST-T abnormalities) Rhythm other than sinus (e.g., atrial fibrillation) Low functional capacity (e.g., inability to climb one flight of stairs with a bag of groceries) History of stroke Uncontrolled systemic hypertension The American College of Cardiology National Database defines recent MI as that occurring between 7 days and less than or equal to 30 days and acute MI as that occuring within 7 days. May include stable angina in patients who are usually sedentary. Abbreviations: MI, myocardial infarction; ECG, electrocardiogram. Source: From Refs. 36, 43.

Table 3 Estimated Energy Requirements for Various Activities 1 MET

4 METs

Greater than 10 METs

Can you take care of yourself? Eat, dress, or use the toilet? Walk indoors around the house? Walk a block or two on level groung at 2 to 3 mph or 3.2 to 4.8 km/h? Do light work around the house, such as dusting or washing dishes? Climb a flight of stairs or walk up a hill? Walk on level ground at 4 mph or 6.4 km/ h? Run a Short distance? Do heavy work around the house, such as scrubbling floors or lifting or moving heavy furniture? Participate in moderate activities such as golf, bowling, dancing, doubles tennis, or throwing a baseball or football? Participate in strenuous sports such as swimming, singles tennis, football, basketball, or skiling?

Adapted from the Duke Activity Status Index and AHA Exercise Standards. Abbreviation: MET, metabolic equivalent. Source: From Ref. 36.

decreases, end-systolic and end-diastolic volumes increase. This increases both end-diastolic and end-systolic ventricular pressures, resulting in increased wall stress, and increased myocardial oxygen consumption. As ventricular compliance decreases, cardiac output increasingly depends on diastolic filling time. Thus tachycardia is poorly tolerated (45,46). The overall five-year mortality in patients with congestive heart failure is 50% (47). Predictors of mortality include poor functional capacity, high pulmonary capillary wedge pressure, low stroke work index, spontaneous ventricular arrhythmias, and elevated plasma levels of norepinephrine and renin (46). Congestive heart failure is a risk factor for perioperative mortality (36). Treatment consists of preload reduction with sodium restriction and diuretics. Digitalis improves myocardial contractility (45). Afterload reduction with isosorbide dinitrate and hydralazine improves cardiac output and reduces long-term mortality (48). Angiotensinconverting enzyme (ACE) inhibitors improve cardiac function, probably by both afterload reduction and interruption of the sodium and water retention characteristic of congestive heart failure (49). ACE inhibitors also reduce long-term mortality (49). Beta-blockers may also be appropriate in patients without refractory heart failure (50). Table 4 Cardiac Riska Stratification for Noncardiac Surgical Procedures High (reported cardiac risk often greater than 5%) Emergent major operations, particularly in the elderly Aortic and other major vascular surgery Peripheral vascular surgery Anticipated prolonged surgical procedures associated with large fluid shifts and/or blood loss Intermediate (reported cardiac risk generally less than 5%) Carotid endarterectomy Head and neck surgery Intraperitoneal and intrathoracic surgery Orthopedic surgery Prostate surgery Low (reported cardiac risk generally less than 1%) Endoscopic procedures Superficial procedure Cataract surgery Breast surgery a

Combined incidence of cardiac death and nonfatal myocardial infarction. Do not generally require further preoperative cardiac testing. Source: From Ref. 36.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

STEP 1

STEP 2

Emergency

Need for noncardiac surgery Urgent or elective surgery

No Yes

Coronary revascularization within 5 yr? No

STEP 3

Postoperative risk stratification and risk factor management

Operating room

surgery

277

Recurrent symptoms or signs?

Yes

Recent coronary angiogram Favorable result and or stress test? no change in symptoms Unfavorable result or

Yes

Recent coronary evaluation No

Operating room

change in symptoms

Clinical predictors

STEP 5 STEP 4 Consider delay or cancel noncardiac surgery

Consider coronary angiography

Medical management and risk factor modification

Subsequent care dictated by findings and treatment results

STEP 6

Clinical predictors

Functional capacity

Minor or no clinical predictors ‡

Intermediate clinical predictors †

Major clinical predictors**

Go to step 7

Go to step 6

Major Clinical Predictors**

. Unstable coronary syndromes . Decompensated CHF . Significant arrhythmias . Severe valvular disease

Intermediate clinical predictors †

Intermediate Clinical Predictors †

. Mild angina pectoris . Prior MI . Compensated or

Moderate or excellent (>4 METS)

Poor (<4 METS)

prior CHF

Surgical risk

STEP 8

Noninvasive testing

Invasive testing

Noninvasive testing

Postoperative risk stratification and risk factor reduction

Operating room

Low risk

Diabetes mellitus .. Renal insufficiency

Low surgical risk procedure

Intermediate surgical risk procedure

High surgical risk procedure

High risk Consider coronary angiography Subsequent care* dictated by findings and treatment results

STEP 7

Minor of no clinical predictors ‡

Clinical predictors

Surgical risk

STEP 8

Noninvasive testing

Invasive testing

High surgical risk procedure

Noninvasive testing

. Advanced age . Abnormal ECG . Rhythm other than sinus . Low functional capacity . History of stroke . Uncontrolled systemic

Moderate or excellent (>4 METS)

Poor (<4 METS)

Functional capacity

Minor Clinical Predictors ‡

Intermediate surgical risk procedure Low risk

hypertension Operating room

Postoperative risk stratification and risk factor reduction

High risk Consider coronary angiography Subsequent care* dictated by findings and treatment results

Figure 2 American College of Cardiology/American Heart Association Algorithm for stratifying perioperative cardiovascular risk. Source: From Ref. 36.

medwedi.ru

278

Part One: General Considerations

Hypertension Chronic hypertension is associated with an increased risk for stroke (particularly lacunar infarcts) (51), renal failure (52), and atherosclerotic diseases, including coronary artery disease, carotid artery disease, and peripheral vascular disease (53,54). Hypertension is also an independent risk factor for myocardial infarction in otherwise healthy-appearing men (55). Left ventricular hypertrophy and congestive heart failure are particularly ominous findings in these patients (56,57). Effective long-term blood pressure contro1 (58) can prevent these complications. Once established, blood pressure control does little to reverse end-organ damage. Hypertension also has deleterious effects that can be minimized in the immediate perioperative period. Hypertension increases myocardial oxygen consumption by increasing myocardial wall tension (40). Hypertensive patients with a preoperative diastolic blood pressure consistently greater than or equal to 100 mmHg have a 33% to 55% incidence of silent myocardial ischemia, whereas well-treated hypertensive patients have a 12% to 20% incidence (59). Hypertension may be arrhythmogenic as well, particularly in patients with a history of ventricular ectopic beats (60). Abrupt withdrawal of antihypertensive medications may result in rebound hypertension. Hypertensive patients with the cardinal symptoms of headache, diaphoresis, and palpitations must have both plasma catecholamines and urinary metanephrines measured to exclude pheochromocytoma (61). Patients with pheochromocytoma may develop hypertensive crisis during periods of stress or stimulation, such as induction of anesthesia or during intubation. Therefore alphal-adrenergic blocking agents, such as prazosin or phenoxybenzamine, should be administered preoperatively. These patients may be chronically volume depleted. Without preoperative fluid repletion, they may become hypotensive following extirpation of the tumor (61). Preoperatively, hypertensive patients should have the following (36): 1. 2. 3.

Antihypertensive medications maintained throughout the perioperative period Systolic blood pressure not to exceed 180 mmHg; diastolic blood pressure not to exceed 110 mmHg Beta-blockers for rapid, effective control of hypertension

Valvular Heart Disease In general, patients with asymptomatic valvular heart disease tolerate operation well. Bacterial endocarditis may develop in any patient with valvular abnormalities. Arrhythmias associated with valvular conditions may increase perioperative morbidity and mortality. Any history of rheumatic heart disease or cardiac murmurs, fevers, chills, dyspnea at rest or with exertion, and syncopal episodes should be sought, and exercise tolerance specifically documented. Valvular heart disease is usually diagnosed during the physical examination by the detection of cardiac murmurs. The examination should also seek to elicit evidence of rhythm disturbances, cardiomegaly, congestive heart failure (rales, jugulovenous distention, S3 gallop, peripheral edema, etc.), or bacterial endocarditis (fever, petechiae, splinter hemorrhages, Janeway lesions, etc.) (62). Mitral Stenosis Mitral stenosis results in impaired diastolic filling of the left ventricle, with elevation of left atrial and pulmonary venous

pressures. In moderate mitral stenosis, symptoms of pulmonary venous hypertension develop with increased cardiac demand, such as with exercise or stress. With further reductions in mitral valve area, sustained pulmonary hypertension and right ventricular failure may ensue, leading to dyspnea even at rest. With left atrial enlargement, atrial fibrillation may occur. Fluid administration should be judicious. Indeed, the dyspneic patient with mitral stenosis often responds well to diuretics (63). Maintenance of stroke volume and cardiac output is exquisitely dependent on left ventricular filling during diastole (64). Heart rate must be well controlled to preserve adequate diastolic filling (65). Mitral Regurgitation Mitral regurgitation results in volume overload of the left ventricle. With left ventricular contraction, a proportion of the stroke volume is regurgitated into the left atrium and the pulmonary veins. The left ventricle eventually dilates and hypertrophies to maintain forward cardiac output. Fatigue, dyspnea, and fluid retention may be seen. Pressure overload of the left atrium and pulmonary veins may occur but is generally less severe than that seen with mitral stenosis. Atrial fibrillation is common as the left atrium enlarges. Afterload reduction with vasodilators improves forward cardiac output. Inotropic agents decrease left ventricular volume, thereby decreasing the diameter of the mitral annulus and the degree of regurgitation (63,65). Aortic Stenosis The classic symptoms of aortic stenosis are angina pectoris, dyspnea, and syncope or dizziness with exertion (66). Aortic stenosis results in an elevation of the left ventricular systolic pressure to maintain cardiac output. Concentric left ventricular hypertrophy develops, leading to increased ventricular wall tension and a greater myocardial oxygen demand. The pressure gradient across the aortic valve decreases systemic diastolic pressure, thereby limiting coronary artery blood flow. Because the myocardial oxygen supply is limited, angina becomes common. Exertional syncope results when the heart is no longer able to increase cardiac output to meet increased demand (fixed cardiac output). Ventricular arrhythmias are common with severe aortic stenosis and may be precipitated by exercise (67). Left ventricular end-diastolic pressure and left ventricular endsystolic volume eventually increase to compensate for left ventricular outflow obstruction (67). Patients with symptomatic aortic stenosis have a poor prognosis with a 30% expected mortality within four years (68). Stroke volume depends on maintaining an adequate left ventricular diastolic pressure and preserving ventricular diastolic filling time. Therefore patients should be well hydrated, and the heart rate should be well controlled (65). Aortic Regurgitation Aortic regurgitation results in left ventricular dilation and hypertrophy. The left ventricle remains compliant so that end-diastolic pressure is only modestly elevated. As the severity of aortic regurgitation increases, left atrial and mitral valve dilation occurs. Symptoms seen with severe regurgitation are usually those of left ventricular failure with dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. Patients respond to diuretics and digitalis. Hypertension should be well controlled. Vasodilators increase forward flow by decreasing ventricular afterload (63,65).

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

Prosthetic Heart Valves A properly functioning prosthetic heart valve in place should require no specific hemodynamic consideration. The patient is at increased risk, however, for endocarditis and thromboembolism. Patients with mechanical valves require long-term anticoagulation with warfarin, whereas those with tissue valves frequently require anticoagulation only for the first three to six months. If atrial fibrillation occurs, even patients with tissue valves should receive long-term anticoagulation (69). Oral anticoagulation with warfarin should be halted three to five days prior to a planned surgical procedure to allow the prothrombin time (PT) to correct to less than 13 seconds, or the INR to less than 1.5. Therapeutic anticoagulation with intravenous heparin should be employed during this period. Heparin should be discontinued 6 to 12 hours prior to surgery and restarted within six hours postoperatively. Warfarin should be restarted as soon as the patient is tolerating oral liquids (70). Reversing anticoagulation with vitamin K or fresh frozen plasma should be reserved for emergency situations because of the risk of thrombosis (70). Endocarditis Patients with significant valvular heart disease or prosthetic heart valves are at increased risk for the development of bacterial endocarditis. In patients at risk, prophylactic antibiotics should be started one hour prior to the procedure and continued for less than 24 hours. The Boxes 2–4, and Tables 5 and 6 review the indications for prophylaxis and the regimens recommended by the American Heart Association (71).

279

Box 2 Cardiac Conditions Associated with Endocarditis Endocarditis prophylaxis recommended High-risk category Prosthetic cardiac valves, including bioprosthetic and homograft valves History of bacterial endocarditis Complex cyanotic congenital heart disease (e.g., single ventricle states, transposition of the great arteries, and tetralogy of Fallot) Surgically constructed systemic pulmonary shunts or conduits Moderate-risk category Most other congenital cardiac malformations (other than those mentioned above and below) Acquired valvar dysfunction (e.g., rheumatic heart disease) Hypertrophic cardiomyopathy Mitral valve prolapse with valvar regurgitation and/or thickened leaflets Endocarditis prophylaxis not recommended Negligible-risk category (no greater risk than the general population) Isolated secundum atrial septal defect Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residual beyond 6 months) History of coronary artery bypass graft surgery Mitral valve prolapse without valvar regurgitation Physiologic, functional, or innocent heart murmurs History of Kawasaki disease without valvar dysfunction History of rheumatic fever without valvar dysfunction Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators Source: From Ref. 71.

Cerebrovascular Disease Patients with carotid artery disease are at increased risk for stroke in the perioperative period. Patients with significant coronary disease or other stigmata of atherosclerosis should be questioned carefully for a history of transient ischemic attacks or amaurosis fugax. The carotid arteries should be evaluated for bruits and neurologic deficits. If any of these are present, duplex scanning provides a reliable, noninvasive screening test for carotid artery disease. All patients with symptomatic carotid artery disease or asymptomatic critical stenosis (>75%) should be evaluated for carotid endarterectomy prior to undergoing spinal or general anesthesia for an elective procedure (72).

Risks of Liver Disease Preoperative evaluation and management of the patient with liver disease is a challenging problem. The liver is involved in numerous metabolic and synthetic processes including amino acid, carbohydrate, and lipid metabolism, excretion of bilirubin, and maintenance of glucose homeostasis. Predicting how a patient will respond not only to surgery but also to the effects of anesthesia can be extremely difficult. The evaluation of the patient with overt liver disease must include the cause of the disease (i.e., alcoholic cirrhosis and hepatitis), the chronicity of the disease, and the degree of hepatocellular injury based on both clinical findings and laboratory abnormalities. The magnitude of the surgery to be performed and the type of anesthesia to be administered must also be considered. Patients without overt liver disease but with abnormal liver function test results may require further workup.

Hepatic Dysfunction Due to Anesthetic Agents Anesthetic agents may exacerbate hepatic dysfunction. Although none of the currently used anesthetic agents are directly hepatotoxic, these agents, whether inhalational, spinal, or epidural, reduce hepatic blood flow by 30% to 50% (73,74). Patients with completely normal liver function can develop asymptomatic elevations in transaminases. Those with known hepatic disease may develop clinically apparent impairment (75). Moreover, impaired liver function may include impaired drug metabolism, thereby prolonging the action of anesthetic agents, sedatives, narcotic analgesics, or induction agents. These agents must be carefully administered with appropriate dosing. Sedative effects and hepatic encephalopathy must be closely monitored (73). Liver disease may lead to coagulopathy by several mechanisms. Hepatic disease can be associated with decreased synthesis and function of coagulation proteins, especially the vitamin K–dependent clotting factors (75). Vitamin K deficiency is common particularly in patients with cholestatic disorders or those receiving antibiotics to suppress endogenous gut flora (76). Liver disease may lead to qualitative or quantitative platelet abnormalities including the splenic sequestration seen with portal hypertension. Coagulation factors must be checked preoperatively in any patient with known or suspected liver disease. Patients with obstructive jaundice should receive parenteral vitamin K preoperatively. Failure of vitamin K to correct a prolonged PT indicates severe hepatocellular function (75,76). In this case, fresh frozen plasma must be used to achieve an adequate PT for surgery. Bleeding time should be obtained in

medwedi.ru

280

Part One: General Considerations

Box 3 Dental Procedures and Endocarditis Prophylaxis

Box 4 Other Procedures and Endocarditis Prophylaxis

Endocarditis prophylaxis recommendeda Dental extractions Periodontal procedures including surgery, scaling and root planing, probing, and recall maintenance Dental implant placement and reimplantation of avulsed teeth Endodontic (root canal) instrumentation or surgery only beyond the apex Subgingival placement of antibiotic fibers or strips. Initial placement of orthodontic bands but not brackets Intraligamentary local anesthetic injections Prophylactic cleaning of teeth or implants where bleeding is anticipated

Endocarditis prophylaxis recommended Respiratory tract Tonsillectomy and/or adenoidectomy Surgical operations that involve respiratory mucosa Bronchoscopy with a rigid bronchoscope Gastrointestinal tracta Sclerotherapy for esophageal varices Esophageal stricture dilation Endoscopic retrograde cholangiography with biliary obstruction Biliary tract surgery Surgical operations that involve intestinal mucosa Genitourinary tract Prostatic surgery Cystoscopy Urethral dilation

Endocarditis prophylaxis not recommended Restorative dentistryb (operative and prosthodontic) with or without retraction cordc Local anesthetic injections (nonintraligamentary) Intracanal endodontic treatment; post placement and buildup Placement of rubber dams Postoperative suture removal Placement of removable prosthodontic or orthodontic appliances Taking of oral impressions Fluoride treatments Taking of oral radiographs Orthodontic appliance adjustment Shedding of primary teeth

Endocarditis prophylaxis not recommended Respiratory tract Endotracheal intubation Bronchoscopy with a flexible bronchoscope with or without biopsyb Tympanostomy tube insertion Gastrointestinal tract Transesophageal echocardiographyb Endoscopy with or without gastrointestinal biopsyb Genitourinary tract Vaginal hysterectomyb Vaginal deliveryb Cesarean section In uninfected tissue: Urethral catheterization Uterine dilatation and curettage Therapeutic abortion Sterilization procedures Insertion or removal of intrauterine devices Other Cardiac catheterization, including balloon angioplasty Implanted cardiac pacemakers, implanted defibrillators, and coronary stents Incision or biopsy of surgically scrubbed skin Circumcision

a

Prophylaxis is recommended for patients with high- and moderate-risk cardiac conditions. b This includes restoration of decayed teeth (filling cavities) and replacement of missing teeth. c Clinical judgment may indicate antibiotic use in selected circumstances that may present with significant bleeding. Source: From Ref. 71.

all patients with less than 100,000 platelets/mm3 and platelet transfusions considered in patients with elevated bleeding times and/or less than 50,000 platelets/mm3 (75,76). Obviously, purely elective surgery should be postponed in the patient with severe acute hepatic disease. Supportive care during the acute phase reduces operative risk. Operative considerations for specific hepatic disorders are discussed briefly in the following sections.

Acute Viral Hepatitis Acute viral hepatitis increases operative morbidity and mortality (77). Laboratory abnormalities seen in these patients include moderate-to-marked elevations in serum transaminase levels and mild elevations in alkaline phosphatase. Jaundice may or may not be present. The specific serologic diagnosis of the viral agent can usually be made (73). If possible, laparotomy should be avoided in the setting of acute viral hepatitis. The increased availability of accurate serologic testing and radiologic and endoscopic diagnostic procedures usually establishes the diagnosis of hepatitis, thereby obviating the need for surgery (73,76).

a

Prophylaxis is recommended for high-risk patients; optional for mediumrisk patients. b Prophylaxis is optional for high-risk patients. Source: From Ref. 71.

elective surgery is not contraindicated, a period of abstinence may be beneficial by avoiding the symptoms of postoperative alcohol withdrawal. Acute alcoholic hepatitis is more severe than acute viral hepatitis. Several studies have shown significantly increased morbidity and mortality of surgery in patients with alcoholic hepatitis (78,79). Diagnosis should be made by percutaneous liver biopsy. Elective surgery is contraindicated in this group of patients and should be postponed until laboratory and clinical parameters are normal.

Alcoholic Liver Disease Alcoholic liver disease can range from fatty liver (hepatic steatosis) to the more severe acute alcoholic hepatitis to cirrhosis. The patient with alcoholic fatty liver is not at increased risk for operative complications (73,76). Mild elevations in transaminase and alkaline phosphatase may be seen and diagnosis confirmed by liver biopsy. Although

Chronic Hepatitis Chronic hepatitis refers to a group of disorders characterized by chronic inflammation of the liver, persisting for at least three to six months (73). Chronic hepatitis is usually divided into chronic persistent form and chronic active form. Patients with chronic persistent hepatitis are usually

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

281

Table 5 Prophylactic Regimens for Dental, Oral, Respiratory Tract, or Esophageal Procedures Situation Standard general prophylaxis Unable to take oral medications Allergic to penicillin

Allergic to penicillin and unable to take oral medications

Regimena

Agent Amoxicillin Ampicillin Clindamycin Or Cephalexinb or cefadroxilb Or Azithromycin or clarithromycin Clindamycin Or Cefazolinb

Adults: 2 g; children: 50 mg/kg orally 1 hr before procedure Adults: 2 g IM or IV; children: 50 mg/kg IM or IV within 30 min before procedure Adults: 500 mg; children: 20 mg/kg orally 1 hr before procedure Adults: 2 g; children: 50 mg/kg orally 1 hr before procedure Adults: 500 mg; children: 15 mg/kg orally 1 hr before procedure Adults: 600 mg/children: 20 mg/kg IV within 30 min before procedure Adults: 1 g; children: 25 mg/kg IM or IV within 30 min before procedure

a

Total children’s dose should not exceed adult dose. b Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins. Abbreviations: IM, intramuscular; IV, intravenous. Source: From Ref. 71.

asymptomatic with only mild laboratory abnormalities. This form is not considered a contraindication to elective surgery and these patients tolerate operation well (73,80). Chronic active hepatitis is a more ominous disorder, which, unlike chronic persistent hepatitis, may progress to cirrhosis. Mild, asymptomatic anicteric patients with chronic active hepatitis tolerate elective surgery well (80), whereas symptomatic patients with jaundice and significantly elevated serum liver function test levels have increased perioperative mortality. Elective operation is contraindicated in these cases (81).

Cirrhosis The Child-Turcotte classification is a well-known system that attempts to correlate the severity of cirrhosis (and therefore the hepatic reserve) with expected operative mortality (82). It grades the degree of ascites, encephalopathy, malnutrition, hyperbilirubinemia, and hypoalbuminemia in the cirrhotic patient. Although the classification was originally intended to evaluate patients undergoing portacaval

shunting, it has since been generalized to nonshunt surgery. Patients are classified (A, B, and C) according to the severity of hepatic insufficiency. Mortality rates of 0% to 10%, 4% to 31%, and 19% to 76% are quoted for classes A, B, and C, respectively, for portacaval shunts and nonshunt operations. In general, patients in Child class A tolerate surgery well, whereas patients in Child class C have a prohibitive operative mortality, thereby contraindicating elective surgery. Patients in Child class B must be assessed individually (Box 5). The preoperative preparation of the cirrhotic patient should include evaluation of the metabolic alterations including hyponatremia, hypoalbuminemia, glucose intolerance, and possible oxygen desaturation (73). Although these abnormalities may not be completely correctable preoperatively, they should be closely monitored both during and after operation. In addition, coagulation parameters must be evaluated and corrected preoperatively. Nutritional status should be optimized preoperatively when possible. Unfortunately, routine liver function biochemical

Table 6 Prophylactic Regimens for Genitourinary/Gastrointestinal (Excluding Esophageal) Procedures Situation

Agentsa

High-risk patients

Ampicillin plus gentamicin

High-risk patients allergic to ampicillin/amoxicillin

Vancomycin plus gentamicin

Moderate-risk patients

Amoxicillin or ampicillin

Moderate-risk patients allergic to ampicillin/amoxicillin

Vancomycin

Regimentb Adults: ampicillin 2 g IM or IV plus gentamicin 1.5 mg/kg (not to exceed 120 mg) within 30 min of starting procedure; 6 hrs later, ampicillin 1 g IM/IV or amoxicillin 1 g orally Children: ampicillin 50 mg/kg IM or IV (not to exceed 2 g) plus gentamicin 1.5 mg/kg within 30 min of starting procedure; 6 hrs later, ampicillin 25 mg/kg IM/IV or amoxicillin 25 mg/kg orally Adults: vancomycin 1 g IV over 1–2 hrs plus gentamicin 1.5 mg/kg IV/IM (not to exceed 120 mg); complete injection/infusion within 30 min of starting procedure Children: vancomycin 20 mg/kg IV over 1–2 hrs plus gentamicin 1.5 mg/kg IV/IM; complete injection/infusion within 30 min of starting procedure Adults: amoxicillin 2 g orally 1 hr before procedure, or ampicillin 2 g IM/IV within 30 min of starting procedure Children: amoxicillin 50 mg/kg orally 1 hr before procedure, or ampicillin 50 mg/kg IM/IV within 30 min of starting procedure Adults: vancomycin 1.0 g IV over 1–2 hrs; complete infusion within 30 min of starting procedure Children: vancomycin 20 mg/kg IV over 1–2 hrs; complete infusion within 30 min of starting procedure

a

Total children’s dose should not exceed adult dose. No second dose of vancomycin. Abbreviations: IM, intramuscular; IV, intravenous. Source: From Ref. 71.

b

medwedi.ru

282

Part One: General Considerations

Box 5 Relative Hepatologic Contraindications for Elective Surgery Active, acute viral hepatitis Active, acute alcoholic hepatitis Fulminant hepatitis Icteric, symptomatic chronic active hepatitis Contemplated ileostomy or colostomy in a cirrhotic Contemplated abdominal surgery in OLT candidate PT greater than 3 seconds prolonged (despite vitamin K) Child C cirrhotic Abbreviations: OLT, orthotopic liver transplantation; PT, prothrombin time. Source: From Ref. 76.

tests (serum aminotransferase and alkaline phosphatase) tend to correlate poorly with the actual degree of hepatic impairment (73). With the availability and routine use of preoperative laboratory tests, the surgeon may encounter patients with unsuspected abnormal results from liver ‘‘function’’ tests while preparing for elective surgery. Although medical consultation may be obtained in these instances, the surgeon should be aware of the necessary further preoperative evaluation of these patients. History of recent drug use, past hepatitis or jaundice, blood transfusions, and general symptoms of liver disease, such as malaise, fatigue, and arthralgia, are important to elicit (83). Physical examination should include potential evaluation for the signs of chronic liver disease, such as cutaneous spider angiomata, parotid swelling, gynecomastia, palmar erythema, Dupuytren’s contractures, organomegaly, ascites, encephalopathy, and poor nutritional status. A serum albumin level and a coagulation profile to assess the functional ability of the liver complement serum levels of bilirubin, alkaline phosphatase, serum glutamic-oxaloacetic transaminase, serum glutamate pyruvate transaminase, and lactate dehydrogenase in assessing injury of the liver (83). Clearly patients with underlying liver disease are at increased surgical risk. Essential preoperative preparation of these patients must include correction of coagulopathy and electrolyte abnormalities (hypokalemia and hyponatremia), and control of ascites, hepatic encephalopathy, and infection (83). Specifically, the PT should be corrected to within three seconds of control, preferably with vitamin K. Massive ascites may require paracentesis preoperatively (83).

Risks of Kidney Disease The kidney performs several important functions, including filtration and elimination of nitrogenous wastes and regulation of fluid volume, electrolyte concentrations, acid–base balance, and blood pressure, and certain endocrine functions. Moreover, urine output in the patient with normal renal function provides an important, albeit indirect, indication of visceral perfusion. Impairment of renal function generally increases both the risk of operation and the incidence of postoperative complications (84–86). Despite the kidney’s many functions, renal insufficiency or failure in the surgical patient presents clinically as either oliguria or a rising serum creatinine level. Patients with preexisting renal disease may have hypertension, hypoalbuminemia, lethargy, or anorexia (87). Acute renal failure can be defined as a recent increase of serum creatinine of at least 0.5 mg/dL and reflects the inability of the kidneys to adequately eliminate nitrogenous wastes (88). Renal creatinine clearance is used to estimate the glomerular filtration

rate (GFR). The minimal obligatory urine volume output for an adult is 0.5 mg/kg/hr (1.0 mg/kg/hr in children), although nonoliguric renal failure may be present with seemingly adequate urine volumes. Chronic renal insufficiency predisposes the patient to further renal injury from either hypoperfusion or nephrotoxins (89). Acute renal failure is due either to prerenal, postrenal, or intrarenal lesions. Prerenal azotemia results from renal hypoperfusion; although this azotemia is reversible, it will progress to ischemic acute tubular necrosis (ATN) with continued hypoperfusion (88). Homeostatic mechanisms maintain renal blood flow and GFR in the presence of hypovolemia or hypotension. The oliguria and azotemia seen in the prerenal state represents autoregulation with reabsorption of sodium and water to maintain or expand the effective circulating volume (88). Causes of prerenal azotemia include hypovolemia, sepsis, neurogenic shock, congestive heart failure, and hepatorenal failure (90). Whereas sodium and water reabsorption with circulating volume expansion is an appropriate response with a low effective circulating volume, it is an inappropriate response in congestive heart failure, which is characterized by an excessive circulating volume (fluid overload). Restoration of renal perfusion reverses prerenal azotemia. This requires volume administration in hypovolemia, and diuresis in congestive heart failure. Generally, the diagnosis of prerenal azotemia is supported by a high blood urea nitrogen/creatinine ratio (> 20:1), a low urine sodium (UNa < 20), or a low fractional excretion of sodium (FENa < 1%) (88,89). Intrarenal acute renal failure may occur from a number of diseases, including the glomerulonephritides; but the most common form encountered in the surgical patient is ATN. ATN results from injury to the renal tubular epithelium, which is responsible for maintaining selective permeability to water and other solutes in ultrafiltrate, as well as for active transport of electrolytes, as is seen in the loop of Henle. Injury may result from hypoperfusion and ischemia or from any number of nephrotoxins. ATN may lead to either oliguric (< 400 mL/day) renal failure or nonoliguric renal failure. The renal injury resulting in nonoliguric ATN is less severe than that resulting in the oliguric form (88). The causes of ischemic ATN are the same as those resulting in prerenal azotemia, although the insult is more severe. Hypovolemic shock, septic shock, neurogenic shock and congestive heart failure, or cardiogenic shock may result in ATN. Generally, ischemic ATN follows a recognizable period of profound hypotension (88). The progression from prerenal azotemia to ATN represents a continuum; often restoration of renal perfusion restores some degree of renal function, representing the tubules of those nephrons that have not yet succumbed to ischemia. The diagnosis of ATN is supported by the presence of tubular casts on urinalysis, a high UNa (> 40) and a high FENa (> 4%) (87,89). Toxins leading to ATN include heme pigments (from myoglobin and hemoglobin), drugs (aminoglycoside antibiotics), and radiographic contrast agents. With rhabdomyolysis, myoglobin released into the circulation is filtered across the glomerulus. It precipitates in the lumen of the renal tubule; under acidic conditions, the heme moiety dissociates from the protein component and is taken up and metabolized by the tubular epithelium, to which it is ultimately toxic. Hemoglobinuria following massive hemolysis, as in transfusion reactions, causes ATN in an analogous fashion. ATN is prevented by maintaining

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

high urine flow rates and alkalinizing the urine to prevent dissociation of the heme pigment from the globin. Aminoglycosides and radiographic contrast agents may both cause ATN in a dose-dependent fashion, possibly by direct toxicity to the tubular epithelium. These agents potentiate the injury incurred by ischemia or other nephrotoxins and are particularly toxic in the face of preexisting renal insufficiency. Obstructive jaundice results in postoperative ATN in approximately 16% to 18% of patients. The mortality rate of renal failure in this setting correlates with serum bilirubin levels (91). Obstructive jaundice causes a decrease in total peripheral resistance, either because of peripheral vasodilation or an impairment of the vasoconstrictor response to pressor agents. This leads to a decrease in the effective plasma volume and explains the exaggerated hypotensive response seen with hemorrhage (91,92). Moreover, obstructive jaundice also decreases renal blood flow (91,92). The postoperative renal failure seen with obstructive jaundice may simply represent an ischemic ATN related to impaired hemodynamic responses and resultant hypotension, although endotoxin may also play a role. Bile salts bind and inactivate endotoxin, thereby preventing its absorption from the gut lumen (92). The absence of bile salts in the gut lumen, as seen with obstructive jaundice, results in endotoxemia. This may explain the systemic and intrarenal hemodynamic effects seen with obstructive jaundice (91,92). The use of oral bile salts appears to prevent endotoxemia (83). Preoperative external biliary drainage has not been shown to be effective in decreasing the incidence of postoperative renal failure (92). Current recommendations include preoperative hydration, avoidance of nephrotoxic agents, preoperative administration of mannitol (500 mL of 10% mannitol infused for a period of one to two hours prior to operation), and oral administration of bile salts preoperatively (sodium deoxycholate 500 mg every eight hours for 48 hours) (92). The perioperative use of low-dose dopamine (3 mg/kg/min) appears not to be of benefit (93). Postrenal azotemia results from obstructive uropathy (85,88). This commonly results from urethral obstruction, either caused by prostatic hypertrophy (in men) or Foley catheter blockage. Unilateral ureteric obstruction does not generally result in azotemia, because the contralateral kidney compensates by hyperfiltration (90). If the obstruction is relieved early, postrenal azotemia is reversible. Persistent obstruction results in irreversible renal injury (94). Foley catheterization usually excludes bladder outlet obstruction, although the Foley catheter itself may be occluded by blood clots or fibrinous exudate. Renal ultrasonography is useful to rule out ureteric obstruction (95). Chronic renal failure may result from any number of causes, including atherosclerosis, diabetes, hypertension, glomerulonephritis, ischemia, or exposure to nephrotoxins (90). It must be recognized that these patients may lack the ability to concentrate or dilute their urine in response to fluid shifts or electrolyte disturbances (96). Therefore fluid balance and electrolyte concentrations must be monitored meticulously. Excessive administration of potassium, magnesium, and phosphate should be avoided. Dosages of drugs that undergo renal excretion should be decreased according to the patient’s estimated GFR. Exposure to nephrotoxins should be avoided. Chronic renal failure may also be associated with anemia, which should be corrected preoperatively (96,97). Risk factors for the development of perioperative renal failure include preexisting renal insufficiency, diabetes

283

mellitus, advanced age, jaundice, and aortic or cardiac surgery (85,98). To preserve renal function, patients should be well hydrated prior to surgery and prior to the administration of potentially nephrotoxic agents. Fluid shifts and electrolyte loads should be minimized. Hypotension should be avoided. Invasive hemodynamic monitoring with pulmonary artery catheterization should be considered both in patients requiring cardiac optimization and in those undergoing surgery in which large fluid shifts can be anticipated. In the presence of oliguria, postrenal factors should be excluded, urine output should be carefully monitored, and prerenal factors (either hypovolemia or inadequate cardiac function) should be corrected (96,97). Patients with ESRD requiring dialysis have an increased risk for perioperative morbidity and mortality (86,99). These patients have a high incidence of associated diseases, including diabetes mellitus, hypertension, and coronary artery disease. Complications include hyperkalemia, sepsis, hemorrhage, cardiac dysfunction, and hemodynamic instability (86). Anemia is common because of decreased erythropoietin production. A hematocrit less than 25% should be corrected, either electively with recombinant human erythropoietin or emergently with blood transfusion (96,100). The qualitative platelet dysfunction may be due to circulating guanidinosuccinic and hydroxyphenolic acids, which inhibit platelet factor 3 activity (101). Dialysis improves platelet function, as will administration of cryoprecipitate, 1-deamino-8-d-arginine vasopressin (DDAVP), or conjugated estrogens. Platelet transfusions are used for significant hemorrhage (101). Ideally, the patient with ESRD should receive dialysis within 24 hours of operation (97). Excessive hydration should be avoided. In patients with significant coronary artery disease, invasive hemodynamic monitoring should be considered.

Risks of Endocrine Disease Diabetes Mellitus Diabetes mellitus is a common disorder or carbohydrate metabolism with an estimated prevalence of between 2% and 5% in the United States (102). The hyperglycemia associated with diabetes results from either a deficiency of insulin (type I) or a resistance to its action (type II). Complications from diabetes mellitus are common and include diabetic retinopathy, nephropathy, neuropathy, and an accelerated atherosclerosis. Diabetic sensory neuropathy usually has a ‘‘stocking and glove’’ distribution. Diabetic autonomic neuropathy may lead to postural hypotension, arrhythmias, gastroparesis, and urinary retention. Diabetes is the most common cause of blindness in the United States and is responsible for more than 25% of new cases of ESRD, and for more than 50% of all lower extremity amputations (103). As a result of the expected long-term sequelae of diabetes mellitus, approximately 50% of all diabetic patients eventually require surgery (104). Because of the high incidence of coronary artery disease and renal dysfunction in this population, the expected perioperative morbidity and mortality in the diabetic patient are higher than that of the nondiabetic patient (102). Furthermore, defects in wound healing and the immune system condemn the diabetic patient to a higher rate of wound complications (105–107). Although no prospective study demonstrates an improved surgical outcome in the euglycemic as opposed to the hyperglycemic patient (108), hyperglycemia may lead to profound fluid and electrolyte depletion, altered immune function, and impaired wound healing (105– 107,109). Adequate insulin administration corrects the defects in granulocyte and fibroblast function seen with

medwedi.ru

284

Part One: General Considerations

hyperglycemia (110). Intuitively, it would seem that perioperative glycemic control should minimize surgical risk. Achieving glycemic control may be challenging because of the diabetogenic response elicited by the stress of surgery, anesthesia, and inflammation (108). Part of the response to stress is an increased release of the counter-regulatory hormones (epinephrine, glucagon, cortisol, and growth factor), each of which either directly or indirectly stimulate glucose production (108). In addition, these hormones are primarily catabolic, thereby promoting significant lipolysis and ketogenesis (108).

Preoperative Assessment Prior to operation, the patient’s type of diabetes should be determined and the patient’s regimen for glycemic control should be clearly ascertained. The adequacy of recent glycemic control may be determined by reviewing blood glucose records and by obtaining a glycosylated hemoglobin level. Patients taking oral hypoglycemics should be screened for episodes of profound hypoglycemia, which is a common complication of these medications. Complications of diabetes should be identified preoperatively as well. Thus a thorough assessment of cardiovascular status and a determination of renal function (screening serum creatinine) are necessary, as is identification of any diabetic sensory or autonomic neuropathy.

Insulin and Fluid Administration Plasma glucose levels should be tightly controlled perioperatively, avoiding hypoglycemia and hyperglycemia. The stress response to infection, inflammation, and surgery increases plasma glucose levels. Even moderate elevations in plasma glucose levels may result in glycosuria and therefore an osmotic diuresis. Although this may lead to volume depletion and electrolyte disturbances in non– insulin-dependent patients, it may progress to overt diabetic ketoacidosis in those who are insulin dependent (108). If diabetic ketoacidosis is present, operation must be postponed until the patient’s fluid volume is restored and the pH, electrolyte, and glucose levels are corrected (102). Preoperatively, the insulin dose must be adjusted for the fasting patient. All diabetic patients, both insulin dependent and non–insulin dependent, should receive insulin therapy during surgery (111). Indications for insulin therapy are summarized in the Box 6. A number of acceptable regimens for administration have been described, and no single regimen has been proved to be superior (111). A common regimen used for insulin-dependent patients is to give fasting patients one-half of their usual morning dose of intermediate-acting insulin subcutaneously on the morning of operation. The serum glucose is then checked every two to four hours and supplemental intermediate-acting insulin is administered according to a sliding scale dosage. This is continued until the patients can eat normally and resume their usual regimen. Subcutaneous administration of insulin may result in erratic absorption and unpredictable serum levels, particularly with the hemodynamic changes seen perioperatively (108,112–114). Intravenous administration of insulin offers the theoretic advantage of more predictable serum levels of insulin. Table 7 provides a guideline for perioperative intravenous insulin administration. Although fixed-rate insulin infusions offer no proven advantage over subcutaneous administration (109,113), variable-rate infusions may be more useful to stabilize glucose levels (115). Continuous

Box 6 Indications for Insulin Therapy During an Operation Always All patients taking insulin—both insulin-dependent diabetes mellitus and NIDDM Patients with NIDDM treated with diet, oral hypoglycemic agents, or both, but having chronic hyperglycemia (FBG > 10 mmol/L and glycosylated Hb > 0.1) Variable Patients with NIDDM treated with diet, oral hypoglycemic agents, or both, under good control Current FBG 10 mmol/L Glycosylated Hb 0.08–0.1 Duration of operation less than 2 hrs Use of glucose solutions not planned Abbreviations: FBG, fasting blood glucose; Hb, hemoglobin; NIDDM, noninsulin-dependent diabetes mellitus. Source: From Ref. 111.

intravenous insulin infusion is clearly superior to other methods when used intraoperatively (116), although this unfortunately remains an underutilized technique (117). If continuous intravenous insulin infusion is used, it generally is continued until the patient begins to eat (108,118). Preoperative intravenous fluids should provide dextrose to prevent hypoglycemia and the accumulation of ketones and free fatty acids. Five percent dextrose should be added to maintenance intravenous fluids, generally halfnormal saline, running at roughly 1 mL/kg/hr for adults. Because lactate is a gluconeogenic precursor, lactated Ringer’s solution administered at a high infusion rate may produce hyperglycemia (119). Thus additional fluid requirements should be met with dextrose-free solutions.

Cortisol Metabolic Dysfunction Cortisol is synthesized, stored, and secreted from cells of the adrenal cortex. Release is controlled primarily by the anterior pituitary hormone adrenocorticotropic hormone (ACTH). Cortisol influences the metabolism of glucose, amino acids, and fatty acids and potentiates the actions of glucagon and epinephrine in the liver. Cortisol secretion, in response to increased ACTH production, is increased by acute stress including fever, pain, hemorrhage, and operative trauma. The glucocorticoid activity of cortisol maintains the responsiveness of small vessels to catecholamines, thereby maintaining vascular tone. Moreover, glucocorticoids influence the distribution of total body water to maintain intravascular volume (120,121). Insufficient cortisol release in response to stress may be life threatening. It may result from primary adrenal gland insufficiency (addisonian crisis) or from suppression of the hypothalamic-pituitary-adrenal cortical axis, as is seen with chronic steroid therapy. Signs and symptoms of chronic adrenal insufficiency are nonspecific and include weakness, nausea, fever, weight loss, lethargy, and even delirium. Hyponatremia and hyperkalemia result from mineralocorticoid (aldosterone) deficiency. Hypoglycemia may reflect glucocorticoid deficiency leading to diminished hepatic gluconeogenesis, even with elevated levels of glucagon and epinephrine. Hypercalcemia is also seen, and blood count differentials may reveal eosinophilia (121). Acute adrenal insufficiency presents clinically as hypotension with a high cardiac output and a

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

285

Table 7 Algorithm Guidelines for Perioperative Diabetes Management of Separate Insulin and Glucose Infusions Insulin Regular, 25 U, in 250 mL normal saline (1 U/10 mL) Infuse insulin intravenously from an infusion pump; flush 50 mL through line before connecting to patient; piggyback this line to the perioperative maintenance fluids infusion line Monitor blood glucose levels hourly during operation and every 2–4 hr before and after operation once stable Perioperative maintenance fluids must contain dextrose (5%) Do the initial blood glucose measurement ‘‘stat’’ in the clinical laboratory Blood glucose mmol/L 4.4 4.5–5.5 5.6–7.8 7.9–10 10.1–12.2 12.3–14.4 14.5–16.6 16.7–18.9 > 18.9

Insulin mg/dL

U/hr

mL/hr

Fluids (mL/hr)

80 81–100 101–140 141–180 181–220 221–260 261–300 301–340 > 341

0 0.5 1 1.5 2 2.5 3 4 5

0 5 10 15 20 25 30 40 50

125 125 125 125 125 100 100 100 100

Blood glucose 4.4 mmol/L, bolus with 50% dextrose in water (25 mL); once blood glucose > 4.4 mmol/L, restart insulin infusion and recheck in 30 min. Decreased insulin needs patients treated with diet, oral agents, or < 50 U insulin per day. Increased insulin needs sepsis, steroid therapy (renal transplantation), coronary artery bypass. If high-dose insulin is anticipated, a more concentrated insulin solution should be prepared to avoid excessive fluid intake. Source: From Ref. 111.

low systemic vascular resistance that is resistant to pressors but responds to glucocorticoid administration (122). Although circulatory collapse caused by adrenal insufficiency is a decidedly uncommon complication of surgery (0.01–0.7% of cases) (123), patients at risk should be identified to receive perioperative stress doses of glucocorticoids. The functional status of the hypothalamicpituitary-adrenal cortical axis should be assessed for patients receiving chronic glucocorticoid therapy, particularly if they show signs of Cushing’s syndrome. While a plasma cortisol level of greater than 500 nmol/L is suggestive of adequate adrenal function, the 30-minute ACTH stimulation test provides an accurate screening test for adrenal dysfunction (123). Recommended stress doses of steroids typically consist of 50 to 100 mg of hydrocortisone given intravenously every six to eight hours, followed by a steroid taper (122). In a recent review, Salem et al. (123) recommended basing glucocorticoid dosing on the magnitude of surgical stress. They recommended the following dosing guidelines: Minor surgical stress: 25 milligrams of hydrocortisone equivalent per day for 1 day Moderate surgical stress: 50–75 milligrams of hydrocortisone equivalent per day for 1 to 2 days Major surgical stress: 100–150 milligrams of hydrocortisone equivalent per day for 2 to 3 days These doses may be continued for postoperative complications that extend the stress response. Patients already receiving baseline glucocorticoid therapy in excess of these recommended stress doses probably do not require additional perioperative coverage.

Pheochromocytoma Pheochromocytomas are rare endocrine tumors of neural crest cells in the adrenal medulla or sympathetic ganglia that secrete catecholamines, often in dangerously high concentrations.

While the majority are located within the adrenal glands, approximately 6% are ectopic. Ten percent of pheochromocytomas may be bilateral (124), and 8% to 10% are malignant (125). These tumors account for hypertension in less than 0.1% of all patients, but they are estimated to cause the deaths of approximately 1000 Americans each year (126). Preoperative preparation of patients known to have this tumor is of major importance if the risks of excess catecholamine release such as malignant hypertension, stroke, myocardial infarction, or death are to be reduced. Suspicion of a pheochromocytoma should be heightened in a patient with unexplained episodic or sustained hypertension, headache, palpitations, and excessive sweating (127) precipitated by stimuli such as stress, exercise, or sexual activity. Other less common symptoms include nervousness and anxiety, tremor, nausea with or without vomiting, weakness, and weight loss. In those patients known to have a pheochromocytoma, preoperative localization is essential to safe, rapid surgical management. Occasionally, pheochromocytomas are found intraoperatively during an unrelated procedure or in females during pregnancy or parturition. In these situations, blood pressure and fluid management becomes critical. Determination of the 24-hour urinary catecholamine levels with or without epinephrine–norepinephrine fractionation (124) is used to confirm the diagnosis. Ninety-eight percent of patients with a pheochromocytoma have an elevated serum or urinary catecholamine level (128). Plasma catecholamine levels greater than 2000 pg/mL are considered diagnostic of a pheochromocytoma. Epinephrine–norepinephrine fractionation has been successfully used in those patients with normal total catecholamine levels, in whom pheochromocytoma is strongly suspected. An epinephrine fraction of greater than 20% correlates with a pheochromocytoma. Pheochromocytomas 1 cm in size or greater are best localized by computed tomography (CT) scan (124,125). If CT scan fails to demonstrate the lesion, selective arteriography should be performed (125). Ultrasound or magnetic resonance imaging may be helpful in pregnant patients.

medwedi.ru

286

Part One: General Considerations

Metaiodobenzylguanidine scintigraphy is most useful for extra-adrenal, recurrent, or metastatic disease (128). Surgical excision is the treatment for pheochromocytomas and should be performed before other elective procedures. Appropriate preoperative preparation reduces the morbidity and mortality associated with possible catecholamine release during induction of anesthesia or surgical manipulation of the tumor. Preoperative alpha-adrenergic blockade serves to re-expand plasma volume, control hypertension, and minimize blood pressure fluctuations intraoperatively. Phenoxybenzamine, 10 to 20 mg three to four times daily for 7 to 10 days before operation, blocks both postsynaptic (alpha1-) and presynaptic (alpha2-) adrenergic receptors (125). More recently, prazosin, a selective alpha1-blocker, has been used (2–5 mg twice daily) (125), which provides acceptable alpha-adrenergic blockade with fewer side effects (124). Preoperative beta-blockade is not routinely necessary in the absence of tachyarrhythmias. Should arrhythmias arise intraoperatively, intravenous propranolol can be administered (124,125). Beta-blockade should never be administered prior to alpha-blockade, because it may induce a pressor response, causing severe hypertension.

Thyroid Dysfunction The normally functioning thyroid gland synthesizes, stores, and releases the thyroid hormones thyroxine (T4) and triiodothyronine (T3). These regulate many aspects of cellular metabolism, including oxygen consumption and heat production, as well as potentiate the effects of the sympathetic nervous system. Release of these hormones into the circulation is mediated by thyroid-stimulating hormone (TSH) produced by the pituitary gland, which itself is regulated by a classic negative feedback system (129). Thyroid hormone concentrations can be altered either as a result of primary thyroid dysfunction or the physiologic disturbances mediated by the body’s stress response. Major operative trauma or injury impairs the normal peripheral conversion of T4 to T3, in part due to a rise in serum cortisol. Both circulating T3 level and the total T4 concentration are reduced, but without the expected rise in TSH concentrations. Presumably, total T4 concentration is decreased with injury, whereas free T4 levels remain normal (129). Hyperthyroidism, or thyrotoxicosis, results from excessive release of thyroid hormone and is associated with signs and symptoms of heat intolerance, sweating, palpitations, increased appetite, weight loss, and fatigue. More worrisome signs are tachycardia, atrial fibrillation, heart failure, and myopathy, which may develop in some patients. Thyrotoxicosis must be both recognized and treated prior to operation. Euthyroidism is the goal of preoperative treatment in order to avoid thyroid storm, which may be precipitated by the stress of anesthesia or surgery. Thyrotoxicosis is usually corrected preoperatively with a combination of antithyroid medication (methimazole or propylthiouracil) to inhibit thyroid hormone synthesis and exogenous thyroxine to counteract the trophic effects of TSH, thereby decreasing the vascularity of the gland (130). Beta-blockade is now standard therapy to control tachycardia and the hypertension perioperatively. Propranolol has been widely used, titrating the dose to maintain the pulse rate less than 80 to 100 beats/min. More recently, selective beta1-blocking agents such as metoprolol have been used to avoid bronchospasm in patients with reactive airway disease. The exclusive use of beta1-blockade to

control thyrotoxicosis perioperatively has been advocated to avoid the low, but finite, incidence of agranulocytosis seen with the antithyroid agents. A prospective randomized trial compared the use of metoprolol to antithyroid agents for control of hyperthyroidism in patients undergoing thyroid surgery. There were no anesthetic or cardiovascular complications in either group; nor was any difference in consistency or vascularity of the gland noted (131). Hypothyroidism is relatively common, occurring in approximately 2% of the adult female population (132). Signs and symptoms include cool dry skin, ‘‘puffy’’ features, cold intolerance, constipation, hoarseness, dry hair, brittle nails, nonpitting edema, slowed reflexes, and bradycardia. Hemodynamically, hypothyroidism is characterized by a low cardiac index, decreased stroke volume, decreased vascular volume, and an increased systemic vascular resistance (133,134). Up to 30% of untreated patients may have pericardial effusions (135). Hypothyroid-induced hypertension (136) and defects in lipid metabolism predispose these patients toward atherosclerosis. The diagnosis of primary hypothyroidism is confirmed by low serum T4 levels and elevated TSH levels. Surgical complications in patients with hypothyroidism include intraoperative hypotension and altered drug metabolism. Gastrointestinal and neuropsychiatric complications are more prevalent, but the risk of infection, operative bleeding, perioperative arrhythmias, hypothermia, and hyponatremia is not increased. Moreover, hypothyroidism predisposes toward heart failure during cardiac surgery (137). The hypothyroidism should be corrected toward euthyroidism prior to elective surgery, although this may be difficult in the patient with preexisting atherosclerotic coronary artery disease. The chronotropic and inotropic effects of thyroid hormone increase myocardial oxygen consumption, potentially leading to myocardial ischemia. Empiric recommendations exist for hormone replacement in patients with hypothyroidism and known or suspected ischemic heart disease. L-Thyroxine is started at a low dose of 25 mg/day and increased in 12.5 to 25 mg increments at four- to six-week intervals. Although the dose is usually reduced if worsening myocardial ischemia is evident, alternatively, beta-blocking agents may be added (132). Myocardial revascularization is indicated in patients unable to tolerate thyroid replacement (132).

RISKS OF HEMATOLOGIC DISEASE Appropriate management of the surgical patient with a known hematologic disorder is extremely important to avoid potentially disastrous complications. More subtle, but no less important, is the workup of the patient in whom a hematologic abnormality is discovered incidentally on routine preoperative testing.

Anemia Preparation of the anemic patient involves consideration not only of the degree of anemia but also the cause of the anemia and how this may affect the patient’s perioperative course (138). The common assertion that the preoperative hemoglobin level should be at least 10 g/dL to avoid complications is not supported in the literature (138). An otherwise healthy patient undergoing minor surgery should tolerate a hemoglobin level of 7 to 8 g/dL. A patient with significant COPD requiring general anesthesia should have a hemoglobin level of at least 10 g/dL even for minor

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

surgery. In general, if significant blood loss is likely or if the general health status of the patient is questionable, the hemoglobin level should be kept around 10 g/dL (139). Workup of the anemia should proceed prior to surgery, because this may uncover a condition (i.e., occult malignancy) that would alter the operative plan (140). Infection from blood transfusion involves a small, but finite, risk. With this in mind it becomes reasonable to determine a ‘‘safe’’ level of hemoglobin on an individual basis taking into consideration patient volume status, cause and chronicity of anemia, age, underlying cardiovascular disease, type of surgery, and anticipated blood loss (138). Postoperatively, mild-to-moderate anemia has not been shown to have an adverse effect on wound healing (141). History, physical examination, and a few routine laboratory tests can usually determine the cause of the anemia. Table 8 shows which tests are helpful in determining the various causes. The surgical patients with sickle cell anemia may have significant comorbidities in addition to anemia, including cardiomyopathy, congestive heart failure, chronic pulmonary disease, renal insufficiency, nephrotic syndrome, chronic liver disease, and other organ dysfunction. These patients usually have normal or increased blood volume and generally tolerate chronic hemoglobin levels of 6 to 9 g/dL without difficulty. Transfusions in these patients are not routinely necessary simply to increase oxygen-carrying capacity, nor are they considered necessary for most surgical procedures (138). For major surgery in which hypoxia, hypotension, or acidosis are likely to occur, exchange transfusions to reduce the hemoglobin S fraction to approximately 20% to 30% of total hemoglobin may be beneficial (142). The patient with an immunohemolytic anemia must be clearly identified and referred to the blood bank far in advance of surgery, because finding compatible crossmatched blood may be extremely difficult, if not impossible, in the event of hemorrhage (140).

Polycythemia Polycythemia or erythrocytosis can be classified as relative or absolute. Relative erythrocytosis is the result of reduced plasma volume. Absolute erythrocytosis is further classified as either primary or secondary. Primary erythrocytosis or polycythemia vera is a neoplastic disorder characterized by increased red blood cell mass, splenomegaly, thrombosis, and leukocytosis. Secondary polycythemia can be physiologically appropriate in association with pulmonary disease, cardiac disease, or high altitudes. Polycythemia may be physiologically inappropriate as seen in patients with renal

287

cysts or tumors of the kidney, liver, uterus, and posterior fossa (138). Patients with polycythemia vera and its associated high hematocrit are known to have increased surgical morbidity and mortality likely caused by the increased risk of thromboembolic events (143,144). Once the cause of the erythrocytosis has been determined, phlebotomy is used to decrease the hematocrit to an acceptable level. Phlebotomy is usually performed by removing 350 to 500 mL of blood every other day until the appropriate hematocrit is reached. Lesser amounts (200–300 mL) should be removed each time in the elderly or those patients with cardiac disease (138). In primary polycythemia vera, the hematocrit should be decreased to less than 45% prior to surgery (138). In patients with physiologically inappropriate erythrocytoses, the hematocrit should be reduced to at least 45% to 50% as well. In cases in which erythrocytosis is physiologically appropriate, one must weigh the risk of thromboembolic events against the risk of decreasing the oxygen-carrying capacity in a patient with cardiac or pulmonary compromise. For these patients, reducing the hematocrit to approximately 50% to 60% is suggested (145).

Disorders of White Blood Cells Abnormalities in white blood cell count, either leukopenia or leukocytosis, are usually associated with an underlying disease. As a result, the perioperative risks often are related to the underlying disorder. Leukocytosis may be seen with infections, neoplasms, or leukemia. Leukopenia may be seen with radiation, chemotherapy, or overwhelming infection (138). An absolute neutrophil count of less than 1000/mL is associated with a higher incidence of bacterial infections (140). Elective surgery should probably be postponed in the face of severe leukopenia. If urgent operation is required, the patient should be aggressively monitored for infection (138,140).

Platelet Disorders Platelet dysfunction must be characterized as either quantitative or qualitative. The patient with thrombocytopenia but without a qualitative platelet function defect has abnormal bleeding related to the platelet count. In general, excessive bleeding, even with severe trauma, is rare with a platelet count greater than 100,000/mL. Platelet counts greater than 50,000/mL are considered adequate for most surgical procedures. Higher counts are usually preferable for most cardiac, neurologic, and some ophthalmologic surgery (138,140). In addition, bleeding risk must be considered in any patient with fever, infection, sepsis, or anemia regardless of the platelet count (138,140).

Table 8 Laboratory Tests to Determine the Cause of Anemia Laboratory value Reticulocyte count Mean corpuscular volume Mean corpuscular volume Red blood cell

Source: From Ref. 138.

Abnormality High Low High with low reticulocyte count Low with low reticulocyte count Low with normal mean corpuscular volume (normocytic anemia)

Further tests to consider

Possible diagnosis

Hemolysis Decreased red blood cell production Macrocytic anemia secondary to vitamin B12, or B12 and folate levels, liver function tests, thyroid function tests, bone marrow folate deficiency, liver disease, hypothyroidism, examination or primary marrow disorders Serum iron, total iron-binding capacity, ferritin Iron deficiency, chronic malignant or inflammatory disease, thalassemia minor level, hemoglobin A2 Renal function tests, Coombs’ test, erythrocyte Uremia, chronic disease, hemolysis, or bone sedimentation rate, lactate dehydrogenase, marrow depression bilirubin

medwedi.ru

288

Part One: General Considerations

Evaluation of thrombocytopenia should identify the cause as being related to either decreased production, sequestration, or increased destruction. Patients with primary production problems such as those secondary to neoplasms, aplastic anemia, or chemotherapeutic agents tend to show erythrocyte and leukocyte abnormalities as well (138). Thrombocytopenia resulting from sequestration is seen with hypersplenism with or without splenomegaly. An accompanying anemia and leukopenia is seen with a normal marrow (138). Thrombocytopenia secondary to increased platelet destruction can be seen with the use of certain drugs, infection, idiopathic thrombocytopenia purpura (ITP), or disseminated intravascular coagulation (DIC) (138). Drug-associated platelet dysfunction such as that seen with salicylates usually corrects within one week following discontinuation of the drug. Some drugs have a more prolonged effect and so repeated count and function should be obtained prior to proceeding with operation. Elective surgery should be postponed until the platelet defect is characterized and the underlying disorder is treated (140,146). A low platelet count due to increased platelet destruction is unlikely to be improved by platelet transfusion. For nonelective surgery, if pathologic bleeding occurs, or if no therapy is available for the underlying disorder, platelet transfusion is appropriate (140,146). In general, one unit of platelets will raise a platelet count by approximately 5000 to 10,000/mL. For platelet consumption and bleeding due to DIC, the underlying cause must be treated and the patient should be transfused with platelet concentrates and fresh frozen plasma (138). Although the normal lifespan of newly produced platelets is approximately 8 to 10 days, the expected lifespan of transfused platelets is between several hours and three days (140). A posttransfusion platelet count is necessary before proceeding with surgery (138,140). Steroids are the initial therapy for ITP. When a response is seen, splenectomy can be considered with the planned operative procedure. For patients not responding to steroids, splenectomy should be performed prior to elective surgery in an attempt to improve platelet counts. Preoperative intravenous gamma globulin should be given to patients unresponsive to steroid or splenectomy (138).

Coagulation Defects Adequate hemostasis is crucial to successful surgery. The history and physical examination are the most valuable screens for potential coagulation defects. However, as technology advances and more screening tests become available to the physician, one must consider which tests are appropriate. Several studies have looked at how useful and

accurate some of these screening tests are and which ones, based on the history and surgery to be performed, should be obtained preoperatively (146). History should focus on any excessive bleeding with previous surgery, trauma or tooth extraction, drug use, renal or liver disease or any family history of bleeding disorders (138). Physical examination should focus on petechiae, ecchymoses, jaundice, or hepatosplenomegaly (138). Although history and physical examination are vital, laboratory screening tests are necessary for several reasons. They may protect against the failure to elicit an adequate history preoperatively. Some patients may not provide a reliable history. The patient may have a coagulation abnormality that causes bleeding only after surgery (e.g., factor XI deficiency), and the patient may never have had a surgical procedure. Moreover, a patient having undergone previous surgery may have only recently developed a coagulopathy (146). A preoperative screening questionnaire is recommended to identify the patient at risk (Box 7). Patients undergoing minor surgery with no suspicious bleeding history require no further studies (138,146). PT, activated partial thromboplastin time (aPTT), and a platelet count should be assessed in patients having a major operation with no evidence of a bleeding history (147). A bleeding time should also be obtained in any patient with a suspicious or suggestive history, who will be undergoing major surgery. This is particularly important in cardiac bypass surgery or prostate surgery where hemostasis could be further impaired or in any type of surgery in which excessive bleeding could be catastrophic (neurosurgery or ophthalmologic surgery) (138). In general, the aPTT evaluates the intrinsic pathway of the coagulation cascade, whereas the PT evaluates the extrinsic and common pathway. Prolongation of the aPTT can be caused by a deficiency of factor XI, antibodies against a specific coagulation factor, by von Willebrand’s disease (factor VIII RWF deficiency), or by a deficiency of factor VIII or IX (hemophilia A or B) in males (138). Lupus anticoagulant causes an artifactual prolongation of the aPTT but actually leads to a hypercoagulable state. Prolongation of the PT can be seen with factor VII deficiency, vitamin K deficiency, or liver disease. A prolongation of both the PT and aPTT is seen with liver disease, DIC, or vitamin K deficiency (138,140). Patients with known hemophilia A (factor VIII deficiency) can be treated specifically with factor VIII concentrate. Patients with severe hemophilia undergoing major surgery should receive 40 U/kg of factor VIII concentrate immediately before surgery (138,140). Postoperatively, the

Box 7 Preoperative Hemostatic Evaluation Have you ever bled for a long time or developed a swollen tongue or mouth after cutting or biting your tongue, cheek, or lip? Do you develop bruises larger than a silver dollar without being able to remember when or how you injured yourself? If so, how big was the largest of these bruises? How many times have you had teeth pulled, and what was the longest time that you bled after an extraction? Has bleeding ever started up again the day after an extraction? What operations have you had, including minor surgery such as skin biopsies? Was bleeding after surgery ever hard to stop? Have you ever developed unusual bruising in the skin around an area of surgery or injury? Have you had a medical problem within the past 5 yr requiring a doctor’s care? If so, what was its nature? What medications, including aspirin or any other remedies for headaches, colds, menstrual cramps, or other pains, have you taken within the past 7 to 9 days? Has any blood relative had a problem with unusual bruising or bleeding after surgery? Were blood transfusions required to control this bleeding? Source: From Ref. 146.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery

289

bleeding correlates with the efficacy of a particular prophylaxis regimen. It is therefore important to stratify the risk of VTE (Table 9), as well as identify the appropriate prophylaxis regimen for each level of risk (Tables 9 and 10) (149).’’

dose is tapered according to the surgery performed, continuing longer for more major procedures. Patients with minor hemophilia undergoing major operative procedures can also be managed with cryoprecipitate that contains factor VIII. In addition, DDAVP can be used in mild hemophilia to raise factor VIII levels to the normal range (138). Patients with known hemophilia B (factor IX deficiency) can be treated similarly to those with hemophilia A. Factor IX concentrate is available; however, it contains activated clotting factors, and therefore the patient must be carefully monitored for thrombotic complications. Preoperative preparation of the patient with von Willebrand’s disease includes the use of DDAVP. A test dose is given preoperatively to evaluate response. Cryoprecipitate should be used for major surgical procedures (138). Liver disease can cause coagulation abnormalities by several mechanisms. The treatment and workup of coagulation problems associated with hepatic disease were discussed earlier in the chapter.

HIV INFECTION AND AIDS Patients infected with the human immunodeficiency virus (HIV), both those who have asymptomatic HIV and those who have progressed to the acquired immunodeficiency syndrome (AIDS), have a greater risk of morbidity and mortality, presumably because of their immunosuppression (150–156). The diagnosis of AIDS requires a positive HIV serology and the presence of either opportunistic infections, opportunistic tumors, neurologic complications resulting in encephalopathy, CD4þ T-lymphocyte percentage of less than 14%, or an absolute CD4þ count of less than 200/mm3 (154). Patients with end-stage AIDS can be expected to have a very poor outcome with surgical intervention, and so only conservative, palliative care should be offered to these patients. The difficulty remains, however, in identifying those HIV-positive and non–end-stage AIDS patients who may benefit from surgical intervention. ‘‘In general, HIV-positive patients on retroviral therapy are presenting for surgery in better condition than in the past, and have acceptable long-term results even after cardiac surgery (155).’’ HIV infection, even in the absence of AIDS, appears to impair wound healing. Safavi et al. (150) presented a series of 48 HIV-positive patients undergoing anorectal surgery. Whereas essentially 100% of the wounds would be expected to heal in healthy patients, Safavi et al. found that only 69% of the wounds in HIV-positive patients healed. In patients with AIDS, only 26% of the wounds healed. CD4þ counts did not correlate with the outcome. ‘‘In HIV-positive patients undergoing resection of anal condylomata, low CD4þ counts did correlate with recurrence (156).’’

PROPHYLAXIS AGAINST THROMBOEMBOLISM Surgical patients are at risk for developing venous thromboembolism (VTE) on the basis of Virchow’s triad (stasis, endothelial damage, and hypercoagulable state). The patient is at high risk of developing DVT while immobilized on the operating table. Effective prophylaxis regimens include the use of sequential compression devices on the lower extremities during surgery and the administration of subcutaneous heparin injections (5000 units every 8 to 12 hours), starting two hours prior to surgery (148,149). ‘‘More recently, low-molecular-weight heparins (LMWHs) have been shown to be efficacious for thromboembolism prophylaxis in both orthopedic and general surgical patients. The use of LMWHs has also been noted to cause fewer wound hematomas than the use of unfractionated heparin (148). The American College of Chest Physicians provides guidelines for prophylaxis against VTE (149). In general, risk of

Table 9 Stratification of Risk for Venous Thromboembolism in Surgical Patients (For Definition of Prevention Strategies, See Regimens to Prevent Venous Thromboembolism.) Level of risk, examples Low risk Minor surgery in patinets < 40 yrs with no additional risk factors Moderate risk Minor surgery in patients with additional risk factors nonmajor surgery in patients aged 40–60 yrs with no additional risk factors; major surgery in patients < 40 yrs with no additional risk factors High risk Nonmajor surgery in patients > 60 yrs or with additional risk factors major surgery in patients > 40 yrs or with additional risk factors Higher risk Major surgery in patients > 40 yrs plus prior history of VTE, cancer, or molecular hyperocagulable state; hip or knee arthroplasty lip fracture surgery major trauma; or spinal cord injury

Calf DVT(%)

Proximal DVT(%)

Clinical PE(%)

Fatal PE(%)

2

0.4

0.2

0.002

No specific measures Aggressive mobilization

10–20

2–4

1–2

0.1–0.4

LDUH q12H, LMWH, ES, or IPC

20–40

4–8

2–4

0.4–1.0

LDUH q8h, LMWH, or IPC

40–80

10–20

4–10

0.2–5

Successful prevention strategies

LMWH, orlal anticoagulating, IPC/ ES þ LDUH/LMWH, or ADH

Abbreviations: DVT, deep venous thrombosis; VTE, venous thromboembolism; LDUH, low-dose unfractionated heparin; LMWH, low-molecular-weight heparin; IPC, intermittent pneumatic compression device; ES, elastic stockings; ADH, antidiuretic hormone. Source: From Refs. 60, 74, 149.

medwedi.ru

290

Part One: General Considerations

Table 10 Treatment Regimens to Prevent Venous Thromboembolism Method LDUH ADH LMWH and heparnoidsa

Perioperative warfarin IPC/ES

Description Heparin 5000 U SC, given q8–12h starting 1–2 hrs before operation Heparin SC, given q8h starting at approximately 3500 U SC and adjusted by500 U SC per dose, to maintain a midinterval aPTT at high normal values General surgery moderate risk: Dalteparin, 2500 U SC 1–2 hrs before surgery and once daily postop Enoxaparin, 20 mg SC, 1–2 hrs before surgery and once daily postop Nadroparin, 2850 U SC 2–4 hrs before surgery and once daily postop Trinzaparin, 3500 U SC 2 hrs before surgery and once daily postop General surgery high risk: Dalteparin, 5000 U SC 8–12 hrs before surgery and once daily postop Danaparold, 750 U SC 1–4 hrs before surgery and q12h postop Enoxaparin, 40 mg SC, 1–4 hrs preop and once dialy postop Enoxaparin, 30 mg SC, q12h starting 8–12 hrs postop Orthopedic surgery Dalteparin, 5000 U SC 8–12 hrs preop and once daily starting 12–24 hrs postop Dalteparin, 2500 U SC 6–8 hrs postop then 5000 U SC once daily Danaparoid, 750 U SC 1–4 hrs prop and q12h postop Enoxaparin, 30 mg SC q12h starting 12–24 hrs postop Enoxaparin, 40 mg SC once daily starting 10–12 hrs preop Nadroparin, 38 U/kg SC 12 hrs preop 12 hrs postop and once daily on postop days 1, 2, and 3; then increase to 57 U/kg SC once daily Trinzaparin, 75 U/kg SC once daily starting 12–24 hrs postop Tinzaparin, 4500 U SC 12 hrs preop and once daily postop Major Trauma Enoxaparin, 30 mg SC q12h starting 12–36 hrs postinjury if hemostatically stable Acute spinal cord injury Enoxaparin, 30 mg SC q12h Medical conditions Dalteparin, 2500 U SC once daily Danaparold, 750 U SC q12h Enoxaparin, 40 mg SC once daily Nadroparin 2850 U SC once dialy Start daily dose with approximately 5–10 mg the day of or the day after surgery adjust the dose for a target INR of 25 (range 2–3) Start immediately before operation; and continue until fully ambulatory

a

Dosage expressed in anti-Xa units (for enoxaparin, 1 mg ¼ 100 anti-Xa units). Abbreviations: ADH, antidiuretic hormone; LDVH, low-dose unfractionated heparin; LMWH, low-molecular-weight heparin; ES, elastic stockings; IPC, intermittent pneumatic compression device; aPTT, activated partial thromboplastin time; Postop, postoperative; SC, subcutaneous. Source: From Ref. 149.

Patients with AIDS, undergoing emergent laparotomy, including appendectomy, have an expected perioperative mortality of 12% and an expected morbidity of 26% (151,152). The presence of opportunistic infections, lack of ongoing prophylactic treatment for AIDS-related disease, and ongoing sepsis at laparotomy correlate with increased morbidity and mortality (152). Binderow et al. (153) tried to predict outcome in 10 HIV-positive patients and 25 patients with AIDS, undergoing major abdominal surgery, excluding appendectomy. The perioperative mortality for the group with AIDS was 33% compared to 10% for the HIV-positive group. Perioperative mortality correlated with serum albumin, which was significantly different in survivors (3.9 g/L) versus nonsurvivors (2.8 g/L). Total and differential white blood cell counts do not seem to correlate with outcome (151–153). Based on the available studies (150–154,156) HIVpositive patients are more likely to benefit from surgery than patients with AIDS. Relatively minor procedures, such as for vascular access, or lymph node biopsy are well tolerated without undue morbidity (154). Ideally, HIV-positive patients and patients with AIDS undergoing elective surgery should be well nourished and free of opportunistic infection at the time of operation.

SUMMARY The physiologic derangements accompanying surgery may, at times, exceed the patient’s physiologic reserve, resulting in significant morbidity and mortality. It is the responsibility of the surgeon to balance the potential risks and benefits of an operative procedure with the management alternatives to provide the patient with an optimal outcome. A thorough history and physical examination not only define the surgical disease process of interest but also identify associated comorbidities. Knowledge of the disease processes involved allows stratification of risk and the determination of the appropriate course of therapy. Ultimately, a thoughtful approach to the preoperative preparation of the surgical patient serves to minimize morbidity and mortality.

REFERENCES 1. Detsky AS, et al. Cardiac assessment for patients undergoing noncardiac surgery; a multifactorial clinical risk index. Arch Intern Med 1986; 16:2131.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery 2. Smith LC, Mullen JL. Nutritional assessment and indications for nutritional support. Surg Clin North Am 1991; 71(3):449. 3. Ellis LM, Copeland EM, Souba WM. Perioperative nutritional support. Surg Clin North Am 1991; 71(3):493. 4. Reisin E, Frohlich ED. Obesity: cardiovascular and respiratory pathophysiologic alterations. Arch Intern Med 1981; 141:431. 5. Mason ED, Renquist KE, Jiang D. Perioperative risks and safety of surgery for severe obesity. Am J Clin Nutr 1992; suppl(55):5735. 6. Perugini RA, et al. Predictors of complication and suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass. Arch Surg 2003; 138:341. 7. Lund CC, Browder NC. Estimation of areas of burns. Surg Gynecol Obstet 1944; 79:352. 8. Baxter CR. Crystalloid resuscitation of burn shock. In: Polk HC, Stone HH, eds. Contemporary Burn Management. Boston: Little Brown, 1971. 9. Polk HC, et al. Guidelines for prevention of surgical wound infection. Arch Surg 1983; 118:1213. 10. Paluzzi RG. Antimicrobial prophylaxis for surgery. Med Clin North Am 1993; 77(2):427. 11. Kaiser AB. Overview of cephalosporin prophylaxis. Am J Surg 1988; 155(suppl 5A):52. 12. Olson M, O’Connor M, Schwartz M. Surgical wound infections: a 5 year prospective study of 20,193 wounds at the Minneapolis VA Medical Center. Ann Surg 1984; 199:253. 13. Neibart E. Preoperative preventive antimicrobial therapy. Mt Sinai J Med 1991; 58(1):19. 14. Goldmann DA, Hopkins CC, Karchmer AW. Cephalothin prophylaxis in cardiac valve surgery: a prospective, doubleblind comparison of two-day and six-day regimen. J Thorac Cardiovasc Surg 1977:470. 15. Kaiser AM. Post-operative infections and antimicrobial prophylaxis. In: Mandel G, Douglas G, Bettett J, eds. Principles and Practice of Infectious Disease. 3rd ed. New York: Churchill Livingstone, 1989. 16. Fleites RA, et al. The efficacy of polyethylene glycol-electrolyte lavage solution versus traditional mechanical bowel preparation for elective colonic surgery: a randomized, prospective blinded clinical trial. Surgery 1985; 98(4):708. 17. Nichols RL, et al. Effect of preoperative neomycin-erythromycin intestinal preparation on the incidence of infectious complications following colon surgery. Ann Surg 1973; 178(4):453. 18. Schoetz JD, et al. Addition of parenteral cefoxitin to regimen of oral antibiotics for elective colorectal operations: a randomized prospective study. Ann Surg 1990; 212(2):209. 19. Zibrak JD, O’Donnell CR, Marton K. Indications for pulmonary function testing. Ann Intern Med 1990; 112:763. 20. Williams-Russo P, et al. Predicting postoperative pulmonary complications: is it a real problem? Arch Intern Med 152:1209, 1992; Fisher BW, Majumdar SR, McAlister FA. Predicting pulmonary complications after nonthoracic surgery: a systematic review of blinded studies. Am J Med 2002; 112:219. 21. Fisher BW, Majumdar SR, McAlister FA. Predicting pulmonary complications after nonthoracic surgery: a systematic review of blinded studies. Am J Med 2003; 167:741. 22. McAlister FA, et al. Accuracy of the preoperative assessment in predicting pulmonary risk after nonthoracic surgery. Am J Respir Crit Care Med 2003; 167:741. 23. Ford GT. Respiratory physiology in upper abdominal surgery. Clin Chest Med 1993; 14(2):237. 24. Hotchkiss RS. Perioperative management of patient with chronic obstructive pulmonary disease. Int Anesthesiol Clin 1988; 26(2):134. 25. Weiman DS, et al. Perioperative respiratory management in cardiac surgery. Clin Chest Med 1983; 14(2):283. 26. Wittgen CM, et al. Preoperative pulmonary function evaluation for laparoscopic cholecystectomy. Arch Surg 1993; 128:880. 27. Warner MA, et al. Role of preoperative cessation of smoking and other factors in postoperative pulmonary

28.

29.

30.

31. 32. 33. 34.

35.

36.

37.

38.

39.

40. 41. 42.

43. 44.

45. 46. 47. 48.

49. 50.

51.

291

complications: a blinded prospective study of coronary artery bypass patients. Mayo Clin Proc 1989; 64:609. Bluman LG, Mosca L, Newman N, Simon DG. Preoperative smoking habits and postoperative pulmonary complications. Chest 1998; 113:883. Moller AM, Pedersen T, Billebro N, Munksgaard A. Effect of smoking on early complications after elective orthopaedic surgery. J Bone Joint Surg Br 2003; 85:178. Sorensen LT, Horby J, Friis E, Pilsgaard B, Jorgensen T. Smoking as a risk factor for wound healing and infection in breast cancer surgery. Eur J Surg Oncol 2002; 28:815. Boysen PG. Perioperative management of the thoracotomy patient. Clin Chest Med 1993; 14(1):321. Sykes LA, Bowe EA. Cardiorespiratory effects of anesthesia. Clin Chest Med 1993; 14(2):211. Ferrante FM, et al. Intrapleural analgesia after thoracotomy. Anesth Analg 1991; 72:105. Sola JE, Bender JS. Use of the pulmonary artery catheter to reduce operative complications. Surg Clin North Am 1993; 73(2):253. Berlauk JF, et al. Preoperative optimization of cardiovascular hemodynamics improves outcome in peripheral vascular surgery: a prospective, randomized clinical trial. Ann Surg 1991; 214(3):289. Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2002; 105:1257. Eagle KA, et al. Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Arch Intern Med 1989; 110:859. Hertzer NR, et al. Coronary artery disease in peripheral vascular patients. A classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984; 199:223. Lieberman RW, et al. Hemodynamic predictors of myocardial ischemia during halothane anesthesia for coronary artery revascularization. Anesthesiology 1983; 59:36. Leung JM. The role of hemodynamics in perioperative myocardial ischemia. Int Anesthesiol Clin 1992; 30(1):63. Tarhan S, et al. Myocardial infarction after general anesthesia. JAMA 1972; 220:1451. Rao TLK, Jacobs KH, EI-Etr AA. Reinfarction following anesthesia in patients with myocardial infarction. Anesthesiology 1983; 59:499. Campeau L. Grading of angina pectoris. Circulation 1976; 54:522–523. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of Atenolol on mortality and cardiovascular morbidity after noncardiac surgery. New Engl J Med 1996; 335:1713. Just H, Drexler H, Hasenfuss G. Pathophysiology and treatment of congestive heart failure. Cardiology 1994; 84(suppl 12):99. Gradman AH, Deedwania PC. Predictors of mortality in patients with heart failure. Cardiol Clin 1994; 12(1):25. McKee PA, et al. The natural history of congestive heart failure: The Framingham Study. N Engl J Med 1971; 285:1441. Cohn JN, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314:1547. Greenberg B. Role of vasodilator therapy in congestive heart failure: effects on mortality. Cardiol Clin 1994; 12(1):87. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the evaluation and management of chronic heart failure in the adult: executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). Circulation 2001; 104:2996. Donnan GA, et al. Hypertension and stroke. J Hypertens 1994; 12:865.

medwedi.ru

292

Part One: General Considerations

52. Epstein M. Hypertension as a risk factor for progression of chronic renal disease. Blood Press1994; (suppl 1):23. 53. Lip GY, Gammage MD, Beevers DG. Hypertension and the heart. Br Med Bull 1994; 50(2):299. 54. Lithell H. Pathogenesis and prevalence of atherosclerosis in hypertensive patients. Am J Hypertens 1994; 7(2):2S. 55. Shaper AG, Wannamethee G, Walker M. Physical activity, hypertension and risk of heart attack in men without evidence of ischaemic heart disease. Hum Hypertens 1994; 8(1):3. 56. Devereux RB, et al. Left ventricular hypertrophy associated with hypertension and its relevance as a risk factor for complications. J Cardiovasc Pharmacol 1993; 21(suppl 2):S38. 57. Schwartzkopff B, et al. Heart failure on the basis of hypertension. Circulation 1993; 87(suppl 5):IV66. 58. Moser M. Effect of diuretics on morbidity and mortality in the treatment of hypertension. Cardiology 1994; 84(suppl 2):27. 59. Allman KG, et al. Resistant hypertension and preoperative silent myocardial ischaemia in surgical patients. Br J Anaesth 1994; 73:574. 60. Sideris DA. High blood pressure and ventricular arrhythmias. Eur Heart J 1993; 14:1548. 61. Gifford RW, Manger WM, Bravo EL. Pheochromocytoma. Endocrinol Metab Clin North Am 1994; 23(2):387. 62. Rackley CE. Valvular heart disease. In: Wyngaarden JB, Smith LH, eds. Cecil Textbook of Medicine. 17th ed. WB Saunders: Philadelphia, 1985. 63. Braunwauld E. Valvular heart disease. In: Braunwauld E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia: WB Saunders, 1992. 64. Leavitt JI, Coats MH, Falk RH. Effects of exercise on transmittal gradient and pulmonary artery pressure in patients with mitral stenosis or a prosthetic mitral valve: A Doppler Echocardiographic Study. J Am Coll Cardiol 1991; 17:1520. 65. Thomas SJ, Lowenstein E. Anesthetic management of the patient with valvular heart disease. Int Anesthesiol Clin 1979; 17(1):67. 66. Danielsen R, Nordrehaug JE, Vi-Mo H. Clinical and haemodynamic features in relation to severity of aortic stenosis in adults. Eur Heart J 1991; 12:791. 67. Driscoll DJ, et al. Cardiorespiratory responses to exercise of patients with aortic stenosis, pulmonary stenosis and ventricular septal defect. Circulation 1993; 87(suppl I):1–102. 68. Kennedy KD, et al. Natural history of moderate aortic stenosis. J Am Coll Cardiol 1991; 17(2):313. 69. Turpie AGG. Preventing thromboembolism in patients with prosthetic heart valves. Cardiol Clin 1994; 12(3):487. 70. Madura JA, Rookstool M, Wease G. The management of patients on chronic coumadin therapy undergoing subsequent surgical procedures. Am Surg 1994; 60:542. 71. Dajani AS, et al. Prevention of bacterial endocarditis. JAMA 1997; 277:1794. 72. Callow AD, Trachtenberg JD. Diagnosis and surgical management of asymptomatic carotid stenosis. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery. 3rd ed. St. Louis: Mosby, 1995. 73. Freidman LS, Maddrey WC. Surgery in the patient with liver disease. Med Clin North Am 1987; 2(3):453. 74. Ngai SH. Current concepts in anesthesiology. N Engl J Med 1980; 302:564. 75. Kelly DA, Tuddenham EGD. Haemostatic problems in liver disease. Gut 1986; 27:339. 76. Gholson CF, Provenza JM, Bacon BR. Hepatologic considerations in patients with parenchymal liver disease undergoing surgery. Am J Gastroenterol 1990; 85(5):487. 77. Harville DD, Summerskill WH. Surgery in acute hepatitis. JAMA 1963; 1984:257. 78. Greenwood SM, Lefler CT, Minkowitz S. The increased mortality rate of open liver biopsy in alcoholic hepatitis. Surg Gynecol Obstet 1972; 134:600. 79. Powell Jackson P, Greenway B, Williams R. Adverse effects of laparotomy in patients with unsuspected liver disease. Br J Surg 1982; 69:449.

80. Runyan BA. Surgical procedures are tolerated well by patients with asymptomatic chronic hepatitis. J Clin Gastroenterol 1986; 8:542. 81. Hargrove MD. Chronic active hepatitis: possible adverse effects of exploratory laparotomy. Surgery 1970; 68:771. 82. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, ed. The Liver and Portal Hypertension. Philadelphia: WB Saunders, 1964. 83. Conn M. Preoperative evaluation of the patient with liver disease. Mt Sinai J Med 1991; 58(1):75. 84. Schepens MA, et al. Risk assessment of acute renal failure after thoracoabdominal aortic aneurysm surgery. Ann Surg 1994; 219(4):400. 85. Novis BK, et al. Association of preoperative risk factors with postoperative acute renal failure. Anesth Analg 1994; 78:143. 86. Pinson CW, et al. Surgery in long-term dialysis patients: experience with more than 300 cases. Am J Surg 1986; 151:567. 87. Rose BD. Diagnostic approach to the patient with renal disease. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 88. Rose BD. Acute renal failure-prerenal disease versus acute tubular necrosis. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 89. Kellen M, et al. Predictive and diagnostic tests of renal failure: a review. Anesth Analg 1994; 78:134. 90. Rose BD, Brenner BM. Mechanisms of progression of renal disease. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 91. Coratelli P, Passavanti C. Pathophysiology of renal failure in obstructive jaundice. Miner Electrolyte Metab 1990; 16:61. 92. Wait RB, Kahng KU. Renal failure complicating obstructive jaundice. Am J Surg 1989; 157:256. 93. Parks RW, et al. Prospective study of postoperative function in obstructive jaundice and the effect of perioperative dopamine. Br J Surg 1994; 81:437. 94. Turka LA. Urinary tract obstruction. In: Rose BD, ed. Pathophysiology of Renal Disease. New York: McGraw-Hill, 1987. 95. Webb JA, et al. Can ultrasound and computed tomography replace high-dose urography in patients with impaired renal function? Q J Med 1984; 53:411. 96. Burke JF, Francos GC. Surgery in the patient with acute or chronic renal failure. Med Clin North Am 1987; 71(3):489. 97. Muller MC. Anesthesia for the patient with renal dysfunction. Int Anesthesiol Clin 1984; 22(1):169. 98. Kellerman PS. Perioperative care of the renal patient. Arch Intern Med 1994; 154:1674. 99. Solomonson MD, Johnson ME, Ilstrup D. Risk factors in patients having surgery to create an arteriovenous fistula. Anesth Analg 1994; 79:694. 100. Ziccardi VB, et al. Management of the oral and maxillofacial surgery patient with end-stage renal disease. J Oral Maxillofac Surg 1992; 50:1207. 101. Bick RL. Acquired platelet function defects. Hematol Oncol Clin North Am 1992; 6(6):1203. 102. Edelson GW, Fachnie JD, Whitehouse FW. Perioperative management of diabetes. Henry Ford Hosp Med J 1990; 38(4):262. 103. Feingold KR, et al. Diabetes mellitus. In: Andreoli TE et al., eds. Cecil Essentials of Medicine. 2nd ed. Philadelphia: WB Saunders, 1990. 104. Root HE. Preoperative care of the diabetic patient. Postgrad Med 1966; 40:439. 105. Goodson WH III, Hunt TK. Wound healing and the diabetic patient. Surg Gynecol Obstet 1979; 149:600. 106. Goodson WH III, Hunt TK. Deficient collagen formation by obese mice in a standard wound model. Am J Surg 1979; 138:692. 107. Gottrup F, Adreassen TT. Healing of incisional wounds in stomach and duodenum: the influence of experimental diabetes. J Surg Res 1981; 313:61. 108. Hirsch IB, McGill JB. Role of insulin in management of surgical patients with diabetes mellitus. Diabetes Care 1990; 13:980.

Chapter 13: Physiologic Principles in Preparing Patients for Surgery 109. Taitelman U, Reese EA, Bessman AN. Insulin in the management of the diabetic surgical patient. JAMA 1977; 237:658. 110. McMurry JF. Wound healing with diabetes mellitus better glucose control for better wound healing in diabetes. Surg Clin North Am 1984; 64(4):769. 111. Gavin LA. Management of diabetes mellitus during surgery. West J Med 1989; 151:525. 112. Galloway JA, et al. Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures. Diabetes Care 1981; 4:366. 113. Hildebrand P, Sestoft L, Nielson SL. The absorption of subcutaneously injected short-acting soluble insulin: influence of injection technique and concentration. Diabetes Care 1983; 6:459. 114. Goldberg NJ, et al. Insulin therapy in the diabetic surgical patient: metabolic and hormone response to low-dose insulin infusion. Diabetes Care 1981; 4:279. 115. Watts NB, et al. Postoperative management of diabetes mellitus: steady state glucose control with bedside algorithm for insulin adjustment. Diabetes Care 1987; 10:722. 116. Pezzarossa A, et al. Perioperative management of diabetic subjects: subcutaneous versus intravenous insulin administration during glucose-potassium infusion. Diabetes Care 1988; 11:52. 117. Farkas-Hirsch R, Boyle PJ, Hirsch IB. Glycemic control in the surgical patient with IDDM [abstract]. Diabetes 1989; 38(suppl 2):39A. 118. Alberti KGMM, Marshall SM. Diabetes and surgery. In: Alberti KGMM, Krall LP, eds. The Diabetes Annual. New York: Elsevier, 1988:248. 119. Felig P, et al. Blood glucose and gluconeogenesis in fasting man. Arch Intern Med 1969; 123:293. 120. Fritz I, Levine R. Action of adrenal cortical steroids and norepinephrine on vascular responses of stress in adrenalectomized rats. Am J Physiol 1951; 165:456. 121. Knowlton AL. Adrenal insufficiency in the intensive care setting. J Intens Care Med 1989; 4:35. 122. Claussen MS, Landercasper J, Cogbill TH. Acute adrenal insufficiency presenting as shock after trauma and surgery: three cases and review of the literature. J Trauma 1992; 32(1):94. 123. Salem M, et al. Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem. Ann Surg 1994; 219(4): 416. 124. Havlik RJ, Cahow E, Kinder BK. Advances in the diagnosis and treatment of pheochromocytoma. Arch Surg 1988; 123:626. 125. Bravo EL, Gifford RW Jr. Pheochromocytoma: diagnosis, location and management. N Engl J Med 1984; 311:1298. 126. Hauptman JB, Modlinger RS, Ertel NH. Pheochromocytoma resistant to alpha-adrenergic blockade. Arch Intern Med 1983; 143:2321. 127. Hull CJ. Pheochromocytoma diagnosis, preoperative preparation and anaesthetic management. Br J Anaesth 1986; 58:1453. 128. Malone MJ, et al. Preoperative and surgical management of pheochromocytoma. Urol Clin North Am 1989; 16(3):567. 129. Gann DS, Foster AH. Endocrine and metabolic responses to injury. In: Schwartz SI, ed. Principles of Surgery. 6th ed. New York: McGraw-Hill, 1994. 130. Heimann P, Martinson J. Surgical treatment of thyrotoxicosis: results of 272 operations with special reference to preoperative treatment with antithyroid drugs and L-thyroxine. Br J Surg 1975; 62:683. 131. Alderberth A, Stenstrom G, Hasselgren PO. The selective betalblocking agent metoprolol compared with antithyroid

132. 133.

134.

135. 136.

137. 138. 139. 140. 141. 142. 143. 144.

145. 146. 147.

148. 149.

150. 151. 152. 153.

154.

155.

156.

293

drug and thyroxine as preoperative treatment of patients with hyperthyroidism. Results from a prospective, randomized study. Ann Surg 1987; 205(2):182. Klein I. Thyroid hormone and the cardiovascular system. Am J Med 1990; 88:631. Amidi M, et al. Effect of the thyroid state on myocardial contractility and ventricular ejection rate in man. Circulation 1968; 38:229. Graettinger JS, et al. A correlation of clinical and hemodynamic studies in patients with hyperthyroidism with and without congestive heart failure. J Clin Invest 1959; 38:1316. Kerber RE, Sherman B. Echocardiographic evaluation of pericardial effusion in myxedema. Circulation 1975; 52:823. Streeten DH, et al. Effects of thyroid function on blood pressure. Recognition of hypothyroid hypertension. Hypertension 1988; 11:78. Ladenson PW, et al. Complications of surgery in hypothyroid patients. Am J Med 1984; 77:261. Fellin F, Murphy S. Hematologic problems in the preoperative patient. Med Clin North Am 1987; 71(3):477. Rawstron RE. Anemia and surgery. A retrospective clinical study. Aust NZ J Surg 1970; 39:425. Calandri C, Rand JH. Preoperative evaluation for hematologic status. Mt Sinai J Med 1991; 58(1):41. Heughan C, Grislis G, Hunt TK. The effect of anemia on wound healing. Ann Surg 1974; 179:163. Dobson MB. Anesthesia for patients with hemoglobinopathies. Int Anesthesiol Clin 1985; 23:197. Wasserman LR, Gilbert HS. Surgical bleeding in polycythemia vera. Ann NY Acad Sci 1964; 15:122. Rigby PG, Leavell BS. Polycythemia vera: a review of fifty cases with emphasis on the risk of surgery. Arch Intern Med 1960; 5:622. Golde DW, et al. Polycythemia: mechanisms and management. Ann Intern Med 1981; 95:71. Rapaport SI. Preoperative hemostatic evaluation: which tests if any? Blood 1983; 61:229. Eisenberg JM, Clarke JR, Sussman SA. Prothrombin and partial thromboplastin times as preoperative screening tests. Arch Surg 1982; 117:48. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism (Sixth ACCP Consensus Conference on Antithrombotic Therapy). Chest Suppl 2001; 119:132S. Safavi A, Gottesman L, Dailey TH. Anorectal surgery in the HIVþpatient: update. Dis Colon Rectum 1991; 34(4):299. Davidson T, et al. Emergency laparotomy in patients with AIDS. Br J Surg 1991; 78:924. Whitney TM, et al. Emergent abdominal surgery in AIDS: experience in San Francisco. Am Surg 1994; 168:239. Binderow SR, Cavallo RJ, Freed J. Laboratory parameters as predictors of operative outcome after major abdominal surgery in AIDS- and HIV infected patients. Am Surg 1993; 59:754. Klatt EC. Surgery and human immunodeficiency virus infection: indications, pathologic findings, risks and risk prevention. Int Surg 1994; 79:1. Mestres CA, Chuquire JE, Claramonte X, et al. Long-term results after cardiac surgery in patients infected with the human immunodeficiency virus type-1 (HIV-1). Eur J Cardio-Thorac Surg 2003; 23:1007. De la Fuente SG, Ludwig KA, Mantyh CR. Preoperative immune status determines anal condyloma recurrence after surgical excision. Dis Colon Rectum. 2003; 46:367.

medwedi.ru

PART TWO: The Alimentary Tract ESOPHAGUS AND STOMACH

14 Physiologic Dysfunction of the Esophagus Nahid Hamoui and Peter F. Crookes

INTRODUCTION The gastrointestinal (GI) tract can be thought of as a long tube subdivided into a series of compartments with unique pH and enzymatic environments, each being separated from the next by a sphincter. Food residue is pumped through a valve into a receptacle, where chemical changes occur, before it is pumped into a more distal compartment. The most proximal is the mouth, where the tongue and pharyngeal muscles pump food through the upper esophageal sphincter (UES) into the proximal esophagus. Food is then pumped through another valve, the lower esophageal sphincter (LES), into the reservoir portion of the stomach, where the pH is strongly acidic, and subsequently pumped by the antrum through the pylorus into another receptacle, the duodenum. In the duodenum the pH is again alkaline, facilitating the action of trypsin and carboxypeptidases, and the residue is further influenced by enzymes from the small bowel itself, before being pumped through another valve, the ileocecal valve, into the cecum, a reservoir portion of the colon. In the colon, fluids and electrolytes are adjusted and the residue is pumped by the descending colon through the anal sphincter to the exterior. The esophagus is the most proximal portion of this system of importance to the surgeon. Its function is simpler to understand and study than most other portions of the GI tract. The esophagus functionally consists of a UES, whose function is largely to protect the airway from contamination by ingested solids and liquids, a tubular portion termed the ‘‘esophageal body,’’ whose function is to propel food into the stomach, and an LES, whose function is to protect the esophageal mucosa from contamination by gastric juice in the face of substantial changes in intragastric pressure or intra-abdominal pressure, while still permitting belching of air when necessary. Diseases of the esophagus can be classified as benign and malignant, and benign disease can be further distinguished as structural and functional. Structural diseases, characterized by anatomical alterations such as hernias, strictures, tumors, or diverticula, generally represent more advanced and life-threatening situations, and are most readily identified on imaging or endoscopic studies. Functional diseases are less commonly a threat to life, but substantially affect quality of life (QoL). The major tools to study esophageal function are esophageal manometry and 24-hour pH monitoring.

ANATOMY AND PHYSIOLOGY Surgical Anatomy The esophagus spans three areas often treated by three different surgical specialists: ENT, thoracic, and general surgeons. In the neck, it lies immediately adjacent to the

vertebral bodies. The cricopharyngeus muscle, which functionally represents the UES, is at the level of C7 at rest and C6 during a swallow. Superiorly are the pharyngeal constrictors, and the cervical esophagus becomes the thoracic esophagus at the level of the thoracic inlet. The trachea is anterior, the carotid sheaths are lateral, and in the grooves between the trachea and esophagus on either side lie the recurrent laryngeal nerves, which innervate the vocal cord mechanism. In the chest, the esophagus enters at the thoracic inlet and lies on the vertebral bodies before moving slightly to the left in the lower chest to pass through the esophageal hiatus. In its upper part, it is crossed by the azygos vein on the right, and it is closely related to the thoracic duct in the lower mediastinum. The entire length of the esophagus may be accessed from the right side of the chest, but access to the cardia is restricted by the liver. The left side of the chest provides direct access to the lower esophagus and cardia, but it is hard to reach the upper esophagus because it is behind the aortic arch. The lower esophagus is visible in the abdomen only after incising the peritoneum and the tissue binding the esophagus to the arch of the crura. Underneath this peritoneum is a fine-curved white line, the phrenoesophageal membrane. When this is incised, it can be pushed off the esophagus to separate it from the crura. The junction of the esophagus and stomach is marked by an anterior pad of fat. The anterior vagus nerve is closely applied to the anterior aspect of the esophagus, and the posterior vagus lies in the mediastinum behind and to the right of the esophagus.

Physiology Food is taken into the mouth where it is chewed and lubricated. Swallowing is initiated voluntarily by posterior movement of the tongue against the hard palate, pinching off a bolus and transferring it to the pharynx. Thereafter it is entirely a reflex action. Several mechanisms combine to ensure safe delivery of the bolus into the esophagus. Breathing is temporarily halted. Contraction of the tensor veli palati muscle occludes the nasopharynx, preventing the pressure generated by the tongue from being dissipated through the nose. The larynx is pulled upwards and forwards by the action of the strap muscles of the neck, chiefly the mylohyoid and thyrohyoid muscles. This not only causes the epiglottis to lie more horizontally, but physically opens the UES. The cricopharyngeus muscle relaxes in concert with contraction of the pharyngeal constrictors. The wave of peristalsis generated by this activity passes down the esophagus. The strap muscles then relax, the larynx returns to its normal location, and the cricopharyngeus muscle resumes its normal tone. This whole process, occurring in skeletal muscle, is rapid, taking less than a second to complete.

medwedi.ru 295

296

Part Two: The Alimentary Tract—Esophagus and Stomach

Within the esophageal body, lubricated food is then propelled distally by peristalsis. A wave of circular muscle contraction, preceded by longitudinal muscle relaxation, passes down the esophagus at about 3 cm/sec. The amplitude of the circular muscle contraction is sufficient to occlude the bolus and propel it distally in a manner analogous to the way in which a surgical drain is ‘‘stripped’’ between finger and thumb to empty its contained secretions. The circular muscle at the gastroesophageal junction (GEJ) has the special property of tonic contraction producing a resting tone of about 15 mmHg. This is the physiologic basis of the LES. It is innervated by cholinergic fibers of both excitatory and inhibitory types. Relaxation of the LES is mediated by stimulating the inhibitory neurons, which secrete vasoactive intestinal polypeptide (VIP) and cause the release of nitrous oxide. Relaxation is induced by swallowing, and begins at the onset of the swallow. The LES pressure reaches a nadir as the peristaltic wave reaches the distal esophagus, and then undergoes a postrelaxation contraction. The LES too opens in response to gastric distention and also undergoes periods of transient loss of tone, often termed ‘‘transient LES relaxations’’ (TLESRs), which may be neurally mediated or be the result of effacement of the LES in the presence of gastric distention.

SYMPTOMS OF ESOPHAGEAL DISEASE It is common to characterize symptoms arising from esophageal disease as either typical or atypical. Typical symptoms, namely heartburn, regurgitation, or dysphagia, immediately suggest the esophagus as their source and prompt esophageal evaluation. Atypical symptoms initially suggest another system. Chest pain is likely to be referred to a cardiologist and the patient will likely undergo a series of more or less invasive studies before heart disease is excluded. Cough, asthma, and recurrent pneumonia are generally referred to a pulmonologist, and patients reporting hoarseness are typically referred to an ENT surgeon.

Typical Symptoms Heartburn, sometimes called pyrosis, is a burning retrosternal discomfort often coming on 30 to 90 minutes after meals and often relieved by antacids and abolished by strong acid suppressants. The patient will often point with the spread fingers spanning the sternum (the ‘‘open hand’’ sign). In the early stages, it occurs only after an unusually rich, voluminous, or late meal. In severe cases, it is provoked even by drinking water, by lying down, or by bending over. Whether it is a daily or only an occasional occurrence, it tends to be milder when the stomach is empty rather than when it is full. Regurgitation is most frequently used to mean the sudden, effortless appearance of gastric contents in the throat or mouth. It may be isolated or occur with a belch, in which case it is sometimes described as a ‘‘hot belch’’ or ‘‘acid belch.’’ Some patients can produce it almost at will, when it is called rumination. This learned disorder is a form of reflux disease, but must be distinguished from bulimia, which is a behavioral disorder characterized by voluntary initiation of vomiting, consciously or unconsciously, in an attempt to lose weight. Regurgitation is also used to describe the forceful ejection of esophageal contents. It occurs most often in achalasia, when the dilated esophagus has a substantial capacity. If more is eaten than can be passed into the stomach, the

patient will eventually be forced to regurgitate, in which case the material tastes bland rather than acidic, indicating that it has never entered the stomach. In this respect it differs from vomiting. The need to regurgitate often comes on suddenly even if the precipitating factors are predictable, as observed by many patients who report that on entering a restaurant they instinctively choose a table near the restroom. Patients sometimes speak of ‘‘bringing up foam’’ especially in the postoperative period. This indicates relative obstruction to esophageal outflow. It may happen after a tight anastomosis or antireflux procedure, or a gastric bypass. Saliva is not emptied from the esophagus and when the patient drinks liquid, it displaces the saliva proximally, causing it to be regurgitated. Dysphagia is a term used to describe any sensation associated with difficulty in passing food from the mouth to the stomach. It actually includes two quite distinct symptoms. Oropharyngeal dysphagia, sometimes called ‘‘transfer’’ dysphagia, describes difficulty getting food from the mouth into the esophagus. This is how the lay person interprets the phrase ‘‘difficulty in swallowing’’ and it tends to be associated with coughing and choking while actually swallowing. Soft solids cause less trouble than liquids or tough solids. In contrast, esophageal or ‘‘transport’’ dysphagia, describes difficulty in passing food down the esophagus into the stomach. Patients with this symptom may deny difficulty in swallowing, but report that food sticks or ‘‘hangs up’’ in the lower chest. Coughing in this situation occurs after eating, not during the act of swallowing. It is broadly true that mechanical obstructions such as stricture or tumor initially cause this symptom only with solids, with liquid transport being unaffected. Difficulty in transporting both solids and liquids generally indicates a motility disorder. One further principle relates the location of the sensation to the location of the lesion. In general, symptoms are never felt distal to the site of the lesion. They are felt at the site of the lesion or referred proximally. As a consequence, the sensation of food sticking in the neck may be from a lesion at that site but could also be from a more distal lesion. In contrast, a sense of food hanging up in the lower chest usually corresponds to a lesion in that site and will not be caused by a problem in the cervical esophagus. Odynophagia or pain on swallowing is typical of esophagitis in the proximal esophagus, typically from nonreflux causes, such as infections and caustic ingestion.

Atypical Symptoms Chest pain resembling angina may be the result of either reflux or a motor disorder of the esophagus, and the patient describes it as a pressure or heaviness, often pointing with the closed fist. It may radiate to the back, jaw, or neck. The serious implications of this symptom in the patients’ mind often overshadow any connection it may have with eating (1). Cough may occur in several ways. Spasms of coughing during eating suggests dysfunction of the UES, such as may occur in any of the above-mentioned neurological conditions, but may also represent a tracheoesophageal fistula where a high esophageal tumor or penetrating esophageal ulcer erodes into the trachea or bronchus. Esophageal problems frequently cause cough on lying down, particularly Zenker’s diverticulum, and any condition such as achalasia where the esophagus cannot empty properly. Patients with underlying gastroesophageal reflux disease (GERD),

Chapter 14:

especially with a large hiatal hernia and a defective LES, commonly wake up coughing at night (2). Asthma suggests GERD when it is nonallergic and occurs for the first time in middle age. The patient with a chronic cough and a normal chest X-ray, a common scenario for the primary care physician, most likely has one of three common conditions: postnasal drip, GERD, or asthma, and in many of those diagnosed with asthma, the etiology will be GERD (3,4). Recurrent pneumonia is a rare occurrence in an otherwise healthy person with a normal immune system. When it occurs, think of aspiration. It may be due to GERD or a neuromuscular disease such as stroke or Parkinson’s disease, which impairs laryngeal protection. Hoarseness may be caused by GERD, in which case, it typically is worse in the mornings, whereas hoarseness, which worsens with voice use, as in teachers or singers, suggests primary laryngeal disease or improper use. It may also have a neurological cause from a generalized disease or from an intrathoracic tumor compressing the recurrent laryngeal nerve. Globus sensation, formerly called globus hystericus, is the sense of something sticking in the throat, in the absence of an anatomical explanation. It is occasionally caused by reflux disease, but is most often regarded as a conversion disorder (5).

Important Nonesophageal Symptoms Some symptoms are important because they actually point away from the esophagus, and yet are frequently misinterpreted. It is important for the surgeon not to be pressurized into operating on a patient because of a symptom misinterpreted as being due to reflux. Nausea is rarely a symptom of esophageal disease. It typically indicates gastric dysfunction and even if associated with heartburn, it is not likely to be improved by antireflux surgery. Halitosis is often thought by lay people and even physicians to originate in the stomach. It may be confused with the sensation of retasting or resmelling food after belching. True halitosis, which is noticed by observers and not the patient, results from overgrowth of bacteria on the posterior tongue with release of volatile sulfur compounds, and the treatment is maintaining oral hygiene, not antireflux therapy. Metallic or acid taste in the mouth is not caused by reflux. It may be due to excessive salivation, sometimes called water brash, which may precede vomiting.

PHYSICAL EXAMINATION Because of the location of the esophagus, it is very rare to find abnormalities detectable on physical exam. Signs of advanced metastatic esophageal cancer include palpable supraclavicular nodes, hoarseness from recurrent laryngeal nerve involvement, signs of superior vena cava syndrome, jaundice or hepatomegaly from liver metastases, and ascites from peritoneal involvement. Patients whose dysphagia has a neuromuscular basis are often easy to recognize at a glance. Dysphonia (soft voice) and dysarthria (inability to articulate) are immediately obvious. Easily recognizable patterns are present for Parkinson’s disease (shuffling gait, pill rolling tremor, dysphonia, and emotionless expression), myasthenia gravis (ptosis, fatigability), amyotrophic lateral sclerosis (dysarthria, muscle wasting with fasciculation), myotonic dystrophy (characteristic cadaverous fascies,

Physiologic Dysfunction of the Esophagus

297

frontal balding, and slow relaxation of contracted muscles), and dermatomyositis (characteristic heliotrope rash on the dorsum of the hands and fingers). Occasionally calluses on the knuckles of the index and middle fingers are observed, and are a sign that the patient makes herself vomit by putting the fingers down the throat.

INVESTIGATIONS Four major modes of investigation dominate the study of esophageal disease, two primarily directed toward identifying structural lesions (endoscopy and contrast radiography) and two toward uncovering functional disturbances (esophageal manometry and 24-hour esophageal pH monitoring). Understanding these four tests is fundamental to intelligent analysis of esophageal diseases.

Barium Radiology Contrast radiology of the esophagus has been used for almost a century, but it still remains one of the most valuable sources of both structural and functional information. In specialized units, the examination is carried out with a strict protocol to yield the maximum information (6). Patients at high risk of aspiration, including those recovering from esophageal surgery, or whose symptoms are localized to the oropharyngeal region, are studied in the upright position. All others have the esophagus examined while lying horizontal, usually prone, and turned to the side to separate the esophagus from the vertebral column. It is easier to assess the efficacy of peristalsis when the effect of gravity is removed. A sequence of five swallows of barium is given. In normal subjects, three or more of these five swallows will be transported by a stripping peristaltic wave that empties the esophagus. This is primary peristalsis. A secondary peristaltic wave is stimulated by esophageal distention. Segmental spasm due to simultaneous contractions in the esophageal body are typical of diffuse esophageal spasm. Radiologists sometimes describe the appearance of repetitive, nonperistaltic, simultaneous contractions as ‘‘tertiary peristalsis’’ even though they are not peristaltic. A typical study is shown in Figure 1. The presence of a stricture, tumor, or hiatal hernia or diverticulum is generally easy to identify. It is useful to measure the diameter of the esophagus. The normal esophagus is rarely larger than 2.5 cm in diameter, and any esophagus wider than 3 cm strongly suggests achalasia. Other obstructions such as a tight Nissen fundoplication or lap band, or stricture or cancer, do not produce such gross esophageal dilation. A Nissen fundoplication is visible as a soft tissue density in the cardia with a narrow channel through it: it should be below the diaphragm. If it is not so, then it implies that the fundoplication has herniated. If there are gastric folds above the soft tissue density, a slipped Nissen is present. To study cricopharyngeal dysphagia or recurrent aspiration, an examination termed a ‘‘modified barium swallow’’ is often carried out in consultation with a speech pathologist, who will administer not just liquid barium, but liquids of different viscosities, including thin barium, thick barium, applesauce, and cookies impregnated with barium (7). Typical findings in these patients are ineffective movement of the tongue and palate, nonocclusive contraction of the pharynx, retention of barium in the recesses of the pharynx (vallecula and pyriform sinuses) and spillover of the barium into the laryngeal vestibule, which may or may not produce coughing, and frank aspiration down into the trachea.

medwedi.ru

298

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 1 Normal barium esophagogram (A) A–P view and (B) lateral view.

Endoscopy Endoscopy should be thought of as the physical examination of the esophagus. It is generally the first investigation recommended in elucidating a patient’s symptoms, unless the presentation is dominated by dysphagia, in which case it is generally wise to obtain a ‘‘road map’’ by first performing a barium swallow. It will detect gross structural alterations such as hernia and cancers and strictures and diverticula, visualize Barrett’s epithelium, and permit biopsy of lesions, and therapeutic measures such as dilation of strictures, insertion of stents, and removal of foreign bodies. Surgeons who operate on the upper GI tract should be expert endoscopists, because gastroenterologists are frequently unfamiliar with the anatomic details of such procedures as gastric pull-up, colon interposition, Roux Y gastric bypass, duodenal switch, partial or total fundoplications, and other frequently performed contemporary operations.

Safety Modern flexible videoendoscopes provide excellent mucosal visualization over most of the esophagus. They carry low risk of perforation or hemorrhage when merely inspecting, but dilating achalasia or an esophageal stricture, or injecting esophageal varices, increases the risk by 3- to 10-fold (8). The major risks are perforation, hemorrhage, aspiration, and oversedation and side effects of sedative medication. When perforation occurs, it tends to be at or just proximal to the site of the pathology, which is commonly at the distal end. The use of dilators, or the large endoscopic ultrasound scope, substantially increases the risk of perforation. The rigid endoscope is rarely used in modern practice except by ENT surgeons. It is more likely than flexible endoscopy to cause perforation, especially in the cervical esophagus. However it remains a valuable instrument in emergency situation because suction is better, grasping forceps are stronger, and sharp or angled foreign bodies can be more safely grasped and withdrawn into the scope. The degree of sedation required is generally called ‘‘conscious sedation,’’ though many patients are not at all conscious. Administering a combination of an opiate

(meperidine or fentanyl) and a short-acting benzodiazepine such as midazolam in small incremental doses is the most common technique. Propofol is an excellent alternative but in most hospitals it must be administered by an anesthesiologist. Oxygen must be administered by nasal cannulae, and pulse, blood pressure, and oxygen saturation must be monitored continuously and recorded every five minutes. It is wise to spray the pharynx with local anesthetic. The patient is then turned on to his left side to allow gastric juice to pool in the fundus away from the cardia and hence reduce the risk of aspiration. A mouth guard is inserted before the patient becomes too drowsy to cooperate. The technique of endoscopy is now well described and is only briefly summarized here. The major principle is to advance the scope with gentleness and under vision. Lock the smaller (left–right) control so that the scope tip only curves in one plane. Turn the larger, outer wheel clockwise to flex the tip of the scope. This will give an image on the screen in the correct orientation with the tongue at the bottom and the uvula at the top. Advance the scope over the tongue, keeping the tip rotated until the epiglottis is reached. Unflex the tip a little to go behind the epiglottis and observe the cords: the anterior junction will be at the bottom of the screen, and the two diverging arytenoids will be near the top. Unflex the scope slightly to go behind the arytenoids. The cricopharyngeus is identified by the slight bunching of folds behind the vocal cords. Gentle pressure and insufflation of air generally causes it to relax and then the scope will be in the proximal esophagus. The presence of any saliva or food residue is noted. The normal squamocolumnar junction, sometimes called the Z-line, is generally seen about 35 to 37 cm from the incisor teeth in females and 37 to 40 cm in males. The GEJ is defined as the top of the rugal folds. The crura of the diaphragm are usually easily seen as a pinching-off point when the patient sniffs or breathes deeply. In normal subjects, these three landmarks are within a centimeter of one another. If the squamocolumnar junction is significantly more proximal than the GEJ, then Barrett’s esophagus is present. If the GEJ is two or more centimeters proximal to the crura, then a hiatal hernia is present.

Chapter 14:

Mucosal abnormalities can be esophagitis, classified according to the type and size of erosions present, or Barrett’s esophagus, recognized as extension of the salmon-orange–colored columnar mucosa into the tubular esophagus. Esophagitis is diagnosed by visual appearance on endoscopy, not on biopsy, but Barrett’s esophagus must be confirmed by finding intestinal metaplasia on biopsy. A lot of information can be obtained by retroflexing the scope, i.e., curving the tip so that it looks up the lesser curve toward the cardia, visualizing the scope itself coming through the cardia. The appearance of the GEJ has been graded by Hill into four categories, which are roughly correlated with the competency of the valve, with Hill Grade I being normal (near complete frenulum, minimal opening in response to distention), Grade II showing some effacement of the frenulum or flap valve, Grade III showing loss of the frenulum and frequent prolonged periods of GEJ opening, and Grade IV indicating a fixed hiatal hernia (Fig. 2) (9). The upper esophagus and pharynx is best examined as the scope is withdrawn. Look for an ‘‘inlet patch’’ of columnar mucosa just below the cricopharyngeus. Sometimes these small areas of columnar mucosa contain parietal cells and secrete acid, and may be responsible for laryngeal symptoms (10). Take the opportunity to inspect the vocal cords as the scope is withdrawn out of the pharynx. Redness, edema, or ulceration may denote reflux laryngitis and a paralyzed cord is easily identified.

Esophageal Histology Endoscopic examination of the esophagus permits the biopsy of mucosal lesions and strictures, and frequently yields useful information even if the mucosa appears visually normal. Esophageal mucosal biopsy can be technically awkward because the forceps are in the same axis as the mucosa, rather than perpendicular. One useful technique is to place the open biopsy forceps adjacent to the area to be biopsied, and apply strong suction and then close the forceps. Insufflation will then confirm that the correct tissue has been grasped. This is especially useful in biopsying Barrett’s esophagus, where multiple biopsies around the circumference are needed. The histological details of individual disease processes are discussed in the relevant sections later in this chapter.

Figure 2 Retroflexed view of the GEJ, showing large hernia extending up into the chest (Hill Grade IV). Abbreviation: GEJ, gastroesophageal junction.

Physiologic Dysfunction of the Esophagus

299

Other Common Imaging Techniques Chest Radiography The information that can be derived from a chest X-ray should not be overlooked. In the emergency situation, look for pneumothorax, pleural effusion, mediastinal, and soft tissue emphysema. A large hiatal hernia presents as a retrocardiac soft tissue shadow with a horizontal air–fluid level, and a dilated esophagus in achalasia will be seen as a curved longitudinal shadow along the left heart border. These features when present act as pointers to referral for a more focused investigation of the esophagus.

Computed Tomography Computed tomography (CT) of the chest shows the esophagus in cross section and is particularly useful in staging malignancies. Generally, the esophagus is observed as collapsed tube containing minimal contrast or air, just anterior to the vertebral bodies. Tumors cause wall thickening and, when advanced, are seen as a bulky mass, and adjacent lymphadenopathy may be observed. If the esophagus appears dilated and contains fluid, perhaps with a fluid level, the most likely diagnosis is achalasia. In the emergency situation, CT scanning can reveal mediastinal, periesophageal air in patients with perforation.

Esophageal Motility The functions of the esophagus are entirely motor. The pharynx contracts and the UES opens. The esophageal body sequentially contracts, causing a stripping wave to pass down the esophagus, propelling its contents distally. The LES begins to relax at the onset of the swallow, and its pressure reaches a nadir as the bolus is propelled into the stomach. The relaxation is followed by a contraction and resumption of resting tone. Any uncleared bolus within the esophageal body stimulates a secondary peristaltic wave. At times, the LES undergoes periods of opening not associated with swallowing. This is most common after gaseous distention of the stomach, for example, after ingestion of carbonated beverages, and is the mechanism of belching. These periods of sphincter opening are often termed ‘‘TLESRs’’ and are the principal steps in the mechanism of episodes of reflux in normal subjects and in many patients with reflux. They are more common after meals, in the upright position, and rarely occur when lying down (11). All of the above functions are identified by esophageal motility testing. Typically, a catheter with pressure sensors 5 cm apart is passed through the anesthetized nostril into the esophagus, and advanced until all the sensors are in the stomach. This is recognizable by the presence of small (2–3 mmHg) elevations of pressure with each breath. The catheter is then drawn back slowly in 1 cm increments. As the most proximal sensor approaches the cardia, these pressure elevations with respiration become much more marked, because the sensor is being squeezed by the crura at each breath, but the pressure returns to normal between breaths. Pulling more proximally brings the sensor into the LES itself, characterized by elevation of the resting pressure off the gastric baseline, but still augmented by respiration. Further withdrawal leads to the point where inspiration causes the pressure to decrease. This point, the respiratory inversion point (RIP), is functionally the point of attachment of the phrenoesophageal membrane. The portion of the LES distal to the RIP is the intra-abdominal portion, and it responds to changes in intra-abdominal pressure. The portion of the LES proximal to the RIP is the intrathoracic portion (Fig. 3). The

medwedi.ru

300

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 3 Manometric tracing of a transducer being pulled through the LES showing the resting pressure, the overall length, and the abdominal length. Abbreviation: LES, lower esophageal sphincter.

best estimate of LES pressure is controversial. The absolute method of measurement is not critical provided the same method is used in normal controls as in patients. Our preference is to measure in mid-inspiration at the RIP. It is vital when interpreting values from other laboratories that the method of interpretation is known. From the pressure tracing in each sensor, a value for the pressure, the overall length, and the intra-abdominal length of the LES will be obtained. The final result is the average of the readings from the individual sensors. The LES can be conceived of as a sequence of resistors connected in series. The length over which its pressure is applied contributes to protection from reflux, because the LES length is reduced with gastric distention, predisposing the patient to reflux. The overall length of the LES is easily calculated as the distance from the distal end to the proximal end of the LES, the final result being an average of the lengths calculated by each transducer on the catheter. Independently of the overall length, the portion of the LES within the abdomen, i.e., between the distal end and the RIP, is important in protecting against fluctuations in intra-abdominal pressure. Loss of this intra-abdominal length predisposes to reflux when the intra-abdominal pressure rises, for example, on straining or bending over. It is a characteristic feature of large hiatal hernias that the intraabdominal length of the LES is reduced. The three important components of the LES are pressure, overall length, and abdominal length (Table 1). A patient who is defective in any one of these parameters is said to have a structurally defective sphincter (12). In health, the LES is surrounded by the crura of the diaphragm. The contraction of the crural diaphragm appears

Table 1 Normal Values for Resting Parameters of the Lower Esophageal Sphincter Based on Study of 50 Normal Subjects in Our Laboratory Parameter Resting pressure Overall length Abdominal length

Mean

Normal range

13.8 mmHg 3.7 cm 2.2 cm

6–27 mmHg 2–5 cm 1–4 cm

to augment the effect of the intrinsic sphincter, and has led to the popularization of the ‘‘two-sphincter’’ hypothesis of reflux protection. However, the relative importance of the diaphragmatic contribution is still debated, but it is undeniable that when a hiatal hernia is present, these two components are separated rather than superimposed, and the crura lose their ability to protect the esophagus from reflux caused by increases in intra-abdominal pressure. The resting tone of the sphincter is maximal in the fasting state. Physical distention of the upper stomach and release of cholecystokinins and other peptides cause the pressure and length to be reduced. Consequently if a defective sphincter is identified in the motility laboratory with the patient in a fasting state, it can only get worse after a meal.

LES Relaxation The dynamic function of the LES is relaxation. This is important in two situations: one when it relaxes too readily, permitting reflux, and the other when it does not relax enough, as in achalasia. Clinically, LES relaxation is measured when the pressure sensor is positioned within the LES and 5 cc boluses of water are given. As swallowing is initiated, the LES begins to relax, and it reaches its nadir as the bolus reaches the distal esophagus (Fig. 4). Failure of relaxation is the hallmark of achalasia but may also be seen after an excessively tight fundoplication or laparoscopic gastric banding or a small infiltrating tumor of the cardia.

Esophageal Body Function The esophageal body contracts in response to a swallow by generating a wave of contraction of the circular muscle, which passes down the esophagus at a rate of 2 to 4 cm/sec. This is termed ‘‘primary peristalsis’’ (Fig. 5). Secondary peristalsis occurs in response to esophageal distention, for example, residual portions of a recently swallowed bolus or reflux of gas from the fundus into the esophagus. It can be produced experimentally by inflating a balloon in the esophagus. ‘‘Tertiary peristalsis’’ is a misnomer and is a term used by radiologists to describe the prolonged simultaneous

Chapter 14:

Physiologic Dysfunction of the Esophagus

301

Figure 4 Manometric tracing of LES relaxation in response to a swallow. Abbreviation: LES, lower esophageal sphincter.

contractions of the esophagus long after a swallow has passed, and is seen in diffuse esophageal spasm. Because of the helical arrangement of the circular muscle fibers of the esophagus, such prolonged contractions can produce the small outpouchings of the lumen, called pseudodiverticula, an appearance sometimes described as ‘‘corkscrew esophagus’’ or ‘‘rosary beading.’’ To transport a bolus, peristalsis must have two qualities: strength and organization. The strength or amplitude of the contraction must be sufficient to occlude the lumen and force the bolus distally, not just indent it. If we consider the analogy of stripping a Jackson-Pratt drain, a defective amplitude corresponds to the situation where the finger and thumb are not squeezed sufficiently strongly, and thus the contained serum or clot is not pushed into the bulb. Similarly, the wave will not transport a bolus if it is not organized sequentially from top to bottom. If the esophagus contracts simultaneously at all points along its length, no net

movement of the bolus will occur. This would be rather like squeezing the Jackson-Pratt tubing with both hands all at once rather than starting at the exit from the skin and squeezing toward the bulb. Amplitude is a property of the muscle and is impaired in diseases that injure or replace the muscle, such as scleroderma or longstanding reflux disease. Bolus transport is seriously impaired if the amplitude of contractions in the distal esophagus falls below 30 mmHg (13). In contrast, organization of peristalsis is a neurologic phenomenon and is impaired in diseases such as diffuse esophageal spasm or achalasia.

Upper Esophageal Sphincter The pharynx and UES are the last areas to be studied during a motility examination. Although the familiar coupling of proximal pump contraction and valve relaxation operates in this area, it is harder to study because it is composed of skeletal muscle and responds much more rapidly than

Figure 5 Manometric tracing of a primary peristaltic wave.

medwedi.ru

302

Part Two: The Alimentary Tract—Esophagus and Stomach

smooth muscle. In addition, the UES moves cranially about 2 cm with each swallow, and the typical transducer may miss the event if it is not positioned accurately. Usually a specialized catheter with more closely spaced transducers is used to make motility recordings. The key elements in the study are to have a transducer in the pharynx and one in the most proximal part of the UES. As the pharynx contracts, the UES opens. Opening of the UES is augmented by the corresponding movement of the larynx and hyoid. They move both upwards and anteriorly, pulling the UES open. This is reflected in the initial rapid drop to subatmospheric pressure, seen on the UES tracing. If the UES transducer is not positioned at the top of the UES, the upward movement of the UES relative to the transducer will cause it to record intraesophageal pressure during the swallow, giving an illusion of relaxation. Outflow resistance can be inferred if the UES does not relax adequately. Indirect evidence of impaired relaxation is seen when the bolus is flowing through the sphincter. The hump or shoulder in the pharyngeal tracings represents the pressure of the bolus immediately prior to the closure of the lumen at the tail of the bolus. The higher this pressure, the greater the resistance to flow (14).

Ambulatory (24-Hour) Esophageal pH Monitoring Reflux is an episodic phenomenon. Recognition of this was the stimulus to develop a method for monitoring the intraesophageal pH for a prolonged period. It was first reported in a clinically useful form in 1974, and the criteria for defining the presence or absence of abnormal reflux have not been improved upon (15). In most cases, a pH sensor, usually of antimony, on a fine (7 Fr) catheter is passed through the nose into the esophagus and positioned 5 cm above the manometrically determined upper border of the LES. The traditional technique is being replaced by a wireless system where a capsule containing a pH sensor and a small battery-powered transmitter is deployed in the esophagus. It dislodges spontaneously two to five days later and is passed in the stool. Early studies show that results are broadly comparable to that obtained with a conventional catheter, but normal ranges are slightly different (16). It is becoming popular to place it transorally at the time of endoscopy, where it is positioned 6 cm above the endoscopically determined squamocolumnar junction. This is convenient, because the patient is already sedated and avoids the need to pass a bulky capsule through the nostril, but may be less accurate. Esophageal acid exposure is generally expressed in terms of the fraction of the monitored period during which acid was detected. The esophagus normally has a pH in the range 5 to 7, whereas the stomach pH is between 1 and 1.5. The most common threshold chosen is pH 4. Very few circumstances other than presence of refluxed gastric acid cause esophageal pH to drop below pH 4. This is also the level at which pepsin ceases to be active. Pepsin is a proteolytic enzyme most active in the range 2 to 3, and its activity is effectively zero at pH 4. For practical purposes, a threshold of pH 4 is the definition of reflux. A typical recording over a 24-hour period is shown graphically in Figure 6. The simplest way to quantify esophageal acid exposure is to express the total time below pH 4 as a percentage of the total monitored time. It is generally about 2% in normal subjects, and the upper limit of normal is 4%. Other features of the pH record, including total number of episodes, percentage of time below pH 4 in the supine position as well as the upright position, duration of the longest episode,

Figure 6 Typical 24-hour esophageal pH record showing episodes of reflux mostly in the upright position.

and number of episodes longer than five minutes in duration, can be combined into a composite score (Table 2). This score, because it takes account of the slight differences between normal ranges for males and females, gives a value independent of sex and appears to be superior to discriminate between normal and abnormal reflux. It may be important to detect reflux of gastric contents more proximally in the esophagus, for example, when laryngeal symptoms predominate and there is minimal heartburn. Normal episodes of acid reflux rarely reach above mid-esophagus. The intrathoracic pressure is maximally negative in mid-thorax, and in the more proximal esophagus, the pressure rises until in the pharynx it is equal to atmospheric. Reflux has to be very severe before it reaches all the way up to the pharynx, and more than 1% of the total monitored period is regarded as pathologic. To study the proximal acid exposure, a catheter with two electrodes 15 cm apart is used, the distal one being 5 cm, and the upper one 20 cm, above the LES (17).

Monitoring of Bile Reflux Nonacidic components of gastric juice may also be injurious. This has led to the development of devices to detect duodenal contents by identifying bilirubin. The bilirubin sensor (Bilitec) has a tiny spectrophotometer at the end of a catheter, which can detect the yellow light emitted by bilirubin. The intensity of the scattered light is proportional to the concentration of bilirubin. It is important to note that bilirubin is itself not the injurious agent, but merely acts as a marker for the presence of duodenal juice. A threshold of detectability is set and the time when bilirubin was detected Table 2 Mean and Upper Limit of Normal for the Typical Parameters of 24 Hours Esophageal pH Recording Parameter

Mean

Upper limit of normal

% time below pH 4 (total) % time below pH 4 (upright) % time below pH 4 (supine) # reflux episodes below pH 4 # reflux episodes > 5 min Duration of longest episode Composite score

1.5 2.2 0.6 19.0 0.8 6.7 6.0

4.5 8.4 3.5 47 3.5 19.8 14.7

Chapter 14:

Physiologic Dysfunction of the Esophagus

303

impedance as the swallowed liquid is transported down the esophagus. The direction of flow—whether antegrade as in swallowing or retrograde as in reflux—is easily determined from the tracings (Fig. 8). The method can be used to identify whether or not the bolus was actually transported, can detect reflux independent of acidity, and determine the proximal extent of the reflux (21). As it becomes more widely available it will have the capacity to provide the same functional information as the videoesophagogram.

Other Tests of Esophageal and Gastric Function Gastric Emptying

Figure 7 Record of simultaneous monitoring of presence of esophageal bilirubin and esophageal pH.

Gastric emptying is measured by ingesting a radiolabeled meal and scanning the stomach with a gamma camera. The decrease in counts with time in the region of interest is a measure of rate at which food empties from the stomach. The time taken for the radioactivity to drop by 50% is the most commonly used measure of gastric emptying (t1/2) and is generally less than 90 minutes.

Gastric Acid Secretion

above that is recorded and expressed as a percentage of the monitored period (Fig. 7) (18,19).

Multilevel Intraluminal Impedance A novel method of assessing intraesophageal events has been developed using changes in intraluminal impedance to mark swallowing and reflux events (20). Impedance can be thought of as resistance to current flow between two electrodes, and in the esophagus, impedance is increased when the catheters are lying in air, for example in belching, and reduced when conducting liquid is present in the esophagus. A swallow causes a momentary rise in impedance as a small quantity of air is swallowed first, followed by a drop in

Occasionally it may be necessary to assess vagal function in the stomach. This is typically when a patient has symptoms after a fundoplication, which are difficult to interpret. The question of whether or not the vagal nerves were injured by the operation is then an important one. Normally functioning vagi may be stimulated by sham feeding, i.e., the patient chews a tasty meal, but spits it out rather than swallow it. This stimulates the cephalic phase of gastric secretion and is vagally mediated. The older test using insulin-induced hypoglycemia has been abandoned because of risks of extreme hypoglycemia. If the vagi are intact, there will be an increase in the stimulated acid output above basal acid output. It has been reported that detecting an increase in serum pancreatic polypeptide following a sham feed may reliably detect functioning vagal nerves. This is a much more attractive option because it avoids the need for intubation of the stomach (22,23).

Figure 8 Simultaneous manometry (lower four tracings) and multilevel intraluminal impedance (upper four tracings) in a patient showing four swallows. Note that the abrupt decline in impedance indicates the passage of the bolus, and that recovery to the previous level indicates that the bolus has passed.

medwedi.ru

304

Part Two: The Alimentary Tract—Esophagus and Stomach

ESOPHAGEAL DISEASES Gastroesophageal Reflux Disease GERD is the most common esophageal disease in Western society (24). Its prevalence is hard to estimate because largescale studies rely solely on symptoms. Despite the limitations of such studies, it is clear that heartburn is very common in Western populations, where 30% of the surveyed population use antacids once a month, and 7% report daily heartburn.

Physiology of GERD It is important to understand that GERD is not a disease caused by too much acid. With rare exceptions, acid secretion is normal in GERD. Nor is it caused by Helicobacter pylori. Large epidemiologic studies have revealed that H. pylori, especially the cagþ strain, is actually less prevalent in severe GERD, and that eradication of H. pylori does not improve, or may even worsen GERD (25). It has been hypothesized that the steady reduction of H. pylori infection in Western society is causally associated with the rising incidence of GERD in the same societies. Excessive reflux of gastric juice occurs because of dysfunction of the LES mechanism. This intuitive concept is still the most important factor in the pathogenesis of GERD. However, once an episode of reflux has occurred, a clearance mechanism is activated: swallowing occurs, causing peristaltic clearance of the majority of the bolus (‘‘volume’’ clearance), and acid remaining in contact with the mucosa is neutralized by the buffering effect of saliva (‘‘chemical clearance’’). It can easily be understood that ineffective peristalsis and defective salivation, such as after head and neck irradiation, both permit a given reflux episode to inflict additional epithelial damage. Fundamental to understanding management of GERD is appreciation of the mechanical factors that prevent reflux in health (12). The intra-abdominal pressure is positive with respect to the atmosphere, but the intrathoracic pressure is negative. This gradient increases with inspiration. Were it not for the physiologic barrier between the stomach and esophagus, reflux would be promoted by every breath. The nature of the barrier has been the subject of investigation for 50 years since its discovery manometrically in 1955. The LES can fail in two ways: (i) the resting parameters of pressure and length can be reduced, a situation described as a structurally defective sphincter and which is easily measurable in the esophageal motility laboratory, or (ii) it can undergo periods of loss of tone (TLESRs). Many TLESRs are not associated with reflux, but in symptomatic patients, the proportion of TLESRs associated with reflux is increased (26). Both of these mechanisms are important. In early disease, when the symptoms are intermittent and provoked by large or rich meals causing gastric distention, episodic loss of tone predominates. In severe disease, permanent reduction of LES length and tone is present, and further deterioration occurs with eating. Several recent observations are relevant in this regard. Consumption of carbonated beverages produces a reduction in the length and pressure of the LES in many subjects. The large and increasing amount of soda consumed by Western populations has been correlated with the increasing incidence of GERD in these communities. It is undeniable that dietary substances that cause reduction in LES pressure and/or delay gastric emptying—such as fat, onions, coffee, chocolate, and alcohol—are commonly consumed by Western populations, and the average portion size has significantly increased in the past generation.

Hiatal Hernia The relationship between hiatal hernia and GERD is complex. Following the seminal report of Allison in 1951, hiatal herniation was assumed to be the cause of the disease and surgical approaches were focused on anatomic reduction of the hernia (27). With the discovery of the LES, the role of hiatal hernia was de-emphasized (28). It is now clear that both factors are independently important (29). Much of the confusion results from the subjectivity of hiatal hernia detection. By convention, sliding hiatal hernia, in which the fundus and GEJ is displaced proximally above the diaphragm in the same axis as the esophagus, is termed ‘‘type I.’’ In type II hernia, the GEJ remains anchored below the crura, but the fundus rolls up alongside the esophagus, hence the term ‘‘paraesophageal hiatal hernia.’’ Type III hernias are large hernias combining both features, and the most extreme case of all, where the entire stomach is drawn up into the chest, is sometimes called type IV or intrathoracic stomach. Type I hernias are by far the most common. They are classified according to the distance between the GEJ and the crura, and are categorized as small (2–3 cm), moderate (3–5 cm), or large (>5 cm). Small type I hernias are extremely common and of limited clinical significance, being present in at least 30% of asymptomatic normal subjects. Moderate and larger hernias have a clearer relationship to reflux disease. They are rare in children and commoner in older subjects, and appear to be the result of attenuation of the phrenoesophageal membrane and other connective tissue structures binding the distal esophagus beneath the diaphragm. Larger hernias tend to be associated with more advanced disease, causing more severe heartburn and extraesophageal manifestations, as well as greater degrees of esophageal injury such as esophagitis and Barrett’s esophagus (30). The mechanisms by which hiatal hernia cause or aggravate reflux disease include (i) physical distraction of the phrenoesophageal membrane leading to attenuation of the function of the LES, (ii) impairment of esophageal emptying, and (iii) phenomenon of ‘‘rereflux’’ where acid in the supradiaphragmatic pouch is propelled back up into the esophagus under the influence of negative intrathoracic pressure (31). Patterns of Acid Reflux The use of pH monitoring has allowed a number of different patterns of reflux to be distinguished. Normal subjects may have 40 or more episodes of reflux daily, but they are brief, and rapidly cleared, and tend to occur after meals. The earliest form of reflux disease is an exacerbation of this phenomenon. Increased numbers of reflux episodes may occur, but in early disease, they tend to be confined to the upright period, with reflux at night being rare. Severe disease is characterized by reflux both day and night (Fig. 9). Supine reflux episodes are longer because esophageal clearance is no longer aided by gravity, and because there is less swallowing and less saliva transported down the esophagus to neutralize the acid. The acid contact time is therefore longer, and more likely to induce esophagitis. It has recently been observed that after a meal, there is a small ‘‘pocket’’ of unbuffered acid within the stomach just below the cardia, and that after a meal, the squamous mucosa of the distal esophagus is exposed to this acid (32). This very distal acid is not detected by conventional probes 5 cm above the LES. In fact, acid exposure immediately above the GEJ is about six times that measured in the conventional position (33). This phenomenon has been recently dubbed ‘‘short-segment reflux’’ and may explain

Chapter 14:

Figure 9 Twenty-four hour esophageal pH monitoring showing severe gastroesophageal reflux in both upright and supine period.

why short-segment Barrett’s esophagus is several times more common than long-segment Barrett’s esophagus.

Clinical Spectrum of GERD GERD may present with symptoms of the disease process itself or with complications. Time and skill are necessary to elicit the exact nature of the patient’s symptoms. Patients reporting heartburn and regurgitation are immediately suspected of having GERD and are frequently started on strong acid suppression by primary care physicians. For reasons indicated in the section on symptomatology, patients’ descriptions are often imprecise. A dramatic response to proton pump inhibitors (PPIs) is a useful, though not absolute, diagnostic feature. Dysphagia in the context of reflux disease may be due to a stricture, to diffuse muscular damage leading to loss of motility, or to the development of adenocarcinoma in Barrett’s esophagus. When GERD causes coughing, wheezing, recurrent pneumonia, or hoarseness, the patient may be referred initially to another specialist before GERD is suspected. Patients being considered for lung transplantation are often evaluated for reflux if the underlying disease is not clearly understood, as in idiopathic pulmonary fibrosis. The other important atypical presentation of GERD is central chest pain, initially suggesting a cardiac problem. This usually prompts a cardiac workup, which, when negative, will lead to consideration of esophageal disease. In about 50% of patients with chest pain but a normal coronary angiogram, the cause is related to the esophagus, and most commonly is GERD (34).

Physiologic Dysfunction of the Esophagus

305

Tissue Injury in GERD Acid and pepsin in the esophagus not only stimulate nerve endings to produce heartburn, but cause cellular damage. The extent and character of the damage is roughly correlated with the degree of acid reflux. It is intuitive that injury from GERD should be concentrated in the most distal esophagus, in contrast with the damage inflicted by ingested agents, which is more severe proximally. Esophagitis is a visual diagnosis based on endoscopic appearance. It has been graded by many systems, of which the most common in use are the Los Angeles system and the new Savary-Miller classification (35,36). Although the details vary slightly, both systems agree that some form of focal erosion is necessary for the diagnosis of esophagitis (Table 3). Mere erythema is not only subjective but can be an artifact of the image-generating system of modern videoendosscopes. In mild disease, the changes are limited to a single mucosal fold, whereas more severe disease shows multiple and even confluent erosions, with the most severe disease being totally circumferential (Fig. 10). The natural history of esophagitis is reasonably well worked out. The important fact to grasp is that for most patients it is a lifelong disease. Prior to the widespread availability of strong acid suppression, a patient found to have esophagitis for the first time had a 50% chance of remaining at that stage, a 25% chance of reverting to a lesser grade, and about a 25% chance of progressing to a more severe grade in the long term. In contemporary practice, most patients can have healing maintained, even if the dose of medications needs to be escalated. But once it is present, it rarely goes away without treatment. Histologic markers of reflux disease are well worked out for erosive disease. The mucosa is characterized by loss of surface epithelium and presence of acute and chronic inflammatory cells in the submucosa. An increasing number of patients are found to have no erosive changes despite prominent symptoms. This situation, called nonerosive (or normal endoscopy) reflux disease or NERD, is increasingly detected, and may reflect a lower threshold to perform endoscopy, as well as the effect of chronic PPI use. In this patient group are some who are undoubtedly true refluxers, but whose mucosa is healed. They may be diluted by other patients whose symptoms are not due to reflux at all. There have been attempts to improve the specificity of diagnosis by histology, most notably by Ismail-Beghi, where the height of the rete pegs in squamous mucosa and the depth of the germinal cell layer were reported to be more sensitive (37). These criteria are too nonspecific to be of much diagnostic value. Histologic Changes of GERD The esophagus is lined by stratified squamous mucosa, and the stomach by columnar mucosa containing parietal cells

Table 3 Two Common Classifications for Describing Endoscopic Appearance of Esophagitis Los Angeles Grade A

Mucosal break 5 mm in length

Savary Miller Grade 1

Los Angeles Grade B

Mucosal break > 5 mm

Savary Miller Grade 2

Los Angeles Grade C

Mucosal break continuous between > 2 mucosal folds Mucosal break 75% of esophageal circumference

Savary Miller Grade 3

Los Angeles Grade D

Savary Miller Grade 4

medwedi.ru

One or more non confluent lesion with erythema and edema Confluent erosive and edematous lesions not covering the complete esophageal circumference The lesion covers the complete esophageal circumference Esophageal ulcer, Barrett’s epithelium, strictures, and other chronic mucosal lesions

306

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 10 Endoscopic appearance of moderately severe esophagitis (Grade 2).

esophagitis are not known. There is clearly a genetic component, highlighted by the predominance in males (sevenfold increased incidence) and whites compared with AfricanAmericans or Latinos. However, the increased incidence in the past 30 years suggests an environmental basis. Dietary factors may play a role, and there is also concern that the relative alkalinization of the stomach, brought about by the chronic use of acid suppressants, may permit colonization of the stomach with bacteria that have the capacity to degrade bile salts. Deconjugated bile salts can produce carcinogens that may be refluxed with the gastric juice. The genetic events that lead to metaplasia and subsequently neoplasia take a very long time to produce visible changes. At some point the process may be irreversible, and this is the explanation for why cancer can develop even after successful abolition of reflux. However, it must be pointed out that most esophageal carcinomas, which develop after antireflux surgery, do so in the first few years after surgery: late cancers usually indicate that the surgical procedure has ceased to be an effective antireflux barrier. Data from studies in the 1980s before the development of modern antireflux surgery are therefore of limited relevance.

Treatment of GERD termed ‘‘oxyntic mucosa.’’ The point of transition between these two is visible endoscopically as the Z-line, which winds circumferentially around the esophagogastric junction. It is usually a sharply visible demarcation. Historically it has been assumed that there is a junctional band of columnar epithelium termed ‘‘cardiac mucosa’’ where there are only mucus glands and no parietal cells. Whether cardiac mucosa is a normal phenomenon or an acquired condition secondary to reflux is controversial, but recent studies of adult and pediatric autopsy material clearly indicate that cardiac mucosa is absent or barely detectable (< 1 mm) at birth and increases throughout life (38,39). When present, it nearly always contains inflammatory cells and is called carditis. If this carditis is associated with widespread inflammation of the fundic mucosa, it is related to H. pylori in the stomach. However, in the absence of generalized inflammation in the stomach, the presence of carditis appears to be an early indicator of reflux disease. In excised specimens removed for reasons not related to reflux, such as upper esophageal tumors, the tissue deep to this mucosa contains submucosal glands, indicating that it has arisen from the esophagus. Proof of association with early GERD is hard to obtain because the pH probes are placed 5 to 6 cm above this area and hence may not detect reflux. It is hypothesized that the healthy squamocolumnar junction is in the region of the LES and is thus largely protected from gastric juice: but in the presence of gastric dilation, it becomes exposed to gastric juice for longer periods and hence undergoes columnar metaplasia. Extension of this process up into the esophagus will follow if the LES deteriorates; it is recognized that there is an inverse relationship between the efficacy of the LES and extent of columnar mucosa. The process then undergoes another key step, namely the development of intestinalization of the columnar mucosa. Histologically this is characterized by the presence of goblet cells. The resulting epithelium is termed ‘‘intestinal’’ or ‘‘specialized’’ epithelium, and it is this epithelium that has the capacity to undergo further transformation to malignancy. Although it appears that the only etiologic factor is GERD, the features of reflux, which cause one person to develop specialized epithelium and another to have simple

The goal of treatment is relief of symptoms and prevention, or reversal, of complications. Uncomplicated reflux disease generally responds well to both medical and surgical treatment. It is customary, especially in the primary care setting, to recommend lifestyle changes as an aid to symptom control. These include losing weight, sleeping with the head of the bed elevated, avoiding tight clothing, and making dietary changes. The dietary changes involve the avoidance of large meals, late meals, and meals rich in fat or containing items such as chocolate, onions, spices, and tomatoes, and cessation of alcohol and tobacco intake. However meritorious dietary strictures may be in their own right, patients rarely comply with them. Acid suppression may be helped in the short term by taking antacids or H2 receptor antagonists (H2RA), all of which are readily available over the counter. The relief tends to be short lived and only of value when symptoms are mild or intermittent. Physiology of Acid Suppression It is not widely appreciated that esophageal damage is not primarily a direct result of acid: rather, the acid acts to facilitate the action of pepsin. Because pepsin cannot be reduced directly, reduction of acid secretion by the parietal cells of the stomach is the only practical way to render refluxed gastric contents less damaging. The parietal cells secrete hydrogen ions (protons) into the gastric lumen in response to various stimuli, of which the three most significant are acetylcholine, gastrin, and histamine. Reducing these stimuli to the parietal cells was the logic behind vagotomy, antrectomy, administration of and H2RA drugs. Each factor is relatively minor in isolation, and though the degree of acid suppression produced by any one of these measures is sufficient to heal peptic ulcers, it is quite inadequate for the treatment of reflux disease. The development of drugs that irreversibly bind the Naþ-Kþ-Hþ pump in the luminal border of the parietal cell marked a new phase in the medical management of peptic diseases. These drugs, commonly called proton pump inhibitors (PPIs), irreversibly bind to the pump when it is in an active condition, and because the lifespan of the gastric mucosa is one to two days, the drug needs to be administered daily.

Chapter 14:

With the introduction of PPIs, it was possible to produce really profound suppression of gastric acid, and patients for the first time could appreciate freedom from heartburn. Many randomized trials comparing H2RAs with PPIs showed the clear superiority of the symptom control and healing of esophagitis produced by PPIs. Most studies of PPIs have as their end point the control of heartburn and healing of esophagitis. In the past decade, several features of PPI treatment have become clear. It works best in the maximally stimulated stomach. If taken without food, the only pumps actively inhibited are the few actually functioning at the time. Subsequent food intake will then stimulate acid as before. It is best to take the pills with food. In addition, it has become clear that many patients require twice daily dosing to maintain the pH elevation in the stomach. Some patients have recovery of acid secretion during the night, the so-called nocturnal acid breakthrough. This is best suppressed by adding an H2RA at bedtime. Although PPIs generally produce excellent relief of heartburn, other symptoms related to the physical process of reflux, such as regurgitation and laryngeal and respiratory symptoms, do not respond so dramatically. Outcome Measures The classical outcome measures in treatment of benign disease are control of symptoms and prevention of complications. In recent years, there has been emphasis on QoL studies using structured validated questionnaires such as the Short Form 36 or a more specific GI QoL. In addition, economic considerations are increasingly factored into treatment algorithms, especially by large health maintenance organizations. The overall costs of treating a common disease by expensive medications or surgery are very high. Comparison of Medical and Surgical Treatment In practice, the choice of treatment is too often determined by the physician’s bias, because there is good support in the literature from uncontrolled series for the efficacy of both medical and surgical treatment. When surgery was compared with the medical treatment available in the 1970s and 1980s in randomized controlled trials, it was shown to be superior. There are very few randomized controlled trials comparing modern medical and modern surgical treatment. Recent trials comparing contemporary laparoscopic Nissen fundoplication, and PPI therapy have shown smaller, but still significant, advantages for surgery. The best data come from Sweden, where the long-term freedom from symptoms was superior after surgery than after PPI treatment (40). The difference between medical and surgical outcomes was reduced if the medically treated patients were allowed to increase the dose of PPI. A much publicized trial by Spechler et al. from the Veterans Administration (VA) initially reported much better subjective and objective results when surgery was compared with use of H2 blockers and antacids. When these patients were followed up 10 years later, the differences had disappeared; many of the surgical patients were back on medication and there was actually a higher death rate among surgical patients from heart disease. However, the unique social spectrum sampled by this VA study makes it difficult to apply to the average patient with GERD (41). It will always be difficult to perform an acceptable clinical trial because the quality of surgery is difficult to standardize, and medical recommendations vary with time. Consequently, the results of any such trial tend to be disputed by the time it is published.

Physiologic Dysfunction of the Esophagus

307

It is much more logical to realize that both forms of treatment have strengths and to tailor the treatment to the disease. Some features of the disease are known to predict advancement or the development of complications: they include the following: young age; marked anatomic disruption (large hiatal hernia); erosive esophagitis at first presentation; reflux at night (supine reflux); and defective LES. Numerous publications attest to the predictive effect of these factors. In a recent study of the outcome of laparoscopic fundoplication in our department, three major factors emerged in multivariate analysis: positive 24-hour pH score, typical symptoms, and a good response to medical treatment. If all three factors were present, 97% of patients were pleased. If none of the factors was present, success was less than 50% (42). Surgical treatment, as well as giving superior durability of symptom control, has also been shown to provide superior protection against tissue injury: strictures need fewer dilations and esophagitis is more reliably healed. However, the issue of protection against malignant change in Barrett’s esophagus is discussed below. It is quite erroneous to suggest that only patients who fail to be controlled by medical treatment should be referred for surgery. Given the efficacy of contemporary medical treatment, patients who do not respond with marked symptom improvement to PPI drugs probably do not have GERD. A good response to strong acid suppression is one of the major predictors of a good outcome of fundoplication. The reason to recommend surgery for such patients is that extraesophageal manifestations tend to dominate the picture even when heartburn is well controlled by PPIs. In addition patients come to resent the need to take pills regularly, and the costs of repeated prescriptions, office visits, and frequent endoscopy. These are substantially reduced after successful surgery. Studies of QoL have repeatedly shown that surgical treatment results in superior improvement in QoL than does medical treatment (43,44). Both medical treatment and surgical treatment are expensive, but the costs of surgery are up-front, whereas the costs of medical treatment are spread out over the rest of the patient’s lifetime. Undoubtedly, some medically treated patients will develop complications and require more interventions such as endoscopy. Equally, there will be a certain percentage of long-term surgical failure, in the region of 10% to 15%, requiring additional medical treatment, endoscopies, and possibly revisional surgery. It is remarkably difficult to estimate actual costs, because most studies simply report the hospital charges; but the costs of medical treatment tend to exceed those of surgery in about 5 to 10 years. Endoscopic Antireflux Procedures The last few years have witnessed the development of attempts to restore competence to the GEJ by an intervention using the endoscope. There are currently four methods approved by the Food and Drug Administration. The Stretta procedure uses radiofrequency energy to produce a series of small lesions in the submucosa and muscular layer of the LES and cardia, causing collagen contraction and tightening. The Enteryx procedure involves injection of an inert polymer into the submucosa of the distal esophagus to create a bulking effect. However, recent complications such as aortoesophageal fistula have led to its withdrawal. The EndoCinch technique involves inserting a stitch to bunch up the GEJ. Finally, the endoscopic plicator is inserted down an overtube and places a staple into the GEJ with the aim of reinforcing the angle of His.

medwedi.ru

308

Part Two: The Alimentary Tract—Esophagus and Stomach

The results of these four methods are all remarkably similar. There is little measurable change in the characteristics of the LES, and acid exposure in the esophagus is reduced by about half. It is rare for acid exposure to be restored to normal. Approximately 50% of patients are able to discontinue the use of PPI drugs. Symptomatic improvement despite significant reduction of acid exposure may be the result of sensory denervation produced by the procedure. Patients most likely to respond are those without a significant hiatal hernia and those with relatively mild disease. It seems intuitive that the relatively minor alterations produced by these endoscopic methods are unlikely to be of benefit in the face of significant anatomical alteration (45). Endoscopic antireflux procedures are relatively safe, but a few deaths have been reported. One was from accidental injection of polymer through the wall of the esophagus into the aorta in an elderly patient, with the production of an aortoesophageal fistula. Other deaths have resulted from unrecognized perforation of the esophagus, probably because the apparent simplicity of the procedure led to complacency in follow-up and insufficient attention was paid to the complaint of chest pain the night following the procedure. Physiology of Surgical Control of Gastroesophageal Reflux. The range of operations commonly used to treat uncomplicated reflux has narrowed down to a small number. Common to all methods are restoration of the distal esophagus into the abdominal cavity, repair of the hiatal hernia, and wrapping of the fundus of the stomach around the distal esophagus, termed fundoplication. In a Nissen fundoplication, the fundus completely encircles the esophagus and the two lips are sutured to each other to create a 360 wrap. Incomplete fundoplications are usually reserved for patients with profound defects in peristalsis, especially achalasia, because they have a lesser tendency to produce obstruction. There are two types, the anterior Dor hemifundoplication and the posterior hemifundoplication described by Toupet, and are further considered in the section on achalasia. Other procedures such as the Belsey procedure, which was essentially a 270 fundoplication performed through the left chest with extensive esophageal mobilization and formal subdiaphragmatic fixation of the wrap, are rarely performed except as salvage procedures or in cases of marked esophageal shortening. Similarly, the Hill posterior gastropexy, despite the excellent results reported by its originator, has not gained wide acceptance. The mechanism of action of fundoplication is still debated. It prevents the shortening of the LES, induced by gastric distention after a meal. When intragastric pressure rises, it is transmitted to the portion of the distal (wrapped) esophagus, causing it to collapse, rather in the manner of a Heimlich valve. Both partial and total fundoplications reduce the frequency of TLESRs. Both accentuate the angle of His, making the LES less liable to be opened as the stomach dilates. These actions are not absolute, and partial fundoplications have less effect than total fundoplication. Choice of Procedure. At one end of the spectrum are surgeons who perform Nissen fundoplication on all patients with GERD, and at the other are those who have tried to tailor the selection of procedure to the characteristics of each patient. In the past decade, there had been broad consensus that GERD roughly follows the ‘‘80/20’’ rule of many disease processes: 80% of patients cause only 20% of the trouble, but 20% of the patients cause 80% of the trouble. The 80% include those with uncomplicated reflux disease,

small hiatal hernias without esophageal shortening, and adequate esophageal motility and are good operative candidates. They are well managed by laparoscopic Nissen fundoplication and this operation is now well established in the armamentarium of community surgeons. The 20% are those patients with such features as esophageal shortening, fixed hiatal hernias, ineffective esophageal motility, and atypical symptoms, and those after a failed previous repair and they may require other procedures, including open transabdominal repair, a transthoracic approach to permit greater esophageal mobilization, the possible addition of a Collis gastroplasty, and, when all else fails, near total gastrectomy with Roux-en-Y diversion, or even esophageal replacement. Technique of Nissen Fundoplication (46). The operation is usually performed with the patient in the modified lithotomy position, with the surgeon standing between the patient’s legs. Increasingly surgeons are performing the procedure with the patient supine, probably because the increasing use of laparoscopic gastric bypass has enhanced familiarity with the approach. In either case, it is important to support the patient to avoid slipping when the table is tilted to the head-up position. Five ports are used: the camera is inserted at or just to the left of the midline six inches below the xiphoid, and pneumoperitoneum established. The patient is then tilted into steep reverse Trendelenburg position and additional ports are inserted under direct vision as follows: the port for the liver retractor is inserted either laterally on the right subcostal position, or at the xiphoid, to elevate the left lateral segment off the lesser omentum and cardia. The liver retractor is fixed by a self-retaining ‘‘iron-intern’’ retractor and once in position does not need to be moved for the remainder of the case. Then a right and left subcostal port is inserted for the surgeon’s left and right hands and a left lateral port for traction on the stomach. The steps of the operation are as follows: Esophageal Mobilization. Identification of the clear area of the lesser omentum (pars flaccida), which is opened to gain entrance to the lesser sac is described below (Fig. 11). The more opaque portion of the lesser omentum above the hepatic branch of the vagus nerve is also opened, and the edge of the right crus identified. The fat is dissected off the right crus to reveal a sulcus between the crus and the right margin of the esophagus. This is separated to mobilize the right and posterior margins of the distal esophagus. If the dissection is too close to the esophageal wall, the right (posterior)

Figure 11 Initial retraction for exposure of the esophageal hiatus. A fan retractor elevates the left lateral segment of the liver. A Babcock clamp retracts the esophageal fat pad.

Chapter 14:

vagus nerve may be injured. The dissection is kept close to the crus and the vagus will remain safe in the periesophageal fat. The tissue overlying the esophagus at the apex of the right crus can be elevated off the esophagus and transected: the anterior vagus nerve is closely adherent to the esophagus and will be safely out of the way. Using a Babcock forceps to pull the fundus down and to the right, the left crus can be identified and the tissue binding it to the cardia and the angle of His can be incised (Fig. 12). A sulcus can be similarly identified on the left side of the esophagus. By working alternately from the right and left side, it will be possible to elevate the esophagus out of the crural tunnel and pass a grasper behind the esophagus over the left crus to emerge in the left upper quadrant, taking care to avoid the spleen. This grasper is then used to pull a Penrose drain behind the esophagus. The Penrose is secured with an Endoloop and all subsequent traction on the distal esophagus is made using this sling. The dissection of the crura is complete when the right and left crura are seen to meet in a V at the bottom of the operative field, and when several centimeters of distal esophagus are freely mobilized within the abdomen. Fundic Mobilization. The fundus is then mobilized by dividing the short gastric arteries with the Harmonic scalpel or Ligasure device. The left lateral Babcock is released from the Penrose sling and used to hold away the greater omentum beginning one-third of the way down the greater curve and proceeding upwards toward the cardia (Fig. 13). The most critical vessels to divide, to ensure adequate mobility of the fundus, are the high and medial vessels binding the cardia to the pancreas. This step is what permits the fundus to be brought behind the esophagus without twisting, and division of the easily accessible vessels on the upper greater curve is only necessary to permit access to these deeper vessels. The dissection is complete when the surgeon can see the caudate lobe from the left side of the cardia and GEJ. Several randomized controlled trials have attempted to study the value of fundic mobilization, without finding a clear advantage. One trial even reported that the symptomatic outcome was worse when the fundus was mobilized. However, it is not clear from the operative descriptions if the mobilization actually included the critical step of liberating the back of the fundus. Crural Repair. In the early days of laparoscopic Nissen, this step was often omitted, leading to an unacceptable

Figure 12 Dissection of the left crus and the angle of His.

Physiologic Dysfunction of the Esophagus

309

Figure 13 Retraction of the gastrosplenic omentum in preparation for division of the short gastric vessels.

risk of wrap migration with hernia recurrence (47). The repair is normally performed from behind the esophagus. A sequence of interrupted nonabsorbable sutures, e.g., O-Ethibond, are inserted into the crura (Fig. 14). Care must be taken not to injure the aorta in suturing the left eras, or the vena cava on the right. A figure-of-8 formation may be employed but risks getting the threads tangled. The resulting aperture should be snug but not tight. When the hernia is large, or has a paraesophageal component, the crura may be attenuated and widely separated. Simple suture then creates a risk of recurrence, a feature of many laparoscopic series. Many surgeons have attempted to reinforce the repair by some kind of prosthetic patch, such as Marlex mesh, in a manner similar to that for inguinal hernia repair. Fears that it would lead to esophageal erosion have not been borne out in practice, and the preponderance of evidence suggests that it is beneficial in reducing recurrence in large hernias where the crura are flimsy (48). Creation of the Wrap. To bring the fundus behind the esophagus, a silk marking stitch is inserted on the posterior fundus at a point measured from the GEJ for 6 cm along the circumference and then 6 cm perpendicular to a tangent at that point. This is the optimal point to form the posterior lip of the fundoplication. This suture is grasped from the right side and the fundus pulled through behind the esophagus (Fig. 15). A portion of anterior fundus is then grasped and

Figure 14 (Left): Closure of the crura with interrupted 2-0 silk. (Right): Penrose drain around esophagus to facilitate exposure of the crura for closure.

medwedi.ru

310

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 16 Fixation of the fundoplication with a single horizontal mattress suture of 2-0 Prolene reinforced by Teflon pledgets. The 60 FG bougie passed just before the wrap is sutured ensures a floppy fundoplication. The inset shows the correct orientation of the wrap. Figure 15 Creation of the fundoplication. The posterior portion of the mobilized fundus is grasped by the Babcock forceps and pulled behind the esophagus.

moved to the right to meet the posterior lip in the right lateral position. The posterior lip should remain in this location without retracting to the left. A large (56 or 60 Fr) Maloney bougie is then passed with extreme care by the anesthesiologist. There is level 1 evidence that the use of such a bougie reduces postoperative dysphagia. Nevertheless it can be dangerous, especially if there is esophagitis or a stricture, and the esophagus and bougie must be thoroughly lubricated. When the bougie is safely in the stomach, the fundoplication appears tighter and some additional manipulation may be required to ensure that it sits without tension. The anterior and posterior lips are then united by a nonabsorbable suture to create a short wrap of 1.5 cm. Generally, we use a single-pledgeted horizontal mattress suture of 2/0 Prolene, which passes through both lips of the fundus as well as the esophageal wall (Fig. 16). Two additional sutures unite the fundic lips, one above and one below this, but they do not incorporate the esophageal wall. Many surgeons prefer to use three simple nonabsorbable sutures to avoid the occasional risk of erosion of the pledgets. Some surgeons reconstitute the phrenoesophageal membrane by suturing the arch of the crura to the distal esophagus above the wrap to reduce the chance of the wrap migrating upwards. To prevent the possibility of inadvertently wrapping the fundus round the proximal stomach instead of the distal esophagus, some surgeons deliberately pass the wrap between the posterior vagus nerve and the esophagus. The posterior vagus nerve is so tightly bound to the upper stomach that it acts as a barrier to wrong placement or future migration. When the operation is done through an open laparotomy, the steps are identical. Exposure is gained by retracting the sternum and costal margin with retractors fixed to a transverse bar at the level of the nipples, the so-called upper hand. Postoperative care is generally simple: the nasogastric tube is removed the next day, and, in fact, many surgeons no

longer use one. Oral liquids are administered the next day, and the patient is usually ready for discharge on the second postoperative day. A subset of fit, motivated, and younger patients who live locally may be discharged on the first day, or even the day of surgery. For such patients, many programs employ an intense regimen of early mobilization, liberal use of local anesthesia in the port sites, and liberal use of intravenous ketoralac (Toradol) in the early postoperative period, and early postoperative review in the office. Patients can drink liquids slowly but will experience difficulty if more than a small quantity is taken at a time. Patients should be able to take soft food in a few days and it is recommended that they avoid bread and meat for the first month, and that all medications be taken in crushed or liquid form. Carbonated beverages should be avoided. Most patients lose 10 to 15 pounds in the first few months, but the weight is generally regained within a year. The crural repair is dependent on a few sutures through muscle and the patient should not lift heavy objects or do vigorous manual labor for about six weeks. Most can return to a sedentary job one to two weeks after discharge. Postoperatively, after major dysphagia has resolved, it is common for patients to notice increased flatulence and looseness of bowel movements. This is so common that patients should be warned about the possibility. Patients will be unable to belch from the stomach, though small eructations of air trapped in the esophagus may occur. It is also hard to vomit, especially in the first year. Although abdominal bloating is often described, it is almost equally common in patients with GERD before surgery, and is rarely a problem unless the wrap is too tight or the patient has the habit of air swallowing. Perioperative Complications of Nissen Fundoplication for Uncomplicated Reflux. The most dreaded intraoperative complications are perforation of the esophagus or the back of the fundus, most commonly caused by dissecting the back of the GEJ without clear vision (49). Maladroit passage of the bougie may also cause perforation, for example, if the Penrose sling has not been relaxed and the bougie develops a ‘‘knuckle,’’ which splits the esophageal wall. If recognized

Chapter 14:

promptly and repaired accurately, the eventual good outcome is generally unaffected. If unrecognized, then the patient presents with unusually severe abdominal or shoulder pain or signs of sepsis a few days postoperatively, sometimes after discharge. It is important to be vigilant and consider the possibility of perforation in any patient reporting unusual pain, fever, or tachycardia after discharge. Hemorrhage most commonly comes from liver damage inflicted by the liver retractor. It also may occur from the short gastric arteries or from splenic injury, and is generally controllable locally. If it affects the ability to see safely, it can often be controlled by a 4 4 gauze sponge inserted down the left upper trocar. Pressure with the sponge for a few minutes generally allows the bleeding point to be seen and controlled. Hemostatic agents such as fibrin glue are helpful in this situation. Vagal injury is occasionally blamed for postoperative gastric discomfort. Recent evidence using a sham feed to stimulate vagally mediated pancreatic polypeptide release suggests that some degree of vagal injury is very common (40%) early after Nissen fundoplication, but that it is not relevant to postoperative symptoms (23). Postoperative Complications. Complications discovered postoperatively may include an excessively tight wrap. This may present with total dysphagia, causing regurgitation of saliva, often described as foam. A barium swallow will resemble achalasia with dilation of the entire esophagus, a fluid level, and minimal passage of barium into the stomach. In most cases, the simplest solution is to return the patient to the operating room (OR). The problem may be an excessively tight crural closure, when release of the uppermost suture may solve the problem, or the wrap may have been too tight or twisted and it must be redone. If done within one to two days, it is generally not difficult. One reported cause of late dysphagia is excessive perihiatal fibrous scarring. This has even been reported in cases where the crura were not sutured, and is thought to be due to excessive use of electrocautery in the esophageal dissection (50). There are several reports of reherniation in the early postoperative period, possibly related to retching and vomiting, and if discovered within the first few days, laparoscopic rerepair is not generally difficult. If discovered late, then it is advisable to wait several months before attempting a repair. It is possible that for many patients, recurrent hiatal herniations may have actually occurred early but may not have been discovered. Early radiologic investigation of symptoms in the immediate postoperative period may identify this situation but laparoscopic reexploration is still relatively easy (51). A super-competent wrap may cause the so-called gasbloat syndrome, characterized by resonant abdominal distention coupled with the inability to burp. This may happen if the patient is a habitual air swallower, and it may improve as edema resolves and the patient adapts, no longer having to swallow as much because there is no longer any acid stimulating the esophagus. In severe cases, it may be necessary to insert a nasogastric tube, or even a percutaneous endoscopic gastrostomy (PEG). Occasionally, such patients are so chronically unhappy that the only solution is to dismantle the fundoplication and perhaps convert to a partial wrap.

Complicated GERD The complications of GERD are caused by tissue injury that produces an overlapping group of abnormalities

Physiologic Dysfunction of the Esophagus

311

including esophagitis, stricture, Barrett’s esophagus, and esophageal shortening. Esophagitis Esophagitis is an endoscopic diagnosis based on the visual appearance of mucosal erosions classified according to either the Los Angeles or the modified Savary-Miller systems. When the muscosa is visually normal, esophagitis is not present, regardless of the presence of inflammatory cells on mucosal biopsy. With the widespread use of PPI medications, it is possible to heal esophagitis in more than 90% of patients, and a normal endoscopy may cause the physician to underestimate the severity of the disease. This emphasizes the need for objective measurement of esophageal acid exposure. Stricture An esophageal stricture is a circumferential narrowing of the esophageal lumen, sufficient to prevent the passage of a 12 mm endoscope. When caused by reflux, it occurs just above the GEJ. GERD was formerly the most common cause of esophageal strictures in the pre-PPI era. Such strictures are now relatively rare. The esophageal strictures seen in practice are now most commonly anastomotic strictures or the result of pill or other caustic ingestion. Many pills, including over-the-counter preparations such as iron, calcium, and vitamin supplements, have been implicated in the creation of esophageal ulcers and strictures. Amongst prescribed medications, the antiosteoporosis agent Fosamax and nonsteroidal anti-inflammatory drugs (NSAIDs) are the worst offenders. Strictures present with dysphagia for solids and are readily visualized on both radiological and endoscopic studies. When seen for the first time, it is important to biopsy the stricture to ensure that it is not a malignancy. Benign strictures generally respond well to dilation. All dilations carry the risk of esophageal perforation. However, the use of through-the-scope balloon dilators has rendered dilation a much safer procedure, because the shearing forces produced by passage of a bougie are not present, and the procedure can be preformed under direct vision. Very tight or tortuous strictures should be dilated in a fluoroscopy suite, a guide wire passed under radiologic control, and Savary bougies passed over the wire. It is important to keep the wire still as the bougie is advanced, to use great gentleness, and to dilate only a small number of steps at any one sitting. When a size 36-Fr bougie has been passed, it should be possible to pass the scope through the stricture, and pass the guide wire under direct vision thereafter. In a tight stricture, no more than three graded bougies should be passed in one session. After dilation, the process that produced the stricture must then be controlled. A reflux stricture represents a failure of medical treatment and is likely to be best served by Nissen fundoplication, if the patient is a good operative risk and peristalsis is adequate. Strictures tend to occur in frail elderly patients who take a lot of other medications, and they are at higher risk of pill injury superimposed on a reflux stricture. Good pharmacologic control of acid secretion is especially important in this population. Undilatable strictures, or strictures that can be physically dilated but produce no symptomatic improvement, fall into the category sometimes called global esophageal failure and may require esophageal replacement (52). Schatzki’s Ring A specific type of stricture presents as a thin shelf at the squamocolumnar junction in association with a hiatal

medwedi.ru

312

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 17 Typical appearance of Schatzki ring. Note the coexistent hiatal hernia.

hernia (Fig. 17). Its association with symptoms of GERD is variable, perhaps because it may represent a very localized response to excessive acid in the distal esophagus, and the localized fibrosis acts rather like an endogenous antireflux device, preventing further effacement of the sphincter and limiting reflux. It characteristically presents with intermittent dysphagia for solid foods. It responds well to dilation, but if improvement of the dysphagia is accompanied by the development of heartburn, the patient should be studied for other evidence of GERD and treated accordingly (53,54). Barrett’s Esophagus In the past decade, Barrett’s esophagus has emerged as the most significant complication of GERD. Improved symptom control by PPI use and reduction in the incidence of stricture is partly responsible. But an absolute increase has also occurred, bringing with it a parallel increase in esophageal adenocarcinoma (55). The cause of this changing epidemiologic pattern is still debated, but important environmental shifts in most Western countries include a reduction in the prevalence of H. pylori infection, and an increase in dietary fat and even carbonated beverage consumption, all of which are known to increase reflux in other situations. A cause and effect relationship has also been proposed between the widespread use of acid suppressant medications and the increasing incidence of esophageal adenocarcinoma, because the two phenomena have increased in parallel since in 1970s. There are theoretical grounds to indicate that prolonged acid reduction in the stomach leads to bacterial colonization,

which can then deconjugate bile salts, which reflux back into the stomach and esophagus. This hypothesis is still speculative at present. However, one common thread in the plethora of theories of the pathogenesis of Barrett’s esophagus appears to be the addition of duodenal-gastric reflux, sometimes called bile reflux, into the esophagus. Many studies using the Bilitec probe or continuous aspiration of esophageal secretions have confirmed that in Barrett’s esophagus, there are higher concentrations of bile salts than in uncomplicated reflux. The problem in interpreting these studies is that Barrett’s esophagus is also associated with the greatest acid reflux as well, and the presence of bile may simply be a nonspecific marker for severity. There seems to be general agreement that there is more bile in the refluxate of patients with Barrett’s than in patients with GERD but without Barrett’s (56). Bile salts have been shown to be mitogenic in other situations, such as in the colon. Regardless of the etiology of the mucosal transformation, Barrett’s esophagus tends to be associated with the most advanced stages of reflux disease: most patients have hiatal hernia, reduced LES length and pressure, reduced peristaltic amplitude in the distal esophagus, and markedly elevated acid exposure on 24-hour pH monitoring. Barrett’s esophagus is characterized endoscopically by the presence of velvety orange–red mucosa lining the tubular esophagus and histologically by the presence of columnar epithelium with intestinal metaplasila (Fig. 18). The visual appearance at endoscopy can sometimes be confused with herniation of normal gastric mucosa above the crura, and, in the past, Barrett’s esophagus was only diagnosed if the columnar mucosa extended 2 cm or more above the esophagogastric junction. The histologic hallmark of Barrett’s esophagus is the presence of ‘‘specialized’’ columnar epithelium, which shows features of intestinal metaplasia, easily recognized by the presence of goblet cells. These features may be seen in biopsies of specimens less than 2 cm above the esophagogastric junction, sometimes called short-segment Barrett’s esophagus (57). Shortsegment Barrett’s esophagus often appears as a small tongue of columnar epithelium extending above the Z-line into the lower esophagus. Barrett’s esophagus may exist on its own or may itself be complicated by ulceration, stricture, dysplasia, and malignant change. Ulceration typically occurs at the upper limit of the specialized mucosa, at the squamocolumnar junction. Barrett’s ulcers resemble duodenal ulcers in having the tendency to penetrate deeply, and to

Figure 18 Endoscopic appearance of Barrett’s esophagus.

Chapter 14:

heal with stricture formation. Thus strictures in Barrett’s esophagus represent the site of a former ulcer, and, for this reason, are typically much higher than conventional peptic strictures, which occur at the GEJ. Malignant transformation of specialized epithelium generally progresses through a sequence of steps that include low-grade dysplasia, high-grade dysplasia, and invasive carcinoma. Irregular biopsy intervals during follow-up and sampling error prevent the sequence from being recorded in every patient, and the rate of transformation is very variable. The risk of malignant transformation in a given patient is hard to determine, though population estimates based on retrospective studies vary from less than 1 per 50 patient years to 1 per 440 patient years. The development of esophageal cancer via the metaplasia-dysplasia-carcinoma sequence is characterized by the accumulation of multiple genetic and epigenetic modifications. Many of these events affect cell growth through modulating the cell cycle, apoptosis, cell signaling, and cell adhesion. These genetic mutations may be useful in the future to identify those patients, with Barrett’s esophagus, at highest risk of developing adenocarcinoma. The early genetic changes detected in the progression of Barrett’s are loss of the p16 gene, loss of the p53 gene, cyclin D1 overexpression, and losses of the APC, Rb, and DCC loci, and aneuploidy (58). However, there appears to be no simple sequence of genetic mutations in the metaplasia-dysplasia-carcinoma path, making it difficult to use these mutations as markers of progressive disease. The environmental influences that initiate these genetic events in the cell are also unknown. Treatment specific to Barrett’s esophagus is controversial. In general, neither medical nor surgical treatment of underlying GERD produces disappearance of the Barrett’s epithelium, though its extent may be reduced, and squamous epithelium may overgrow the metaplastic epithelium, without replacing it. Many gastroenterologists doubt that the mere presence of Barrett’s epithelium requires any additional treatment beyond routine PPI treatment for underlying GERD. However, this policy underestimates the severity of the disease and underplays the effect of symptoms other than heartburn. While it is true that there is no conclusive proof that more total reflux control, as produced by fundoplication, can prevent cancer, there is strong evidence from several studies that dysplasia and progression to cancer are very rare after effective Nissen fundoplication. Most cancers, which do develop after fundoplication, either occur relatively early (within the first three years) or after the Nissen has become defective (59,60). However, in the absence of conclusive evidence, it is still recommended that patients with Barrett’s undergo regular endoscopic surveillance after antireflux surgery. Ablation of Barrett’s Mucosa. Removal of the abnormal epithelium has been intensively studied in the past decade. The two major methods in current use are the thermal technique in which thermal energy is directed from a heating electrode [multipolar electrocautery (MPEC)] and photodynamic therapy in which a sensitizing agent known as a protoporphyrin is given systemically and ultraviolet (UV) light is directed into the distal esophagus. The sensitizing agent is preferentially taken up into the abnormal mucosa, and absorption of the UV light is concentrated in that segment. The cardinal problem is that most methods of removing the mucosa also cause damage to the submucosa, producing a more scarred and ulcerated lesion that will at best heal with a stricture (61).

Physiologic Dysfunction of the Esophagus

313

Removal of Barrett’s mucosa with these methods is variable, and buried islands of glandular mucosa frequently remain after squamous mucosa regenerates. Consequently, they have been reserved for high-risk patients and those with dysplasia. However, a newer method using closely spaced rings to deliver radiofrequency energy on the outside of an inflatable intraesophageal balloon (Barrx) has shown great potential, because the depth of injury can be precisely controlled. This accomplishes the twin goals of total mucosal removal without damaging the underlying submucosa, permitting healing to occur without stricture. Early results with this method are extremely promising. Surveillance in Barrett’s Esophagus. The rationale for regular surveillance is that if a cancer develops, it will be found at an early stage and will be more amenable to curative treatment. It has been clearly shown that cancers discovered in the course of regular surveillance are highly curable (90% five-year survival), in contrast with cancers discovered after the patient presents with dysphagia, when 10% to 30% fiveyear survival is the rule. The approved protocol is to take biopsies from four quadrants of the circumference every 2 cm of Barrett’s mucosa (62,63). In the absence of dysplasia, surveillance is recommended every two years, and more frequently if dysplasia is identified. The features of low-grade dysplasia have much in common with reactive changes associated with active inflammation, and when diagnosed, the patient should have a course of really intensive acid suppression and then undergo repeat biopsy after 6 to 12 weeks. In many cases, the dysplasia will not be detected on this repeat biopsy, suggesting that it was mistaken on the first occasion. High-grade dysplasia is synonymous with carcinoma in situ, but is generally not diagnosed until confirmed by a second pathologist experienced in this area (64). The treatment of high-grade dysplasia is discussed in the section on esophageal carcinoma. Special Situations Esophageal Shortening. Most experienced esophageal surgeons recognize the situation where the GEJ is fixed higher in the crural tunnel or the mediastinum and it cannot be brought down below the diaphragm without tension. Preoperatively, it is more common in the presence of a large (> 5 cm) hiatal hernia, especially if fixed or associated with an esophageal stricture, in which case the shoulders of the supradiaphragmatic pouch will be sloping rather like a chardonnay bottle, rather than horizontal like a cabernet bottle. The appearance is caused by transmural scarring pulling the stomach upwards, and is the radiologic hallmark of a fixed or irreducible hernia. This is a difficult situation to deal with. If an unsuspected short esophagus is discovered intraoperatively, the options are to perform some kind of Collis gastroplasty and, create a neoesophagus that will then lie in the abdomen and can be wrapped by remaining fundus, the so-called Collis–Nissen operation. If shortening is detected at laparoscopy, a similar Collis gastroplasty may be performed by inserting the GIA stapler via the right fourth intercostal space and bringing it out in the hiatus, where it is at the correct angle, parallel to the esophagus. The fundoplication can then be completed by wrapping the fundus around the neoesophagus (65). Other solutions are to complete as much of the dissection as possible through the abdomen, close, and then turn the patient left side up and perform a thoracotomy through the sixth or seventh intercostal space. This will allow more extensive esophageal mobilization up to

medwedi.ru

314

Part Two: The Alimentary Tract—Esophagus and Stomach

the aortic arch, and more esophageal length can be obtained by dividing the direct branches from the aorta and the bronchial arteries, as well as some of branches of the vagal plexus near the hilum of the left lung. Once enough length has been obtained, a transthoracic Nissen may be performed and the crura closed. This approach imposes a longer hospital stay, the need for intercostal tube underwater seal, and the risk of persistent post-thoracotomy pain later on. If adequate length cannot be obtained, a Collis gastroplasty is easily carried out with a GIA stapler and the remaining fundus wrapped around this segment. The initial results of these procedures tend to be very pleasing but the continued secretion of acid mucosa above the wrap leads to long-term failure in a significant proportion (66). The Hypomotile Esophagus. A patient with severe GERD and poor esophageal motility may have secondary, refluxinduced damage, or may have an underlying disease such as scleroderma in which the muscle of the distal esophagus is gradually replaced and peristalsis is lost (Fig. 19). Having to deal with such a case after a fundoplication has gone wrong emphasizes the need to assess esophageal motility before operating. Scleroderma and achalasia misdiagnosed as GERD are the two serious diagnoses that should not be missed. Most other forms of nonspecific motor disorder will respond well to Nissen fundoplication, provided the amplitude of peristalsis is greater than 20 mmHg in the lower esophagus. The paradox of this situation is that the cases that have the worst peristalsis and the highest risk of post-Nissen dysphagia are the very patients in whom the maximal reflux protection provided by the Nissen is most desirable (67,68). When there is very poor amplitude, it often coexists with esophageal shortening, and such cases are best approached through the chest. In the comparatively rare situation of a hypomotile esophagus with normal esophageal length, a laparoscopic partial fundoplication is an acceptable solution.

GERD in Morbidly Obese Patients. It is undeniable that a fundoplication, whether open or laparoscopic, is more difficult in obese patients, and there is some evidence that the outcome of fundoplication is less satisfactory (69). Other surgeons have found no difference in outcome (70). Patients with both GERD and morbid obesity may well be candidates for a primarily bariatric operation, because both Roux-en-Y gastric bypass and the adjustable gastric band have been found to reduce GERD. Consideration should be given to offering gastric bypass to such patients. Key to the selection will be a history of repeated failure of dietary and other conservative measures to achieve or sustain weight loss. Such patients are more than ready to accept the limitations imposed by a bariatric operation, and the freedom from reflux symptoms is a welcome bonus. However, an obese patient presenting primarily with reflux symptoms, who is not troubled by her weight and has made no concerted effort to lose weight, is probably an unsuitable candidate for bariatric surgery and likely to be intolerant of the dietary restrictions it would produce. Such a patient should be counseled about weight loss by nonsurgical means prior to scheduling antireflux surgery, because even short-term weight loss will improve the exposure and make the liver easier to retract. Reflux Causing End-Stage Lung Disease. In tertiary referral centers with large transplant programs, surgeons may be asked to consider antireflux surgery in potential lung transplant recipients. It is wise to confirm or exclude GERD in all potential lung transplant recipients where the lung pathology is not clearly understood. Diagnoses such as ‘‘idiopathic pulmonary fibrosis’’ or ‘‘usual interstitial pneumonitis’’ are commonly caused by GERD, and examination of the excised lungs sometimes reveals particles of vegetable matter that have presumably been aspirated (71). In contrast, when the disease is known, as in cystic fibrosis, reflux is unlikely to be a contributing factor.

Figure 19 Motility tracing of a patient with scleroderma, showing low-amplitude ineffective peristaltic contractions in the esophageal body.

Chapter 14:

The characteristic features of reflux-induced lung disease are that heartburn and regurgitation are relatively minor symptoms, and may be absent, because the presentation is dominated by more serious or worrying symptoms such as extreme dyspnea. The esophageal mucosa often looks normal at endoscopy. The only satisfactory way to rule out GERD is by 24-hour pH monitoring. When reflux is found, it makes sense to perform surgery prior to lung transplant. Some degree of gastroparesis may be induced by the perihilar dissection, causing vagal injury and exacerbating preexisting reflux. Fundoplication is not especially difficult, but prolonged CO2 insufflation will lead to hypercarbia and the patient may need to remain intubated overnight to restore the pCO2 to its baseline level. Failed Antireflux Surgery. As the numbers of patients undergoing surgery for GERD increases, it is inevitable that patients with an unsatisfactory result will be referred to surgeons, especially in larger referral centers. The common patterns are either recurrence of the former symptoms or the development of new symptoms, such as dysphagia or abdominal pain, bloating, flatulence, or diarrhea. Up to 30% of patients after Nissen fundoplication will be found to be back on PPI therapy after surgery. When these patients are studied, less than one-third actually have any evidence of recurrent reflux (72). In the remainder, it has been prescribed by a primary care physician or gastroenterologist as empiric treatment. This practice is to be deplored, but it continues to fuel the unsubstantiated claim that fundoplication is only a short-term solution. Common patterns include recurrence of the hiatal hernia, breakdown of the fundoplication, a slipped Nissen fundoplication, and excessively tight fundoplication. These will present with recurrent heartburn and regurgitation or pulmonary symptoms, and worse or new-onset dysphagia. Abdominal symptoms such as bloating may be due to vagal denervation. A patient with a failed Nissen fundoplication requires a thorough workup to elucidate the cause of failure and plan remedial surgery if necessary. Barium esophagogram and upper endoscopy will establish if the fundoplication is intact or disrupted, if the wrap has migrated above the diaphragm, or if it is around the proximal stomach (slipped Nissen). The appearance of a herniated Nissen on endoscopy is characteristic, and easily distinguished from a correctly sited Nissen fundoplication (Fig. 20). Manometry will confirm if there is outflow obstruction by the presence of elevated LES pressure with failure to relax on swallowing,

Physiologic Dysfunction of the Esophagus

315

and if there is peristaltic failure. Recurrent reflux can be diagnosed by 24-hour pH monitoring. The original operative report and preoperative evaluation should be reviewed where possible, because this will give a clue to the presence of underlying esophageal disease. It was common in the past to perform most revisional surgery transthoracically. They are increasingly performed through the abdomen, and in many experienced centers, laparoscopic revisions are routine. Whether open or laparoscopic, it must be emphasized that revisional antireflux operations are much more difficult than primary procedures and there is a greater incidence of inadvertent gastric or esophageal perforation and vagal injury (73). If the cause of failure can be identified, a repeat operation can be expected to give a good result in 80% of cases. Third-time revisions are more problematic. A good result may still be obtained if a clear cause of failure can be identified and corrected. However, it is often the case that the distal esophagus and fundus are encased in dense scar tissue, and liberating the fundus in such circumstances results in a rather traumatized area with the creation of gastrotomy or esophageal perforation, and the vagus nerves are almost inevitably transected. These cases are usually best managed by near-total gastrectomy or by esophageal replacement with a colon interposition in a specialist referral center. Nonreflux Esophagitis. Cases of esophagitis due to causes other than reflux will occasionally present to a surgeon. Typically, there is more intense odynophagia than heartburn, and acid suppression is not of benefit. Infectious etiologies predominate, most often in the immunocompromised patient such as those with HIV/AIDS or on chemotherapy for malignancy elsewhere. The most common varieties are Candida, often easily recognizable by the presence of typical thrush lesion in the throat and white cheesy exudates on the esophageal mucosa, and viral causes such as herpes and cytomegalovirus, which present as punched-out ulcers throughout the esophagus (Fig. 21). These are treated by attacking the underlying cause and providing purely symptomatic relief by avoiding provocative or irritant foods. A second important cause is the toxicity of ingested caustic agents or pills, as described in the section on strictures. One recently described form of esophagitis in both children and adults is characterized by a narrow-caliber esophagus, sometimes with a series of circumferential ridges in the mucosa on endoscopy, described as ‘‘feline’’ esophagus. The characteristic on histology is the presence of eosinophils (> 20 per high power field) and for this

Figure 20 Endoscopic appearance of (A) correctly sited Nissen fundoplication and (B) herniated wrap, where the fundoplication can be seen passing up through the hiatus.

medwedi.ru

316

Part Two: The Alimentary Tract—Esophagus and Stomach

diverticulum develops, because it appears to be due to an outpouching of the mucosa through a defect just above the nonrelaxing sphincter (Fig. 22). A Zenker’s diverticulum frequently presents with the coughing and choking typical of incomplete UES relaxation, but in addition the physical presence of the diverticulum allows the accumulation of food and saliva, which then causes coughing and regurgitation, when the patient lies down.

Treatment of Zenker’s Diverticulum

Figure 21 Endoscopic appearance of viral esophagitis.

reason it is known as eosinophilic esophagitis (74). The dominant symptom is dysphagia, and there is broad agreement that dilation tends to cause a long spiral tear in the mucosa, associated with severe chest pain. Frank perforation, however, is rare. It may have an autoimmune or allergic etiology and has been found to respond to leukotriene inhibitors.

Although often occurring in elderly, high-risk patients with other comorbidities, symptomatic Zenker’s diverticulum is so disabling that treatment is required, and only surgical treatment offers any prospect of improvement. The conventional approach is to perform cricomyotomy, which corrects the underlying physiologic defect, and the treatment of the actual diverticulum then depends on its size. A small diverticulum is generally taken up into the mucosa and requires no other treatment. Moderate-sized diverticula, once dissected out, can be suspended from the anterior longitudinal ligament, avoiding the need for actually opening the diverticulum. The largest (> 6 cm) should be excised, generally using a GIA stapler with a bougie in the esophagus to protect it from excessive narrowing. If a cricomyotomy is not performed, merely excising the diverticulum is likely to lead to

ESOPHAGEAL MOTOR DISORDERS Esophageal motor disorders primarily affect either the pharyngoesophageal segment or the esophageal body and LES. Although they are rare, there is increasing recognition that they can be a source of considerable morbidity and even mortality, which can result from either aspiration or complications of endoscopic treatment. Motor disorders affecting the UES present with difficulty in swallowing, choking, and coughing during eating, and most commonly result from a more general neurological cause, either vascular or degenerative. Some information can be obtained from a carefully performed videoesophagogram or modified barium swallow to detect aspiration and observe the movement of the epiglottis, larynx, and pharynx during swallowing. Treatment generally focuses on speech and swallowing therapy to teach airway protection, and provision of a PEG may be necessary to maintain nutrition. Exercises taught by therapists include teaching the patient to hold the breath, and deliberately to swallow twice in quick succession before breathing again. A special subgroup of usually elderly patients may present with dysphagia and choking due to defective UES relaxation. This appears to be localized to the cricopharyngeus muscle, because age-related metabolic deficiencies in the mitochondria of this frequently exercised skeletal muscle eventually cause fibrotic changes in the muscle, which then becomes stiff and loses compliance. This can be identified manometrically as impaired UES relaxation in the face of normal pharyngeal contraction. The typical findings are elevated residual pressure in the UES during a swallow, and indirectly, the presence of an elevated intrabolus pressure, because this is the manometric equivalent of impaired UES opening. Radiologically, there is an indentation or bar in the barium column when swallowing. Not all cricopharyngeal bars are symptomatic, but if it occupies more than 60% of the circumference of the esophageal lumen at that point, it is likely to cause serious symptoms. This physiologic situation is the underlying reason that Zenker’s

Figure 22 Typical appearance of Zenker’s diverticulum. Note the narrow opening of the UES with the origin of the diverticulum proximal to it. Abbreviation: UES, upper esophageal sphincter.

Chapter 14:

failure of the staple line with a long-term salivary fistula, and even if it does heal, the diverticulum is likely to recur because the underlying condition, which produced it, was not corrected.

Cricomyotomy for Other Pharyngoesophageal Disorders Patients with degenerative or vascular neurologic conditions affecting the swallowing mechanism occasionally benefit from cricomyotomy if the pharyngeal muscles are sufficiently strong and coordinated to propel a bolus into the hypopharynx (14). This can be fairly easily established by detailed manometry, but a simple clinical guide to the adequacy of more proximal oropharyngeal dysfunction is to listen to the patient speak. Dysarthria, if present, indicates severe proximal involvement of the tongue and palate, and cricomyotomy is unlikely to be beneficial.

Technique of Cricopharyngeal Myotomy It should be remembered that patients requiring cricopharyngeal myotomy are often elderly, with arthritis of the cervical spine, and many are on anticoagulation. Oral anticoagulants must be stopped a week ahead of time and the patient maintained on heparin until it is safe to restart it. Sometimes the edema that accompanies the operative exposure makes swallowing worse before it improves it, and such patients may require assisted nutrition for a few weeks until they are able to eat comfortably and without coughing and choking. Such patients often benefit from a concomitant PEG insertion because it is rather worrying to perform it in the postoperative period if it should prove necessary. Exposure of the cervical esophagus is a fundamental skill that is also applicable to performing esophagectomy, repair of perforations, or creation of esophagostomy (Fig. 23). The patient is positioned supine with a roll between the shoulders, the neck slightly extended, the head resting on a donut, and the chin turned very slightly to the right. The skin is prepped to the level of the ear lobe. An incision is made along the anterior border of the left sternocleidomastoid muscle and deepened down through the

Physiologic Dysfunction of the Esophagus

317

platysma. The omohyoid muscle is seen crossing the neck obliquely and is divided. The strap muscles are divided just above their attachments to the manubrium. This allows the space to be opened between the larynx and trachea and thyroid medially and the carotid sheath laterally. By opening this space, the finger can easily reach the cervical spine and mobilize the posterior wall of the esophagus from the hyoid bone down into the mediastinum. The cervical esophagus is then easily identified in this paravertebral position. Care should be taken not to retract the larynx and trachea medially with a metal retractor: the recurrent laryngeal nerve is in the groove between the trachea and the esophagus and is easily traumatized. It is easiest to begin the myotomy on normal cervical esophagus well below the level of the larynx and divide first the longitudinal and then the circular muscle. Once the plane between the circular muscle and submucosa is reached, it is relatively easy to carry the myotomy down into the upper thoracic esophagus, and upwards, dividing the thick circular muscle of the cricopharyngeus, and carrying the incision upwards on to the pharyngeal constrictors. Excessive cautery should be avoided, because this could cause a small area of necrosis and lead to delayed perforation. Postoperative hematoma is a bothersome complication that will delay the patient’s functional recovery for several weeks. Every effort should be made to obtain perfect hemostasis, if necessary by tilting the patient head down to identify small bleeders and applying a topical agent such as fibrin glue. The platysma and skin should be closed precisely to avoid puckering because it will subsequently cause difficulty shaving.

Transoral Treatment of Zenker’s Diverticulum The modern treatment of moderate-sized Zenker’s diverticulum involves the passage of a specially designed rigid scope, and then a modified GIA type stapler so that one limb is in the diverticulum and the other in the esophageal lumen. When the gun is fired, the UES is automatically transected and the mucosa stapled, and the diverticulum is incorporated into the esophageal lumen. It can be performed as an outpatient procedure and avoids many of the risks, including recurrent nerve palsy, associated with open cricopharyngeal myotomy (75).

Recurrent Nerve Paralysis

Figure 23 Initial exposure for cricomyotomy via a left neck incision.

Damage to the recurrent laryngeal nerve in the neck is a known risk of any cervical esophageal operation. Anatomic variations of the course of the recurrent nerve are more common on the right, which is one reason why most esophageal mobilization is approached from the left side. Temporary injury may be caused by retraction or nearby cautery, and actual transection of the nerve is a risk if the anterior surface of the esophagus is mobilized, because the nerve lies in the groove between the anterior wall of the esophagus and the posterior wall of the trachea. The mobilization of the cervical esophagus for esophagectomy is more extensive and in its distal portion it is often done bluntly, and the incidence of nerve injury is correspondingly higher. Regardless of the cause, the effect of the injury is serious. Severe hoarseness will be present immediately afterwards, and swallowing is more difficult and aspiration is common. But the most severe functional problem is inability to cough effectively. The cough is instantly recognizable as a hollow ‘‘bovine’’ sound, and should immediately focus attention on airway protection and chest physical therapy.

medwedi.ru

318

Part Two: The Alimentary Tract—Esophagus and Stomach

Treatment of the condition depends on whether recovery is expected. If the nerve was clearly seen and protected, it may be assumed that recovery will occur in a few weeks. Functional improvement in the voice and in coughing mechanics may be produced by injecting the affected cord to increase its bulk and permit the healthy vocal cord to oppose it more easily. Injection may be with glycerol, which is the shortest acting, with liquid fat, or with Teflon paste. If the nerve is known to be permanently injured, a thyroplasty operation may be performed. In this procedure, the thyroid cartilage is opened and the affected cord medialized by inserting a piece of nonabsorbable material such as Gore-Tex between the cord and the ala of the thyroid cartilage.

Motor Disorders of the Esophageal Body and LES Esophageal motor disorders affecting the esophageal body usually present with dysphagia and chest pain. Unlike mechanical obstruction, which presents with difficulty in eating solids, esophageal motor disorders classically present with dysphagia for both liquids and solids. They are diagnosed primarily by esophageal manometry. Endoscopy is often normal, and the disordered transit identified on barium studies is not sufficiently quantitative to categorize the disorder. Precise diagnosis is difficult for several reasons: the causes of most of the abnormalities are not known, many manometric abnormalities have no apparent physiologic consequences, and even when the manometric abnormality is corrected, the symptom may not resolve. Further, the symptoms can also be mimicked by other disease processes, most notably angina. Historically, there have been four named esophageal motor disorders: achalasia, diffuse esophageal spasm, nutcracker esophagus, and hypertensive LES, and a fifth category termed nonspecific esophageal motor disorder (NEMD), which is an umbrella term to describe tracings that are clearly abnormal but which do not fall into one of the above named categories (76).

up food finely. When under pressure to eat quickly, the symptoms get worse and they frequently prefer to eat in isolation rather than in company. With progression of the disease, most patients also develop regurgitation. Generally, it occurs during or at the end of a meal, and the material tastes bland rather than sour or bitter. It can also occur at night, causing staining of the pillow, and at times may wake the patient from sleep because of coughing or choking. Regurgitation may lead to avoidance of eating in company, and, sometimes, social isolation. Patients may be told that their symptoms are due to stress and may be taking antidepressive or anxiolytic medication. Chest pain also occurs in some patients, and may lead to the disease being confused with GERD. Most patients with achalasia have some weight loss, although this is not always the case, and the disease has been diagnosed even in the context of morbid obesity. The diagnosis is most commonly suspected on barium swallow. The classic findings of achalasia are a dilated esophagus with an air–fluid level and a smooth, tapered ‘‘bird’s beak’’ appearance representing the poorly relaxing LES (Fig. 24). In the early stages of the disease, the diameter of the esophagus may be normal. The late stage of achalasia is characterized by a tortuous, sigmoid esophagus, and an epiphrenic diverticulum may develop (Fig. 25). Because the esophagus empties only when the hydrostatic pressure of the fluid column overcomes the LES pressure, air remains

Achalasia Achalasia is the best known primary motility disorder of the esophagus. The cause is unknown, although degenerative, autoimmune, and infectious etiologies have been hypothesized (77). Pathologic examination shows an inflammatory response in the esophageal myenteric plexus, resulting in a selective loss of postganglionic inhibitory neurons containing nitric oxide and vasoactive intestinal peptide. Unopposed cholinergic stimulation leads to high basal LES pressures and inadequate relaxation of the sphincter. Inhibitory influences are also necessary for normal peristalsis. There is also some experimental evidence that obstruction at the GEJ may produce a condition with the radiologic and manometric features of achalasia. This corresponds to the clinical situation where features of achalasia develop in response to an infiltrating tumor of the cardia or after a tight Nissen fundoplication or placement of an adjustable gastric band. This evidence suggests that in some situations, the increased outflow resistance is a primary phenomenon and the degeneration of the esophageal body is secondary (78–80). Chagas’ disease, which is caused by infection with the parasite Trypanosoma cruzi, can also cause an achalasia-like syndrome in the esophagus. Patients with achalasia often present with dysphagia for solids and liquids. Careful questioning may be necessary to elicit this symptom. Patients may deny dysphagia, but may have developed methods of compensating for it, such as avoiding certain foods, eating slowly, or cutting

Figure 24 Barium study of patient with achalasia showing bird’s beak appearance of lower esophagus.

Chapter 14:

Physiologic Dysfunction of the Esophagus

319

neoplasm, which causes this pseudoachalasia, is an infiltrating tumor of the cardia, which can only be seen when the endoscope is retroflexed. Patients who appear to have extrinsic compression of the esophagus should be referred for more definitive imaging via endoscopic ultrasonography, or CT. Manometry is the key test by which to establish the diagnosis of achalasia (Fig. 26). The classic features on stationary manometry are as follows: 1. 2. 3. 4.

Figure 25 Barium study of advanced achalasia with sigmoid deformity and esophageal dilation with air–fluid level.

in the esophagus above the fluid, and hence there may be no visible gastric air bubble on upright chest X-ray. Upper endoscopy will often confirm findings reflected on barium studies, such as retained food and esophageal dilation. It is important to perform endoscopy to rule out a neoplasm of the esophagus, stomach, or mediastinum, all of which can cause symptoms that mimic achalasia. The most common

Elevated LES pressure Incomplete LES relaxation Absence of esophageal body peristalsis Positive intraesophageal body pressure

The resting LES pressure is usually raised, but can be normal in as many as 50% of patients. It is never low in untreated achalasia. Some abnormality of LES relaxation is seen in all patients: in 70% to 80% it is absent or incomplete, and in the remainder the relaxations are complete, but are of short duration (usually less than 6 seconds) and are functionally inadequate. In classic achalasia, the esophageal body is aperistaltic and intraesophageal pressure is positive, reflecting resistance to outflow. On swallowing, an isobaric low-pressure wave is usually seen simultaneously in all levels in the esophagus, representing the pressure generated by the pharynx being transmitted to the esophageal body. However, some patients may have normal or even high-amplitude simultaneous contractions in the esophageal body. This has led to description of a subgroup termed ‘‘vigorous achalasia.’’ It is not clear whether this is a separate disease or if it represents a stage in the evolution of classic achalasia. No treatment for achalasia can restore peristalsis or normal LES relaxation. Thus, every treatment option is designed to reduce the pressure gradient across the LES, thus facilitating esophageal emptying by gravity. The mainstay of long-term treatment centers round pneumatic dilation and surgical myotomy, but endoscopic injection of botulinum toxin into the LES and even some oral medications are occasionally recommended.

Figure 26 Classic manometric tracing of achalasia patient showing isobaric waves in response to a swallow, and positive intraesophageal body pressure.

medwedi.ru

320

Part Two: The Alimentary Tract—Esophagus and Stomach

Smooth muscle relaxants including sublingual isosorbide dinitrate or calcium channel blockers can be taken prophylactically before meals, or as necessary for pain or dysphagia. These drugs provide variable relief of symptoms, and their effectiveness tends to decrease with time and their side effects such as headache and hypotension are intolerable. Botulinum toxin inhibits the calciumdependent release of acetylcholine from nerve terminals, thus countering the effect of the selective loss of inhibitory neurotransmitters. When injected directly into the LES at endoscopy, it is initially effective in relieving symptoms in about 85% of patients. The treatment is conceptually very attractive because the risk of perforation is very low, but symptoms recur in most patients within six months, possibly because of regeneration of the affected receptors. In addition, it is possible that myotomy may be more difficult after injection because of submucosal scar. Older patients and those with vigorous achalasia are more likely to have a sustained response (81). Because of its short duration of action, botulinum toxin injection has largely been abandoned except in high-risk patients. Thus, the two major treatments for achalasia remain pneumatic dilation and surgical myotomy. Pneumatic dilation involves placing a balloon over a guide wire so as to straddle the LES, which is then inflated to a pressure adequate to tear the muscle fibers of the sphincter. It is best performed in the fluoroscopy suite and the inflation is continued until the ‘‘waist’’ in the balloon is eliminated. The most commonly used dilators are the Rigiflex polyethylene balloons (Microvasive, Boston, Massachusetts, U.S.A.), which come in three diameter sizes ranging from 3 to 4 cm. The procedure can be done on an outpatient basis and has minimal recovery time. The attractions of convenience have to be balanced against the risk of perforation (up to 2% in modern series) and a response rate that is somewhat poorer than that of surgical treatment, especially in younger patients (82). Approximately 30% of patients will require subsequent dilations. Surgical myotomy was traditionally performed by either an open abdominal or thoracic approach. The development of thoracoscopic myotomy was a steppingstone to laparoscopic myotomy, which is currently the most commonly performed operation for achalasia (83). The approach to the operation is similar to a laparoscopic Nissen, except that circumferential mobilization of the esophagus is not necessary. The anterior aspect of the esophagus is dissected free from the left crus, and then the muscle fibers of the LES are divided proximally 4 to 5 cm until the esophageal body is clearly reached. The myotomy is carried 1 to 2 cm onto the stomach. A partial fundoplication is performed to prevent reflux. The Dor approach is currently preferred over a posterior wrap (Toupet) because it avoids the need to perform circumferential mobilization of the esophagus. It is not known why a Dor fundoplication appears to be superior for reflux protection in achalasia, but the posterior fundoplication is better for primary reflux disease (84). It is most likely because the underlying pathophysiology of postmyotomy reflux in achalasia is different from that of conventional GERD, which tends to be associated with hiatal hernia and some degree of esophageal shortening. Some surgeons have suggested that a partial wrap is unnecessary; however, this approach risks performing an inadequate myotomy through fear of causing reflux (85). The laparoscopic Heller myotomy with a Dor wrap can thus be considered the gold standard for surgical treatment of achalasia. Good to excellent results are reported in 80% to 100% of patients. The main

complication is uncontrolled gastroesophageal reflux, which occurs in about 10% of patients (86). Regardless of the mode of treatment, patients usually dramatically improve symptomatically in the first few months. If symptoms alone are used as an end point, both myotomy and dilation appear to yield excellent results in 70% to 90% of patients. Objective studies are hard to obtain, especially if they involve passing tubes. One simple semiquantitative study is the use of a timed barium swallow, in which the height of the barium column is measured one minute and five minutes after swallowing a defined amount of barium, to quantify esophageal emptying (87). Advanced and Recurrent Disease In end-stage achalasia, patients may not be able to empty the esophagus even after myotomy. A very dilated esophagus eventually develops a sigmoid deformity because it is fixed at either end. When this occurs, there is a dependent loop of esophagus, which resembles a drain beneath a kitchen sink. There are recent reports of cases where laparoscopic myotomy was performed in such patients with a good outcome (88). Most experienced surgeons have found that myotomy is unlikely to be successful for such patients and recommend esophagectomy. Transhiatal esophagectomy may be hazardous in this group of patients because blood vessels supplying the enlarged esophagus are likely to be dilated, and transthoracic esophagectomy may be safer. The etiology of failed myotomy depends somewhat on the time course in which the patient becomes symptomatic. Early failure (within one year after operation) is more likely to be the result of an error in technique, and repeat myotomy is more likely to be helpful. Dysphagia that occurs more than one year after surgery is most likely due to reflux stricture. Often, the only treatment that can be offered to the patient at this point is esophagectomy. Patients with morbid obesity may develop achalasia, although this is rare. Presentation is usually atypical in that regurgitation and respiratory symptoms are often more predominant than dysphagia. Care should be taken not to perform a bariatric procedure that may exacerbate resistance at the LES, such as laparoscopic banding or gastric bypass with Roux-en-Y. We have successfully combined Heller myotomy with biliopancreatic diversion/duodenal switch for several of these patients (89).

Other Motility Disorders Diffuse esophageal spasm presents most commonly with recurrent chest pain and dysphagia. The chest pain is not exertional, but can be confused with cardiac angina in that it may respond to nitroglycerin. Dysphagia is nonprogressive, associated with both liquids and solids, and can be precipitated by stress, liquids of extreme temperatures, or rapid eating. The cause is unknown. Patients have been shown to be hypersensitive to cholinergic and pentagastrin stimulation; it has also been suggested that gastroesophageal reflux and stressful events can produce spasm (90). Enhanced sensitivity may be mediated by a defect in neural inhibition related to decreased availability of nitric oxide. However, unlike achalasia, there are no specific histologic features in the myenteric plexus in patients with diffuse esophageal spasm (91). Radiographic studies may be normal in patients with diffuse esophageal spasm, or may show tertiary contractions with segmentation of the esophagus, known as ‘‘corkscrew esophagus.’’ Ambulatory 24-hour pH monitoring may show associated GERD in 20% to 50% of patients (92). Diffuse

Chapter 14:

Physiologic Dysfunction of the Esophagus

321

Figure 27 Typical manometric tracing of a patient with diffuse esophageal spasm.

esophageal spasm is defined manometrically by the presence of simultaneous contractions in 20% or more wet swallows, with an amplitude exceeding 30 mmHg (Fig. 27). However, this definition is somewhat arbitrary and is often debated. Other manometric findings found less consistently include long-duration contractions, repetitive waves, spontaneous non–swallow-induced contractions, and abnormalities of LES pressure or relaxation (93,94). Diffuse esophageal spasm is a benign disease in that it rarely causes nutritional problems and does not lead to lifethreatening complications. For this reason, symptom control is the major goal of treatment. Some patients may respond to reassurance that symptoms have an esophageal origin and are not cardiac in nature. Gastroesophageal reflux should be treated. Long-acting nitrates, calcium channel blockers, anticholinergics, and Sildenafil have all been used to treat this condition; although they can decrease high-amplitude contractions, they do not consistently relieve chest pain (95–98). Antidepressant medications can improve symptoms, although they do not affect esophageal motility (99). Pneumatic dilation and botulinum toxin have also been used to treat patients with complaints of severe dysphagia, as has long surgical myotomy (100–102). Surgery is more effective in relieving dysphagia than chest pain (103). Nutcracker esophagus is a hypercontractile disorder in which esophageal contraction amplitude in the distal esophagus exceeds two standard deviations above the mean of normal individuals (generally > 180 mmHg). Peristalsis is normally transmitted. If the resting pressure of the LES is above the normal range, hypertensive LES is present. These two abnormalities often coexist, suggesting that they may represent a spectrum of hypercontractile esophagus. Radiography and endoscopy are usually normal. Patients with coexisting GER may be identified on 24-hour pH testing. Unlike achalasia, the neural basis for the abnormality is not known. The relationship between symptoms and manometric abnormalities is unclear. Chest pain is not predictably relieved after reduction of contraction amplitude by either

medications or myotomy; therefore, treatment results are unpredictable. However there are encouraging reports of the use of Sildenafil. The one feature that appears to carry unequivocal benefit is treatment of associated GER. ‘‘Hypocontractile esophagus,’’ or ineffective esophageal motility, is a term recently coined to describe patients with either low-amplitude (< 30 mmHg) peristaltic or simultaneous contractions in the distal esophagus or failed peristalsis in which the wave does not propagate throughout the length of the esophagus. It is the one subcategory of NEMDs of clinical significance. Many patients with ineffective esophageal motility have GER, often associated with respiratory or ear, nose, and throat complaints (104,105). Similar motility abnormalities may also be found in patients with scleroderma, which causes vascular obliteration and secondary fibrosis, leading to damage of esophageal smooth muscle and its innervation (106). Other connective tissue diseases that can less frequently cause ineffective esophageal motility are mixed connective tissue disease, rheumatoid arthritis, and systemic lupus. No drug is currently available, which reliably increases peristaltic amplitude. Treatment of ineffective esophageal motility is therefore limited to control of associated GER.

ESOPHAGEAL EMERGENCIES Four common emergencies affecting the esophagus may present to the surgeon: hemorrhage, perforation, caustic ingestion, and food or foreign body impaction. Common to all is the need for skillful endoscopic assessment, the potential to cause or exacerbate injury by injudicious manipulation, and the ever present need to protect the airway. Variceal hemorrhage is discussed in Chapter 20. Nonvariceal hemorrhage may originate from diffuse mucosal inflammation, most commonly severe reflux esophagitis. Peptic ulcers of the esophagus, now a rarity but formerly a common complication of Barrett’s esophagus, tend to be deep and penetrate into major vessels feeding the distal

medwedi.ru

322

Part Two: The Alimentary Tract—Esophagus and Stomach

esophagus. A rare cause of massive esophageal bleeding is aortoesophageal fistula, which is caused by a thoracic aortic aneurysm eroding into the esophagus. If the underlying condition is known, passing a Sengstaken–Blakemore tube to produce tamponade while the patient is prepared for the OR has been found to be successful by a few isolated reports. Focal bleeding from primary esophageal lesions responds to local endoscopic measures, and diffuse bleeding is best managed medically by aggressively suppressing acid. Caustic ingestion is now rare in the United States as the hazards of ingested cleaning agents have become more widely known. Accidental ingestion still occasionally occurs in children. Most cases are suicidal in their intent and are characterized by severe corrosive injury to the mouth, pharynx, airway, and esophagus. Strong alkali is more damaging than strong acid, because the acid causes coagulative necrosis, which limits further damage. Alkali produces liquefactive necrosis allowing deeper penetration. Total necrosis of the stomach and even adjacent organs such as the trachea and the transverse colon may occur. The priorities are to protect the airway, to replace fluid losses and maintain the circulation, and to provide adequate broad-spectrum antibiotic coverage because of the wide range of organisms found within the esophagus. Attempts to induce emesis are harmful because the caustic agent does further damage in the process of vomiting. After resuscitation, the extent of the injury is assessed. Traditional teaching used to advocate endoscopy only as far as the major lesion, because of fears of exacerbating the injury, but this advice stemmed from the era of rigid endoscopy, and the modern narrow-caliber flexible endoscopy may be safely used if handled with skill and gentleness. It is important to avoid excessive air insufflation, not to advance where the lumen cannot be seen, and to avoid tight curvatures of the scope tip. There is value in assessing the extent of damage to the stomach and pylorus, because it may be necessary in future even to perform a PEG or to use the stomach as an esophageal substitute, and if it is necrotic, it may need to be excised (107). Exploration is likely to be necessary if the patient is very toxic and shocked despite resuscitation. A blunt esophagectomy may be performed by exposing the esophagus in the abdomen and then exposing the cervical esophagus, and stripping using the varicose vein stripper. The proximal end is brought out as a cervical esophagostomy. If the stomach is healthy it is retained and a gastrostomy is created. Subsequent reconstruction is best delayed for several months because the scarring process continues for months and tends to proceed proximally. If an anastomosis is created, it may subsequently develop a very dense stricture. The most difficult lesions to reconstruct are those involving the pharynx and pyriform sinuses. A colopharyngeal anastomosis may function well if one pyriform sinus is preserved, but if both are fibrosed, it almost invariably leads to intolerable aspiration (108). In this situation it is likely that the patient will have to choose between being able to speak but not eat, or eat but not speak. Adequate and safe alimentation can be restored only by a pharyngolaryngectomy with an end tracheostomy. For milder degrees of injury, resection will not be required, but strictures are likely to develop. Systemic steroids have been found to be of no value in preventing or limiting the extent of a stricture (109). Esophageal perforations are of two types, spontaneous (Boerhaave’s syndrome) and endoscopic. The latter are more common, but generally less severe because the examination is done when the stomach is empty and it may be detected very shortly afterwards. In either case,

the typical symptom is severe chest pain and there may be circulatory collapse and subcutaneous emphysema in the neck. Extraesophageal air may be seen on chest X-ray (Fig. 28). Once the diagnosis of perforation is made, it is generally advisable to get a gastrografin swallow to establish its location, because this will determine the surgical approach. Perforations close to the cardia can be managed via the abdomen, but most will require a thoracotomy. A small subset of perforations may be managed nonoperatively by keeping the patient nil per os, providing adequate hydration, antibiotics, and nutrition for five to seven days. Cases suitable for this approach have perforations that are small, not associated with systemic sepsis, and where the swallowed contrast is seen to drain back into the esophagus and not lie in an undrained mediastinal cavity (110). All others should be repaired, and the key factor in determining the outcome is the delay between the event and the repair. If delayed more than 24 hours, the tissues may be so edematous and distorted that repair is very likely to break down, and such a case may do better by diverting the esophagus in the neck. There is increasing recognition that the mucosa remains strong even if the surrounding muscle is flimsy and degenerate. It may even be necessary to extend the apparent length of the perforation to ensure that the apex of the mucosal rent is identified and sutured accurately. If such a repair is attempted, the suture line should be buttressed with a flap of pleura or better still, intercostal muscle. Food impaction occurs in the presence of esophageal strictures and presents with total inability to swallow anything. Well-meaning bystanders often attempt to give the patient more to drink, exacerbating the distress and risking aspiration. The patient will tend to regurgitate saliva. This is a true emergency and is best managed by immediate endoscopy. The use of meat tenderizers is not recommended, because they are as likely to digest the esophagus as the impacted food (111). Usually it is a piece of meat, and it can be removed with rat-tooth forceps or sometimes pushed into the stomach with gentleness.

Figure 28 Chest X-ray showing subcutaneous emphysema in a patient with esophageal perforation. The arrow points to periesophageal air above the left clavicle and this is sometimes the earliest sign of perforation on plain X-ray.

Chapter 14:

Physiologic Dysfunction of the Esophagus

323

Irregular foreign bodies swallowed by children and psychiatrically disturbed or edentulous adults are more hazardous, and sometimes damage is inflicted by maladroit attempts at removal. The range of objects is very large, and includes batteries, dentures, and sharp objects such as pins, nails, and broken glass. Many of these can be removed by the use of an overtube or a rigid endoscope. The object is pulled back into the scope and the whole assembly then removed.

significant risk factor is Barrett’s esophagus (113,114). The incidence in Western countries is about 4 per 100,000 in the United States and 8 per 100,000 in the United Kingdom. In patients known to have Barrett’s, the risk has been estimated at about 0.5% patient per year, as discussed in the previous section on Barrett’s esophagus. There is strong evidence that the increase is real and not due to greater detection rates or reclassification of tumors of the upper stomach and cardia, as these are also increasing (115).

ESOPHAGEAL TUMORS Leiomyoma

Presentation

The only benign tumor of any significance is the esophageal leiomyoma. It is often discovered incidentally when a barium study or endoscopy is carried out for some other symptom. Occasionally, vague chest pain or dysphagia for solids may be reported. The characteristic appearance is a nonobstructing, smooth indentation covered by normal mucosa. Biopsy is useless; it rarely gets deeper than the mucosa, and if it does, it will render the excision more difficult because there will be an area of adherence to the mucosa, which may lead to a perforation when the lesion is removed surgically. Fine-needle aspiration may be performed, and the tissue characterized by special stains. Typical leiomyomas are positive for desmin and smooth muscle actin, and negative for CD34 and CD117. Unlike similar stromal tumors more distally in the GI tract, which are frequently positive for CD117, esophageal leiomyomas have a low propensity to recur and are adequately treated by being enucleated (112). It may be done by thoracotomy or thoracoscopy, but in either case taking care not to injure the vagal nerves as the esophagus is mobilized. Tumors less than 8 cm can be safely enucleated in this way, and the muscle wall is generally reapproximated to prevent subsequent diverticulum formation. The functional results are excellent and recurrence is extremely rare.

Esophageal cancer is a disease affecting patients of advancing age, with dysphagia and weight loss being by far the most common symptoms at the time of diagnosis. In a few patients dysphagia does not occur, and symptoms arise from invasion of the primary tumor into adjacent structures or from metastases. Unfortunately, when dysphagia does occur, it is usually late in the natural history of the disease. As a result, the dysphagia becomes severe enough to motivate the patient to seek medical advice only when a large proportion of the esophageal circumference is infiltrated with cancer. Increasingly, however, the diagnosis is being made on endoscopy as part of a surveillance program of patients known to have Barrett’s esophagus, in which case the tumors are usually detected at an early stage. Clinically, the diagnosis can be suspected on barium esophagogram, in which an ulcerating, irregular lesion is usually seen (Fig. 29). Endoscopy will show a friable mass, and biopsies are easily obtained. Difficulties can occur with esophageal strictures, where biopsies are hard to obtain, and in presumed achalasia, where a small infiltrating tumor of

Cancer of the Esophagus Esophageal carcinomas are of two types, squamous carcinoma and adenocarcinoma, which although differing profoundly in epidemiology, etiologic factors, relative incidence, and response to radiation therapy, present a similar clinical picture and are treated similarly from the surgeon’s point of view. The surgeon’s options depend more on the location and stage of the tumor than the histologic type. Squamous carcinoma accounts for most of esophageal carcinomas worldwide, but in the West it has been overtaken by adenocarcinoma as the leading type of esophageal cancer. Its incidence is highly variable, ranging from around 2 per 100,000 in the United States to 160 per 100,000 in highrisk areas of South Africa and the Hunan province of China. The environmental factors responsible for these sharply localized high incidences have not been conclusively identified, although both additives from local foodstuffs (nitroso compounds in pickled vegetables and smoked meats) and deficiencies (zinc and molybdenum) have been suggested. In the United States, smoking and alcohol consumption are strongly linked with squamous carcinoma and it most commonly occurs in African-Americans. Other definite associations link squamous carcinoma with long-standing achalasia, lye strictures, tylosis (an autosomal dominant disorder characterized by hyperkeratosis of the palms), and human papilloma virus. Adenocarcinoma of the esophagus is now the fastest increasing cancer in the Western world, and the only

medwedi.ru

Figure 29 Barium esophagogram in a patient with a large esophageal carcinoma demonstrating the ‘‘apple core’’ appearance.

324

Part Two: The Alimentary Tract—Esophagus and Stomach

the cardia may produce manometric and radiologic features indistinguishable from those of achalasia. The tumor may only be seen when the scope is retroflexed and the cardia is viewed from below.

Staging Esophageal cancer is classified according to the 2002 American Joint Committee on Cancer tumor-node-metastasis (TNM) classification system, which depends on the depth of penetration of the primary tumor and the presence of lymph node or distant metastases. In practice, the T-stage is commonly classified as either intramucosal, intramural, or transmural (Fig. 30). Of patients presenting with dysphagia, up to 50% have unresectable or metastatic disease at the time of presentation. Some idea of advanced spread can be obtained from clinical examination and features of the esophagogram or on endoscopy (tumors > 8 cm in length). Staging requires other imaging techniques to assess lesser degrees of spread. CT scanning is widely used but is not accurate in staging small tumors. Magnetic resonance imaging (MRI) has not been shown to have any advantage over CT scanning in this regard. Patients with smaller tumors may benefit from further evaluation with endoscopic ultrasonography (Fig. 31). This technique is able to predict the depth of tumor invasion in 80% to 90% of patients and the extent of lymph node involvement by metastatic disease in 70% to 80% of patients (116). Lymph nodes can also be sampled using ultrasonographically guided fine-needle aspiration. Positron-emission tomography with fluorodeoxyglucose F18 can also be used to identify disease that has spread to regional lymph nodes. The increasing detection of earlier tumors has concentrated attention on the early spread of esophageal cancer. Tumors confined to the mucosa (T1) have a very low incidence of positive lymph nodes, and any involved nodes tend to be close to the tumor. In contrast, once the tumor extends into the submucosa, the incidence of involved lymph nodes increases to 50% (117). The rich submucosal plexus of esophageal lymphatics presents little barrier to the spread of tumor (Fig. 32).

Figure 30 Schematic representation of depth of penetration of tumors.

Figure 31 Appearance of an early esophageal carcinoma on endoscopic ultrasonography. The normal layers of the esophagus are clearly visible.

New proposals for staging have emerged because of the increasing prevalence of adenocarcinoma in the region of the cardia. It may be hard to determine if a tumor that straddles the GEJ originated in the distal esophagus or the proximal stomach. The current TNM staging system presents difficulty in interpreting lymph node metastases in cancers straddling the GEJ. If they are viewed as esophageal cancers, then positive nodes at the celiac axis would be viewed as distant metastatic disease. It is more logical to view the nodal status of these patients based on the numbers of lymph nodes involved rather than their location (118). Siewert et al. have proposed the following classification: Type I carcinomas arise from the distal esophagus, usually in a segment of Barrett’s epithelium, and may infiltrate the GEJ from above, type II carcinomas appear to arise from

Figure 32 Lymphatic drainage of the esophagus.

Chapter 14:

the true junction of the esophagus and stomach, and type III carcinomas are subcardial gastric cancers that infiltrate the GEJ from below. Based on this classification, they propose that type II cancers should be treated with total gastrectomy and transhiatal resection of the distal esophagus (119). The goal of treatment in esophageal carcinoma may be either curative or palliative. The factors that govern whether a curative or palliative operation should be done are based on the location of the tumor, the age and fitness of the patient, and the stage of the disease.

Principles of Curative Surgery In esophageal cancer where the tumor can be completely removed, leaving no residual disease (R0 resection), the patient has the potential for long-term cure. The ability to perform R0 resection depends on the stage of the tumor and the physiologic fitness of the patient. By combining the endoscopic, histologic, and CT scan characteristics of the lesions, tumors may be classified as follows: High-Grade Dysplasia in Barrett’s Esophagus Convention wisdom has recommended subtotal esophagectomy for high-grade dysplasia, provided the diagnosis is confirmed by a knowledgeable pathologist. Even with careful preoperative endoscopy, on average, 40% of such excised specimens will have small intramucosal tumors detected (120). However, there is some evidence that patients can coexist with high-grade dysplasia for a considerable time, often many years. This allows for several endoscopies at three-month intervals to solidify the diagnosis, especially in elderly patients in whom conventional esophagectomy carries a high risk. If small intramuscoal tumors are detected on biopsy of Barrett’s with high-grade dysplasia, the risk of lymph node spread will determine whether or not en bloc esophagectomy is necessary. The most critical factor is the visual appearance of the mucosa. If there is no visible focal lesion on endoscopy, the chance of involved lymph nodes is very small, and a limited esophagectomy may be safely

Physiologic Dysfunction of the Esophagus

325

recommended. In this situation we perform vagal-sparing esophagectomy. Technique of Vagal-Sparing Esophagectomy (121) Through an upper midline abdominal incision, the right and left vagal nerves are identified and isolated. A limited, highly selective proximal gastric vagotomy is performed along the upper 4 cm of the lesser curve. The stomach is divided just below the GEJ. A left neck incision is then made and the esophagus is divided at the level of the thoracic inlet. The proximal staple line of the gastric division is then opened and a vein stripper passed up the esophagus into the neck wound and secured. The stripper is then pulled back into the abdomen, inverting the esophagus as it transverses the posterior mediastinum. This strips the branches of the esophageal plexus off the longitudinal muscle of the esophagus, preserving the esophageal plexus along with the proximal vagal nerves and the distal vagal trunks. The transverse colon is then used to reestablish intestinal continuity. This operation has been shown to preserve vagal function and prevent postoperative dumping and diarrhea, as well as result in improved meal capacity. In contrast to the situation where there is no visible lesion on endoscopy, the presence of a visible ulcer or tumor makes it likely that lymph node spread has already occurred, and en bloc esophagectomy is recommended. En bloc resection implies removal of a tissue block surrounded on all sides by normal tissue and requires a subtotal esophagectomy and a two-thirds gastrectomy in continuity with a block of tissue containing the following nodal groups: subcarinal, inferior paraesophageal, left gastric, celiac, hepatic, and splenic artery nodes. The dissection is limited anteriorly by the pericardium, laterally by the left and right mediastinal pleura, and posteriorly by the intercostal arteries, aorta, and anterior vertebral ligaments. The proximal margin is the carina, the inferior margin is the celiac axis and common hepatic artery, and the lateral margins are the mediastinal pleura and a collar of diaphragmatic muscle around the esophageal hiatus (Fig. 33). The resection

Figure 33 Extent of resection in en bloc esophagectomy. (A) Thoracic resection, (B) abdominal resection.

medwedi.ru

326

Part Two: The Alimentary Tract—Esophagus and Stomach

is done through three incisions in the following order. First, exploration of the abdomen is performed through an upper midline incision and the porta hepatic and subpancreatic nodes are examined by biopsy. If no metastases are identified, the incision is closed, and an en bloc dissection of the esophagus through a right posterolateral thoracotomy is performed with mobilization of the esophagus above the aortic arch. The thoracotomy is closed, the patient repositioned in the supine position, and the upper midline abdominal incision reopened to permit en bloc dissection of the stomach and associated lymph nodes. The spleen and the splenic artery with its associated lymph nodes are removed by dissecting them off the superior border of the pancreas. A left neck incision is made to allow proximal division of the esophagus. The mobilized esophagus is removed transhiatally, and the stomach is divided at the incisura angularis. GI continuity is reestablished with a left colon interposition. In our experience, operative mortality of an en bloc esophagectomy is 6% and five-year survival is 52% (Fig. 34) (122). More advanced tumors presenting with dysphagia are less likely to be resectable for cure. In adenocarcinoma of the distal esophagus, the most common kind in current Western practice, it is simplest to perform transhiatal esophagectomy and make a conduit out of the stomach, preserving the right gastric and right gastroepiploic arteries. The excision is performed by mobilizing the distal esophagus, taking a rim of diaphragm and mediastinal tissue, and bluntly by using the fingers of the surgeon’s right hand to detach the esophagus from its surroundings. Usually some tough branches of the vagus nerve to the esophagus must be sharply divided. The esophagus is mobilized in the neck, and the operator makes contact with the operator from below to free the esophagus from the pleura laterally and the trachea and left main bronchus anteriorly. This approach is more dangerous in tumors of the middle or upper thoracic esophagus, because of the risk of injury to the tracheobronchial tree. For this reason, we prefer to perform right thoracotomy to establish a safe excision in more proximal tumors. In tumors of the cervical esophagus, the thoracic esophagus is removed by blunt dissection through a cervical

and upper abdominal incision. A simultaneous en bloc bilateral neck dissection is performed, sparing the jugular veins on both sides. A total laryngectomy in combination with esophagectorny is usually necessary. The stomach is pulled up through the esophageal bed, and a permanent tracheostomy stoma is constructed. More limited tumors may be excised without sacrificing the larynx, and continuity established using a forearm skin flap based on the radial artery. It is constructed into a tube and sutured between the pharynx and the esophagus at the root of the neck, and the artery and vein of the skin flap anastomosed to the external carotid artery and internal jugular vein, respectively. Choice and Technique of Esophageal Reconstruction After excising the cancer, continuity is generally restored either by using the stomach or the left colon as a conduit. The so-called gastric pull-up is created by dividing the omentum from the greater curve of the stomach, preserving the right gastroepiploic artery. Care is taken as the fundus is detached from the spleen to preserve as much tissue as possible. On the lesser curve side, the right gastric artery is preserved, and the left gastric artery divided at its junction with the celiac, taking all the lymph node tissue with the specimen. A wedge of stomach on the lesser curve is excised with the specimen. A pyloroplasty is generally performed to guard against aspiration of the contents of a nonemptying gastric tube. The mobilized gastric tube is sutured to a large funnel-shaped esophageal prosthesis such as a Mousseau-Barbin tube or even a very large chest tube, which is then passed up the posterior mediastinum to emerge in the neck incision, where an anastomosis is easily made with a single layer of interrupted monofilament sutures with the knots on the inside. The left colon is also a satisfactory esophageal substitute (123). It is created by mobilizing the colon completely and dividing the middle colic artery close to its origin from the superior mesenteric, preserving the Y-shaped branching pattern, which maintains the marginal artery. This works well because the marginal artery closely follows the line of the colon, allowing it to be straightened out. The proximal end of the graft is sutured to the cervical esophagus and the colon divided without transecting the mesocolon, to preserve blood supply. The distal end of the transposed segment is anastomosed to the stomach, either end to end to the antrum if the proximal stomach is excised, or to the posterior aspect of the fundus if the vagi have been preserved. If the reconstruction is done as a delayed procedure, for example, after perforation or caustic injury, the posterior mediastinal route is not accessible, and a substernal tunnel can be created. It is usually necessary to excise the distal left clavicle and the left side of the manubrium to create more room and avoid constriction and angulation of the conduit.

Adjuvant Therapy

Figure 34 Survival after en bloc EBE vs. THE for cancer. Abbreviations: EBE, esophagectomy; THE, transhiatal esophagectomy.

Because of the overall poor prognosis of patients with esophageal cancer, there has been much interest in multimodal therapy involving different combinations of surgery, radiation, and chemotherapy. Preoperative chemotherapy or radiation therapy in isolation has been found to confer no benefit. Currently neoadjuvant therapy—chemotherapy or radiation given before resection—has shown the most promise, with several phase II trials suggesting improved locoregional control and survival (124,125). However, phase III trials have not conclusively demonstrated improved

Chapter 14:

survival, although they do suggest benefit for complete pathologic responders (126). The so-called multimodal therapy, involving preoperative chemotherapy and radiation therapy in doses up to 4000 Gray, has been shown in only one trial to have some survival benefit (127). On the basis of this single trial, multimodal therapy has been touted as being the standard of care. However the benefits were slight, the surgical excisions performed were not oncologically sound, and the graphical representation of the survival curves did not correspond to those reported in the text. Another recent trial of preoperative chemotherapy reported a median survival benefit of 512 days in the chemotherapy group compared to 405 days after surgery alone. All other trials of neoadjuvant therapy reported to date do not show an overall survival benefit. It is common to point out that some patients apparently respond to preoperative therapy so well that no viable tumor is found in the excised specimen. These patients have a greatly improved survival (80% at five years) compared with those having only a partial response or no response at all. At present there is no reliable method to predict response to chemotherapy, but analysis of the expression of genes relevant to the mode of action of chemotherapy may be helpful. Patients demonstrating lower levels of thymidylate synthase respond better to chemotherapeutic agents such as 5-Fluorouracil (128). Consequently, analysis of gene expression may permit the response to chemotherapeutic agents to be identified, and will allow the chemotherapy regimen to be tailored to the patient’s tumor.

Management of the Patient after Esophagectomy Esophagectomy is a major undertaking, whether for benign or malignant disease, and should ideally be carried out in specialist centers. There is good evidence that the results of esophagectomy are related to the caseload. In centers performing five or fewer esophagectomies per year, the mortality is steeply increased (129,130). The reasons for the improved outcome in high-volume centers are complex and are not just due to better standardized surgical technique: anesthesia, postoperative intensive care, and nursing and respiratory care all need to be optimized to obtain the best results. Early recognition and definitive management of complications, when they do occur, is better in experienced centers. The major complications that follow esophagectomy are leakage of the anastomosis, ischemia of the transposed stomach or colon, and aspiration pneumonia. The manifestations of these complications may be subtle, and include not only tachycardia, fever, leukocytosis, hypoxia, and metabolic acidosis, but also mild elevations of glucose, BUN, and creatinine, thrombocytopenia, and the new onset of atrial fibrillation. In the intensive care unit, it is vital to have good central venous access and a working nasogastric tube and to nurse the patient with the head of the bed elevated 30 . This is one of the few remaining areas in surgery where the nasogastric tube is vital, and until the conduit drains adequately the patient is at risk of aspiration from a stagnant stomach or colon interposition. The development of any these nonspecific signs of sepsis should prompt a proactive search for a source, and it is especially valuable to be able to endoscope the patient in the early postoperative period to check the integrity of the anastomosis and the health of the conduit. Frankly necrotic mucosa is occasionally seen, but relative ischemia is characterized by the presence of an exudate that does not wash off. After the early perioperative period has passed, patients still remain at risk for aspiration pneumonia. The

Physiologic Dysfunction of the Esophagus

327

relative merits of the stomach compared with the colon as the ideal esophageal substitute have been debated for years. Most surgeons perform gastric pull-up because it is quicker, is simpler, and requires only one anastomosis rather than three, and recovery is probably quicker. With prolonged survival, however, the disadvantages of the gastric pull-up emerge, including proximal esophagitis of the squamouslined remnant of the upper esophagus and even the development of Barrett’s esophagus. The function of the colon interposition seems to improve with time, and hence it is more suitable for the treatment of benign disease. Many of the abdominal symptoms following esophagectomy may actually be caused by the effect of vagotomy on the intestinal tract, and hence the operation of vagal-sparing esophagectomy is clearly superior from the functional point of view.

Palliative Therapy If the patient’s condition is considered incurable on preoperative or intraoperative evaluation, the severity of dysphagia or other incapacitating symptoms are assessed. Dysphagia for even semisolids is an indication for palliative resection. It is well documented that a transhiatal esophageal resection and reconstruction with esophagogastrostomy offers the best palliation, provided that the patient is physiologically fit. It allows the patient to eat without dysphagia and prevents the local complications of perforation, hemorrhage, fistula formation, and incapacitating pain. Tumors may be unresectable because of distant metastases or because of direct invasion of the aorta, spine, or heart in distal tumors, and in squamous tumors of the mid-esophagus, the trachea and bronchi are frequently invaded. Further, the patient’s general condition may be too poor to justify an extensive surgical procedure. In this situation, relief of dysphagia requires reestablishing a conduit through which food may pass. Most malignant strictures can be intubated using the flexible endoscope under sedation. Self-expanding metal stents are now available for this purpose, and have a lower complication rate than polyvinyl tubes. However, esophageal perforation, reflux of gastric contents, obstruction of the tube by tumor or food, and stent migration can still occur. The median survival after insertion of an esophageal tube for carcinoma is two to four months, but the benefit to the patient is well worth the risk, particularly in those who are unable to swallow even saliva. Other methods of establishing a lumen in unresectable esophageal cancers are laser ablation or electrocoagulation. The former carries few complications but requires frequent repetition to maintain patency, while the latter is useful only in circumferential tumors and requires fluoroscopy to position the heating electrode.

Chemoprevention of Esophageal Cancer Adenocarcinoma could theoretically be prevented if all reflux were stopped before the development of Barrett’s esophagus. Because there is no way to accomplish this, attention has focused on other steps within the sequence from metaplasia to neoplasia. This is the rationale for the use of cyclooxygenase-2 (COX-2) inhibitors in the chemoprevention of cancer. The COX-2 enzyme, which is induced at sites of inflammation, is involved in arachidonic acid metabolism. Because arachidonic acid is a potent inducer of apoptosis, COX-2 inhibitors promote apoptosis. Regular use of aspirin has been found to reduce the incidence of colon cancer, and there are strong grounds for expecting that esophageal cancer may be similarly reduced by NSAID use. However, withdrawal of selective COX-2 inhibitors such as rofecoxib and

medwedi.ru

328

Part Two: The Alimentary Tract—Esophagus and Stomach

celecoxib has recently tempered enthusiasm for this approach. The value of regular aspirin in preventing the transformation of Barrett’s esophagus to esophageal cancer is being investigated in a large-scale trial based in the United Kingdom.

SUMMARY While often thought of as a tube to transport food from the mouth to the stomach, the esophagus is a dynamic organ whose presence becomes most noticed when it is affected by one of three disorders: a motility disease, gastroesophageal reflux, or neoplasia. Of these, reflux is by far the most common and afflicts millions of patients each year. While symptoms may vary from patient to patient, the hallmark associated with reflux is ‘‘heart-burn,’’ secondary to the mucosal irritant effects elicited by the refluxing gastroduodenal secretions. Fortunately, a variety of treatment options are available to manage this disorder. For most patients, effective management can be induced initially with acid suppression utilizing a proton pump inhibitor. For patients refractory to this therapy or whose symptomatology overrides what was initially efficacious, surgical intervention with Nissen fundoplication has proved to be a durable alternative. The most life-threatening complication of reflux disease is Barrett’s esophagus because of its premalignant potential. When Barrett’s mucosa becomes severely dysplastic, esophagectomy is currently the best treatment option to provide cure for this in situ cancer. Of the motor disturbances affecting the esophagus, Zenker’s diverticulum and achalasia are the most commonly encountered. Depending on size, a surgical myotomy is often all that is needed to manage Zenker’s disease. While dilatation of the obstructed esophagus can provide long-term management for achalasia, the most durable therapeutic option is again surgical myotomy. The most lethal problem affecting the esophagus is carcinoma. Both squamous and adenocarcinoma can occur, with the occurrence of the latter histologic variety being on the increase, possibly due to the reflux of bile and pancreatic juice. The adenocarcinoma most commonly develops in the Barrett’s mucosa, which undergoes severe dysplastic changes. If detected early enough, curability is possible. In contrast, squamous cell carcinoma is for the most part an incurable disease because ‘‘early detection’’ is so uncommonly encountered. In patients with this problem, palliation with attempts to improve swallowing is often the only treatment that can be offered.

REFERENCES 1. Eslick GD, Talley NJ. Non-cardiac chest pain: predictors of health care seeking, the types of health care professional consulted, work absenteeism and interruption of daily activities. Aliment Pharmacol Ther 2004; 20:909–915. 2. Malagelada JR. Review article: supra-oesophageal manifestations of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2004; 19(suppl 1):43–48. 3. D’Urzo A, Jugovic P. Chronic cough. Three most common causes. Can Family Physician 2002; 48:1311–1316. 4. Theodoropoulos DS, Pecoraro DL, Efstratiadis SE. The association of gastroesophageal reflux disease with asthma and chronic cough in the adult. Am J Respir Med 2002; 1:133–146. 5. Corso MJ, Pursnani KG, Mohiuddin MA, et al. Globus sensation is associated with hypertensive upper esophageal

6.

7.

8. 9.

10.

11.

12.

13.

14.

15.

16. 17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

sphincter but not with gastroesophageal reflux. Dig Dis Sci 1998; 43:1513–1517. Hewson EG, Ott DJ, Dalton CB, Chen YM, Wu WC, Richter JE. Manometry and radiology. Complementary studies in the assessment of esophageal motility disorders. Gastroenterology 1990; 98:626–632. Ott DJ, Hodge RG, Pikna LA, Chen MY, Gelfand DW. Modified barium swallow: clinical and radiographic correlation and relation to feeding recommendations. Dysphagia 1996; 11:187–190. Jones WG II, Ginsberg RJ. Esophageal perforation: a continuing challenge. Ann Thorac Surg 1992; 53:534–553. Hill LD, Kozarek RA, Kraemer SJ, et al. The gastroesophageal flap valve: in vitro and in vivo observations. Gastrointest Endosc 1996; 44:541–547. von Rahden BH, Stein HJ, Becker K, Liebermann-Meffert D, Siewert JR. Heterotopic gastric mucosa of the esophagus: literature-review and proposal of a clinicopathologic classification. Am J Gastroenterol 2004; 99:543–551. Schoeman MN, Tippett MD, Akkermans LM, Dent J, Holloway RH. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology 1995; 108:83–91. Zaninotto G, DeMeester TR, Schwizer W, Johansson K-E, Cheng SC. The lower esophageal sphincter in health and disease. Am J Surg 1988; 155:104–111. Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988; 94:73–80. Mason RJ, Bremner CG, DeMeester TR, et al. Pharyngeal swallowing disorders: selection for and outcome after myotomy. Ann Surg 1998; 228:598–608. Streets CG, DeMeester TR. Ambulatory 24-hour esophageal pH monitoring: why, when, and what to do. J Clin Gastroenterol 2003; 37:14–22. Pandolfino JE. Bravo capsule pH monitoring. Am J Gastroenterol 2005; 100:8–10. Dobhan R, Castell DO. Normal and abnormal proximal esophageal acid exposure: results of ambulatory dual-probe pH monitoring. Am J Gastroenterol 1993; 88:25–29. Bechi P, Cianchi F. Technical aspects and clinical indications of 24-hour intragastric bile monitoring. Hepato-Gastroenterology 1999; 46:54–59. Vaezi MF, Richter JE. Duodenogastroesophageal reflux and methods to monitor nonacidic reflux. Am J Med 2001; 111(suppl 8A):160S–168S. Tutuian R, Vela MF, Shay SS, Castell DO. Multichannel intraluminal impedance in esophageal function testing and gastroesophageal reflux monitoring. J Clin Gastroenterol 2003; 37:206–215. Shay S, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004; 99:1037–1043. Balaji NS, Crookes PF, Banki F, Hagen JA, Ardill JE, DeMeester TR. A safe and noninvasive test for vagal integrity revisited. Arch Surg 2002; 137:954–958. DeVault KR, Swain JM, Wentling GK, Floch NR, Achem SR, Hinder RA. Evaluation of vagus nerve function before and after antireflux surgery. J Gastrointest Surg 2004; 8:883–888. Delaney BC. Review article: prevalence and epidemiology of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2004; 20(suppl 8):2–4. Cremonini F, Di Caro S, Delgado-Aros S, et al. Meta-analysis: the relationship between, Helicobacter pylori infection and gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2003; 18:279–289. Mittal RK, McCallum RW. Characteristics of transient lower esophageal sphincter relaxation in humans. Am J Physiol 1987; 252(5 Pt 1):G636–G641. Allison PR. Reflux esophagitis, sliding hiatal hernia, and the anatomy of repair. Surg Gynecol Obstet 1951; 92:419.

Chapter 14: 28. Cohen S, Harris LD. Does hiatus hernia affect competence of the gastroesophageal sphincter? N Engl J Med 1971; 284(19): 1053–1056. 29. Sloan S, Rademaker AW, Kahrilas PJ. Determinants of gastroesophageal junction incompetence: hiatal hernia, lower esophageal sphincter, or both? Ann Intern Med 1992; 117: 977–982. 30. Patti MG, Goldberg HI, Arcerito M, Bortolasi L, Tong J, Way LW. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. Am J Surg 1996; 171:182–186. 31. Mittal RK, Lange RC, McCallum RW. Identification and mechanism of delayed esophageal clearance in subjects with hiatus hernia. Gastroenterology 1987; 92:130–135. 32. Fletcher J, Wirz A, Young J, Vallance R, McColl KE. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology 2001; 121:775–783. 33. Fletcher J, Wirz A, Henry E, McColl KE. Studies of acid exposure immediately above the gastro-oesophageal squamocolumnar junction: evidence of short segment reflux. Gut 2004; 53:168–173. 34. DeMeester TR, O’Sullivan GC, Bermudez G, Midell AI, Cimchowski GE, O’Drobinak J. Esophageal function in patients with angina like chest pain and normal coronary angiograms. Ann Surg 1982; 196; 488–498. 35. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999; 45: 172–180. 36. Savary M, Miller G. The Oesophagus Handbook and Atlas of Endoscopy. Solothurn, Switzerland: Verlag Glassmann AG, 1978. 37. Ismail-Beigi F, Horton PF, Pope CE II. Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970; 58:163–174. 38. Chandrasoma PT, Der R, Ma Y, Dalton P, Taira M. Histology of the gastroesophageal junction: an autopsy study. Am J Surg Pathol 2000; 24:402–409. 39. Kilgore SP, Ormsby AH, Gramlich TL, et al. The gastric cardia: fact or fiction? Am J Gastroenterol 2000; 95:921–924. 40. Lundell L, Miettinen P, Myrvold HE, et al. Continued (5-year) follow-up of a randomised clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll Surg 2001; 192:172–179. 41. Spechler SJ, Lee E, Ahnen D, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease. JAMA 2001; 285:2331–2338. 42. Campos GM, Peters JH, DeMeester TR, et al. Multivariate analysis of factors predicting outcome after laparoscopic Nissen fundoplication. J Gastrointest Surg 1999; 3:292–300. 43. Fernando HC, Schauer PR, Rosenblatt M, et al. Quality of life after antireflux surgery compared with nonoperative management for severe gastroesophageal reflux disease. J Am Coll Surg 2002; 194:23–27. 44. Streets CG, DeMeester SR, DeMeester TR, et al. Excellent quality of life after Nissen fundoplication depends on successful elimination of reflux symptoms and not the invasiveness of the surgical approach. Ann Thorac Surg 2002; 74: 1019–1024. 45. Triadafilopoulos G. Stretta: an effective, minimally invasive treatment for gastroesophageal reflux disease. Am J Med 2003; 115(suppl 3A):192S–200S. 46. Bowrey DJ, Peters JH. Current state, techniques, and results of laparoscopic antireflux surgery. Sem Laparosc Surg 1999; 6: 194–212. 47. Soper NJ, Dunnegan D. Anatomic fundoplication failure after laparoscopic antireflux surgery. Ann Surg 1999; 229: 669–676. 48. Targarona EM, Bendahan G, Balague C, Garriga J, Trias M. Mesh in the hiatus: a controversial issue. Arch Surg 2004; 139:1286–1296.

Physiologic Dysfunction of the Esophagus

329

49. Schauer PR, Meyers WC, Eubanks S, Norem RF, Franklin M, Pappas TN. Mechanisms of gastric and esophageal perforations during laparoscopic Nissen fundoplication. Ann Surg 1996; 223:43–52. 50. Watson DI, Jamieson GG, Mitchell PC, Devitt PG, BrittenJones R. Stenosis of the esophageal hiatus following laparoscopic fundoplication. Arch Surg 1995; 130:1014–1016. 51. Yau P, Watson DI, Devitt PG, Game PA, Jamieson GG. Early reoperation following laparoscopic antireflux surgery. Am J Surg 2000; 179:172–176. 52. Zaninotto G, DeMeester TR, Bremner CG, Smyrk TC, Cheng S-C. Esophageal function in patients with reflux-induced strictures and its relevance to surgical treatment. Ann Thorac Surg 1989; 47:362–370. 53. Pezzullo JC, Lewicki AM. Schatzki ring, statistically reexamined. Radiology 2003; 228:609–613. 54. Jamieson JR, Hinder RA, DeMeester TR, Litchfield D, Barlow AP, Bailey RT. Analysis of thirty-two patients with Schatzki’s ring. Am J Surg 1989; 158:563–566. 55. Demeester SR, Peters JH, Demeester TR. Barrett’s esophagus. Curr Prob Surg 2001; 38:558–640. 56. Martinez de Haro L, Ortiz A, Parrilla P, et al. Intestinal metaplasia in patients with columnar lined esophagus is associated with high levels of duodenogastroesophageal reflux. Ann Surg 2001; 233:34–38. 57. Schnell TH, Sontag SJ, Chejifec G. Adenocarcinoma arising in tongues or short segments of Barrett’s esophagus. Dig Dis Sci 1992; 37:137. 58. Jenkins GJ, Doak SH, Parry JM, D’Souza FR, Griffiths AP, Baxter JN. Genetic pathways involved in the progression of Barrett’s metaplasia to adenocarcinoma. Br J Surg 2002; 89:824–837. 59. Parrilla P, Martinez de Haro LF, Ortiz A, et al. Long-term results of a randomized prospective study comparing medical and surgical treatment of Barrett’s esophagus. Ann Surg 2003; 237:291–298. 60. McDonald ML, Trastek VF, Allen MS, Deschamps C, Pairolero PC, Pairolero PC. Barretts’s esophagus: does an antireflux procedure reduce the need for endoscopic surveillance? J Thorac Cardiovasc Surg 1996; 111:1135–1138. 61. Wang KK, Sampliner RE. Mucosal ablation therapy of Barrett esophagus. Mayo Clin Proc 2001; 76:433–437. 62. Sampliner RE and the Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 1998; 93:1028–1032. 63. Provenzale D, Schmitt C, Wong JB. Barrett’s esophagus: a new look at surveillance based on emerging estimates of cancer risk. Am J Gastroenterol 1999; 94:2043–2053. 64. Montgomery E, Bromner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett’s esophagus. Hum Pathol 2001; 32:368–378. 65. Horvath KD, Swanstrom LL, Jobe BA. The short esophagus: pathophysiology, incidence, presentation, and treatment in the era of laparoscopic antireflux surgery. Ann Surg 2000; 232:630–640. 66. Ritter MP, Peters JH, DeMeester TR, et al. Treatment of advanced gastroesophageal reflux disease with Collis gastroplasty and Belsey partial fundoplication. Arch Surg 1998; 133:523–529. 67. Oleynikov D, Eubanks TR, Oelschlager BK, Pellegrini CA. Total fundoplication is the operation of choice for patients with gastroesophageal reflux and defective peristalsis. Surg Endosc 2002; 16:909–913. 68. Patti MG, Robinson T, Galvani C, Gorodner MV, Fisichella PM, Way LW. Total fundoplication is superior to partial fundoplication even when esophageal peristalsis is weak. J Am Coll Surg 2004; 198:863–869. 69. Perez AR, Moncure AC, Rattner DW. Obesity adversely affects the outcome of antireflux operations. Surg Endosc 2001; 15:986–989. 70. Fraser J, Watson DI, O’Boyle CJ, Jamieson GG. Obesity and its effect on outcome of laparoscopic Nissen fundoplication. Dis Esoph 2001; 14:50–53.

medwedi.ru

330

Part Two: The Alimentary Tract—Esophagus and Stomach

71. Tsai P, Peters J, Johnson W, Cohen R, Starnes V. Laparoscopic fundoplication 1 month prior to lung transplantation. Surg Endosc 1996; 10:668–670. 72. Lord RV, Kaminski A, Oberg S, et al. Absence of gastroesophageal reflux disease in a majority of patients taking acid suppression medications after Nissen fundoplication. J Gastrointest Surg 2002; 6:3–9. 73. Papasavas PK, Yeaney WW, Landreneau RJ, et al. Reoperative laparoscopic fundoplication for the treatment of failed fundoplication. J Thorac Cardiovasc Surg 2004; 128:509–516. 74. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004; 351(9):940–941. 75. van Overbeek JJ. Pathogenesis and methods of treatment of Zenker’s diverticulum. Ann Otol Rhinol Laryngol 2003; 112: 583–593. 76. Spechler SJ, Castell DO. Classification of oesophageal motility abnormalities. Gut 2001; 49:145–151. 77. Paterson WG. Etiology and pathogenesis of achalasia. Gastrointest Endosc Clin N Am 2001; 11:249–266, vi. 78. Awad ZT, Selima MA, Filipi CJ. Pseudoachalasia as a late complication of gastric wrap performed for morbid obesity: report of a case. Surg Today 2002; 32:906–909. 79. Stylopoulos N, Bunker CJ, Rattner DW. Development of achalasia secondary to laparoscopic Nissen fundoplication. J Gastrointest Surg 2002; 6:368–376. 80. Wiesner W, Hauser M, Schob O, Weber M, Hauser RS. Pseudo-achalasia following laparoscopically placed adjustable gastric banding. Obes Surg 2001; 11:513–518. 81. Neubrand M, Scheurlen C, Schepke M, Sauerbruch T. Longterm results and prognostic factors in the treatment of achalasia with botulinum toxin. Endoscopy 2002; 34:519–523. 82. Eckardt VF, Gockel I, Bernhard G. Pneumatic dilation for achalasia: late results of a prospective follow up investigation. Gut 2004; 53:629–633. 83. Patti MG, Pellegrini CA, Horgan S, et al. Minimally invasive surgery for achalasia: an 8-year experience with 168 patient. Ann Surg 1999; 230:587–593. 84. Wiechmann RJ, Ferguson MK, Naunheim KS, et al. Videoassisted surgical management of achalasia of the esophagus. J Thorac Cardiovasc Surg 1999; 118:916–923. 85. Richards WO, Torquati A, Holzman MD, et al. Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: a prospective randomized double-blind clinical trial. Ann Surg 2004; 240:405–412. 86. Zaninotto G, Costantini M, Molena D, et al. Treatment of esophageal achalasia with laparoscopic Heller myotomy and Dor partial anterior fundoplication: prospective evaluation of 100 consecutive patients. J Gastrointest Surg 2000; 4: 282–289. 87. de Oliveira JM, Birgisson S, Doinoff C, et al. Timed barium swallow: a simple technique for evaluating esophageal emptying in patients with achalasia. AJR 1997; 169:473–479. 88. Mineo TC, Pompeo E. Long-term outcome of Heller myotomy in achalasie sigmoid esophagus. J Thorac Cardiovasc Surg 2004; 128:402–407. 89. Almogy G, Anthone GJ, Crookes PF. Achalasia in the context of morbid obesity: a rare but important association. Obes Surg 2003; 13:896–900. 90. Anderson KO, Dalton CB, Bradley LA, Richter JE. Stress induces alterations of esophageal pressures in healthy volunteers and non-cardiac chest pain patients. Dig Dis Sci 1989; 34:83–91. 91. Champion JK, Delise N, Hunt T. Myenteric plexus in spastic motility disorders. J Gastrointest Surg 2001; 5:514–516. 92. Peters LJ, Mass LC, Petty D, et al. Spontaneous non-cardiac chest pain: evaluation by 24 hour ambulatory esophageal motility and pH monitoring. Gastroenterology 1988; 94:878–886. 93. Richter JE, Castell DO. Diffuse esophageal spasm: a reappraisal. Ann Intern Med 1984; 100:242–245. 94. DiMarino Al Jr, Cohen S. Characteristics of lower esophageal function in symptomatic diffuse esophageal spasm. Gastroenterology 1997; 66:1–6.

95. Orlando RC, Bozymski EM. Clinical and manometric effects of nitroglycerin in diffuse esophageal spasm. N Engl J Med 1973; 289:23–25. 96. Davies HA, Lewis MJ, Rhodes J, Henderson AH. Trial of nifedipine for prevention of esophageal spasm. Digestion 1987; 36:81–83. 97. Hongo M, Traube M, McCallum RW. Comparison of effects of nifedipine, probantheline bromide, and the combination on esophageal motor function in normal volunteers. Dig Dis Sci 1984; 29:300–305. 98. Eherer AJ, Schwetz I, Hammer HF, et al. Effect of sildenafil on oesophageal motor function in health subjects and patients with oesophageal motor disorders. Gut 2002; 50:758–764. 99. Cannon RO, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med 1994; 330:1411–1417. 100. Ebert EC, Ouyang A, Wright SH, Cohen S. Pneumatic dilation in patients with symptomatic diffuse esophageal spasm and lower esophageal sphincter dysfunction. Dig Dis Sci 1983; 28:481–485. 101. Fishman VM, Parkman HP, Schiano TD, et al. Symptomatic improvement in achalasia after botulinum toxin of the lower esophageal sphincter. Am J Gastroenterol 1996; 91:1724–1730. 102. Henderson RD, Ryder D, Marryatt G. Extended esophageal myotomy and short total fundoplication hernia repair in diffuse esophageal spasm: five-year review in 34 patients. Ann Thorac Surg 1987; 43:25–31. 103. Eypasch EP, DeMeester TR, Klingman RR, Stein HJ. Physiologic assessment and surgical management of diffuse esophageal spasm. J Thorac Cardiovasc Surg 1992; 104:859–868. 104. Leite LP, Johnston BT, Barrett J, et al. Ineffective esophageal motility (IEM): the primary finding in patients with nonspecific esophageal motility disorder. Dig Dis Sci 1997; 42: 1853–1858. 105. Fouad YM, Katz PO, Hatlebakk JG, Castell DO. Ineffective esophageal motility: the most common motility abnormality in patients with GERD-associated respiratory symptoms. Am J Gastroenterol 1999; 94(6):1464–1467. 106. Lock G, Holstege A, Lang B, Scholmerich J. Gastrointestinal manifestations of progressive systemic sclerosis. Am J Gastroenterol 1997; 92:763–771. 107. Estrera A, Taylor W, Mills LJ, Platt MR. Corrosive burns of the esophagus and stomach: a recommendation for an aggressive surgical approach. Ann Thorac Surg 1986; 41:276–283. 108. Tran Ba Huy P, Celerier M. Management of severe caustic stenosis of the hypopharynx and esophagus by ileocolic transposition via suprahyoid or transepiglottic approach. Analysis of 18 cases. Ann Surg 1988; 207:439–445. 109. Anderson KD, Rouse TM, Randolph JG. A controlled trial of corticosteroids in children with corrosive injury of the esophagus. N Engl J Med 1990; 323:637–640. 110. Cameron JL, Keffer RF, Hendrix TR, Mehigan DG, Baker RR. Selective non-operative management of contained intra-thoracic esophageal perforations. Ann Thorac Surg 1979; 27: 404–408. 111. Hall ML, Huseby JS. Hemorrhagic pulmonary edema associated with meat tenderizer treatment for esophageal meat impaction. Chest 1988; 94:640–642. 112. Lee LS, Singhal S, Brinster CJ, et al. Current management of esophageal leiomyoma. J Am Coll Surg 2004; 198: 136–146. 113. Bollschweiler E, Wolfgarten E, Gutschow C, Holscher AH. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer 2000; 92:549–555. 114. Lagergren J. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut 2005; 54:i1–i5. 115. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Can Inst 2005; 97:142–146. 116. Van Dam J. Endosonographic evaluation of the patient with esophageal cancer. Chest 1997; 112(suppl):184S–190S. 117. Nigro JJ, Hagen JA, DeMeester TR, et al. Prevalence and location of nodal metastases in distal esophageal adenocarcinoma

Chapter 14:

118. 119. 120.

121.

122.

123.

124.

confined to the wall: implications or therapy. J Thorac Cardiovasc Surg 1999; 117:16–25. Hardwick RH, Williams GT. Staging of oesophageal adenocarcinoma. Br J Surg 2002; 89:1076–1077. Siewert JR, Stein HJ, Fink U. Surgical resection for cancer of the cardia. Semin Surg Oncol 1999; 17:125–131. Heitmeiller RF, Redmond M, Hamilton SR. Barrett’s esophagus with high-grade dysplasia: an indication for prophylactic esophagectomy. Ann Surg 1996; 224:66–71. Banki F, Mason R, DeMeester SR, et al. Vagal-sparing esophagectomy: a more physiologic alternative. Ann Surg 2002; 236:324–336. Hagen JA, DeMeester SR, Peters JH, Chandrasoma P, DeMeester T. Curative resection for esophageal adenocarcinoma: analysis of 100 en bloc esophagectomies. Ann Surg 2001; 234:520–531. DeMeester TR, Johansson K-E, Franze I, et al. Indications, surgical technique, and long-term functional results of colon interposition or bypass. Ann Surg 1988; 208:460–474. Stewart JR, Hoff SJ, Johnson DH, et al. Improved survival with neoadjuvant therapy and resection for adenocarcinoma of the esophagus. Ann Surg 1993; 218:571–576.

Physiologic Dysfunction of the Esophagus

331

125. Ferguson MK, Reeder LB, Hoffman PC, Haraf DJ, Drinkard LC, Vokes EE I. Intensive multimodality therapy for carcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol 1995; 2:101–106. 126. Visser BC, Venook AP, Patti MG. Adjuvant and neoadjuvant therapy for esophageal cancer: a critical reappraisal. Surg Oncol 2003; 12:1–7. 127. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TPJ. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462–467. 128. Harpole DH, Moore M, Herndon JE, et al. The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res 2001; 7:562–569. 129. Patti MG, Corvera CU, Glasgow RE, Way LW. A hospital’s annual rate of esophagectomy influences the operative mortality rate. J Gastrointest Surg 1998; 2:186–192. 130. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA. Surgical volume and quality of care for esophageal resection: do high-volume hospitals have fewer complications? Ann Thorac Surg 2003; 75:337–341.

medwedi.ru

15 Gastric Physiology and Acid-Peptic Disorders Kenneth S. Helmer and David W. Mercer

INTRODUCTION The gastrointestinal (GI) system is a boundary between the external world and the internal environment of the human body. The stomach plays an important role in the GI system, not only by helping to protect the internal environment from outside pathogens by the bactericidal activity of gastric acid, but also in preparing food for digestion and absorption of nutrients. The stomach functions to act as a reservoir for food by accommodating large quantities of ingested food through receptive relaxation. Through contraction and relaxation of the stomach musculature the stomach mixes and liquefies food with gastric juice, which partially digests food and emulsifies fats. Although simplified here, an intricate and complex relationship between exocrine, endocrine, paracrine, and neurocrine pathways are involved. The aim of this chapter is to summarize these complex interactions as well as to illustrate the physiologic anatomy as it relates to surgical diseases.

NORMAL PHYSIOLOGY Stomach Embryology During the fourth week of gestation, the primitive gut forms as the dorsal part of the yolk sac is incorporated into the embryo. The epithelia at the cranial and caudal ends of the tract develop into the ectoderm of the primitive mouth (stomodeum) and primitive anal pit (proctodeum), respectively. The epithelium and glands of the digestive tract are formed by the endoderm of the primitive gut, while the splanchnic mesenchyme, which surrounds the endoderm, forms the muscular tissue, connective tissue, and other layers comprising the wall of the digestive tract. The foregut goes on to develop into the adult derivatives of the primitive pharynx, lower respiratory system, esophagus, stomach, duodenum (proximal to the common bile duct), liver, biliary system, and pancreas. The artery of the foregut develops into the celiac artery, which supplies these structures except the pharynx derivatives, respiratory tract, and proximal esophagus. The stomach begins as a simple tubular structure in the distal part of the foregut and dilatation during the middle of the fourth week designates the future site of the stomach. The stomach initially enlarges in a ventrodorsal fashion in the median plane. The greater curvature of the stomach, which is demarcated as the dorsal plane, grows faster than the ventral plane (lesser curvature). As this takes place, the stomach slowly rotates 90 in a clockwise direction around its longitudinal axis. This rotation explains the unique axis of the stomach. The lesser curvature (ventral border) moves to the right and the greater curvature (dorsal border) to the left, which effectively changes the stomach’s ventral–dorsal designation. The original left side of the

primitive stomach now becomes the ventral surface, and the original right side becomes the dorsal surface. Similarly, the cranial portion, which develops into the fundus, moves to the left and inferiorly, while the caudal region, which develops into the pyloric antrum, moves to the right and superiorly. This rotation, which begins at around 28 days and extends to about 48 days, gives the stomach its final position, which is almost transverse to the long axis of the body. This explains why the anterior wall of the stomach is supplied by the left vagus nerve and the posterior wall supplied by the right vagus nerve (1). Figures 1 and 2 demonstrate early embryologic development and rotation.

Gastric Anatomy Divisions The stomach is generally divided into four anatomic regions as shown in Figure 3. Although these divisions are useful to the surgeon in describing anatomical resections, they do not necessarily denote histological, secretory, or muscular physiology of the stomach. The most proximal portion of the stomach is the cardia, which is just distal to the gastroesophageal (GE) junction. The cardia contains mucous cells and attaches the stomach to the esophagus. The fundus is the portion of the proximal stomach, which is the most superior and extends above the GE junction. The fundus is bounded superiorly by the diaphragm and laterally by the spleen. The angle of His is an anatomic angle, which the fundus forms with the left margin of the esophagus. The body of the stomach is also the largest portion and is contained between the relatively straight lesser curvature on the right and the longer greater curvature on the left. The body is also referred to as the corpus. The angularis incisura is an abrupt angle along the lesser curvature that directs the distal stomach to the right. This angle designates where the body of the stomach ends and the antrum begins. It can also be identified grossly by the confluence of vasculature along the lesser curvature at the angle. The pylorus, which resides in the distal antrum, connects the stomach to the proximal duodenum. The pyloric opening is surrounded by a thickened ring of gastric circular muscle, which constitutes the pyloric sphincter.

Blood Supply The stomach receives the majority of blood from the right and left gastric and right and left gastroepiploic arteries. The majority of the blood supply originates from the celiac artery. Additionally, blood may also be supplied by the inferior phrenic arteries and short gastric arteries from the spleen. Figure 4 demonstrates the arterial supply of the stomach. The left and right gastric arteries supply the

medwedi.ru 333

334

Part Two: The Alimentary Tract—Esophagus and Stomach

the left toward the gastric cardia, giving off esophageal and hepatic branches before turning to the right and running along the lesser curvature of the stomach within the lesser omentum. It runs from superior to inferior and anastomoses with the right gastric artery. An aberrant left hepatic artery may originate from the left gastric artery approximately 15% to 20% of the time. This is important because, if present, proximal ligation of the left gastric artery may result in left-sided hepatic ischemia, because occasionally an aberrant left hepatic artery is the only arterial blood supply to the left hepatic lobe. The right gastric artery is a branch-off from the common hepatic artery and runs to the pylorus and then upward along the lesser curvature of the stomach. Occasionally, the gastroduodenal artery may supply the right gastric artery. The left and right gastroepiploic arteries supply the greater curvature of the stomach. The left gastroepiploic artery runs to the right along the greater curvature of the stomach and is supplied by the splenic artery. The right gastroepiploic artery also runs to the left along the greater curvature and anastomoses with the left gastroepiploic artery. It is supplied by the gastroduodenal artery and also supplies the greater omentum. The short gastric arteries also supply the greater curvature and they are branches of the splenic artery. Fortunately, because of the superiorly extensive anastomotic connections between the four major arteries supplying the stomach, gastric viability can be preserved after ligation of all but one primary artery. This anastomotic network of arteries is advantageous to the surgeon performing gastric resection and reconstruction. Furthermore, in instances of celiac artery occlusion, gastric blood supply may be maintained by the superior mesenteric artery via collaterals from the pancreaticoduodenal arcade. Unfortunately for the patient, the rich anastomosis also means that gastric hemorrhage is not amenable to ligation of gastric arteries. The venous drainage of the stomach generally parallels the arterial supply. The left gastric (coronary) and right gastric veins usually drain into the portal vein. The right gastroepiploic vein drains into the superior mesenteric vein and the left gastroepiploic vein drains into the splenic vein.

Lymphatic Drainage

Figure 1 Drawings illustrating development and rotation of the stomach and formation of the omental bursa (lesser sac) and greater omentum. (A) About 28 days. (B) About 35 days. (C) About 40 days. (D) About 48 days. Source: From Ref. 1, with permission of Elsevier.

lesser curvature of the stomach. The left gastric artery is the first and smallest branch of the celiac trunk. However, it is the largest artery to the stomach. It runs upward and to

The lymphatic drainage of the stomach generally parallels the gastric venous return. Figure 5 demonstrates lymphatic drainage. The antral portion of the greater curvature (Zone I) drains to the subpyloric and omental nodal group. Lymph from the proximal greater curvature (Zone II) traverses through the pancreaticosplenic nodes to the left gastroepiploic and splenic group of nodes. The lymph from the superior portion of the lesser curvature (Zone III) drains into the superior gastric group of lymph nodes surrounding the left gastric artery and subsequently into the left gastric, paracardial, and celiac nodes. The suprapyloric lymph nodes (Zone IV) drain the distal or antral portion of the lesser curvature. Drainage from all of these lymphatic basins subsequently drains into the celiac group of lymph nodes before traversing into the thoracic duct. Because of the extensive intramural and extramural communication of the lymphatic system of the human stomach, gastric cancer metastasis may drain to any of the nodal basins regardless of cancer location within the stomach. As a consequence, there is frequently microscopic evidence of malignant cells many centimeters from a primary cancer site, and malignant cells are frequently identified in the tissue margin of resection.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

335

Figure 2 Diagrams illustrating development of the stomach and its mesenteries, and formation of the omental bursa (lesser sac). (A) Five weeks development. (B) Transverse section showing clefts in the dorsal mesogastrium. (C) Later stage after coalescence of the clefts to form the omental bursa. (D) Transverse section showing the initial appearance of the omental bursa. (E) The dorsal mesentery has elongated and the omental bursa has enlarged. (F and G) Transverse and longitudinal sections, respectively, showing elongation of the dorsal mesogastrium and expansion of the omental bursa. (H) Six weeks, showing the greater omentum and expansion of the omental bursa. (I and J) Transverse and longitudinal sections, respectively, showing the inferior recess of the omental bursa and the omental (epiploic) foramen. Source: From Ref. 1, with permission of Elsevier.

Innervation The stomach’s innervation consists of an extrinsic system and an intrinsic system. The extrinsic innervation of the stomach consists of parasympathetic, sympathetic, and a nonadrenergic, noncholinergic (NANC) system. The intrinsic nervous system is made of primarily networks formed by submucosal and myenteric plexuses, which are also termed as the ‘‘enteric nervous system.’’ Together this multi-integrated network of communication is referred to as part of the autonomic nervous system. We have no conscious control over this system and are mostly unaware of its activity. The parasympathetic nervous system of the stomach is innervated via the vagus nerve. The vagus nerve originates in the vagal nucleus in the floor of the fourth ventricle and descends through the neck in the carotid sheath before aligning alongside the esophagus in the thorax. Prior to traversing the diaphragm, the vagal nerves form a periesophageal plexus by dividing into several branches. These branches

then coalesce into the left and right vagal trunks before passing through the esophageal hiatus of the diaphragm, as shown in Figure 6. The left vagus nerve traverses anterior to the esophagus and the right vagus traverses posteriorly. This is secondary to the 90 rotation of the stomach during gestation, as described previously. The left vagus gives off a hepatic branch, which innervates the liver and the biliary system. After giving off this branch, the vagus traverses anteriorly along and innervates the lesser curvature of the stomach. Here it is called the anterior nerve of Latarjet. The right or posterior vagus nerve branches into a division to the celiac plexus and another to the posterior aspect of the lesser curvature. The ‘‘criminal’’ nerve of Grassi is the first branch of the right vagus nerve and, if left undivided during vagotomy, is a potential etiology of recurrent gastric ulcers. The majority (> 90%) of vagal fibers are afferent and carry information from the GI tract to the central nervous system (CNS). Efferent fibers originate in the dorsal nucleus of the medulla and synapse with postsynaptic neurons in the

medwedi.ru

336

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 3 Schematic of the anatomical regions of the stomach.

myenteric and submucosal plexuses in the gastric wall. The efferent fibers directly innervate smooth muscle and epithelial cells. The vagus nerve mainly functions to influence gastric motor function, especially the accommodation reflex, and gastric secretion. Acetylcholine is the major neurotransmitter of the vagus nerve, but nitric oxide (NO) has also recently been shown to act as a neurotransmitter as well. The sympathetic nervous system of the stomach originates from the spinal segments T5–T10. The afferent fibers pass directly from the stomach to the dorsal spinal roots without any synapse. Afferent fibers are responsible for the sense of pain from the stomach. Efferent fibers pass from the spinal nerve roots via gray rami communicantes and synapse at the prevertebral ganglia. Presynaptic fibers then pass through the greater splanchnic fibers to the celiac plexus. Here they synapse again with postsynaptic sympathetics. These fibers travel alongside the arterial system of celiac origin. Sympathetic neurons release adrenergic as well as cholinergic neurotransmitters.

Figure 4 Gastric arterial supply. Source: Adapted from Ref. 2.

Figure 5 Lymphatic drainage of the stomach. There are four zones of drainage. Zone I (inferior gastric) drains lymph into the subpyloric and omental nodes. Zone II (splenic) drains into the pancreaticosplenic nodes. Zone III (superior gastric) drains lymph into the superior gastric nodes. Zone IV (hepatic) drains into the suprapyloric gastric nodes.

A third and newly identified innervation of the stomach is via a NANC pathway within the myenteric plexus, which is mediated by NO together with vasoactive intestinal polypeptide (VIP) as a parallel cotransmitter (3). Studies in animals have demonstrated that NO has been identified as a major inhibitory NANC neurotransmitter in the GI tract and stomach (4). NO is synthesized by the

Figure 6 Schematic of the vagus nerve and its divisions in the thorax and abdomen. Left and right vagus nerves coalesce above the hiatus to form the anterior and posterior vagal trunks. Other configurations exist. Source: Adapted from Ref. 2.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

activation of neuronal NO synthase (nNOS) in the myenteric plexus. It has been demonstrated in animals that NO released in response to nerve stimulation of the myenteric plexus causes relaxation of the smooth muscle and appears to regulate the accommodation reflex of the fundus. Research suggests that nitric oxide synthase (NOS) expression in the gastric myenteric plexus is also controlled by the vagal nerve and nicotinic synapses because truncal vagotomy and administration of hexamethonium significantly reduced NANC relaxation, the catalytic activity of NOS, the number of NOS-immunoreactive cells, and the density of NOS-immunoreactive bands and NOS mRNA bands obtained from gastric tissue. This may be secondary to the Ca2þ-dependent protein kinase C pathway, which appears to upregulate nNOS mRNA expression and nNOS synthesis in the gastric myenteric plexus (5). Previous studies in animals have also shown that NOS inhibitors delay gastric emptying. The reduction of nNOS expression, associated with impaired local production of NO, may be responsible for motility disorders in the GI tract and motility disorders after vagotomy. It appears that extrinsic denervation may upregulate nNOS expression, resulting in enhanced muscular relaxation and disturbed peristalsis. Furthermore, NO from the neuronal form of NOS appears to play a significant role in relaxation of the pyloric and lower esophageal sphincters (6). The intrinsic innervation of the stomach consists of a submucosal plexus that is located between the muscularis mucosae and the circular muscle. This plexus is also termed Meissner’s plexus. The myenteric plexus, also called Auerbach’s plexus, lies between the longitudinal and circular muscles, or the muscularis externa. Together, the intrinsic nervous system of the stomach functions to relay information to and from the extrinsic nervous system and also to relay information within the stomach. Because of the rich synaptic connections within the stomach, local reflex responses and information can be forwarded from one part of the stomach to another without any involvement of the extrinsic system. The stomach has a network of interstitial cells of Cajal (ICCs) associated with the Auerbach’s plexus, as well as intramuscular ICC. Recently, these cells have been shown to play an important role in neural transmission (7). ICCs are critical for slow-wave generation, making ICC the pacemaker cells of the gut, allowing rhythmic peristaltic motor patterns in the mid and distal stomach. There are two types of ICCs within the stomach. The first are spindle-shaped cells within the circular and longitudinal muscle layers from the fundus to the distal antrum. These intramuscular ICCs are closely associated with inhibitory and excitatory nerves. They appear to serve as mediators between enteric nerves and smooth muscle cells. They also appear to mediate slow-wave activity. Intramuscular ICCs have been found to have close association with enteric neurons that release NO, acetylcholine, and substance P. The second type of ICCs have highly branching networks within the myenteric (Auerbach’s) plexus between the longitudinal and circular muscle layers of the corpus and antrum. These ICCs function in pacemaker generation by generating slow-wave activity (7). Cholinergic, serotonergic, NANC, and peptidergic neurons are present within the intrinsic nervous system of the stomach, which are the neural fibers of Auerbach’s and Meissner’s autonomic plexus. The neuropeptides identified that regulate gastric physiology include acetylcholine, serotonin, substance P, calcitonin-gene–related peptide, bombesin, NO, VIP, cholecystokinin (CCK), and somatostatin.

337

Peritoneal Reflections and Omentum The dorsal mesentery attaches the stomach to the dorsal wall of the abdominal cavity, and after being carried to the left during rotation of the stomach forms a recess between the posterior wall of the stomach and the posterior abdominal wall, called the omental bursa or lesser sac of peritoneum. This bursa communicates with the main part of the peritoneal cavity through a small opening called the epiploic (omental) foramen, which is posterior to the free edge of the lesser omentum in the adult. The dorsal mesentery further develops to become the greater omentum. The ventral mesentery develops into the lesser omentum and attaches the lesser curvature of the stomach and the proximal 2 cm of the duodenum to the liver via the hepatogastric and hepatoduodenal ligaments. The omentum is a large sheet of fatty mesentery that plays a protective role in the abdomen by walling off inflammatory processes or visceral perforations, thereby preventing peritonitis, as well as serving as a depository for tumor metastases. It is often called the ‘‘watchdog’’ of the abdomen. The greater omentum surgically is divided into two parts: the true greater omentum, which hangs freely into the peritoneal cavity from the transverse colon, and the gastrocolic ligament, which connects the greater curvature of the stomach and the transverse colon. The lesser omentum is a double layer of peritoneum extending from the porta hepatis of the liver to the lesser curvature of the stomach and the first portion of the duodenum. The lesser omentum is important surgically because it contains the left and right gastric vessels, which run between its two layers, and its right free margin contains the hepatic artery, bile duct, and portal vein. The lesser omentum consists of the hepatogastric and hepatoduodenal ligaments and forms the anterior wall of the lesser sac of the peritoneal cavity. The anatomy of the peritoneal ligaments that are attached to the stomach are important because, not only must they be transected during resection of the stomach, but also because of the vasculature that may be present within them. As mentioned above, the hepatogastric ligament attaches the stomach to the liver along the lesser curvature. The gastrosplenic (lienogastric) ligament extends from the left portion of the greater curvature of the stomach to the hilum of the spleen. It contains the short gastric vessels and the left gastroepiploic vessels. The gastrophrenic ligament runs from the upper portion of the greater curvature of the stomach to the diaphragm. The gastrocolic ligament extends from the greater curvature of the stomach to the transverse colon as mentioned above. Figure 7 demonstrates the mesenteric attachments of the stomach.

Gastric Morphology The luminal surface of the stomach is covered in large infoldings, which are called rugae. Rugae consist of mucosa and submucosa that are most prominent in the proximal stomach and extend longitudinally toward the antrum. Rugae allow the stomach to distend to accommodate a meal as well as increase the epithelial surface area. The mucosa interacts with the luminal milieu and contains most of the glandular digestive and endocrine cells of the stomach. The mucosal layer consists of epithelium, lamina propria, and muscularis mucosa. The lamina propria is a thin connective tissue layer that contains the blood supply, lymphatics, and nerves to support the surface epithelium. The submucosa is adjacent to the muscularis mucosa and is the strongest layer of the gastric

medwedi.ru

338

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 8 Transverse cross section of the layers of the gastric wall.

Figure 7 Schematic of the mesenteric attachments of the stomach.

wall because of its collagen-rich layer of connective tissue. The submucosa is a very vascular layer of the gastric wall. Here there is a rich anastomosis of arterial and venous collaterals as well as lymphatics. The Meissner’s plexus of autonomic nerves also resides in the submucosa. The muscularis mucosa consists of low-density smooth muscle cells. Auerbach’s myenteric plexus resides within the muscularis externa, which is the next layer of the gastric wall. The muscularis externa consists of three muscular sublayers—inner oblique, middle circular, and outer longitudinal. The middle circular layer becomes thicker at the pylorus and functions as a true anatomic sphincter. The longitudinal layer of the muscularis can be separated into two different categories: a longitudinal layer that is common with the esophagus and ends in the corpus, and a longitudinal layer that originates in the corpus and spreads into the duodenum. Figure 8 depicts the transverse section of the gastric wall.

Gastric Microscopic Organization The gastric mucosa consists of a multitude of cells that vary according to the region in the stomach in which they are found and also vary by depth within the mucosa. The superficial epithelial lining of the mucosa consists of columnar glandular epithelia. These surface epithelial cells are mucin secreting and have basal nuclei, with mucin-containing granules in the apical region. The apex has short microvilli and a thin apical coating of glycocalyx. These cells also exist deep within the gastric pits where they are coined ‘‘neck cells.’’ Neck cells have a lower content of mucin granules and increased mitosis. Neck cells are also thought to be the progenitor cells that give rise to the surface epithelium, as well as the cells of the gastric glands. The gastric cardia contains mostly mucinous cells, which are indistinguishable from the neck cells of the gastric pits. The mucinous neck cells throughout the pits function to maintain a thin layer of mucous gel that covers the gastric mucosa. The gastric

pits themselves drain several gastric glands. The fundus and body of the stomach contain mucin-secreting surface epithelia and neck cells, parietal cells, chief cells, and few neuroendocrine cells. Parietal cells are recognized by their abundant mitochondria, which stain brightly pink on hematoxylin and eosin preparations and are found in greatest numbers in the body of the stomach. The high content of mitochondria is indicative of the high energy requirements of gastric acid secretion. The neck and base of the gastric pits contain parietal cells and chief cells, which stain purple because of their large basophilic zymogen granules. The antrum not only contains mucinous cells, but also neuroendocrine cells such as gastrin (G) cells or somatostatin (D) cells. The neuroendocrine cells can be classified as either open or closed. Endocrine cells that have their microvilli in direct contact with gastric luminal contents are considered open type. Chemical and pH sensors on the microvilli likely stimulate the cell to secrete their prestored peptides. Closed-type endocrine cells do not contact the lumen and likely function by sensing the interstitial milieu. For example, G-cells and D-cells in the antrum are open-type cells and appear to sense the luminal concentration of acid and digesting meal. They respond by releasing gastrin or somatostatin, respectively. In contrast, D-cells in the fundus and body are of the closed type and intimately interact with parietal cells through their microvilli. Enterochromaffin cells, which secrete serotonin and other peptides, and enterochromaffin-like (ECL) cells, which secrete histamine, are also located within the mucosa. Gastric pits within the stomach further increase the epithelial surface area and also differ by region, as does the glandular epithelium. In the cardia, the pits are short and the glands are branched. The fundus and body contain more tubular glands and long gastric pits. The antrum again has branched glands and shorter pits. Biopsy specimens taken from human stomachs show that the content of epithelial cells consists of 13% parietal cells, 44% chief cells, 40% mucus cells, and 3% endocrine cells. Figure 9 demonstrates the basic histology of a gastric pit.

GASTRIC PHYSIOLOGY Both neural and hormonal mediators regulate the function of gastric relaxation, motility, and gastric secretion. Neural

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

339

and emptying. Pre- and postprandial gastric motility are separate entities and are explained in more detail below.

Fasting (Preprandial) Gastric Motility

Figure 9 The gastric pit. Schematic of the histologic cell types of the stomach. Abbreviations: G, gastric; ECL, enterochromaffin-like.

The electrical activity of the stomach functions to clear the gastric lumen of indigestible food particles, digestive secretions, and sloughed-off cells via interdigestive motor cycles that occur every 90 to 120 minutes. These motor cycles are termed the migrating myoelectric complex (MMC) and begin with the depolarization of pacemaker cells located high on the greater curvature of the body of the stomach. These pacemaker cells are a collection of specialized smooth muscle cells that generate cyclic pacemaker potentials, which propagate in a circumferential and antegrade fashion toward the pylorus. These slow waves of potential are initiated at three cycles per minute and are capable of depolarizing smooth muscle cells, thereby producing action potentials that are associated with gastric muscle contractions. Each cycle of MMC is made up of four phases of electrical activity. Phase I is the quiescent phase where slow wave potentials are present, but they neither depolarize smooth muscle cells nor produce action potentials. Phase I of the MMC has no gastric contractions, but only increased gastric tone. Phase II consists of slow wave potentials with irregular depolarization of smooth muscle cells, or motor spikes, which cause occasional gastric contractions. In Phase III of the MMC, regular motor spike activity is associated with the slow waves, causing forceful gastric contractions every 15 to 20 seconds, which sweeps intraluminal contents toward the pylorus to clear the stomach. The brief recovery period prior to the next MMC cycle is Phase IV (9,10).

Postprandial Gastric Motility regulation is accomplished by an intricate network of adrenergic, cholinergic, and NANC neural pathways. Hormonal and peptide interactions are accomplished through one of three pathways: endocrine, paracrine, or neurocrine. The exocrine function of the stomach also plays a role in gastric secretion. All of these pathways of gastric physiology are intertwined and the precise action of a target cell depends on the relative balance of mediators acting upon it.

Neural/Electrical Regulation Motility The neuromuscular apparatus of the stomach functions to store an ingested meal, prepare it for digestion through mixing and trituration, and deliver it to the duodenum in usable quantities (emptying). This is accomplished through neural mechanisms and myogenic potentials, which regulate the electrical and motor activity of the organ. Extrinsic neural controls are mediated through the adrenergic (sympathetic) and cholinergic (parasympathetic-vagal) pathways. The myenteric plexus mediates the intrinsic neural pathway, which is termed the NANC pathway and is mediated through the release of NO from the nNOS at the nerve terminal (4,6,8). The myogenic pathway involves action potentials generated by the excitatory membranes of smooth muscle cells, and results in muscle contraction. Similar to action potentials within neurons, when the cell membrane resting potential exceeds its threshold value, an action potential is generated, which results in smooth muscle contraction. The gastric pacemaker cells of Cajal regulate this process. The electrical and motor activities of the stomach are responsible for gastric relaxation, mixing, trituration,

The fasting cycle of the stomach is disrupted when feeding occurs. When feeding begins, the function of the stomach switches to accommodate the meal, begin digestion, and deliver appropriate volumes and sizes of a meal into the duodenum. During a swallow, the proximal stomach relaxes at the same time that the lower esophageal sphincter relaxes in order to accept the food bolus (receptive relaxation). After the bolus enters the stomach, further relaxation is stimulated to accommodate the meal (accommodation reflex). The intraluminal pressure then returns slowly to basal levels, which are essentially equal to the intra-abdominal pressure. This process facilitates the stomach to receive volumes as high as 1500 mL without significant increases in pressure. The relaxation of the stomach is mediated by the vagovagal reflex, which feeds information via vagal afferents to the CNS and back to the gastric smooth muscle via vagal efferents. Vagotomy can abolish this reflex so that higher intragastric pressures are present in the presence of a meal. For this reason, vagotomy is often associated with a feeling of early satiety by patients (11–14). Gastric emptying of liquids is thought to be controlled by the proximal stomach via low-amplitude tonic contractions of the fundus, which creates a pressure gradient between the stomach and duodenum and facilitates emptying of liquids. In contrast, solids are mixed with gastric juice and broken down into digestible amounts prior to emptying. This is accomplished through repetitive forceful ring contractions from the mid body and antrum, which propel food particles against a closed pylorus, compressing them, with subsequent retropulsion of solids and liquids back again, which assures mixing of food particles. Food is thereby thoroughly mixed with gastric juice, liquefied, partially digested,

medwedi.ru

340

Part Two: The Alimentary Tract—Esophagus and Stomach

and fats emulsified. Pacemaker cells in the mid-stomach initiate these forceful contractions by initiating membrane potentials and subsequent action potentials of the smooth muscle cells. Contractions occur every three to five minutes and last from 2 to 20 seconds. Furthermore, the contractions increase in both velocity and speed as they travel distally toward the pylorus, as demonstrated in Figure 10. As the peristaltic contractions increase in speed they actually overtake the majority of gastric contents ahead of the wave, propelling a small amount of contents into the duodenum while the majority of contents are retropulsed back because the force of the contraction wave closes the distal antrum. Breakdown of food particles in this manner ensures that food particles less than 1 mm in size will be emptied into the duodenum. The length of time that the food remains in the stomach varies considerably depending on many factors. In general liquids empty faster than solids. The T12 of gastric emptying for water is approximately 10 to 20 minutes and depends on the tone of the proximal stomach. Gastric emptying of solids varies from one to four hours and depends on the ease of liquefaction as well as the intensity of peristaltic contractions. Again, flow of food into the duodenum to change into chyme occurs as particles less than 1 mm become suspended in the gastric effluent. The content of a meal also determines the rate of emptying. Generally, the emptying rate for carbohydrates is greater than that for proteins, which is greater than that for fats. The enterogastric reflex consists of neural and hormone-mediated reflexes that regulate gastric motor activity. Psychic stimuli, pain, taste, or smell can alter gastric motility and emptying through vagal cholinergic and adrenergic sympathetic fibers. Receptors in the duodenum are also sensitive to changes in osmolarity, pH, lipid content, or stretching of the duodenal wall and inhibit gastric emptying through neural and hormonal mechanisms. For example, increased osmolarity and acidity of chyme have feedback inhibition on gastric emptying. Peptides that inhibit gastric motility and emptying include CCK, secretin, glucagon, vasoactive inhibitory peptide, and gastric inhibitory polypeptide. Figure 11 demonstrates the enterogastric reflex.

Figure 10 Schematic of postprandial gastric motility. Measurements of gastric intraluminal pressures demonstrate that as gastric contractions move distally toward the pylorus, the force of contraction increases. The letters correspond to location in the stomach.

Figure 11 The enterogastric reflex. The accommodation reflex and stimulation of gastric motility have differential pathways, which vary between the proximal and distal stomach. Source: From Ref. 1, with permission of Elsevier.

Hormonal/Peptide Regulation Gastrin Gastrin was the second true hormone to be identified in 1905, because of its ability to stimulate acid secretion. The name gastrin literally means ‘‘to stimulate the stomach.’’ Although its existence was controversial for the next 43 years, gastrin is now known as a major hormonal regulator of acid secretion. Gastrin is produced by the G-cells of the antral mucosa and exists as three distinct gastrin peptides: G-34 (big gastrin), G-17 (little gastrin), and G-14 (minigastrin). All of these molecular forms of gastrin are found in both antral tissue and in the circulation, and exist in both sulfated (gastrin II) and unsulfated forms (gastrin I). A pentapeptide at the carboxyl terminus of gastrin confers biological activity. G-17 accounts for about 90% of gastrin released from the antral mucosa. However, in the circulation, G-34 predominates because its half-life is about five times that of G-17 (15–17). Endogenous and exogenous gastrins regulate gastric acid secretion and do so through interactions with gastrin receptors on the parietal cell. However, the effects of gastrin may also be regulated via release of histamine (see below) from ECL cells. Evidence for this is suggested by the finding that H2-receptor antagonists significantly blunt gastrin-stimulated acid secretion from parietal cells. However, on a molar basis, gastrin is 1500 times more potent than histamine in stimulating acid secretion (18–20). Gastrin also displays considerable trophic effects on parietal and ECL cells. In the Zollinger–Ellison syndrome (ZES), high levels of circulating gastrin cause marked hypertrophy of the rugae of the proximal stomach. In fact, hypergastrinemia from any cause can lead to mucosal hypertrophy and hyperplasia of parietal cells as well as an increase in the number of ECL cells, and rarely is associated with the development of gastric carcinoid tumors (21). Although acid secretion and trophic effects are the major physiologic actions of gastrin, at pharmacologic doses, gastrin also

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

Table 1 Causes of Hypergastrinemia Ulcerogenic causes Antral G-cell hyperplasia or hyperfunction Retained excluded antrum Zollinger–Ellison syndrome Gastric outlet obstruction Short-gut syndrome

Nonulcerogenic causes Antisecretory agents (PPIs) Atrophic gastritis Pernicious anemia Acid-reducing procedure (vagotomy) Helicobacter pylori infection Chronic renal failure

Abbreviation: PPIs, proton-pump inhibitors.

stimulates pepsinogen, intrinsic factor, and pancreatic enzyme secretion, increases lower esophageal sphincter pressure, stimulates intestinal and gallbladder motility, and renders the stomach less susceptible to injury from luminal irritants. The release of gastrin is regulated by luminal peptides and amino acids contained within a meal. These are the most potent stimulators of gastrin release. Other mediators of gastrin release include gastric distention, vagal stimulation, vagotomy, calcium, and prolonged luminal alkalinization. An important feedback inhibition of gastrin release is acidification of the gastric luminal contents to below pH 3. Somatostatin (see below) is another potent inhibitor of gastrin release, and in the antrum, gastrin and somatostatin release are inversely proportional and functionally linked. Hypergastrinemia can occur when there is inhibition of acid secretion. It can occur with administration of antisecretory agents such as H2-receptor antagonists or proton-pump inhibitors (PPIs), or following surgical procedures such as vagotomy or retained gastric antrum after gastrectomy. Disease states that are associated with hypergastrinemia are separated into those that are ulcerogenic (excess acid secretion) and those that are nonulcerogenic (normal or low acid secretion). Table 1 lists common causes of chronic hypergastrinemia. Gastrin gene knockout mice have demonstrated that maturation of parietal and ECL cells was disturbed and also that the number of parietal cells was reduced. However, there was no general atrophy of the gastric mucosa. Genetic lack of gastrin also impaired basal acid secretion and almost completely inhibited histamine- and acetylcholine-induced gastric acid secretion. Furthermore, achlorhydria from lack of gastrin allowed for bacterial overgrowth in the stomachs of the gastrin knockout mice, consistent with the important role the stomach plays in helping to protect the internal environment from outside pathogens by the bactericidal activity of gastric acid (22).

Somatostatin Somatostatin was originally isolated from the hypothalamus and known as growth hormone release inhibitory factor. However, the majority of somatostatin is found in the GI system and is an inhibitor of insulin, glucagon, and gastrin release, as well as an inhibitor of gastric acid secretion. In the stomach, it is produced by D-cells in the antrum and fundus, and also is released by nerve endings; therefore it functions as a paracrine and neurocrine factor. Somatostatin exists endogenously as either somatostatin-14 or somatostatin-28. The primary actions of somatostatin within the stomach are via a paracrine effect wherein D-cells release somatostatin in the vicinity of parietal cells and G-cells, thereby inhibiting them from gastric acid secretion and gastrin release, respectively. Inhibition of gastric acid secretion occurs by either directly inhibiting the parietal cell or by indirectly inhibiting acid secretion through inhibition of

341

gastrin release and downregulation of histamine release from ECL cells. Stimulation for somatostatin release in the stomach is mainly via antral acidification, while vagal activation inhibits its release (23–28).

Vasoactive Intestinal Polypeptide VIP is a 27–amino acid peptide that has many of the effects of secretin, gastric inhibitory polypeptide, and glucagon. VIP is released mainly by nerves around the gastroesophageal and pyloric sphincters and mediates the relaxation of GI smooth muscle. Both vagal stimulation and gastric distention mediate VIP release. VIP may inhibit gastric acid secretion, but its main functions are as an inhibitory neurotransmitter that causes relaxation of the lower esophageal sphincter, proximal stomach, and antral smooth muscle (29). NO mediates, together with VIP as a parallel cotransmitter, the NANC neurotransmission of the proximal stomach, which functions to produce gastric relaxation upon food intake (3,4,30).

Gastrin-Releasing Peptide Bombesin, a potent acid and gastrin-stimulating peptide, was first identified from extracts of the frog, Bombina bombina (31,32). Gastrin-releasing peptide (GRP) is a structurally similar mammalian peptide that stimulates gastric acid secretion through binding to receptors on G-cells and subsequently stimulating release of gastrin. GRP is primarily found at nerve endings in the acid- and gastrin-secreting portions of the stomach, and is an important mediator of vagally stimulated gastrin release. Also, bombesin plays a role in gastroprotection primarily by stimulating the release of endogenous gastrin (33). There is also recent evidence that GRP and bombesin-like peptides may play an important role in the control of food intake and obesity by suppressing the drive to feed. Knockout mice for the bombesin receptor subtype-3 demonstrated a phenotype that displayed hyperphagia and obesity (34,35).

Histamine Histamine is not a peptide, but is found within acidic granules of ECL cells and resident mast-like cells within the lamina propria. Histamine plays an important role in parietal cell acid secretion as it potentiates the actions of gastrin and acetylcholine. In fact, administration of H2-receptor antagonists, such as cimetidine, almost completely abolishes gastrin- and acetylcholine-induced gastric acid secretion by the parietal cell. This suggests that histamine plays an intermediary role in gastric acid secretion. The release of histamine is stimulated by gastrin, acetylcholine, and epinephrine through specific receptor–ligand interactions on the ECL cell. The ECL cell also has somatostatin receptors, which act to inhibit gastrin-stimulated histamine release (36,37).

Ghrelin Ghrelin is a 28–amino acid peptide predominantly produced by endocrine cells of the oxyntic mucosa of the stomach, with substantially lower amounts derived from the bowel, pancreas, and other organs. Removal of the acid-producing part of the stomach decreases circulating ghrelin by 80%. Ghrelin appears to be under endocrine and metabolic control, has a diurnal rhythm, and likely plays a major role in the neuroendocrine and metabolic response to changes in nutritional status, and may be a major anabolic hormone. Ghrelin displays a strong growth hormone-releasing action,

medwedi.ru

342

Part Two: The Alimentary Tract—Esophagus and Stomach

which is mediated by the activation of growth hormone secretagogue receptor type 1a. Human studies have shown a dose-dependent stimulation of growth hormone release with exogenous administration of ghrelin. Although the most significant response to ghrelin is growth hormone release, exogenous administration also causes increases in prolactin, adrenocorticotropin hormone, cortisol, and aldosterone through mechanisms that are as yet unclear (38). Recent studies have reported ghrelin to affect the insulinsignaling system, implicating ghrelin in glucose homeostasis (39,40). Two studies have demonstrated that ghrelin administration reduces insulin secretion (41), and that ghrelin has powerful effects on islet cells, suggesting that endogenous ghrelin may contribute to the physiological control of insulin and glucagon release (42). In studies of human volunteers by Wren et al., intravenous ghrelin administration was shown to enhance appetite and increase food intake (43). Interestingly, in patients who have undergone a gastric bypass, Cummings et al. have demonstrated that ghrelin levels are 77% lower than levels in matched obese controls. Furthermore, the decrease in ghrelin levels after gastric bypass surgery is not seen with other forms of antiobesity surgery (44). This suggests that ghrelin may be responsive to the normal flow of nutrients across the stomach. Other studies have also suggested this because ghrelin levels are decreased by inducing gastric distention with 50% dextrose, but not by gastric distention with saline, which further suggests a role for gastric chemosensory afferents in ghrelin secretion. However, the mechanisms underlying suppression of ghrelin in gastric bypass surgery are still unknown. Several other studies have also suggested that ghrelin leads to a switch toward glycolysis and away from fatty acid oxidation, which would favor fat deposition (45). Tschop et al. showed that it leads to an increase in fat mass through an increase in adiposity in the rodent (46). Although it appears that ghrelin may be upregulated in times of negative energy balance and downregulated in times of positive energy balance, the role of ghrelin in energy metabolism is still unclear. However, it may come to have a role in the treatment and prevention of obesity. Defective ghrelin signaling from the stomach could contribute to abnormalities in energy balance, growth, and associated GI and neuroendocrine functions (47).

Exocrine Regulation The stomach secretes approximately 3 L of gastric juice a day. Physiologically active components of gastric juice are pepsinogens, mucus, hydrochloric acid, and intrinsic factor. Gastric juice is secreted in the tubular glands or gastric pits by parietal cells, chief cells, and mucus cells. Gastric juice also contains constituents of swallowed saliva and duodenal refluxate. At all rates of secretion, gastric juice is essentially isotonic to plasma. However, the rate of secretion causes different ionic compositions. Basal rates of secretion form the gastric juice, which is primarily a solution consisting of NaCl with lesser amounts of Hþ and Kþ. With the stimulation of acid secretion, the concentration of Hþ increases and Naþ decreases. Therefore at maximal rates of acid secretion, the gastric juice consists of mainly HCl with small amounts of Naþ and Kþ. However, even at basal rates of acid secretion the fluid is very acidic. Hþ concentration may range from 10 mEq/L basally up to 150 mEq/L at peak rates. Differences in ionic composition are secondary to two different phases of secretion. Nonparietal cell secretion contains primarily NaCl with Kþ and HCO3 present in amounts approximately

equal to their concentrations in plasma. With stimulation of acid secretion, the parietal cell secretes a solution across a concentration gradient, which is composed of approximately 150 mEq/L HCl with 10 to 20 mEq/L of KCl. At all rates of secretion, however, gastric juice is essentially a mixture of these two components. In patients who lose significant volumes of gastric juice, either by nasogastric decompression or vomiting for example, knowledge of these components is important to guide the replacement of these electrolytes. Gastric acid is important in the process of early digestion. It functions to begin the digestive process as well as protect the GI system from ingested bacteria because the acid is bacteriostatic. Acid also is necessary for the conversion of inactive pepsinogen into the active enzyme pepsin, which begins digestion of dietary protein. Mucus secretion in the stomach serves not only as a protective barrier against intraluminal acid, but also as a physical lubricant to protect the epithelial layer from ingested material. Mucus and bicarbonate within the mucous secretions act to buffer the luminal surface epithelium from HCl and maintain neutral pH of the solution that is in contact with this layer. Intrinsic factor binds vitamin B12 to allow absorption of vitamin B12 in the ileum.

Pepsinogen Pepsinogen is a proenzyme that has a molecular weight of 42,500 kDa and is stored and secreted by chief cells and mucus cells. At an intraluminal pH < 5, pepsinogen is cleaved into pepsin, which is the physiologically active protein. Pepsin then acts to autocatalyze the conversion of more pepsinogen to pepsin as well as to digest proteins preferably at sites where tyrosine or phenylalanine follow toward the carboxyterminal of the peptide chain. Two types of pepsinogens are secreted. Group I pepsinogens are secreted by chief cells and by mucus cells located in the oxyntic acid–secreting portion of the stomach. Group II pepsinogens are secreted by mucus cells, not only in the oxyntic gland mucosa of the acid-secreting portion of the stomach, but also in the antrum and proximal duodenum. Group II pepsinogens are active over a wider range of pH values than Group I pepsinogens, which become inactivated at pH > 5 (48,49). Most of the pepsinogen secretion is during the cephalic and gastric phases (see below) of acid secretion and is through vagal stimulation. Hence, acetylcholine is the strongest stimulator of pepsin secretion. Acid is not only necessary for the cleavage of pepsinogens, but also stimulates pepsinogen secretion by triggering a cholinergic reflex, which stimulates chief cells. Acid also increases secretin release from the duodenum, which further enhances pepsinogen secretion. Cholinomimetic drugs and CCK may also stimulate its secretion. Atropine and vagotomy are potent inhibitors of pepsin secretion (50).

Intrinsic Factor Intrinsic factor is a mucoprotein with a molecular weight of 60 kDa that is secreted by the parietal cell. Intrinsic factor is the only secretory product of the stomach necessary for life because it combines with vitamin B12 to form a complex, which is required for the absorption of the vitamin by an active process in the terminal ileum. The secretion of intrinsic factor parallels gastric acid secretion, but is not necessarily linked to acid secretion, because administration of PPIs does not block the absorption of labeled vitamin B12. The absence of intrinsic factor leads to pernicious anemia, a disease associated with achlorhydria and the absence of

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

343

parietal cells. Because the liver stores vitamin B12 for a number of years, the manifestations of this disease usually occur several years after the disease process has begun. Patients with pernicious anemia or total gastrectomy require vitamin B12 supplementation (51–54).

Gastric Acid Secretion The acid secretory process is regulated by the parietal cell and is a process of active transport that requires the consumption of adenosine triphosphate (ATP). The hydrogen/potassiumadenosinetriphosphatase (Hþ/Kþ-ATPase) within the parietal cell is an ATP-driven proton pump, which transports Hþ ions into the lumen of the gastric pits in exchange for Kþ ions. Cl also follows hydrogen into the lumen by passive diffusion. For every Hþ ion that is secreted, one HCO3 ion is transported out of the basolateral membrane in exchange for passive diffusion of a Cl ion into the parietal cell. The HCO3 is formed with the aid of the catalyst carbonic anhydrase from CO2 and OH, which is accumulated within the cell. The Kþ, which is required for the Hþ/Kþ-ATPase, is supplied by accumulation of Kþ into the parietal cell from the basolateral membrane with the aid of an active Naþ/Kþ-ATPase. Kþ pumped into the parietal cell by the Naþ/Kþ-ATPase is then passed luminally via passive diffusion through a Kþ channel. The Kþ therefore is being recycled. Furthermore, insertion of the potassium and chloride channels into the luminal membrane is essential to acid secretion (55,56). The cellular processes that demonstrate production and secretion of HCl are demonstrated in Figure 12. The ultrastructure of the parietal cell is unique to the stomach and is designed to allow for the secretion of HCl against a large concentration gradient. The parietal cells can secrete HCl in concentrations up to 160 mEq/L and secrete up to 2 L/day. This solution can have a pH of less than 1, and because the pH of blood is 7.4, this means that the parietal cell requires large amounts of energy in the form of ATP to fuel acid secretion. This ATP energy is supplied by large concentrations of mitochondria. The parietal cell for this reason has the largest concentration of mitochondria of any cell in the body. The Hþ/Kþ-ATPase is the final common pathway for gastric acid secretion by the parietal cell and is composed of a catalytic alpha subunit and a glycoprotein beta subunit. During the nonsecreting state, gastric parietal cells store the Hþ/Kþ-ATPase subunits within intracellular tubular and vesicular membranes called tubulovesicles. While attached to the tubulovesicular membranes, the alpha and beta subunits of the Hþ/Kþ-ATPase are stored separately. The secretory canaliculus in a resting parietal cell is closed to the gastric lumen, but with stimulation of acid secretion these canaliculi fuse with the tubulovesicular membrane, expand, and open into the gastric lumen. Furthermore, the microvilli of the secretory canaliculus increase greatly in number and length, so that the surface area for secretion increases greatly. Following removal of the stimulus for acid secretion, the secretory canaliculus rearranges and collapses losing its luminal connection, and the Hþ/Kþ-ATPase heterodimer disassembles and returns to the cytoplasmic tubulovesicles (57–60). This entire process is referred to as the membrane recycling hypothesis (61). An example of this complex morphologic transformation is shown in Figure 13. The degree of acid secretion by the parietal cells depends on the overall influence of acid secretory and inhibitory pathways. Basal and stimulated gastric acid

Figure 12 HCl secretion of the parietal cell. The proton pump (H/KATPase) actively secretes hydrogen ions in exchange for potassium. Kþ passively returns to the gastric lumen via Kþ channels, which must be activated for Hþ secretion to occur. Cl also passively diffuses into the lumen. For every Hþ secreted into the lumen, one HCO3 ion passively enters the bloodstream in exchange for Cl. Abbreviation: H/K-ATPase, hydrogen/ potassium-adenosinetriphosphatase.

secretions are ultimately regulated by the Hþ/Kþ-ATPase, but three stimuli regulate its function. Acetylcholine, gastrin, and histamine all account for stimulation of acid secretion by the parietal cell (20,62–64). Acetylcholine is released from the vagus nerve and parasympathetic ganglion cells and is the principal neurotransmitter regulating acid secretion. Acetylcholine from vagal fibers not only directly stimulates the parietal cell, but also indirectly stimulates it by innervating G-cells and ECL cells, stimulating them to release gastrin and histamine, respectively (63). Release of gastrin by G-cells has direct hormonal effects on the parietal cell and also stimulates histamine release. The ECL cells release histamine, which has a paracrine-like effect on the parietal cell. Histamine plays a central role in the regulation of acid secretion because it potentiates the effects of gastrin and acetylcholine. Similarly, potentiation also exists between gastrin and acetylcholine. These effects of potentiation can be demonstrated by the fact that H2-receptor antagonists also block secretory responses to acetylcholine and gastrin. Likewise, atropine blocks histamine and gastrinstimulated acid secretion. Thus, not only does the degree of acid secretion depend on the sum of its stimulators, but potentiation also allows for small amounts of secretory stimuli to produce near maximal effects. The ability of the

medwedi.ru

344

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 14 Vagal control of gastric acid secretion and potentiation by histamine and gastrin. Psychic stimuli during the cephalic phase stimulates acid secretion via Ach either directly by activating Ach receptors on the parietal cell or by stimulating G-cells or ECL cells to release gastrin and histamine, respectively. Luminal stimulants such as distention or peptides also stimulate acid secretion via vagal afferents. Synaptic connections exist in the myenteric and submucosal plexus. Abbreviations: Ach, acetylcholine; ECL, enterochromaffin-like.

Figure 13 Electron micrograph demonstrating parietal cell conformational differences between an unstimulated and histamine-stimulated parietal cell. C, chief cell; M, mitochondria; N, nucleus; T, tubulovesicles; S, secretory membranes; arrow represents lumen of secretory canaliculus. Original magnification 7500. Source: Adapted from Ref. 57, with permission from the American Gastroenterological Association.

parietal cell to allow for potentiation is a result of having different second messenger systems for acid secretion. Acetylcholine, which binds to the M3 subtype of the muscarinic receptor, stimulates the formation of inositol triphosphate (IP3) and the subsequent release of intracellular calcium. Histamine binding to histamine receptors, which are G-protein coupled receptors, stimulates adenylate cyclase, resulting in increases in intracellular cyclic adenosine monophosphate (AMP) levels. The second messenger system for gastrin is intracellular calcium, which increases after gastrin interaction with its receptor. Gastrin receptors belong to the

CCK receptor family, are classical G-proteins, and are classified as either type A or type B. The type A CCK receptors have affinity for sulfated CCK analogs and a low affinity for gastrin. Type B CCK receptors have a high affinity for both gastrin and CCK and are the receptors responsible for increasing acid secretion. Figure 14 is a schematic of vagal acid stimulatory pathways and interaction of histamine and gastrin. In the absence of a stimulus for acid secretion, basal acid secretion is 10 to 20 mEq/L, is approximately 10% of maximal acid output, and has a circadian variation with night-time acid secretion being greater than that at daytime. Basal acid secretion appears to be regulated via a combination of cholinergic and histaminergic signals because vagotomy or atropine reduce basal acid secretion by approximately 75% to 90% and H2 receptor antagonists reduce it by approximately 90%. However, stimulation of gastric secretion is more complex and is described as consisting of three interrelated and concurrent phases: cephalic, gastric, and intestinal.

Cephalic Phase The cephalic phase (Fig. 15A) is also considered to be the psychic-neural phase of gastric secretion. This phase originates with the thought, sight, smell, or taste of food, and can be conditioned with the anticipation of a meal.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

345

Figure 15 Differential influences on gastric acid stimulation. (A) Psychic or neural influences on acid secretion are via vagal inputs, directly or indirectly via stimulation by gastrin or histamine. (B) Local gastric influences are via mechanical distention or chemical stimulation. (C) The intestinal phase of acid secretion begins when chyme enters the duodenum. Source: From Ref. 1, with permission of Elsevier.

Emotions such as aggression may stimulate secretion, while fear inhibits it. Also hypoglycemia may stimulate this reflex arc. While the exact mechanisms of how the afferent limbs of sight, smell, taste, and emotions or thoughts stimulate secretion are still to be fully elucidated, several higher centers in the brain have been identified and include the dorsal vagal complex, nucleus tractus solitarius, and dorsal motor nucleus and may involve the release of thyrotropin-releasing hormone. The efferent limb of the cephalic reflex is the vagus nerve. Besides directly activating the parietal cell via acetylcholine that binds to muscarinic receptors, the vagus indirectly activates secretion via stimulation of histamine and gastrin release. Indirect stimulation may be through acetylcholine or other mediators because although atropine attenuates the direct effects on the parietal cell, it does not block the release of gastrin during this phase. It appears that gastrin release via the vagus is mediated by acetylcholine as well as GRP. Although the secretory response in the cephalic phase is greater than that in the other phases, it accounts for approximately only 30% of the total volume of gastric acid produced because of the short duration of reflex. The entire cephalic phase can be blocked by vagotomy (65).

Gastric Phase When food enters the stomach, the gastric phase (Fig. 15B) of secretion begins. When the gastric contents reach the antrum, mechanical stretching and chemical stimulation (peptides, amino acids, calcium, ethanol, etc.) cause release of gastrin. Endocrine release of gastrin from antral G-cells into the bloodstream stimulates acid secretion. Protein components of a meal, particularly the aromatic amino acids phenylalanine and tryptophan, stimulate gastrin release. This release of gastrin is not blocked by vagotomy or atropine, but is blocked by acidification of the antral mucosa to below pH 3. Food also causes acid secretion via mechanical distention. Gastric distention activates

mechanoreceptors or stretch receptors in the stomach, which initiate both an intramural reflex that stimulates parietal cells directly via acetylcholine, and an extramural or vagovagal reflex that stimulates parietal cells directly via acetylcholine and stimulates gastrin release via GRP, and subsequent parietal cell stimulation indirectly. The vagovagal extramural reflex is identical to the cephalic phase and may be abolished by vagotomy. The entire gastric phase accounts for most (60–70%) of meal-stimulated acid output with mechanical distention accounting for approximately 30% to 40% of the response (65).

Intestinal Phase Entry of chyme into the duodenum begins the intestinal phase (Fig. 15C) of gastric secretion. Although the intestinal phase is poorly understood, it is believed that stretching of the intestinal wall and the absorbed amino acids stimulate gastric secretion. A stimulatory peptide hormone, now called enterooxyntin, released from the small bowel may mediate this phase. Although gastrin is found in the intestinal mucosa it is not released under normal conditions in humans. A low pH and fat in duodenal chyme inhibit acid secretion and this appears to be mediated via secretin, gastric inhibitory peptide, or somatostatin. The intestinal phase of gastric secretion appears to be designed to allow the quantity and composition of the chyme leaving the stomach to meet the requirements for digestion within the small intestine. With regard to acid secretion, the intestinal phase only accounts for 10% of the response to a meal (65).

Gastric Mucosal Barrier Gastric Mucus and Bicarbonate The presence of intraluminal gastric acid and its injurious effects warrants a protective mechanism to prevent the stomach from autodigestion. This is accomplished, in part,

medwedi.ru

346

Part Two: The Alimentary Tract—Esophagus and Stomach

by secretion of a gelatinous layer containing proteins, glycoproteins, mucopolysaccharide, and bicarbonate, which lines the superficial gastric epithelium to form a barrier between luminal contents and gastric mucosal cells. This mucuscontaining barrier is dynamic and constantly replenished by the surface epithelium. It functions as a buffer, neutralizing intraluminal acid to maintain a more physiologic pH at the mucosal surface. Furthermore, bile salts, pepsin, lysolecithin, and other luminal irritants, including those ingested, are retarded by the gel mucus layer. Release of mucus from vacuoles is stimulated by cholinergic activity as well as by the intraluminal application of acetylcholine and prostaglandins (66). Inhibition of mucus secretion is caused by agents that inhibit cyclooxygenase (COX), such as aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) (67). The mucus layer by itself is incapable of attenuating proton mobility and maintaining a neutral pH at the mucosal surface. Therefore, the mucosal barrier maintains an aqueous, alkaline layer on the mucosal surface by trapping bicarbonate secreted by mucosal cells located in the acid-secreting and antral portions of the stomach. This barrier maintains a steep pH gradient across it, which ranges from a pH of 2 on the luminal side to a pH of 7 on the epithelial side. Acid secretion is much greater than bicarbonate secretion and data suggests that transport of protons via channels away from the epithelial surface may serve to maintain this bicarbonate-rich layer (68). Recent evidence further suggests that prostaglandins produced by the constitutive isoform of COX also appear to play a large role in the secretion of bicarbonate and maintenance of the mucus layer (69). In addition, the increased utilization of NSAIDs by patients suggests a connection between nonselective COX inhibition and ulcer disease in humans (70,71). It also appears that the release of NO from the neuronal isoform of NOS contained within the superficial gastric epithelial cells functions as an important mediator in maintaining the gastric mucosal barrier (72). Furthermore, nonselective NOS inhibition has been shown to decrease gastric mucosal prostaglandin E2 release and aggravate gastric injury caused by luminal irritants (72–74). It also appears that low levels of NO released by constitutive NOS maintain gastric mucosal integrity and are gastroprotective, while high levels of unregulated NO release from inducible nitric oxide synthase (iNOS) contributes to gastric injury. It has also been shown that exogenous low-dose NO administration is gastroprotective while high-dose exogenous NO administration causes gastric injury (72,75).

Epithelial Barrier Not only is the mucosal barrier responsible for protection of the gastric mucosa, but an intact layer of surface epithelium also provides protection. Gastric surface epithelial cell membranes, tight junctions, and cellular renewal play a significant role in gastric defense. In normal gastric mucosa, there is a potential difference across the mucosa, which is the result of active transport maintained by the activity of the Na/K-ATPase, which pumps chloride into the lumen in exchange for sodium. Loss of this transmucosal electrical potential difference coincides with increased permeability of the epithelium, which predisposes the surface epithelium to further damage as protons flux into the mucosa in exchange for an efflux of sodium, proteins, water, and glucose into the lumen. Luminal irritants such as aspirin, NSAIDs, ethanol, bile salts, pepsins, Helicobacter pylori, and lysolecithin can damage the epithelial layer and cause changes in its

permeability. Fortunately, the gastric surface epithelium replaces itself faster than any other epithelial surface in the body. The turnover rate for surface epithelium is approximately every three days. Mucous neck cells, which are found between the gastric pit and gland, migrate luminally and become surface epithelium. This migration of cells functions to replace injured surface epithelium and represents a component of epithelial defense against injury. A more rapid defense mechanism of the epithelium is called restitution or re-epithelialization. This process occurs during superficial gastric injury and consists of the migration of epithelial cells across denuded or superficially injured areas (76–78). Repair in this fashion is rapid and occurs within 60 minutes. Restitution does not require cell division, but it does require an intact muscularis mucosae.

Gastric Mucosal Blood Flow Gastric mucosal blood flow also plays a major role in gastroprotection (73,79,80). Blood flow not only ensures the proper delivery of oxygen and nutrients to the gastric mucosa, but also ensures prompt removal of any protons that may have traversed the epithelial barrier. Because the gastric mucosa is vulnerable to injury when the pH falls below 4, prompt removal of hydrogen ions by the rich network of capillaries represents another defense mechanism. Furthermore, blood flow functions to remove any toxic oxidative radicals that may be liberated during times of stress or from ischemia and reperfusion. Low pH and oxygen-derived free radicals may injure the gastric mucosa by causing derangements in cellular membranes or subcellular organelles, or by compromising various enzymatic functions. Hypoperfusion of the gastric mucosa also causes a relative anaerobic state secondary to depletion of ATP, which is necessary for aerobic metabolism. Depletion of ATP further compromises enzymatic functions, especially functions of the Na/K and H/KATPases. Given the rich blood supply of the stomach, it tolerates most reductions in blood flow reasonably well. However, when gastric mucosal blood flow is reduced by 40% of normal values, gastric injury may occur (81). When blood flow is reduced by more than 70%, marked mucosal injury results, and the presence of luminal irritants or acid greatly exacerbates injury (81). Locally produced NO and prostaglandins represent potent vasodilators in the gastric mucosa that serve to enhance mucosal blood flow in the face of a damaging luminal insult and thereby limit the extent of gastric injury (80,82,83).

ABNORMAL PHYSIOLOGY Stress Gastritis Stress gastritis remains an important clinical concern especially in the intensive care unit (ICU) setting. Although improvements in ICU care, recent advances in the understanding of the pathophysiology of gastritis, and the availability of more potent antisecretory agents have decreased the incidence of this problem, life-threatening gastric bleeding from stress ulcerations can still occur (84). Stress gastritis is typically seen in critically ill patients and appears to be associated with alterations in gastric mucosal defense and barrier function. The presence of gastric acid is also a predisposing factor, although acid secretion is not necessarily increased. These lesions are associated with a number of clinical predisposing conditions, including multiple traumatic injuries, endotoxemia or sepsis, shock, cardiac dysfunction, and multiple organ failure (84). Other terms used

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

to describe this condition include stress erosive gastritis, hemorrhagic gastritis, and hemorrhagic erosive gastritis. Stress ulcerations are characterized by their endoscopic appearance and typically change over time. When they appear within the first 24 hours after a stressor or injury, they are referred to as acute stress gastritis. In this setting, the gastritis is characterized by multiple superficial erosions in discrete areas of the gastric mucosa, with or without focal hemorrhage or an adherent clot. These lesions typically begin in the proximal or acid-secreting portion of the stomach and appear microscopically as small wedgeshaped mucosal hemorrhages with coagulation necrosis of the superficial mucosal cells. If acute stress gastritis lesions progress, they can erode into the submucosa and the underlying vasculature to cause frank hemorrhage. When these lesions progress to ulceration, or if clot organization or an inflammatory exudate develops, the lesions are classified as the late form of acute stress gastritis. This usually occurs 24 to 72 hours after a stressor or injury (84). These late lesions have extension of hemorrhage, inflammatory cell infiltration, and coagulation necrosis into the muscularis mucosa layers of the stomach when viewed microscopically. In addition, they appear identical to that of regenerating mucosa around a healing gastric ulcer.

Pathophysiology Recent experimental observations have identified a number of factors that appear to contribute to stress erosive gastritis. However, the precise mechanisms responsible for the development of this condition still remain to be fully elucidated. The common theme for its development appears to be dysfunctional intrinsic gastric mucosal defense mechanisms as opposed to an increase in acid secretion. However, stressinduced gastric lesions do appear to require the presence of acid. Stress gastritis lesions are most commonly found in critically ill patients, and by definition they occur after physical trauma, shock, sepsis, hemorrhagic shock, renal failure, respiratory failure, prolonged intubation, head trauma, or severe burns. The factors that appear to predispose to the development of gastritis from the above injuries or physiologic changes include reduced gastric mucosal blood flow, a reduction in mucus or bicarbonate secretion, or a reduction in endogenous NO or prostaglandin secretion (75,80,82,85). Another common factor is the development of mucosal ischemia such as that seen when hypoxia, sepsis, or organ failure occurs. In this setting, mucosal ischemia is thought to cause a breakdown of normal defense mechanisms. As a result, luminal acid is then able to damage the more susceptible mucosa by increased back-diffusion of hydrogen ions into the mucosa (86,87). That such back-diffusion of protons occur with gastric barrier disruption has been confirmed experimentally (88). It is also thought that this back-diffusion might elicit histamine release with vasodilatation and eventual bleeding if there is erosion into the mucosa (89). Although the diffusion of protons into the gastric mucosa is thought to be partly responsible for the development of gastritis lesions, there is little evidence to suggest that this-back diffusion is caused by increased gastric acid secretion. In fact, it has been shown in animal models that during endotoxemia and ischemia-reperfusion, basal and pentagastrin-stimulated acid secretion is decreased (72,90,91). Nevertheless, the presence of luminal acid still appears to be a prerequisite for gastritis to occur. Moreover, complete neutralization of luminal acid or treatment with antisecretory agents precludes the development of stress gastritis (92).

347

Stress gastritis lesions occur in several clinical settings. The first setting occurs in patients who experience some form of major stress. Included in this category are patients with severe illnesses or multiple organ failure, polytrauma, sepsis, hemorrhagic shock, or ischemia-reperfusion injuries. When lesions occur in this setting, there is a possibility for significant hemorrhage if the erosion extends into the larger submucosal vessels. Hemorrhagic bleeding from these forms of stress erosions can be life threatening and may require urgent endoscopy or surgical intervention. Mucosal ischemia with production of damaging free radicals is thought to be a predominant factor responsible for causing derangements in the intrinsic gastric mucosal defense system. Alternatively, in rat models of endotoxemia, a reduction in NO from the constitutive isoform of NOS and excessive NO production from the inducible isoform of NOS cause injury to the cytoskeletal components within cells of the gastric epithelium, rendering the stomach more susceptible to injury from luminal irritants (72). Defects in cyclooxygenase metabolism have also been proposed as a possible etiologic factor (93). The second clinical scenario is not necessarily related to a defect in mucosal defense, but rather related to elevated levels of serum gastrin and secondary increases in acid secretion. These lesions are most commonly seen in patients who have sustained head trauma, with acute injury to the CNS, the so-called ‘‘Cushing’s ulcer.’’ These lesions are characteristically deeper than other acute erosions and are more likely to erode through the stomach. Often the Cushing’s ulcer presents as a single ulcerative focus that can develop in the stomach or duodenum. The third scenario is the ‘‘Curling’s ulcer,’’ which occurs in patients with extensive burns. This variety frequently extends from the stomach into the duodenum and may be demonstrable only there, in contrast to most forms of stress ulcers, which are more commonly confined to the proximal stomach. Despite the potential for hemorrhage, the incidence of this life-threatening problem has significantly diminished in recent years, presumably due to improvements in our ability to manage critically ill patients and our ability to identify and prophylactically treat patients at risk. Risk factors for developing hemorrhagic gastritis include the presence of adult respiratory distress syndrome, multiple trauma (especially head trauma), prolonged intubation, major burns over 35% of the body surface area, oliguric renal failure, large transfusion requirements, hypotension, sepsis, hepatic obstruction, prolonged surgical procedures, and sepsis from any source as predisposing factors. In addition, there has been a direct correlation between acute upper GI hemorrhage and the severity of underlying critical illness (94).

Presentation and Diagnosis The predominant clinical sign of gastritis is painless upper GI bleeding. More than 50% of patients develop their stress gastritis within one to two days following a traumatic event. The clinical signs may present in a delayed fashion because the erosive lesions must erode into the submucosal vessels for bleeding to occur. Typically, gastric bleeding from gastritis is slow and intermittent and may only be detectable by a few flecks of blood in the nasogastric tube or by an unexplained drop in the hemoglobin levels. Similarly, heme-positive stool may be detected on rectal examination, although melena and hematochezia are rare. If hemorrhage occurs, endoscopy must be performed to differentiate stress gastritis from other sources of GI hemorrhage and to

medwedi.ru

348

Part Two: The Alimentary Tract—Esophagus and Stomach

potentially provide endoscopic therapy. Upper endoscopy is diagnostic in greater than 90% of patients and is the diagnostic modality of choice (95). If the development of upper GI bleeding from gastritis is not identified and treated appropriately, profound hemorrhage can develop, accompanied by hematemesis and hemorrhagic shock.

and all bleeding points are secured, the incidence of rebleeding is low (85,101). In contrast, some surgeons prefer to perform a partial gastrectomy in combination with vagotomy. However, the only indication for total gastrectomy is in the rare patient who presents with life-threatening hemorrhage refractory to other forms of therapy.

Therapy

Prophylaxis

Any patient who presents with significant upper GI bleeding requires prompt fluid resuscitation, with correction of any coagulation or platelet abnormalities as well as the administration of blood if it is required. The initial treatment should consist of saline lavage of the stomach through a nasogastric tube to remove blood and clots that may prolong bleeding through fibrinolysis. Placement of a nasogastric tube also helps to prevent gastric distention, which could stimulate gastrin release and cause a secondary increase in gastric acid secretion. Nasogastric decompression and/or gastric lavage also removes gastric acid, bile, and pancreatic juice that may have refluxed back into the stomach, all of which may potentially further exacerbate gastric mucosal injury. This approach ceases upper GI hemorrhage from gastritis in over 80% of patients and allows visualization during endoscopy (96–98). Once bleeding has ceased as demonstrated by clear nasogastric tube aspirates, the intraluminal gastric pH should be maintained at greater than 5.0 with antisecretory agents. The mainstay of treatment is with a PPI. Alternatively, histamine receptor antagonists, with or without the combination of an antacid, can also be used. Furthermore, sepsis must be treated with appropriate antimicrobials in conjunction with control of the infectious source. While endoscopy is useful to determine the etiology of upper GI bleeding, there is little evidence to suggest that endoscopic treatment with electrocautery or heater probe coagulation has any benefits in the therapy of bleeding from acute stress gastritis. Another treatment modality is the selective infusion of vasopressin into the splanchnic circulation via the left gastric artery because some studies suggest that it may be effective at controlling acute bleeding (99,100). If vasopressin instillation is instituted, it is administered by continuous infusion through a catheter at a rate of 0.2 to 0.4 IU/min for a maximum of 48 to 72 hours. Vasopressin should not be used in patients with underlying cardiac or liver disease. However, while vasopressin may decrease blood loss, it has not been shown to result in improved survival (100). Because of the extensive submucosal plexus of arterial vessels within the stomach, interventional radiology using angiography techniques has also been tried, but for the most part is unsuccessful. Surgical intervention is not usually required for acute stress gastritis. However, if there is recurrent or persistent bleeding that requires more that six units of blood, surgery may be indicated. If surgery is attempted, one approach is through a long anterior gastrotomy in the proximal stomach because most lesions of stress gastritis are found in this region. The gastric lumen is then cleared of blood and the specific bleeding points identified. Bleeding areas are managed with figure of eight stitches taken deep within the gastric wall. Any actively bleeding site needs to be secured by suture. Most superficial gastric erosions are not actively bleeding at the time of surgery and therefore do not usually require ligature unless a blood vessel is seen at the base. After completing the operation by closing the anterior gastrotomy, a truncal vagotomy and pyloroplasty should be performed to reduce acid secretion. If the surgeon is diligent

In light of the high mortality rates associated with acute gastritis in patients who develop massive upper GI hemorrhage, prophylaxis is recommended for high-risk ICU patients. In patients at risk, treatment of any metabolic derangements, underlying organ dysfunction, or untreated sepsis needs to be initiated. This includes resuscitation to correct any perfusion deficits from shock and administration of antibiotics and source control for sepsis. Ventilatory support should be optimized in addition to correcting any systemic acid–base abnormalities. Furthermore, nutritional support is mandatory, preferably via the enteral route, because it is associated with fewer infectious complications (102). In addition to the aforementioned modalities to optimize patient care, prophylactic therapy should be given to those patients at high risk. The patients at risk for stress gastritis in the intensive care setting appear to be patients with respiratory failure who require mechanical ventilation or who have hypotension, sepsis, or an underlying coagulopathy (103). Prophylactic therapy is usually aimed at neutralizing or preventing acid secretion. In the past, antacids were administered as prophylaxis for stress gastritis and had an efficacy of 96%. This usually required hourly administration of antacids via the nasogastric tube and intraluminal gastric pH was maintained above 3.5. For most patients, attempts were made to maintain the pH above 5.0 as more than 99.9% of acid is neutralized and pepsin is inactivated. Several controlled prospective trials have demonstrated that titration of gastric pH with antacids is effective at preventing GI bleeding in patients at risk for stress gastritis in the ICU setting (104–107). H2 receptor antagonists have also been used as prophylactic agents to prevent stress ulceration. However, there does not appear to be any advantage to prevention of acute stress gastritis when comparing antacids versus H2 blockers (108). Nevertheless, H2receptor antagonists have about a 97% efficacy when used as medical prophylaxis for stress gastritis (108). Sucralfate is another agent that has been employed for prophylaxis against stress gastritis and is extremely efficacious in the 90% to 97% range. It may be given in a dose of 1 g every six hours and may be just as effective as antacids or H2 receptor antagonists (105,109). Furthermore, this form of prophylaxis has the added benefit of allowing the stomach to maintain its normal pH and thus prevent bacterial overgrowth. This latter effect may be beneficial because several studies have suggested that gastric luminal alkalinization predisposes the stomach to bacterial overgrowth and subsequent nosocomial pneumonia (110,111), although a review of the published literature does not necessarily support this (112). Lastly, exogenous prostaglandins have also been tried as stress gastritis prophylaxis agents. However, their efficacy appears to be less than that of the other agents.

Peptic Ulcer Disease Epidemiology Peptic ulcer disease remains one of the most prevalent and costly GI diseases. In the United States, the annual incidence

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

of active ulcer (gastric ulcer and duodenal ulcer) is about 1.8% or roughly 500,000 thousand new cases per year. In addition, there are approximately 4,000,000 ulcer recurrences yearly (113). In the last two decades, elective admissions have decreased dramatically, while admissions for complications related to ulcer disease have shown little change (114). Each year, it is estimated that three to four million patients are seen by a physician for diagnosis and treatment of peptic ulcer disease, and an additional three to four million patients are self-medicating. Furthermore, it is estimated that over 130,000 operations are performed yearly for peptic ulcer disease, and approximately 9000 patients die from complications related to their peptic ulcer disease. While hospitalization rates for duodenal ulcers have decreased, they have remained relatively stable for gastric ulcer (113,115,116). However, admissions for bleeding gastric ulcers have increased over the last several years and they are more likely to occur in elderly patients (113,117,118). This increase in the occurrence of gastric ulcers complicated by bleeding is also associated with an increase in NSAID ingestion. Interestingly, the incidence in peptic ulcer has increased in women in the United States while it has decreased in men (113). It is speculated that the increase in the number of women with peptic ulcer disease is in part due to an increase in the prevalence of smoking and an increase in NSAID ingestion. The most common cause of death in patients with peptic ulcer disease is bleeding in patients who have major medical problems or are over the age of 65 (113,116,118). In patients with peptic ulcer disease that presents with upper GI bleeding, approximately 80% of these bleeds are selflimited. However, there is approximately a 10% incidence of mortality (113,116,118). The national American Society for Gastrointestinal Endoscopy (ASGE) survey on upper GI bleeding demonstrated that mortality increases with age, rebleeding, and with comorbid conditions. In patients under 60 years of age the mortality was 8.7%. For those over 60, the mortality was 13.4%. Recurrent bleeding increases the mortality rate to approximately 30% to 44%. For patients with no comorbid conditions, the mortality rate was 2.5%. However, with three significant comorbid conditions the mortality rate increased to 15%, and with six comorbid conditions the mortality rate rose to 67%. Other factors of an adverse outcome from upper GI hemorrhage are a visible vessel on endoscopy, oozing of bright red blood, and fresh blood clot at the base of the ulcer. Pumping or oozing lesions had a significantly greater need for surgical management and were associated with a higher mortality, 24% and 16%, respectively (119,120). Perhaps the most drastic change in our understanding of peptic ulcer disease is the identification of H. pylori and the realization that peptic ulcer disease is in reality an infectious disease. Human gastric bacteria were first discovered in the early 1900s. In the 1920s, urease was erroneously thought to be produced by humans and to be protective. In the 1950s, these previously observed bacteria were dismissed as contaminates. However, in the 1970s, gastric bacteria were rediscovered and found to be associated with inflammation. Twelve years later, the first successful culture of the organism was accomplished by Marshall and Warren, who named it Campylobacter pyloridis (121). Then, in 1987, it was reported that eradication of the organism reduced duodenal ulcer recurrence (122). Following reclassification of the organism to H. pylori in 1989, the National Institutes of Health (NIH) convened a consensus panel that issued guidelines for management of ulcer disease, taking H. pylori into account. Consequently, any treatment plan for peptic

349

ulcer disease, both medical and surgical, requires that H. pylori be considered. The association between H. pylori and peptic ulcer disease is discussed in more detail in the section on ‘‘Pathogenesis.’’ Despite our advances in medical therapy to inhibit acid secretion and to eradicate H. pylori, surgery remains important in managing patients suffering from peptic ulcer disease. Over the last two decades, there has been an increase in emergency operations performed for complications of peptic ulcers while the number of operations for elective indications has decreased markedly (113). Moreover, there is a high recurrence rate for peptic ulcerations following discontinuation of medical therapy. As a result, there is a renewed interest in operative management of patients with peptic ulcer disease, although the indications for surgery have not changed (bleeding, perforation, obstruction, intractability, etc.). However, the type of operation performed for peptic ulcer disease has changed in the H. pylori era (123–125). While some of the earliest surgical procedures for peptic ulcer disease usually involved some type of gastrectomy, later operations involved denervating the parietal cell secreting mass with some sort of vagotomy (see below). However, recent studies indicate that vagotomy may not even be necessary in some situations such as perforation of the duodenum, provided that H. pylori is eradicated (124).

Location and Type of Ulcer Peptic ulcer disease can be divided into gastric and duodenal ulcers. Both types tend to occur near mucosal junctions. Duodenal ulcers usually occur at the duodenal-pyloric junction, whereas gastric ulcers tend to occur at the oxynticantral junction, the antral-pyloric junction, or the esophagogastric junction. By definition, an ulcer extends through the muscularis mucosa, in contrast to an erosion, which is superficial to the muscularis mucosa. Duodenal ulcer disease usually occurs in the first portion of the duodenum just beyond the pyloric sphincter (i.e., duodenal bulb). It is almost always associated with the secretion of acid and pepsin in conjunction with either H. pylori infection or the ingestion of NSAIDs (126). Occasionally, it may occur in more distal parts of the duodenum if caused by the ZES (see below). In comparison, gastric ulcer may present in four forms (Fig. 16). Type 1 gastric ulcers are most common, accounting for about 60% to 70% of the total. These are typically located on the lesser curvature at or proximal to the incisura, near the junction of the oxyntic and antral mucosa. Most are associated with diffuse antral gastritis or multifocal atrophic gastritis. Type 2 gastric ulcers (about 15%) occur in the exact location as the Type 1 lesion, but are associated with either active or chronic duodenal ulcer disease. Type 3 gastric ulcers (20%) are usually located within 2 cm of the pylorus. The fourth type of gastric ulcer is located in the proximal stomach or in the cardia and is rare in the United States and Europe but common in Latin America. Types 2 and 3 gastric ulcers appear to behave more like duodenal ulcers in that they are associated with excess acid secretion. In contrast, Type 1 and Type 4 gastric ulcers are usually not associated with excess acid secretion. Moreover, gastric cancers may ulcerate and resemble gastric ulcers. Furthermore, ulcers may be caused by nonacid conditions or other peptic disorders such as Crohn’s disease, pancreatic rests, syphilis, Candida, or malignant diseases such as Kaposi’s sarcoma, lymphoma, carcinoma, or pancreatic carcinoma.

medwedi.ru

350

Part Two: The Alimentary Tract—Esophagus and Stomach

Figure 16 Location of gastric ulcers. Type 1 gastric ulcers are located in the gastric body usually within the lesser curvature. Type 2 ulcers are Type 1 ulcers associated with a duodenal ulcer. Type 3 ulcers are located within the prepyloric gastric antrum. Type 4 gastric ulcers are located high on the lesser curvature near the cardia.

Pathogenesis H. pylori Infection H. pylori is believed to be associated with approximately 90% of duodenal ulcers and approximately 75% of gastric ulcers. The organism was first identified and isolated by Marshall and Warren (121). They were also the first to appreciate the relationship between H. pylori infection and gastritis. The organism is a helical-shaped gram-negative rod with four to six flagellae and is found within gastric epithelium or within sites of gastric metaplasia in the esophagus, duodenum, rectum, or Meckel’s diverticulum. H. pylori is usually only found in gastric epithelium because the epithelium expresses specific adherence receptors that are recognized by the bacterium (127,128). Its pathogenicity is related to the production of endotoxin and other toxic products that cause local tissue injury, production of urease, local mucosal immune responses, or increased gastrin levels with an associated increase in acid secretion. The virulence factors that are most often implicated in H. pylori–induced mucosal injury are CagA and VacA cytotoxins, ammonia, protease, lipase, and urease enzymes (129–131). H. pylori– induced release of proinflammatory mediators and cytokines such as NO via iNOS, COX-2, tumor necrosis factor-a, gamma interferon, interleukin (IL)-1b, IL-4, IL-6, IL-8, IL-10, endothelin-1, and nuclear factor-kappa beta have also been implicated in mucosal injury, apoptosis, and gastric cancer (132–137). Other injurious effects of H. pylori are related to its ability to induce apoptosis and abrogate cell-cycle progression and cellular proliferation (134,135). Locally produced toxic mediators include breakdown products of urease (i.e., ammonia), cytotoxins, mucinase, which degrades mucus and glycoproteins, phospholipases, which damage mucus and epithelial cells, and platelet activating factor, which causes microcirculation thrombosis and mucosal injury (129,131). H. pylori production of chemotactic factors also causes a local inflammatory reaction with infiltration and recruitment of neutrophilic polymorphonuclear cells, lymphocytes, plasma cells, macrophages, and eosinophils, and later with the development and recruitment of specifically committed cells [lymphocytes sensitized to H. pylori antigens and B-cells producing immunoglobulin

(Ig) (IgA, IgG, and possibly IgE antibodies)] against a variety of H. pylori surface and flagellar proteins. Subsequently, there is formation of lymphoid follicles, which are not normally present in the gastric mucosa (138,139). In patients with H. pylori infection and duodenal ulcer disease, basal and stimulated gastrin levels are significantly increased (140–144). Some data suggest that the mechanism responsible for increased gastrin levels is the H. pylori infection that causes a reduction in antral D-cells (141). A reduction in D-cells leads to a reduction in somatostatin synthesis, which causes an increase in gastrin synthesis due to disinhibition of antral G-cells (i.e., loss of tonic somatostatin inhibition) (141). Other mechanisms suggested for changes in these gut hormones are from ammonia produced by H. pylori and monochloramine, the effect on somatostatin receptor subtype-2, the action of lipopolysaccharide from H. pylori on somatostatin receptors, infiltration of inflammatory cells and release of inflammatory mediators, and diversity of bacterial strains (140). Regardless of the mechanisms, eradication of H. pylori leads to an increase in antral D-cells, with an increase in somatostatin synthesis and a concomitant decrease in gastrin levels (141,145). While H. pylori infection appears to cause a reduction in antral D-cells, with a reduction in somatostatin and a concomitant increase in serum gastrin levels, there is not necessarily an increase in gastric acid secretion. Although H. pylori–infected patients with duodenal ulcers do have a marked increase in acid secretion, H. pylori–positive healthy volunteers have a small increase or no increase in acid secretion when compared to H. pylori–negative volunteers (142). In addition, other studies suggest that increased acid secretion in duodenal ulcer patients is a result of increased parietal cell mass that is independent of, or not related to, H. pylori infection (142,145). Peptic ulcers are also strongly associated with antral gastritis. Even before identification of H. pylori, it was known that almost all peptic ulcer patients had histologic evidence of antral gastritis. However, it is now well recognized that most cases of histologic gastritis are due to H. pylori infection. In fact, the only patients with gastric ulcers and no gastritis are those ingesting aspirin or other NSAIDs. In one study the occurrence of antral inflammation, atrophy, and intestinal metaplasia did not differ between patients with H. pylori– negative and H. pylori–positive ulcers, but activity of gastritis was more common in H. pylori–positive than in H. pylori– negative patients (94.9% vs. 47.1%, respectively) (147). H. pylori–negative peptic ulcer disease was independently associated with older age, bile reflux, the use of nonsteroidal anti-inflammatory analgesics, and intestinal metaplasia, while H. pylori–positive peptic ulcer disease was associated with active inflammation of the antral mucosa and tendency to ulcer recurrence (147). In most cases, the infection tends to be confined initially to the antrum with a resultant antral inflammatory reaction. Further evidence supporting a causal role for H. pylori in histologic gastritis is the finding that eradication of H. pylori improves gastric histology, although gastritis does not necessarily equate with symptoms of dyspepsia (148). H. pylori represents a chronic infection found worldwide. Once a person is infected, usually in childhood, it is probably for life because spontaneous remission is rare. There also tends to be an inverse relationship between infection and the socioeconomic status. The reasons for this remain poorly understood, but may be due to factors such as sanitary conditions, familial clustering, and crowding. The etiology of transmission is still elusive although a fecal–oral or oral–oral

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

route has been suggested because there is a strong relationship between children and familial crowding and H. pylori infection, which suggests person-to-person transmission. In fact, several studies have documented familial clustering of H. pylori infection, demonstrating that H. pylori in one household member is associated with a greater chance of infection in other members (149–151). In another study, H. pylori infection was most common in the lowest socioeconomic class (85%), intermediate in the middle class (52%), and lowest in the highest class (11%) (152). The odds ratio for H. pylori infection comparing the highest childhood crowding index with the lowest crowding was 4.5 (95% confidence interval of 3.3–5.7), indicating a marked and significant effect of childhood crowding on H. pylori infection (152). These data provide strong evidence that the infection is transmitted by a person-to-person route and that the infection is commonly acquired early in life. H. pylori infection is associated with a number of common upper GI disorders. It is virtually always present in the setting of active chronic gastritis and is present in the majority of duodenal and gastric ulcer patients. In several studies H. pylori was found in 75% to 95% of duodenal ulcers and 70% of gastric ulcers (153,154). Noninfected gastric ulcer patients tend to be NSAID users. There is a less strong association with nonulcer dyspepsia, which is probably in the range of about 50%. In addition, a substantial number of gastric cancer patients show evidence of past H. pylori infection. There is also a strong association between mucosalassociated lymphoid tissue (MALT) lymphoma and H. pylori infection. Interestingly, regression of these lymphomas has been demonstrated following eradication of the organism and therefore H. pylori eradication should be attempted before chemotherapy (155). Limited data are available to estimate the lifetime risk of developing an ulcer in patients with H. pylori infection. However, Sullen et al. from Australia performed a serologic study with a mean period of evaluation of 18 years. During this time frame, 15% of H. pylori–positive subjects developed verified duodenal ulcer as compared to 3% of seronegative individuals (156). Another study by Sipponen et al. evaluated patients after 10 years in Scandinavia. This study was related to the presence or absence of histologic gastritis at the time of their initial assessments. Because H. pylori causes most cases of histologic gastritis, this observation was used as a marker for H. pylori infection. In this study, 11% of the patients with histologic gastritis developed peptic ulcer disease over a 10-year period as compared with only 1% of those without gastritis (157). It should also be noted that the incidence of ulcers in these two studies may have been underestimated as many patients with asymptomatic or minimally symptomatic ulcers may not have presented for medical evaluation. However, another factor implicating a causative role for H. pylori in ulcer formation is that eradication of H. pylori dramatically reduces ulcer recurrence (158,159). Although ulcers are easily cured using a variety of medications, they tend to recur if H. pylori is not eradicated or acid-lowering surgery is not performed. However, a large number of prospective trials now document that patients with H. pylori infection and ulcer disease who have documented eradication of the organism, virtually never (< 2%) develop recurrent ulcers (154,160,161) and the rate of reinfection with H. pylori is less than 5% (154,161,162). If H. pylori is not eradicated after treatment, a significant number (50–75%) may have an ulcer recurrence by one year (159,163–166); however, in the presence of antiulcer

351

maintenance therapy with acid inhibitors, this rate decreases to approximately 25% at 12 months (164,166). In this latter group, in those patients who do develop recurrent ulcers, they are usually associated with NSAID utilization. In the Cochrane Database Review of recurrent bleeding from peptic ulcer disease after treatment, seven studies with a total of 578 patients demonstrated that the mean percentage of rebleeding with H. pylori eradication therapy was 2.9%, and without H. pylori eradication therapy, in groups without subsequent long-term maintenance antisecretory therapy, it was 20% (167). In three other studies with a total of 470 patients, the mean percentage of rebleeding in H. pylori eradication therapy group was 1.6%, and in noneradication therapy group with long-term maintenance anti-secretory therapy it was 5.6% (167). Nonsteroidal Anti-Inflammatory Drugs After H. pylori infection, ingestion of NSAIDs is the most common cause of peptic ulcer disease. As previously mentioned, hospitalizations for bleeding upper GI lesions are increasing along with increased NSAID use. Most of the increased NSAID utilization has occurred in women above the age of 50, which is also the group with the increase in bleeding gastric ulcers (168). The increased risk of bleeding has been documented in placebo-controlled trials with chronic aspirin utilization for prevention of recurrent heart attack or stroke (169). Furthermore, the increased risk of bleeding and ulcerations is proportional to the daily dosage of NSAID (170). Consequently, the ingestion of NSAIDs remains an important factor in ulcer pathogenesis, especially in relationship to the development of complications and death (170). The role of NSAIDs in peptic ulcer disease becomes even more meaningful if one considers the fact that roughly three million people in the United States take NSAIDs daily and about 1 in 10 patients taking daily NSAIDs have an acute ulcer. In addition, 2% to 4% of NSAID users have GI complications each year and greater than 3000 deaths and over 25,000 hospitalizations per year are attributable to NSAID-induced GI complications. Moreover, when compared to the general population, NSAIDs increase the risk of GI complications approximately 2- to 10-fold (170). NSAID ingestion not only causes acute gastroduodenal injury, but also is associated with chronic gastroduodenal injury. This risk of mucosal injury and/or ulceration is roughly proportional to the anti-inflammatory effect associated with each NSAID (170). While acute epigastric pain is common during the acute phase, it does not necessarily correlate with mucosal lesions. However, the presence of chronic epigastric pain is more suggestive of ulceration. The acute gastroduodenal lesions typically appear within one to two weeks of ingestion of the NSAIDs and range from mucosal hyperemia to superficial gastric erosions. In contrast, chronic injury typically occurs after one month and may be seen in the stomach as erosions or ulcerations in the gastric antrum or in the duodenum. Again, ulcer risk is dose related and the acute mucosal response does not necessarily predict subsequent ulcer risk. In comparison to H. pylori ulcers, which are more frequently found in the duodenum, NSAID-induced ulcers are more frequently found in the stomach. H. pylori ulcers are also nearly always associated with chronic active gastritis, whereas gastritis is not frequently found with an NSAID-induced ulcer, occurring only about 25% of the time. In addition, when NSAID use is discontinued, the ulcers usually do not recur, whereas with H. pylori–related ulcers, there is a 50% to 80% recurrence rate in one year unless the organism is eradicated with therapy (154).

medwedi.ru

352

Part Two: The Alimentary Tract—Esophagus and Stomach

Acid There is a linear relationship between maximal acid output and parietal cell number. However, gastric acid secretory rates are altered in patients with upper GI diseases. Basal acid secretion is normally in the 1 to 8 mmol/hr rate and the response to pentagastrin ranges from 6 to 40 mmol/hr. In Types 1 and 4 gastric ulcers, basal as well as pentagastrin-stimulated acid output is decreased. In contrast, gastric secretory rates are increased in patients with duodenal ulcers and gastrinoma. In fact, an adequate level of acid secretion is a prerequisite for duodenal ulcers and their presence is rare in patients who have a maximal acid output of less than 12 to 15 mmol/hr. For Types 1 and 4 gastric ulcers, which are not associated with excessive acid secretion, acid acts as an important cofactor, exacerbating the underlying ulcer damage and retarding the ability of the stomach to heal. For patients with Type 2 or 3 gastric ulcers, gastric acid hypersecretion does seem to be more common, and consequently they behave more like duodenal ulcers. Duodenal Ulcer Pathophysiology Duodenal ulcer is a disease of multiple etiologies. Its development usually requires acid and pepsin secretion in combination with either infection with H. pylori or ingestion of NSAIDs. In addition, these patients have a variety of secretory abnormalities (Table 2) (171). The more common secretory abnormalities relate to decreased bicarbonate secretion, increased nocturnal acid secretion, increased duodenal acid load, and increased daytime acid secretion. There is also a strong correlation between parietal cell number and maximal acid output. Interestingly, mean parietal cell number is increased in duodenal ulcers patients but not in gastric ulcer patients (172). However, at least two-thirds of duodenal ulcer patients and gastric ulcer patients fall within the normal range. Additionally, there is considerable overlap in gastric acid secretion between duodenal ulcer patients and normal patients without ulcer disease. Because the overlap between duodenal ulcer patients and normal subjects is so great, acid secretory testing is of little value in establishing a diagnosis of duodenal ulcer. Nevertheless, subjects with maximal acid secretion less than 10 mmol/hr are unlikely to develop or have duodenal ulcer disease. Gastric Ulcer Pathophysiology Gastric ulcers can occur anywhere in the stomach, although they usually present on the lesser curvature near the incisura angularis as shown in Figure 16. Approximately 60% of ulcers are located in this location and are classified as Type 1 gastric ulcers. These ulcers generally are not associated with excessive acid secretion and usually have low to normal acid output. Most occur within 1.5 cm of the histologic transition zone between the fundic and antral Table 2 Frequency of Duodenal Ulcer Secretory Abnormalities Decreased duodenal bicarbonate secretion (70%) Increased nocturnal acid secretion (70%) Increased duodenal acid load (65%) Increased daytime acid secretion (50%) Increased pentagastrin-stimulated maximal acid output (40%) Increased sensitivity to gastrin (35%) Increased basal gastrin (35%) Increased gastric emptying (30%) Decreased pH inhibition of gastrin release (25%) Increased postprandial gastrin release (25%)

Table 3 Conditions Associated with Gastric Ulceration Age > 40 Female > male (2:1) Aspirin/NSAIDs Abnormalities in acid–pepsin secretion Gastric stasis Delayed gastric emptying Burns Head trauma

Duodenal ulcer Duodenal gastric reflux of bile Gastritis Helicobacter pylori Tobacco Alcohol Corticosteroids Infection/sepsis

Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.

mucosa. In contrast, Type 2 gastric ulcers are located in the body of the stomach in the same location as a Type 1, but occur in combination with a duodenal ulcer. These types of ulcers usually are associated with excess acid secretion. Type 3 gastric ulcers are prepyloric ulcers and account for about 20% of the lesions. These ulcers also behave like duodenal ulcers and are associated with hypersecretion of gastric acid. Type 4 gastric ulcers occur high on the lesser curvature near the GE junction. The incidence of Type 4 gastric ulcers is less than 10% and they are not associated with excessive acid secretion. Lastly, some ulcers may appear on the greater curvature of the stomach but the incidence is less than 5% (173,174). The peak incidence of gastric ulcers occurrence is between 55 and 65 years of age; they rarely develop before the age of 40. They are more likely to occur in the lower than in the higher social economic classes and are slightly more common in the nonwhite than the white population. The exact pathogenesis of a benign gastric ulcer remains unknown. Some conditions that may predispose to gastric ulceration are shown in Table 3. With respect to acid and pepsin secretion, the presence of acid appears to be essential to the production of gastric ulcers; however the total secretory output appears to be less important. Nevertheless, it is noteworthy that rapid healing follows antacid therapy, antisecretory therapy, or vagotomy, even when the lesion-bearing portion of the stomach is left intact, because in the presence of gastric mucosal damage, acid is ulcerogenic even when present in normal or less than normal amounts.

Clinical Manifestations Duodenal Ulcer Abdominal Pain. The most common symptom associated with duodenal ulcer disease is well-localized mid-epigastric abdominal pain. The pain is usually tolerable and frequently relieved by food. The pain may also be episodic, seasonal in the spring and fall, or it may relapse during periods of emotional stress. For these reasons and because it is relieved, many patients do not seek medical attention until they have had the disease for many years. The presence of constant pain suggests that there is deeper penetration of the ulcer and referral of pain to the back is usually a sign of penetration into the pancreas. Diffuse peritoneal irritation is usually a sign of free perforation. Perforation. About 5% of the time, a penetrating ulcer will penetrate through the duodenum into the free peritoneal cavity to elicit a chemical peritonitis. The patient can typically recall the exact time of onset of abdominal pain that is frequently accompanied by fever, tachycardia, dehydration, and ileus. Abdominal examination reveals exquisite tenderness, rigidity, and rebound. A hallmark of free perforation

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

is the demonstration of free air underneath the diaphragm on an upright chest radiograph. This complication of duodenal ulcer disease represents a surgical emergency. Once the diagnosis is made, operation should be performed in an expeditious fashion following appropriate fluid resuscitation. Bleeding. The most common cause of death in patients with peptic ulcer disease is bleeding in patients who have major medical problems or are over the age of 65 (116,118). Because the duodenum has an abundant blood supply and the gastroduodenal artery lies directly posterior to the duodenum bulb, GI bleeding from a duodenal ulcer is fairly common. Fortunately, most of the ulcers are superficial or are located in portions of the duodenum that are not adjacent to the large gastroduodenal artery or its branches. Consequently, most duodenal ulcers present with only minor bleeding episodes that are detected by the presence of melenotic or guaiac-positive stool. Bleeding duodenal ulcers account for about 25% of all upper GI bleeding patients who present to the hospital. Obstruction. Acute inflammation of the duodenum may also lead to a functional gastric outlet obstruction manifested by delayed gastric emptying, anorexia, or nausea accompanied by vomiting. In cases of prolonged vomiting, patients may become dehydrated and develop a hypochloremic hypokalemic metabolic alkalosis secondary to loss of gastric juice rich in hydrogen, chloride, and potassium ions. In this setting, fluid resuscitation requires replacement of the chloride and potassium deficiencies, in addition to nasogastric suction for relief of the obstructed stomach. In addition to acute inflammation, chronic inflammation of the duodenum may lead to recurrent episodes of healing followed by repair and scarring with, ultimately, fibrosis and stenosis of the duodenal lumen. In this situation, the obstruction is accompanied by painless vomiting of large volumes of gastric contents with similar metabolic abnormalities as seen in the acute situation. The stomach can become massively dilated in this setting and it rapidly loses its muscular tone. Marked weight loss and malnutrition are also common in this situation. Gastric Ulcer Gastric ulcers represent a clinical challenge in that it is often impossible to differentiate between gastric carcinoma and benign ulcers. Like duodenal ulcers, gastric ulcers are also characterized by recurrent episodes of quiescence and relapse. Surgical intervention is required in 8% to 20% of those patients developing complications from their gastric ulcer disease. The most frequent complication of gastric ulceration, however, is perforation. Most perforations occur along the anterior aspect of the lesser curvature. In general, larger ulcers are associated with more morbidity and higher mortality rates. Hemorrhage occurs approximately 35% to 40% of the time at some point during the course of gastric ulceration. Usually, patients who develop significant bleeding from their gastric ulcers are older, less likely to stop bleeding, and have a higher morbidity and mortality than patients bleeding from duodenal ulcers. Hemorrhage is most frequently observed in patients with Type 2 and Type 3 gastric ulcers. Similar to that in duodenal ulcers, gastric outlet obstruction can also occur in patients with Type 2 or Type 3 gastric ulcers. However, one must carefully differentiate between benign obstruction and obstruction secondary to antral carcinoma. On occasion, benign ulcers have also been found to result in spontaneous gastrocolic fistulas.

353

Zollinger–Ellison Syndrome ZES is a disease caused by a tumor, known as gastrinoma, because it continuously releases gastrin into the circulation. Such tumors are usually located either in the pancreas or duodenum, or in the regional lymph nodes adjacent to these organs. As many as 90% of these tumors are found in the socalled gastrinoma triangle, bounded superiorly by the point where the cystic duct joins the common duct, inferiorly by the junction of the inferior margin of the second and third parts of the duodenum, and left laterally by the junction of the head and neck of the pancreas. Not only does the excessive amount of gastrin released by these tumors stimulate gastric acid hypersecretion, but it also stimulates parietal cell hyperplasia, which potentiates their acid-secretory capacity (175). The clinical triad of this syndrome consists of gastric acid hypersecretion, severe peptic ulcer disease, and a non–beta islet cell tumor. These gastrinomas usually occur sporadically (75%), are multiple about 50% of the time but roughly 25% are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In the past, most gastrinomas were found to be malignant, but the advent of better and earlier screening has lead to the discovery of more benign neoplasms. However, up to 66% of gastrinomas are still found to be malignant (176,177). Hypergastrinemia associated with ZES accounts for most, if not all, of the clinical symptoms experienced by patients. Abdominal pain and peptic ulcer disease are the hallmarks of the syndrome and typically occur in more that 80% of patients. About one half of patients also exhibit diarrhea secondary to increased gastric acid secretion. Weight loss and steatorrhea also occur secondary to decreased duodenal/jejunal pH and the inactivation of lipase. Esophagitis from gastroesophageal reflux is also common. Endoscopy frequently demonstrates prominent gastric rugal folds, reflecting the trophic effect of hypergastrinemia on the gastric fundus, in addition to evidence of peptic ulcer disease. Gastrinoma and ZES should always be considered and ruled out in patients who have recurrent or intractable peptic ulcer disease despite eradication of H. pylori and appropriate antisecretory therapy; multiple or atypically located ulcers; peptic ulcer disease associated with significant diarrhea; peptic ulcer disease associated with symptoms of MEN1 such as hyperparathyroidism or in kindreds of MEN1 patients; large gastric rugae on endoscopy; or in those patients with other pancreatic endocrine tumors. Similarly, patients undergoing elective surgical intervention for peptic ulcer disease should have the possibility of gastrinoma included in their preoperative evaluation. Provocative tests are usually not required to establish the diagnosis of ZES, because fasting and stimulated plasma gastrin levels are usually elevated. Most patients with gastrinoma have elevated fasting serum gastrin levels ( > 200 pg/mL), and values greater than 1000 pg/mL may be diagnostic. However, hypergastrinemia may be present in other disease states. Basal acid output of greater than 15 mEq/hr (or > 5 mEq/hr in those with previous antiulcer surgery) supports this diagnosis. The secretin test is the most sensitive and specific provocative test for gastrinoma and aids in the differentiation between gastrinomas and other causes of ulcerogenic hypergastrinemia (Table 1). Serum gastrin samples are measured before and after intravenous administration of secretin (2 U/kg), at five-minutes intervals for 30 minutes. An increase in the serum gastrin level of greater than 200 pg/mL above basal levels is specific for gastrinoma versus other causes of hypergastrinemia, which do not demonstrate this response (177).

medwedi.ru

354

Part Two: The Alimentary Tract—Esophagus and Stomach

After diagnosis of gastrinoma, acid suppression therapy should be initiated, preferably with a proton-pump inhibitor. Medical management is indicated preoperatively and in patients with metastatic and/or unresectable gastrinoma. Localization of the gastrinoma should be performed before undertaking an operative intervention. Noninvasive methods include computed tomography scanning, magnetic resonance imaging, endoscopic ultrasound, and 111In-octreotide scintigraphy (somatostatin receptor imaging). Invasive modalities may be used if noninvasive methods fail to localize the tumor. These include selective visceral angiography, percutaneous transhepatic portal venous sampling for gastrin, and the selective arterial secretin stimulation test (176,177). In patients with resectable gastrinomas, surgical resection should be performed that includes tumor resection from the duodenum, pancreas, or regional lymph nodes. Total gastrectomy is rarely indicated, and is reserved for patients who are noncompliant with acid suppression therapy or when the tumor cannot be localized.

Diagnosis History and physical examination are probably of limited value in distinguishing between gastric and duodenal ulceration. Routine laboratory studies include a complete blood count, liver chemistries, serum creatinine, and calcium levels. A serum gastrin level should also be obtained in patients with ulcers that are refractory to medical therapy or require surgery. An upright chest radiograph is usually performed for ruling out perforation. The two principal means of diagnosing peptic ulcers are upper GI radiographs and fiberoptic endoscopy. Contrast radiography is less expensive and most (90%) can be diagnosed accurately. However, about 5% of ulcers that appear radiographically benign are malignant. As endoscopy is becoming more cost-effective, many clinicians are now using this modality as the sole method for diagnosis. H. pylori testing should also be done in all patients with suspected peptic ulcer disease. H. pylori Testing Diagnostic tests for H. pylori are divided into noninvasive and invasive tests. Noninvasive tests do not require endoscopy whereas invasive tests do and require a sample of gastric mucosa. The noninvasive tests available are serology and the carbon-labeled urea breath test. The invasive tests available are the rapid urease test, histology, and culture. Serology. Serology can be used to diagnose H. pylori because H. pylori infection elicits a local as well as a systemic IgG-mediated immune response. Serology is the diagnostic test of choice when endoscopy is not indicated and has about 90% sensitivity and specificity associated with it (178–180). Because antibody titers can remain high for a year or more, the serology test should not be used to assess eradication following therapy. However, two studies have shown that a decrease in antibody titers of 25% at six months does correlate with eradication of H. pylori, with a sensitivity greater than 75% and a specificity of greater than 95% (179,180). Urea Breath Test. Another noninvasive test used for diagnosing H. pylori is the carbon-labeled urea breath test. This test is based on the ability of H. pylori to hydrolyze urea. Its sensitivity and specificity are both greater than 95% (181). The test is performed by having the patient ingest carbon isotope–labeled urea, using either C14 or C13. If C13 is used, mass spectrometry is required, whereas C14 does not,

but is associated with a low level of radiation exposure. Following ingestion of the carbon isotope, urea will be metabolized to ammonia and labeled bicarbonate if H. pylori infection is present. The labeled bicarbonate is excreted in the breath as labeled carbon dioxide, which is then quantified. The urea breath test is less expensive than endoscopy and samples the entire stomach. False negatives can occur if the test is done too soon after treatment, so it is usually best to test four weeks after therapy is finished. The urea breath test is the method of choice to document eradication (182). Rapid Urease Assay. The method of choice to diagnose H. pylori if endoscopy is employed is the rapid urease test. This test is also based on the ability of H. pylori to hydrolyze urea. The enzyme urease catalyzes degradation of urea to ammonia and bicarbonate, creating an alkaline environment that can be detected by a pH indicator. Mucosal biopsies are placed into a liquid or solid medium containing urea and a pH indicator. Sensitivity is approximately 90% and specificity is 98%, and the results are available within hours (183–185). Histology. Endoscopy can also be performed to obtain biopsy samples of gastric mucosa followed by histologic visualization of H. pylori. H. pylori is identified by its appearance and colonization sites with routine hematoxylin and eosin stains or with special stains such as silver, Giemsa, or Genta, for improved visibility. Sensitivity is about 95% and specificity 99%. This test is widely available and affords the clinician the ability to assess the severity of gastritis as well as to confirm the presence or absence of the organism. Culture. Culturing of gastric mucosa obtained at endoscopy can also be performed to diagnose H. pylori. The sensitivity is approximately 80% and specificity is 100%. However, it requires laboratory expertise and diagnosis requires up to three to five days. Nevertheless, it does provide the opportunity to perform antibiotic sensitivity testing on isolates should the need arise. H. pylori Testing Summary In summary, it is not necessary to perform endoscopy to diagnose H. pylori. Serology is the test of choice for initial diagnosis when endoscopy is not required. If, however, endoscopy is to be performed, the rapid urease assay or histology are both excellent options, but the cost advantage lies with the rapid urease assay. To document eradication after treatment, the urea breath test is the method of choice, but again should not be performed until four weeks after therapy ends. If the breath test is unavailable, endoscopy may be performed in selected patients such as those with bleeding ulcers or other complications of their peptic ulcer disease. Upper GI Radiography A relatively safe method of diagnosing peptic ulcer disease is by upper GI radiography. Upper GI radiography requires the patient to swallow barium and then radiographs are obtained, which outline the intraluminal cavity of the stomach and duodenum. Demonstration of an ulcer is performed by visualizing an ulcer crater, which is usually round or oval, that disrupts the intact gastric or duodenal mucosa. The study is useful to determine location and depth of penetration of the ulcer as well as the extent of deformation and fibrosis. The limiting factor of barium swallow in upper GI radiography is that it is technician dependent and also requires the diagnostic skills of a radiologist, which may

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

be physician dependent. When air is included in the upper GI barium radiograph (double-contrast study), the sensitivity of detecting ulcer craters can be increased to 80% to 90% from 50% when air is not included (single-contrast study). The location of a gastric ulcer is of little predictive value in establishing malignancy because benign and malignant ulcers can occur anywhere in the stomach. However, the size of the gastric ulcer may have some predictive value in that larger lesions are more likely to be malignant than smaller ones. In addition, the finding of an ulcer with an associated mass; interrupted, fused, or nodular mucosal folds approaching the margin of the crater; or an ulcer with irregular filling defects in the ulcer crater is suggestive of a malignancy. Fiberoptic Endoscopy Endoscopy is the most reliable method of diagnosing a gastric ulcer, with an accuracy of over 97%. In addition, if multiple biopsies and brushings for cytology are performed, the probability of diagnosing a malignancy is also in excess of 97%. In general, benign ulcers have smoother, more regular, rounded edges with a flat smooth ulcer base. Malignancy is more often associated with a mass that may protrude into the lumen or have folds surrounding the ulcer crater that are nodular, clubbed, fused, or stop short of the ulcer margin. Again, multiple biopsy specimens are necessary for any of these ulcers because ruling out a malignancy is mandatory. Clinical symptoms or signs that may prompt early endoscopic evaluation include major weight loss, symptoms of gastric outlet obstruction, a palpable abdominal mass, guaiac-positive stool, or blood-loss anemia. In addition to providing diagnostic abilities, endoscopy provides the ability to sample tissue for H. pylori testing and may also be used for therapeutic purposes in the setting of GI bleeding (see treatment of bleeding below) or in the therapy of obstruction (see the following section).

Treatment Medical Management The use of medicinal products for the treatment of symptoms of disturbances in gastric physiology has a long history in all cultures. Recent advances in understanding molecular mechanisms have given us the opportunity to not only understand peptic ulcer disease, but also regulate the cellular mechanisms that cause ulcer disease. We now have an arsenal of therapeutic interventions that allow us to target several different areas related to peptic ulceration. Antagonists of histamine, gastrin, and acetylcholine receptors; PPIs; and agents that alter mucosal defenses all have the potential to make an impact on ulcer reduction and prevention. Recently, treatment of H. pylori, cessation of NSAIDs use, inhibition of acid secretion, buffering of gastric acidity, and understanding of the mucosal barrier have all played a significant role in the treatment of ulceration. Alterations in patient lifestyles also play a significant role in ulcer healing. Cessation of cigarette smoking and tobacco use should be emphasized to the patient, as tobacco has been shown to delay ulcer healing. If possible, the use of COX inhibitors such as aspirin and NSAIDs should also be avoided. In those patients for whom anti-inflammatory drugs are needed, the physician should consider the use of the more selective COX-2 inhibitors, which are associated with a lower incidence of ulceration. The ingestion of alcohol and coffee should also be moderated because they damage the mucosa and stimulate acid secretion, respectively.

355

Antacids. Antacids have the benefit of being able to quickly buffer acid and raise the pH of the gastric fluid. They reduce gastric acidity by reacting with hydrochloric acid, forming a salt and water to inhibit peptic activity by raising the pH. Increasing pH also secondarily inhibits pepsin activity. Antacids differ greatly in their buffering ability, absorption, taste, and side effects. They are most effective when ingested one hour after a meal. If taken on an empty stomach, the antacids are emptied rapidly and have only a transient buffering effect. However, if taken after meals, they are retained in the stomach and exert their buffering action for longer periods of time. The minimum dose of antacids required to produce optimal healing rates represents only a few tablets or liquid doses of antacids per day, usually in doses of 200 to 1000 mmol/day. This dosage level produces minimal side effects and results in approximately 80% ulcer healing at one month. The mechanism for ulcer healing at lower doses is not clear because gastric acidity is only neutralized for brief periods. Historically, antacids have been used for prophylaxis and treatment of gastritis, as well as for treatment of gastric and duodenal ulcers. When used as prophylaxis against stress gastritis in critically ill patients, antacids are as efficacious as H2-receptor antagonists in protection against bleeding. Similarly, antacids are as effective as H2-receptor antagonists in the healing of gastric and duodenal ulcers. Magnesium antacids tend to be the best buffers, but can cause significant diarrhea by a cathartic action. In contrast, aluminum acids precipitate with phosphorous and can occasionally result in hypophosphatemia and sometimes constipation. Consequently, while antacids may heal duodenal ulcers with an efficacy comparable to that observed with H2-receptor antagonists, the frequent dosing schedule and side effects of antacids have caused a decline in their use in favor of more selective inhibitors of acid secretion. H2-Receptor Antagonists. H2-receptor antagonists were the first class of selective acid inhibitors to be developed. They function by reversibly binding to the histamine receptor of the parietal cell by mimicking the imidazole ring of histamine, which the histamine receptor recognizes. Variations in the ring structure and side chains have allowed for the development of several generations of H2-receptor antagonists, which all differ in their potency and half-life. These variations allow for longer duration as well as for decreased side effects. The older generation of H2-receptor antagonists, such as cimetidine and ranitidine, has the undesirable side effects of metabolism in the liver by the hepatic microsomal enzyme system. Because these older drugs undergo hepatic metabolism, they have the ability to increase serum levels and pharmacologic effects of medications that also rely on hepatic metabolism. Historically, continuous intravenous infusion of H2-receptor antagonists has been shown to produce more uniform acid inhibition than intermittent administration, but newer generations of these drugs are just as effective owing to greater potency and longer half-lives (186). The fluctuating effects of intermittently administered older H2-receptor antagonists are probably caused by the relatively short half-life of these agents, which ranges from 1.5 to 3 hours. Split-dose, evening and nighttime therapy are all effective, but again continuous intravenous infusion produces the most uniform acid inhibition. Many randomized controlled trials indicate that all H2-receptor antagonists result in gastric and duodenal ulcer healing rates of 70% to 80% after four weeks and 80% to 90% after eight weeks of therapy (187–191). However, in patients

medwedi.ru

356

Part Two: The Alimentary Tract—Esophagus and Stomach

who are infected with H. pylori, cessation of H2-receptor antagonists without treating H. pylori results in significant ulcer recurrence within a year (192). Proton-Pump Inhibitors. The final common pathway for all stimulation of gastric acid secretion is the H/K-ATPase of the parietal cells. Therefore, it is not surprising that antagonists for the proton pump have been developed. PPIs, of which omeprazole is the classic prototype, are a class of benzimidazoles which covalently bond to the catalytic alpha subunit of the H/K-ATPase, thereby permanently inhibiting gastric acid secretion of any given parietal cell affected. Because the proton pump is the final common pathway for all acid secretion, inhibition by PPIs negates all acid secretion from affected parietal cells from all types of acid stimulation. Basal acid secretion, meal-stimulated acid secretion, and secretagogue-stimulated acid secretion are all suppressed. Therefore, PPIs are the most potent class of acid-inhibiting agents and provide more consistent inhibition. Furthermore, inhibition of acid secretion is of longer duration with this class of agents because binding to the proton pump is irreversible. Generally, inhibition lasts for longer than 18 hours. To resume acid secretion, new proton pumps must be synthesized. PPIs are weak bases, which require an acidic environment to become ionized and activated (193,194). Usually a pH of less than three is needed for this activation to occur. PPIs that are taken by the oral route require acidic gastric luminal fluid to become activated. Consequently, antacids and H2-receptor antagonists should not be used in conjunction with PPIs. As a result, various oral preparations have been developed, which limit intragastric degradation and promote systemic absorption and increased bioavailability. Newer agents have also been developed, which may be administered intravenously and subsequently have improved bioavailability. The properties of PPIs allow for the advantage of selectivity of gastric parietal cells over other forms of acid-reducing agents. Specifically, PPIs are very selective to binding to the parietal cell H/K-ATPase and also require an acidic environment to become activated, which allows for the accumulation of PPIs within the acidic environment of the parietal cell secretory canaliculus. Another advantage of PPIs is that they have less interaction with the hepatic microsomal enzyme system and therefore have less effect on metabolism of other medications (193,194). One concern about the use of PPIs is that such significant inhibition of acid secretion causes secretion of gastrin. Hypergastrenemia has been observed with use of these agents, as well as ECL cell hyperplasia (193,194). However, concerns about these side effects do not appear to be clinically relevant in comparison to the necessary treatment of ulcer disease. Currently, five PPIs are approved by the Food and Drug Administration. These are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. The newer agents have been developed subsequent to omeprazole and offer several advantages, particularly with respect to quicker onset of action, and reduced potential for pharmacokinetic variation and drug interactions. All of the PPIs appear to have similar efficacy in relation to healing of peptic ulcer disease. PPIs also appear to have a more rapid healing of ulcers than other forms of medical treatment. In relation to H2-receptor antagonists, PPIs have a 14% advantage at two weeks and a 9% advantage at four weeks when compared to cimetidine. Also improvement of symptoms is more quickly achieved with these agents. They also

produce more rapid healing of ulcers than the standard H2-receptor antagonists. Three meta-analyses of over 1000 patients in more than 30 randomized studies have demonstrated a gastric and duodenal ulcer healing rate of 85% at four weeks and 96% at eight weeks (195–197). Antacids and H2-receptor antagonists should not be used in combination with PPIs because these agents require an acidic environment within the gastric lumen in order to become activated and bind to the proton pump at the secretory canaliculus. The utilization of antacids or H2-receptor antagonists in combination with PPIs could have deleterious effects by promoting an alkaline environment and thereby preventing activation of the PPI. The medical management of ZES is another indication for the use of PPIs. Sucralfate. Sucralfate is an additional agent that has been evaluated and used for prophylaxis against stress gastritis as well as peptic ulcer disease. Sucralfate is the aluminum salt of sucrose octasulfate. For sucralfate to be activated, it needs to be in an environment of acidic pH. At a pH below 3.5, sucralfate polymerizes into a viscous gel that has the ability to coat the ulcer and adhere to the gastroduodenal mucosa. Although the exact mechanism of sucralfate is still debated, some of its mechanisms of action appear to be by providing a protective barrier through inhibiting the actions of pepsin, binding bile salts, and increasing the production of mucosal prostaglandins, bicarbonate, and mucus, and microvascular blood flow. Sucralfate has also been shown to bind epidermal growth factor, delivering it to the gastroduodenal mucosal layer. Studies in animals and humans have also demonstrated that sucralfate stimulates the proliferation of epithelium at ulcer margins. Because sucralfate has no systemic absorption, it has a benefit of not interacting with the metabolism of other medications. Likewise, sucralfate is recommended for the treatment of peptic ulcer in pregnancy or in those patients who need long-term antiulcer therapy. Gastric and duodenal ulcer healing after four to six weeks of treatment with sucralfate (1 g q.i.d.) is superior to placebo and comparable to H2-receptor antagonists such as cimetidine (198,199). Similar healing rates have been reported with twice daily dosing (2 g b.i.d. 30 minutes before breakfast and at bedtime). At least one study has also shown that sucralfate is as efficacious as maximal H2-blocker therapy for gastric stress ulceration prophylaxis and would save approximately $30,000/ICU bed/yr in patient charges versus H2-receptor antagonists (109). Treatment of H. pylori Infection. There are three major goals for treating patients with ulcer disease. First, symptoms need to be relieved. Second, the ulcer needs to be healed, and third, one must prevent recurrence. Antisecretory agents with acid suppression have traditionally achieved the first two goals. With NSAID-related ulcers, discontinuation of NSAIDs achieves the third goal. However in the setting of non-NSAID ulcers, which are usually secondary to H. pylori, eradication of H. pylori can also almost completely prevent recurrence of ulcers. For duodenal ulcers, the recurrence rate following successful healing is roughly 72% if no additional therapy is employed. If H2-receptor antagonists are used as maintenance therapy, patients still have a 25% recurrence rate (153). However, if H. pylori is eradicated, only 2% of the patients have an ulcer recurrence (153,161). The gold standard in the past for eradicating H. pylori was triple therapy in combination with a bismuth-based therapy for two weeks. However, various triple regimens for H. pylori eradication have emerged. Most of these employ

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

a PPI in combination with antibiotics such as metronidazole, chlorythromycin, or amoxicillin. These regimens are one to two weeks in duration, have the advantage of not containing bismuth, and are only given twice a day. Some of these triple regimens are currently available in a packet such as Helidac and are taken anywhere from 7 to 10 days to 2 weeks. Eradication rates for these new triple regimens are in the 80% to 95% range. For acute ulcers, all three drugs are given for one week, followed by two additional weeks of a PPI alone, or treatment for four to six weeks with a full-dose H2-receptor antagonist. In February of 1994, the NIH convened a consensus conference on H. pylori in peptic ulcer disease. At this conference, a number of recommendations were made (Table 4) (200). All patients with gastric or duodenal ulcers who were infected with H. pylori should be treated, regardless of whether first presentation or recurrence. H. pylori–infected ulcer patients receiving maintenance treatment or with a history of complicated or refractory disease should also be treated. They added that there was no reason to consider routine detection or treatment in the absence of ulcers and concluded that NSAID use should not alter treatment. The NSAID should be discontinued if possible, but if H. pylori is present, H. pylori should be treated. For patients with complications such as bleeding or perforation, documentation of eradication was imperative. Again, this is most easily performed with a urea breath test. Although not recommended by NIH, it is also appropriate to treat H. pylori– positive patients with MALT lymphoma for the previously mentioned reasons. Nevertheless some controversial treatment issues still exist. In nonulcer dyspepsia, the infected patient who insists upon eradication of H. pylori needs to be advised of the benefits or lack of benefits H. pylori eradication might have because it is unlikely that eradication will improve symptoms, and it is possible that it will contribute to the emergence of antibiotic resistance. It is also important to remember that the success of therapy for H. pylori depends upon the correct use of the regimens. One cannot substitute ampicillin for amoxicillin and one cannot substitute doxycycline for tetracycline. Appropriate dosages need to be used, the recommended frequency of administration adhered to, and the duration of drug therapy enforced (200). For treatment of active NSAID ulcers, it is best to discontinue the NSAID if at all possible, while the ulcer is being treated. If patients must continue their NSAIDs, cotherapy with misoprostol, a prostaglandin analogue,

Table 4 NIH Concensus Panel Treatment Recommendations for Helicobacter pylori 1. Patients with active peptic ulcer disease who are H. pylori positive a. Use of NSAIDs should not alter treatment. b. Document eradication in those with complications. 2. Ulcer patients in remission who are H. pylori positive, including patients on maintenance H2-receptor antagonist therapy. 3. H. pylori positive–patients with MALT lymphoma. 4. Controversial issues in H. pylori positive–patients. a. First-degree relatives of gastric cancer patients. b. Immigrants from countries with high prevalence of gastric cancer. c. Individuals with gastric cancer precursor lesions (intestinal metaplasia). d. Nonulcer dyspepsia patients who insist upon eradication (benefit vs. risk). e. Patients on long-term antisecretory therapy for reflux disease. Abbreviations: NIH, National Institutes of Health; NSAIDs, non steroidal antiinflammatory drugs; MALT, mucosal-associated lymphoid tissue.

357

might be of benefit (201,202). Testing should be performed for H. pylori and if present treatment administered. For patients with gastric ulcers, PPIs have been shown to be more effective that H2-receptor antagonists in patients taking NSAIDs (201,202). Approach to the Patient Bleeding from Peptic Ulcer Disease. Approximately 80% of upper GI bleeds are selflimited. The overall mortality of 8% to 10% for those who continue to bleed or in whom bleeding recurs has not changed dramatically over the last several decades despite an older and probably sicker patient population. The initial step in management is adequate initial and ongoing resuscitation. Following resuscitation, endoscopy is performed to assess the cause and severity of the bleed, which will dictate the required intensity of therapy and predict the risk of further bleeding and/or death. Several factors are associated with continued or recurrent bleeding and increase the risk of mortality. Most studies have demonstrated that mortality increases with age such as the ASGE study, which found a mortality of 8.7% for patients 60 years old or less and 13.4% for those above 60 years (119,120). The severity of the initial bleed is also an adverse prognostic factor and this might include the presence of shock, a high transfusion requirement, or bright red blood in the nasogastric tube or in the stool (119,120). Interestingly, recurrent bleeding increased the mortality rate from 7% to a range of 30% to 40% (119,120,167). The onset of bleeding in a hospital was also associated with a higher mortality rate (33%) compared to those who bled outside of the hospital or prior to admission (7%). In the ASGE study, the absence of any concomitant disease was associated with a mortality rate of 2.5%. If there were three concomitant diseases, the mortality rate rose to 14.6%. With six concomitant diseases, the mortality rate rose to 66.7% (119,120). Stigmata of recent hemorrhage from peptic ulcers also represent an adverse prognostic sign. These stigmata included a visible vessel on endoscopy, oozing of bright red blood, and fresh or old blood clot at the base of the ulcer (119,120). When a visible vessel was seen, it was associated with a 50% rebleeding rate, while other signs were associated with a lower rebleeding rate of about 8% (119,120). In the ASGE study, pumping or oozing lesions had a significantly greater mortality (16%) and need for surgery (24%), when compared to those with clot or no blood (mortality 6.7%, surgery 11%) (119,120). In addition, patients undergoing emergency surgery had a 30% mortality rate compared to 10% for those undergoing elective surgery (119,120). Mortality also rises with increased severity of bleeding, which correlates with transfusion requirement. If no units are transfused, the mortality rate is approximately 2%, for one to three units, approximately 5%, for four to six units, approximately 12%, for seven to nine units, approximately 15%, and when more than 10 units are used, the mortality rate rises to approximately 35% (119,120). A pumping or oozing lesion in the ASGE study was associated with a transfusion requirement greater than five units (37.6%), which was significantly different when compared to patients who had a clot or no blood on the lesion (119,120). In the latter group, only 20% required more than five units of blood. The risk of rebleeding in a patient with no active bleeding and overlying clot varies from 8% to 30%. The visible vessel is regarded as the one stigma of recent hemorrhage that is associated with the highest incidence of rebleeding. In patients with a visible vessel, rebleeding occurred in 56% of patients compared to 8% in those with oozing and 0% in with no stigmata of recent

medwedi.ru

358

Part Two: The Alimentary Tract—Esophagus and Stomach

hemorrhage (119,120). Mortality was also limited to those patients with visible vessels. Endoscopy remains the investigation of choice for patients with upper GI bleeding from peptic ulcer disease. Bleeding can be controlled with a variety of modalities, including thermotherapy (heater probe, multipolar or bipolar electrocoagulation) as well as injection of ethanol or epinephrine solutions. After bleeding is controlled, long-term medical therapy includes antisecretory agents usually in the form of a PPI plus testing for H. pylori, with treatment if positive. If H. pylori is present, documentation of eradication should be performed following therapy. If the bleeding continues or recurs, surgery may be indicated, and this will be discussed under duodenal and gastric ulcer disease individually. Surgical Procedure for Peptic Ulcer and Its Complications Indications for surgery in peptic ulcer cases are intractability, hemorrhage, perforation, and obstruction. Elective surgery for intractability is becoming more and more rare as medical therapy becomes more effective. The recognition of H. pylori and its eradication suggest that the intractability indication for surgery may apply only to patients in whom the organism cannot be eradicated or who cannot be taken off NSAIDs. In contrast to uncomplicated ulcers, the incidence of ulcers with complications requiring surgery does not seem to have diminished, and therefore familiarity with the various methods for treating bleeding, perforation, and obstruction is essential. The surgical options are shown in Figure 17. Specific recommendations are depicted in Table 5. One goal of ulcer surgery is to prevent gastric acid secretion. Subtotal gastrectomy was considered optimal management for duodenal and gastric ulcers until Dragstedt’s description of vagotomy and its impact on ulcer healing and recurrence (203). As described below, there are three levels of vagotomy that can be performed and these are shown in Figure 17. Vagotomy decreases peak acid

output by approximately 50%, while vagotomy plus antrectomy, which removes the gastrin-secreting portion of the stomach, decreases peak acid output by approximately 85%. Truncal Vagotomy. As shown in Figure 17, truncal vagotomy is performed by division of the left and right vagus nerves above the hepatic and celiac branches just above the GE junction. Most surgeons employ some form of drainage procedure in combination with truncal vagotomy. Usually it is combined with a Heineke-Mikulicz pyloroplasty, although when the duodenal bulb is scarred, a Finney’s pyloroplasty or Jaboulay gastroduodenostomy may be necessary. From a technical standpoint, truncal vagotomy with pyloroplasty represents an uncomplicated procedure that can be performed quickly. Highly Selective Vagotomy (Parietal Cell Vagotomy). The highly selective vagotomy is also called the parietal cell vagotomy or the proximal gastric vagotomy. This procedure was developed after recognition that truncal vagotomy in combination with a drainage procedure or gastric resection adversely affected the pyloral antral pump function. This procedure divides only the vagus nerves supplying the acid-producing portion of the stomach gastric within the corpus and fundus. This procedure preserves the vagal innervation of the gastric antrum so that there is no need for routine drainage procedures (Fig. 17). Consequently, there are fewer postoperative complications. Ideally, two or three branches to the antrum and pylorus should be preserved. The ‘‘criminal nerve of Grassi’’ represents a very proximal branch of the posterior trunk of the vagus and great attention needs to be taken to avoid missing this branch in the division process because it predisposes for ulcer recurrence if left intact. The recurrence rates following highly selective vagotomy are variable and depend on the skill of the operator and the duration of follow-up. Lengthy longitudinal follow-up is

Figure 17 Surgical approaches to treat peptic ulcer disease.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

Table 5 Surgical Treatment Recommendations for Complications Related to Peptic Ulcer Disease 1. Duodenal ulcer a. Intractable—parietal cell vagotomy b. Bleeding—truncal vagotomy with pyloroplasty and oversewing of bleeding vessel c. Perforation—patch closure with treatment for Helicobacter pylori d. Obstruction—rule out malignancy and parietal cell vagotomy with gastrojejunostomy 2. Gastric ulcer a. Intractable—Type 1—distal gastrectomy with Billroth I. Type 2 or Type 3—distal gastrectomy with truncal vagotomy b. Bleeding—Type 1—distal gastrectomy with Billroth I—Type 2 or Type 3—distal gastrectomy in combination with truncal vagotomy c. Perforated—Type 1—stable, distal gastrectomy with Billroth I; unstable; biopsy, patch, and treatment for H. pylori—Type 2 and Type 3—patch closure with treatment for H. pylori d. Obstruction—rule out malignancy and parietal cell vagotomy with gastrojejunostomy e. Type 4 depends on ulcer size, distance from the GE junction and degree of surrounding inflammation. See text f. Giant gastric ulcers—distal gastrectomy with vagotomy reserved for Type 2 and Type 3 gastric ulcers Abbreviation: GE, gastroesophageal.

necessary to evaluate the results of this procedure because of the consistently reported rise in recurrent ulceration with time. Recurrence rates of 10% to 15% are reported for this procedure when performed by skilled surgeons (204–206). These compare very favorably with or are even slightly higher than those reported after truncal vagotomy in combination with pyloroplasty. However, truncal vagotomy with pyloroplasty is more commonly associated with postvagotomy dumping syndrome and postvagotomy diarrhea. The moderate ulcer recurrence rate with highly selective vagotomy is considered acceptable by many surgeons because recurrences in this scenario are usually responsive to medical therapy with PPIs. Interestingly, when the results of this procedure are broken down by the preoperative ulcer site, there appears to be strong data suggesting that prepyloric ulcers are more likely to be associated with recurrence than duodenal ulcers for unclear reasons (207,208). As a result, it may not be the procedure of choice for prepyloric ulcers. Truncal Vagotomy and Antrectomy. The most common indications for antrectomy or distal gastrectomy are gastric ulcer and large benign gastric tumors. Relative contraindications include cirrhosis, extensive scarring of the proximal duodenum, which leaves a difficult or tenuous duodenal closure, and previous operations on the proximal duodenum, such as choledochoduodenostomy. When done in combination with truncal vagotomy, the recurrence rate for ulceration after truncal vagotomy and antrectomy is approximately 0% to 2% (209,210). However, this low recurrence rate needs to be balanced against postgastrectomy and postvagotomy syndromes, which rarely occur following highly selective vagotomy, but appear in 20% of the patients undergoing this procedure. As shown in Figure 17, GI continuity after distal gastrectomy can be accomplished by either a gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II). For benign diseases, gastroduodenostomy is usually favored because it avoids the problem of retained antrum syndrome, duodenal stump leak, and afferent loop obstruction associated with gastrojejunostomy following resection. If the duodenum is significantly scarred,

359

gastroduodenostomy may be technically more difficult necessitating gastrojejunostomy. If a gastrojejunostomy is performed, the loop of jejunum chosen for anastomosis is usually brought through the transverse mesocolon in a retrocolic fashion rather than in front of the transverse colon in an antecolic fashion. The retrocolic anastomosis minimizes the length of the afferent limb and decreases the likelihood of twisting or kinking, which could potentially lead to afferent loop obstruction and predispose to the devastating complication of a duodenal stump leak. Although vagotomy and antrectomy are clearly effective at managing ulcerations, they are used infrequently today in the treatment of patients with peptic ulcer disease, as described below. In general, operations of lesser magnitude are performed more frequently in the H. pylori era. The overall mortality rate for antrectomy is about 2% but is obviously higher in patients with comorbid conditions such as insulin-dependent diabetes or immunosupression. Approximately 20% of patients develop some form of postgastrectomy and/or postvagotomy complications. Subtotal Gastrectomy. Subtotal gastrectomy is rarely performed today for treatment of patients with peptic ulcer disease. It is usually reserved for patients with underlying malignancies or patients who have developed recurrent ulcerations following truncal vagotomy and antrectomy. The latter scenario assumes that medical therapy has been unable to heal the recurrent ulcer and that ZES has been ruled out. Following subtotal gastrectomy, restoration of GI continuity can be accomplished with either a Billroth II anastomosis or via a Roux-en-Y gastrojejunostomy. Laparoscopic Procedures. Not surprisingly, since the advent of laparoscopic cholecystectomy, many surgeons have applied minimally invasive surgical approaches to gastric surgery. Both parietal cell vagotomy and posterior truncal vagotomy with anterior seromyotomy (Taylor procedure) can be accomplished laparoscopically and represent effective antiulcer operations. However, long-term results are still unavailable for comparison with those of the openly performed procedures. Dumping syndrome and postvagotomy diarrhea have similar incidence rates to that observed after open highly selective vagotomy. Major concerns regarding this operation relate primarily to its efficacy in the prevention of recurrent ulcers. Because incomplete innervation predisposes patients to recurrent ulcerations following highly selective vagotomy, anterior seromyotomy might place patients at risk for recurrence due to failure to completely denervate the parietal cell mass. Laparoscopic approaches can also be used for repair of simple perforations by omental patching and offer clear advantages as opposed to the formal laparotomy required in open procedures (211). Surgical Indications Surgical therapy serves several purposes. It salvages patients from life-threatening complications associated with perforation, hemorrhage, and gastric outlet obstruction. It provides cure for the disease in the form of protection from recurrence, and it rules out the potential for malignancy in the case of gastric ulcerations. The indications for surgery are intractable abdominal pain, bleeding, perforation, and obstruction. For all ulcers being considered for elective surgery, antisecretory agents should probably be discontinued for about 72 hours prior to operation to allow gastric acidity

medwedi.ru

360

Part Two: The Alimentary Tract—Esophagus and Stomach

to return to normal levels, which minimizes bacterial overgrowth and the extent of contamination. Intractable Duodenal Ulcer. Intractability implies failure of an ulcer to heal after an initial trial of 12 weeks of therapy or a relapse in patients once therapy has been discontinued. Although rarely seen today, intractable duodenal ulcer should be treated by parietal cell vagotomy. While this can be performed openly, many prefer a laparoscopic approach. The laparoscopic technology available to us today allows us to perform parietal cell vagotomy in exactly the same way it is performed openly and probably provides better visualization. Proximal gastric vagotomy is associated with a morbidity of less than 1% and a mortality of less than 0.5%. Unfortunately, the recurrence rate is roughly 5% to 25% (212–214). Some surgeons prefer a Taylor procedure in which the posterior truncal vagotomy is performed laparoscopically and then an endoscopic GI stapler is used to perform a seromyotomy across the anterior portion of the stomach to divide all the vagal fibers coursing through the seromuscular layer. Although some are concerned about dividing vagal innervation to the celiac ganglion and to the rest of the viscera, there is considerable evidence that preserving vagal innervation of the celiac axis and small bowel does little to reduce the side effects of vagotomy. Thus, the Taylor procedure appears to be equivalent to parietal cell vagotomy and the side effects are not any greater. Taylor has published data that suggest that anterior lesser curve seromyotomy and posterior truncal vagotomy result in acid suppression that is similar in magnitude to that achieved following highly selective vagotomy or truncal vagotomy with drainage (215,216). Gastric emptying following the Taylor procedure is also similar to that of highly selective vagotomy (increased emptying of liquids and normal emptying of solids), and dumping and diarrhea are less than that observed following truncal vagotomy and drainage (216). Intractable Gastric Ulcer. Type 1 Gastric Ulcer. For Type 1 gastric ulcers, malignancy remains a major concern and excision of the ulcer is mandatory. Distal gastrectomy is probably the best operation in this clinical situation. Reestablishment of intestinal continuity can be performed with a Billroth I or Billroth II, but again, a Billroth I is the preferred choice, providing malignancy has been ruled out. The morbidity associated with a distal gastrectomy without vagotomy and Billroth I reconstruction is approximately 3% to 5% for elective treatment of Type 1 gastric ulcers. Mortality ranges from 1% to 2% and is associated with recurrence rate of less than 2%. It is important to remember, however, that the presentation of a nonhealing gastric ulcer in the H. pylori era should raise serious concerns about the presence of underlying malignancy. If malignancy is encountered, a subtotal gastrectomy with a Billroth II gastrojejunostomy or Roux-en-Y gastrojejunostomy should be performed. Vagotomy is usually not necessary for the Type 1 gastric ulcer because it is not dependent upon gastric acid. Although technically more difficult, a parietal cell vagotomy with wedge excision of the ulcer could also be performed. However, because intractable peptic ulcer disease is so uncommon, it is important to insure that adequate time has elapsed and appropriate therapy has been administered to allow healing of the ulcer to occur. This includes confirmation that H. pylori has been eradicated and that NSAIDs have been eliminated as a potential cause. Most patients with a Type 1 gastric ulcer should in fact heal following appropriate medical therapy.

Type 2 or Type 3 Gastric Ulcers. If Type 2 or 3 gastric ulcers have not healed and H. pylori has been eradicated, a distal gastrectomy in combination with vagotomy should be performed. Several studies suggest that patients undergoing highly selective vagotomy for Type 2 or Type 3 gastric ulcers have a worse outcome than those undergoing resection (205,206). The type of vagotomy performed in combination with the resection can be either a selective or truncal vagotomy. However, there are still some who advocate performing a laparoscopic parietal cell vagotomy and reserve resection for those who develop ulcer recurrence. Management of Type 4 gastric ulcers will be discussed separately. Bleeding Duodenal Ulcers. As a result of aggressive endoscopic management, there has been a significant reduction in the number of patients who require surgery to control their bleeding. The patients who come to surgery are usually sicker, more elderly, and more likely to have complications. Laine and Peterson demonstrated that you can treat endoscopically at least one recurrence of bleeding, with no increase in mortality and morbidity and have long-term control of hemorrhage in approximately half of the patients (217). However, these patients need to be observed closely and treatment with endoscopy needs to be as prompt and aggressive as possible. Although the therapeutic endoscopist is able to stop the bleeding and is confident that the bleeding can be managed endoscopically, the patient still requires therapy with a PPI and must undergo therapy for H. pylori after testing, including documentation of eradication after treatment. For those patients who continue to bleed, or who are referred by the endoscopist, the duodenal bleeding is usually controlled by opening the duodenum and oversewing the ulcer with a U stitch to stop bleeding from either the pancreaticoduodenal artery or gastroduodenal artery. After obtaining control of the bleeding an acid-reducing procedure is performed. As most of these patients are elderly, have bled a lot, and have some degree of hypotension, the more time consuming parietal cell vagotomy is usually not indicated. Instead, a truncal vagotomy with pyloroplasty is performed. Although not proven, there are some who advocate opening the duodenum, ligating the gastroduodenal vessel, closing the duodenum, and then eradicating H. pylori. The clear exception to this would be if the patient had received therapy in the past for H. pylori and failed or if the patient was known to be H. pylori negative. In this situation, an acid-reducing procedure is clearly indicated. Most surgeons would not perform any type of gastrectomy for a bleeding duodenal ulcer. Bleeding Gastric Ulcers. For bleeding Type 1 gastric ulcers, a distal gastrectomy with Billroth I anastomosis is usually performed. Some have advocated adding vagotomy for patients who continue to be on NSAIDs, although the data on this is likewise unclear. However, even if patients need to stay on NSAIDs, they should be given misoprostol, a prostaglandin analog, because it has been found to have a 40% reduction in serious GI complications in those patients who have to stay on NSAIDs (218). For Type 2 and Type 3 gastric ulcers, distal gastrectomy in combination with vagotomy is indicated. Perforated Duodenal Ulcers. For perforated duodenal ulcers, simple patching followed by eradication of H. pylori is indicated. However, this assumes that the patient is H. pylori positive and will be compliant with therapy to eradicate H. pylori. If the patient is known to be H. pylori negative,

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

then an acid-reducing procedure (i.e., truncal vagotomy with pyloroplasty or parietal cell vagotomy) should be performed (124). Patch closure of the duodenum can be performed either laparoscopically or openly (211,219). In some cases, patients present with a sealed perforation. One of the first studies assessing this group of patients came out of Hong Kong, where a series of patients were treated prospectively and successfully with nonoperative management (220). These patients were hemodynamically stable and without signs of toxicity. Unfortunately, the patients who failed were the ones in whom it would be most desirable to use nonoperative management (i.e., the elderly and the very ill). In this situation, upper GI radiography must be performed to confirm that the ulcer is indeed sealed as suggested by Burn and Donovan (221). Nonoperative therapy in this situation would include treatment for H. pylori and acid suppression. For all perforated duodenal ulcer patients who are H. pylori positive, documentation of H. pylori eradication with a urea breath test is mandatory, and it is paramount that the patients are compliant with their medications to treat H. pylori regardless of whether they are managed surgically or nonoperatively. Perforated Gastric Ulcer. For perforated Type 1 gastric ulcers that occur in hemodynamically stable patients, distal gastrectomy with Billroth I reanastomosis is indicated. However, simple patching of the gastric ulcer, testing for H. pylori, and treatment if positive, can also be considered. However, the risk of malignancy needs to be ruled out and therefore biopsy of the ulcer bed also needs to be performed. In addition, even if initial biopsies are negative, documentation of healing needs to be undertaken at a later date with repeat endoscopy and rebiopsying of the ulcer if it has not healed. Adding vagotomy for perforated Type 1 gastric ulcers is unlikely to be of any value. Because Type 2 and Type 3 gastric ulcers behave like duodenal ulcers, they can be simply treated with patch closure followed by treatment for H. pylori, provided the gastric ulcer is biopsied. Again, this assumes that patients are H. pylori positive. Gastric Outlet Obstruction. Gastric outlet obstruction is more common with duodenal and Type 3 gastric ulcers, but can occur in patients with a Type 2 ulcer. Obstruction is an unusual presentation for Type 1 gastric ulcers and its presence should suggest an occult malignancy. All patients with gastric outlet obstruction require preoperative nasogastric decompression for several days, correction of fluid and electrolyte imbalances, antisecretory therapy, and endoscopy with biopsies prior to surgical intervention. The first principle is to categorize the patient as either acutely or chronically obstructed. If the patient is acutely obstructed, the patient should be treated nonoperatively with nasogastric decompression, intravenous fluid, nutritional support as needed, and acid-suppressive therapy. H. pylori should be tested for and treated. On the other hand, if the patient has chronic gastric outlet obstruction, as might be the case from a chronic duodenal ulcer with fibrosis, operative therapy is usually indicated to open up the gastric outlet. In addition, an acid-reducing procedure is necessary. The preferred procedure for those patients presenting with a gastric outlet obstruction is parietal cell vagotomy with a gastrojejunostomy. Gastrectomy can be done if technically feasible. Alternatively, gastrojejunostomy with truncal vagotomy is also an option and technically much easier. The physiologic argument for doing the parietal cell vagotomy with a gastrojejunostomy as opposed to truncal vagotomy, is that it

361

maintains innervation to the chronically obstructed antrum. As a result, the patient may have fewer chronic emptying problems than if you perform truncal vagotomy. The only randomized trial examining the management of operation for gastric outlet obstructions was done by Csendes et al. (222). He found that gastroduodenostomy in conjunction with a highly selective vagotomy yielded the poorest results of the three operations, in terms of symptomatic relief, the other two being selective vagotomy with antrectomy and highly selective vagotomy with gastroenterostomy. Endoscopic balloon dilatation has also been tried in this situation, although those who benefit from this procedure are likely those with acute gastric outlet obstruction and not those with chronic gastric outlet obstruction (223). These patients also require therapy for H. pylori. Type 4 Gastric Ulcers. The Type 4 gastric ulcer presents a difficult management problem (224). The surgical treatment depends upon the ulcer size, the distance from the GE junction, and the degree of surrounding inflammation. Whenever possible, the ulcer should be excised. The most aggressive approach would be to perform a distal gastrectomy including a small portion of the esophageal wall and ulcer with a Roux-en-Y esophagogastrojejunostomy to restore intestinal continuity. For Type 4 gastric ulcers that are located 2 to 5 cm from the GE junction, a distal gastrectomy with a vertical extension of the resection to include the lesser curvature with the ulcer can be performed. After resection, bowel continuity is restored with an end-to-end gastroduodenostomy. Some have even advocated leaving the ulcer in place or locally excising it in conjunction with the truncal vagotomy and pyloroplasty. Giant Gastric Ulcers. Giant gastric ulcers are defined as ulcers with a diameter of 3 cm or greater. They are usually found on the lesser curvature and only 4% occur along the greater curvature. It is not uncommon for these ulcers to penetrate into contiguous structures such as the spleen, pancreas, liver, or transverse colon, and be falsely diagnosed as unresectable malignancy, despite normal biopsy results. The incidence of malignancy probably ranges from 6% to 30% and increases with the size of the ulcer. Giant gastric ulcers have a high likelihood of developing complications (i.e., perforation, bleeding, etc.), and therefore early operation is thought to be the treatment of choice. The operation of choice is resection including the ulcer bed, with vagotomy reserved for Type 2 and Type 3 gastric ulcers. In the high-risk patient with significant underlying comorbid conditions, a local excision combined with vagotomy and pyloroplasty may be considered; otherwise resection has the highest chance for successful outcome. Postoperative Complications Associated with Peptic Ulcer Disease Management. The overall mortality rate for vagotomy and pyloroplasty or a vagotomy with antrectomy is about 1% or less, whereas for highly selective vagotomy it is around 0.05%. Postoperative complications include bleeding, infection, and delayed gastric emptying, which can occur in roughly 5% of patients following vagotomy and pyloroplasty or vagotomy and antrectomy. Highly selective vagotomy has the lowest rate of associated complications, which occur in only about 1% of patients. In addition to these early complications, gastric surgery results in a number of physiologic derangements due to loss of reservoir function, interruption of the pyloric sphincter mechanism, and the type of gastric reconstruction and from vagal nerve transection.

medwedi.ru

362

Part Two: The Alimentary Tract—Esophagus and Stomach

These disorders are collectively referred to as postgastrectomy syndromes. Although the physiologic derangements account for the majority of symptoms, there are also some psychological elements associated with the disease process, which remain poorly understood. Approximately 25% of the patients who undergo surgery for peptic ulcer disease subsequently develop some degree of postgastrectomy syndrome, although this frequency is much lower in patients who underwent highly selective vagotomy. Fortunately, only about 1% of them become permanently disabled from their symptoms. When these postgastrectomy symptoms develop, it becomes more apparent that every attempt should be made to avoid reoperation because many of these patients lack a clearly mechanical or physiological defect, and because many of the problems persist despite reoperation. If reoperation is attempted, it should not be performed until an adequate trial of conservative therapy has been administered and for an adequate period of time. A detailed discussion of these postgastrectomy syndromes can be found in the Chapter on Alterations in Gastrointestinal Function Secondary to Previous Operation.

SUMMARY The stomach is the first organ to participate in the digestive process following the ingestion of a meal. Upon receiving food, it acts as a giant reservoir by accommodating large quantities through a process known as receptive relaxation. It then becomes a mixing bowl in which repetitive contraction and relaxation of the gastric musculature enables churning and food liquification in an environment of acid and pepsin secretion, so that the resultant gastric chyme, which consists of partially digested protein and emulsified fat, is ready for further processing after discharge into the proximal duodenum. These actions are all accomplished through an intricate and complex relationship involving exocrine, endocrine, paracrine, and neurocrine pathways. Under most circumstances, the balance among these various physiologic processing units is exquisitely controlled, so that the resultant acid chyme is not damaging to the lining of the stomach or the first portion of the duodenum. Occasionally, this balance is perturbed by bacterial infestation with H. pylori, excessive use of mucosal damaging agents such as NSAIDs or an endocrinopathy like ZES. The result of all of these aberrations is an inability of the gastric and/or duodenal mucosa to resist the damaging effects of the stomach’s secreted acid and pepsin. Fortunately, major breakthroughs in our understanding of acidpeptic disorders over the past two to three decades has enabled effective management of many of these diseases and even cure in some. In contrast to 30 years ago, when surgical intervention with vagal denervation and various degrees of gastric resection were the only means of controlling acid/peptic disorders, most patients can now live meaningful lives that are productive and pain free using a variety of nonoperative treatment strategies.

REFERENCES 1. Moore KL, Persaud TVN. The digestive system. In: Moore KL, Persaud TVN, eds. Developing Human. Philadelphia: W. B. Saunders Company, 1993:237–239. 2. Skandalakis JE, Gray SW, Rowe JS Jr. Anatomical Complications in General Surgery. New York: McGraw-Hill Book Company, 1983.

3. Lefebvre RA, Smits GJ, Timmermans JP. Study of NO and VIP as non-adrenergic non-cholinergic neurotransmitters in the pig gastric fundus. Br J Pharmacol 1995; 116:2017–2026. 4. Lefebvre RA. Pharmacological characterization of the nitrergic innervation of the stomach. Verh K Acad Geneeskd Belg 2002; 64:151–166. 5. Nakamura K, Takahashi T, Taniuchi M, Hsu CX, Owyang C. Nicotinic receptor mediates nitric oxide synthase expression in the rat gastric myenteric plexus. J Clin Invest 1998; 101:1479–1489. 6. Takahashi T. Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. J Gastroenterol 2003; 38:421–430. 7. Huizinga JD. Physiology and pathophysiology of the interstitial cell of Cajal: from bench to bedside. II. Gastric motility: lessons from mutant mice on slow waves and innervation. Am J Physiol Gastrointest Liver Physiol 2001; 281: G1129–G1134. 8. Holzer P, Wachter C, Heinemann A, Jocic M, Lippe IT, Herbert MK. Sensory nerves, nitric oxide and NANC vasodilatation. Arch Int Pharmacodyn Ther 1995; 329:67–79. 9. Chen JD, Pan J, McCallum RW. Clinical significance of gastric myoelectrical dysrhythmias. Dig Dis 1995; 13:275–290. 10. Sarna SK. Cyclic motor activity; migrating motor complex: 1985. Gastroenterology 1985; 89:894–913. 11. Harper AA, Kidd C, Scratcherd T. Vago-vagal reflex effects on the motility of the stomach and small intestine. J Physiol 1956; 132:54–55P. 12. Ohga A, Nakazato Y, Saito K. An analysis of the vago-vagal reflex relaxation of the stomach. Nippon Seirigaku Zasshi 1969; 31:92–93. 13. Paintal AS. Vagal sensory receptors and their reflex effects. Physiol Rev 1973; 53:159–227. 14. Lundgren O. Vagal control of the motor functions of the lower esophageal sphincter and the stomach. J Auton Nerv Syst 1983; 9:185–197. 15. Sawada M, Dickinson CJ. The G cell. Annu Rev Physiol 1997; 59:273–298. 16. Sachs G, Zeng N, Prinz C. Physiology of isolated gastric endocrine cells. Annu Rev Physiol 1997; 59:243–256. 17. Rayford PL, Thompson JC. Gastrin. Surg Gynecol Obstet 1977; 145:257–268. 18. Barocelli E, Ballabeni V. Histamine in the control of gastric acid secretion: a topic review. Pharmacol Res 2003; 47: 299–304. 19. Schubert ML, Shamburek RD. Control of acid secretion. Gastroenterol Clin North Am 1990; 19:1–25. 20. Khanna MU, Abraham P. Determinants of acid secretion. J Assoc Physicians India 1990; 38(suppl 1):727–730. 21. Koh TJ, Chen D. Gastrin as a growth factor in the gastrointestinal tract. Regul Pept 2000; 93:37–44. 22. Friis-Hansen L. Gastric functions in gastrin gene knock-out mice. Pharmacol Toxicol 2002; 91:363–367. 23. Tulassay Z. Somatostatin and the gastrointestinal tract. Scand J Gastroenterol Suppl 1998; 228:115–121. 24. DelValle J. The stomach as an endocrine organ. Digestion 1997; 58(suppl 1):4–7. 25. Lloyd KC. Gut hormones in gastric function. Baillieres Clin Endocrinol Metab 1994; 8:111–136. 26. Ertan A, Arimura A. Somatostatin and the stomach. Dig Dis 1987; 5:13–20. 27. McIntosh CH. Gastrointestinal somatostatin: distribution, secretion and physiological significance. Life Sci 1985; 37:2043–2058. 28. Creutzfeldt W, Arnold R. Somatostatin and the stomach: exocrine and endocrine aspects. Metabolism 1978; 27: 1309–1315. 29. Thomas PA, Akwari OE, Kelly KA. Hormonal control of gastrointestinal motility. World J Surg 1979; 3:545–552. 30. Lefebvre RA. Non-adrenergic non-cholinergic neurotransmission in the proximal stomach. Gen Pharmacol 1993; 24: 257–266.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders 31. Erspamer V, Erpamer GF, Inselvini M. Some pharmacological actions of alytesin and bombesin. J Pharm Pharmacol 1970; 22:875–876. 32. Anastasi A, Erspamer V, Bucci M. Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia 1971; 27:166–167. 33. Castaneda AA, Kim YS, Chang LK, Cui Y, Mercer DW. Nitric oxide synthase inhibition negates bombesin-induced gastroprotection. Surgery 2000; 128:422–428. 34. Yamada K, Wada E, Wada K. Bombesin-like peptides: studies on food intake and social behaviour with receptor knock-out mice. Ann Med 2000; 32:519–529. 35. Merali Z, McIntosh J, Anisman H. Role of bombesin-related peptides in the control of food intake. Neuropeptides 1999; 33:376–386. 36. Hakanson R, Sundler F. Histamine-producing cells in the stomach and their role in the regulation of acid secretion. Scand J Gastroenterol Suppl 1991; 180:88–94. 37. Waldum HL, Sandvik AK. Histamine and the stomach. Scand J Gastroenterol 1989; 24:130–139. 38. Wang G, Lee HM, Englander E, Greeley GH Jr. Ghrelin—not just another stomach hormone. Regul Pept 2002; 105:75–81. 39. Erdmann J, Topsch R, Lippl F, Gussmann P, Schusdziarra V. Postprandial response of plasma ghrelin levels to various test meals in relation to food intake, plasma insulin, and glucose. J Clin Endocrinol Metab 2004; 89:3048–3054. 40. Teff KL, Elliott SS, Tschop M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 2004; 89:2963–2972. 41. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Oikawa S. Effects of insulin, leptin, and glucagon on ghrelin secretion from isolated perfused rat stomach. Regul Pept 2004; 119: 77–81. 42. Salehi A, de la Cour CD, Hakanson R, Lundquist I. Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. Regul Pept 2004; 118: 143–150. 43. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86:5992. 44. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346:1623–1630. 45. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50:707–709. 46. Tschop M, Flora DB, Mayer JP, Heiman ML. Hypophysectomy prevents ghrelin-induced adiposity and increases gastric ghrelin secretion in rats. Obes Res 2002; 10:991–999. 47. Inui A, Asakawa A, Bowers CY, et al. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. Faseb J 2004; 18:439–456. 48. Basson MD, Modlin IM. Pepsinogen: biological and pathophysiologic significance. J Surg Res 1988; 44:82–97. 49. Hirschowitz BI. Pepsinogen. Postgrad Med J 1984; 60:743–750. 50. Hersey SJ, Norris SH, Gibert AJ. Cellular control of pepsinogen secretion. Annu Rev Physiol 1984; 46:393–402. 51. Nicolas JP, Gueant JL. Gastric intrinsic factor and its receptor. Baillieres Clin Haematol 1995; 8:515–531. 52. Grasbeck R, Gueant JL. Mechanism of cobalamin absorption: intrinsic factor and its receptor. J Nutr Sci Vitaminol (Tokyo) 1992; Spec No:110–113. 53. Festen HP. Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol Suppl 1991; 188:1–7. 54. Rodbro P. Human gastric intrinsic factor secretion. Scand J Gastroenterol 1969; 4:473–475. 55. Sachs G, Prinz C, Loo D, Bamberg K, Besancon M, Shin JM. Gastric acid secretion: activation and inhibition. Yale J Biol Med 1994; 67:81–95.

363

56. Forte JG, Black JA, Forte TM, Machen TE, Wolosin JM. Ultrastructural changes related to functional activity in gastric oxyntic cells. Am J Physiol 1981; 241:G349–G358. 57. Zalewsky CA, Moody FG. Stereological analysis of the parietal cell during acid secretion and inhibition. Gastroenterology 1977; 73:66–74. 58. Miller ML, Judd LM, Van Driel IR, et al. The unique ultrastructure of secretory membranes in gastric parietal cells depends upon the presence of Hþ, Kþ-ATPase. Cell Tissue Res 2002; 309:369–380. 59. Forte JG, Forte TM, Black JA, Okamoto C, Wolosin JM. Correlation of parietal cell structure and function. J Clin Gastroenterol 1983; 5(suppl 1):17–27. 60. Agnew BJ, Duman JG, Watson CL, Coling DE, Forte JG. Cytological transformations associated with parietal cell stimulation: critical steps in the activation cascade. J Cell Sci 1999; 112(Pt 16):2639–2646. 61. Forte TM, Machen TE, Forte JG. Ultrastructural changes in oxyntic cells associated with secretory function: a membranerecycling hypothesis. Gastroenterology 1977; 73:941–955. 62. Prinz C, Kajimura M, Scott D, et al. Acid secretion and the H,K ATPase of stomach. Yale J Biol Med 1992; 65:577–596. 63. Debas HT, Carvajal SH. Vagal regulation of acid secretion and gastrin release. Yale J Biol Med 1994; 67:145–151. 64. Lloyd KC, Soll AH. Multiple pathways controlling acid secretion. J Gastroenterol 1994; 29(suppl 7):77–79. 65. Konturek SJ. Cholinergic control of gastric acid secretion in man. Scand J Gastroenterol Suppl 1982; 72:1–5. 66. Seidler U, Sewing KF. Ca2þ-dependent and -independent secretagogue action on gastric mucus secretion in rabbit mucosal explants. Am J Physiol 1989; 256:G739–G746. 67. Hawkey CJ. Non-steroidal anti-inflammatory drug gastropathy: causes and treatment. Scand J Gastroenterol Suppl 1996; 220:124–127. 68. Kaunitz JD, Tanaka S. Regulation of intracellular pH: role in gastric mucosal defence. Keio J Med 1996; 45:155–160. 69. Wilson DE. Role of prostaglandins in gastroduodenal mucosal protection. J Clin Gastroenterol 1991; 13(suppl 1):S65–S71. 70. Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer. Nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997; 24:2–17. 71. Garcia Rodriguez LA. Nonsteroidal antiinflammatory drugs, ulcers and risk: a collaborative meta-analysis. Semin Arthritis Rheum 1997; 26:16–20. 72. Helmer KS, West SD, Shipley GL, et al. Gastric nitric oxide synthase expression during endotoxemia: implications in mucosal defense in rats. Gastroenterology 2002; 123:173–186. 73. Mercer DW, Castaneda AA, Denning JW, Chang L, Russell DH. Effects of endotoxin on gastric injury from luminal irritants in rats: potential roles of nitric oxide. Am J Physiol 1998; 275:G449–G459. 74. Konturek PC, Brzozowski T, Sliwowski Z, et al. Involvement of nitric oxide and prostaglandins in gastroprotection induced by bacterial lipopolysaccharide. Scand J Gastroenterol 1998; 33:691–700. 75. Lopez-Belmonte J, Whittle BJ, Moncada S. The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa. Br J Pharmacol 1993; 108:73–78. 76. Bhowmik A, Oksala N, Roivainen R, et al. Regulation of restitution after superficial injury in isolated guinea pig gastric mucosa. Apmis 2004; 112:225–232. 77. Lacy ER. Rapid epithelial restitution in the stomach: an updated perspective. Scand J Gastroenterol Suppl 1995; 210:6–8. 78. Silen W, Ito S. Mechanisms for rapid re-epithelialization of the gastric mucosal surface. Annu Rev Physiol 1985; 47:217–229. 79. Szabo S. Mechanisms of gastric mucosal injury and protection. J Clin Gastroenterol 1991; 13(suppl 2):S21–S34. 80. West SD, Helmer KS, Chang LK, Cui Y, Greeley GH, Mercer DW. Cholecystokinin secretagogue-induced gastroprotection: role of nitric oxide and blood flow. Am J Physiol Gastrointest Liver Physiol 2003; 284:G399–G410.

medwedi.ru

364

Part Two: The Alimentary Tract—Esophagus and Stomach

81. Leung FW, Itoh M, Hirabayashi K, Guth PH. Role of blood flow in gastric and duodenal mucosal injury in the rat. Gastroenterology 1985; 88:281–289. 82. Holm L. Gastric mucosal blood flow and mucosal protection. J Clin Gastroenterol 1988; 10(suppl 1):S114–S119. 83. Denizbasi A, Yegen C, Ozturk M, Yegen B. Role of nitric oxide in gastric injury induced by hemorrhagic shock in rats. Pharmacology 2000; 61:106–112. 84. Duerksen DR. Stress-related mucosal disease in critically ill patients. Best Pract Res Clin Gastroenterol 2003; 17:327–344. 85. Marrone GC, Silen W. Pathogenesis, diagnosis and treatment of acute gastric mucosal lesions. Clin Gastroenterol 1984; 13:635–650. 86. Menguy R. Role of gastric mucosal energy metabolism in the etiology of stress ulceration. World J Surg 1981; 5:175–180. 87. O’Brine P, Silen W. Influence of acid secretory state on the gastric mucosal tolerance to back diffusion of Hþ. Gastroenterology 1976; 71:760–765. 88. Ritchie WP Jr. Acute gastric mucosal damage induced by bile salts, acid, and ischemia. Gastroenterology 1975; 68:699–707. 89. Hung CR, Chen HM. Role of histamine and acid back-diffusion in modulation of gastric microvascular permeability and haemorrhagic ulcers in betel-quid-fed rats. Inflammopharmacology 2004; 12:277–287. 90. Castaneda A, Vilela R, Chang L, Mercer DW. Effects of intestinal ischemia/reperfusion injury on gastric acid secretion. J Surg Res 2000; 90:88–93. 91. Helmer KS, West SD, Vilela R, et al. Lipopolysaccharideinduced changes in rat gastric H/K-ATPase expression. Ann Surg 2004; 239:501–509. 92. Miller TA, Tornwall MS, Moody FG. Stress erosive gastritis. Curr Probl Surg 1991; 28:453–509. 93. Mercer DW, Smith GS, Miller TA. Cyclooxygenase inhibition attenuates cholecystokinin-induced gastroprotection. Dig Dis Sci 1998; 43:468–475. 94. Steinberg KP. Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit. Crit Care Med 2002; 30:S362–S364. 95. Cheung LY. Treatment of established stress ulcer disease. World J Surg 1981; 5:235–240. 96. Lee SD, Kearney DJ. A randomized controlled trial of gastric lavage prior to endoscopy for acute upper gastrointestinal bleeding. J Clin Gastroenterol 2004; 38:861–865. 97. Sandlow LJ, Becker GH, Spellberg MA, et al. A prospective randomized study of the management of upper gastrointestinal hemorrhage. Am J Gastroenterol 1974; 61:282–289. 98. Tryba M, May B. Conservative treatment of stress ulcer bleeding: a new approach. Scand J Gastroenterol Suppl 1992; 191:16–24. 99. Melson GL, Geisse G, Stanley RJ. Selective intraarterial infusion of vasopressin for control of gastrointestinal bleeding: experience with 35 cases. Gastrointest Radiol 1976; 1:59–65. 100. Stump DL, Hardin TC. The use of vasopressin in the treatment of upper gastrointestinal haemorrhage. Drugs 1990; 39:38–53. 101. Menguy R, Gadacz T, Zajtchuk R. The surgical management of acute gastric mucosal bleeding. Arch Surg 1969; 99:198–208. 102. Gramlich L, Kichian K, Pinilla J, Rodych NJ, Dhaliwal R, Heyland DK. Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? A systematic review of the literature. Nutrition 2004; 20:843–848. 103. Martin LF, Booth FV, Reines HD, et al. Stress ulcers and organ failure in intubated patients in surgical intensive care units. Ann Surg 1992; 215:332–337. 104. Zinner MJ, Rypins EB, Martin LR, et al. Misoprostol versus antacid titration for preventing stress ulcers in postoperative surgical ICU patients. Ann Surg 1989; 210:590–595. 105. Bresalier RS, Grendell JH, Cello JP, Meyer AA. Sucralfate suspension versus titrated antacid for the prevention of acute

106.

107.

108. 109. 110.

111.

112.

113. 114. 115.

116.

117.

118. 119.

120.

121.

122.

123.

124.

125.

126. 127.

128.

stress-related gastrointestinal hemorrhage in critically ill patients. Am J Med 1987; 83:110–116. Priebe HJ, Skillman JJ, Bushnell LS, Long PC, Silen W. Antacid versus cimetidine in preventing acute gastrointestinal bleeding. A randomized trial in 75 critically ill patients. N Engl J Med 1980; 302:426–430. Hastings PR, Skillman JJ, Bushnell LS, Silen W. Antacid titration in the prevention of acute gastrointestinal bleeding: a controlled, randomized trial in 100 critically ill patients. N Engl J Med 1978; 298:1041–1045. Smythe MA, Zarowitz BJ. Changing perspectives of stress gastritis prophylaxis. Ann Pharmacother 1994; 28:1073–1085. Maier RV, Mitchell D, Gentilello L. Optimal therapy for stress gastritis. Ann Surg 1994; 220:353–60; discussion 360–363. Heyland D, Mandell LA. Gastric colonization by gramnegative bacilli and nosocomial pneumonia in the intensive care unit patient. Evidence for causation. Chest 1992; 101: 187–193. Driks MR, Craven DE, Celli BR, et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. The role of gastric colonization. N Engl J Med 1987; 317:1376–1382. Simms HH. Gastric alkalinization does not increase the risk of pneumonia in critically ill patients. Semin Respir Infect 1994; 9:222–227. Kurata JH. Ulcer epidemiology: an overview and proposed research framework. Gastroenterology 1989; 96:569–580. Sonnenberg A. Costs of medical and surgical treatment of duodenal ulcer. Gastroenterology 1989; 96:1445–1452. Sonnenberg A. Changes in physician visits for gastric and duodenal ulcer in the United States during 1958–1984 as shown by National Disease and Therapeutic Index (NDTI). Dig Dis Sci 1987; 32:1–7. Kurata JH, Elashoff JD, Haile BM, Honda GD. A reappraisal of time trends in ulcer disease: factors related to changes in ulcer hospitalization and mortality rates. Am J Public Health 1983; 73:1066–1072. Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 1987; 28:527–532. Susser M. Period effects, generation effects and age effects in peptic ulcer mortality. J Chronic Dis 1982; 35:29–40. Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. Gastrointest Endosc 1981; 27:80–93. Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. I. Study design and baseline data. Gastrointest Endosc 1981; 27:73–79. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; 1:1311–1315. Coghlan JG, Gilligan D, Humphries H, et al. Campylobacter pylori and recurrence of duodenal ulcers—a 12-month follow-up study. Lancet 1987; 2:1109–1111. Tytgat GN. Review article: treatments that impact favourably upon the eradication of Helicobacter pylori and ulcer recurrence. Aliment Pharmacol Ther 1994; 8:359–368. Ng EK, Lam YH, Sung JJ, et al. Eradication of Helicobacter pylori prevents recurrence of ulcer after simple closure of duodenal ulcer perforation: randomized controlled trial. Ann Surg 2000; 231:153–158. Dempsey DT, Ashley SW, Mercer DW, Sillin LF. Peptic ulcer surgery in the H. pylori era: Part 2: indications for operation. Contemporary Surgery 2001; 57:433–441. Soll AH. Pathogenesis of peptic ulcer and implications for therapy. N Engl J Med 1990; 322:909–916. Rubinsztein-Dunlop S, Guy B, Lissolo L, Fischer H. Identification of two new Helicobacter pylori surface proteins involved in attachment to epithelial cell lines. J Med Microbiol 2005; 54:427–434. Evans DJ Jr, Evans DG. Helicobacter pylori adhesins: review and perspectives. Helicobacter 2000; 5:183–195.

Chapter 15: Gastric Physiology and Acid-Peptic Disorders 129. Rieder G, Fischer W, Haas R. Interaction of Helicobacter pylori with host cells: function of secreted and translocated molecules. Curr Opin Microbiol 2005; 8:67–73. 130. Gebert B, Fischer W, Haas R. The Helicobacter pylori vacuolating cytotoxin: from cellular vacuolation to immunosuppressive activities. Rev Physiol Biochem Pharmacol 2004; 152: 205–220. 131. Dhar SK, Soni RK, Das BK, Mukhopadhyay G. Molecular mechanism of action of major Helicobacter pylori virulence factors. Mol Cell Biochem 2003; 253:207–215. 132. Konturek PC, Kania J, Konturek JW, Nikiforuk A, Konturek SJ, Hahn EG. H. pylori infection atrophic gastritis cytokines gastrin COX-2 PPAR gamma impaired apoptosis in gastric carcinogenesis . Med Sci Monit 2003; 9:SR53–SR66. 133. Torok AM, Bouton AH, Goldberg JB. Helicobacter pylori induces interleukin-8 secretion by Toll-like receptor 2-Toll-like receptor 5-dependent -independent pathways. Infect Immun 2005; 73:1523–1531. 134. Yamaoka Y, Yamauchi K, Ota H, et al. Natural history of gastric mucosal cytokine expression in Helicobacter pylori gastritis in Mongolian gerbils. Infect Immun 2005; 73:2205–2212. 135. Bodger K, Crabtree JE. Helicobacter pylori gastric inflammation. Br Med Bull 1998; 54:139–150. 136. Shimada T, Terano A. Chemokine expression in Helicobacter pylori-infected gastric mucosa. J Gastroenterol 1998; 33: 613–617. 137. Kim JM, Kim JS, Jung HC, et al. Helicobacter pylori infection activates NF-kappaB signaling pathway to induce iNOS and protect human gastric epithelial cells from apoptosis. Am J Physiol Gastrointest Liver Physiol 2003; 285:G1171–G1180. 138. Ahmad A, Govil Y, Frank BB. Gastric mucosa-associated lymphoid tissue lymphoma. Am J Gastroenterol 2003; 98:975–986. 139. Genta RM. The immunobiology of Helicobacter pylori gastritis. Semin Gastrointest Dis 1997; 8:2–11. 140. Kaneko H, Konagaya T, Kusugami K. Helicobacter pylori gut hormones. J Gastroenterol 2002; 37:77–86. 141. Queiroz DM, Mendes EN, Rocha GA, et al. Effect of Helicobacter pylori eradication on antral gastrin- and somatostatinimmunoreactive cell density and gastrin and somatostatin concentrations. Scand J Gastroenterol 1993; 28:858–864. 142. Peterson WL, Barnett CC, Evans DJ Jr, et al. Acid secretion and serum gastrin in normal subjects and patients with duodenal ulcer: the role of Helicobacter pylori. Am J Gastroenterol 1993; 88:2038–2043. 143. Peach HG, Barnett NE. Determinants of basal plasma gastrin levels in the general population. J Gastroenterol Hepatol 2000; 15:1267–1271. 144. Kamada T, Haruma K, Komoto K, Mihara M, Sumii K, Kajiyama G. Comparison of meal-stimulated serum gastrin response in Helicobacter pylori-positive duodenal ulcer and asymptomatic volunteers with and without H. pylori infection. Helicobacter 1999; 4:170–177. 145. Milutinovic AS, Todorovic V, Milosavljevic T, Micev M, Spuran M, Drndarevic N. Somatostatin and D cells in patients with gastritis in the course of Helicobacter pylori eradication: a six-month, follow-up study. Eur J Gastroenterol Hepatol 2003; 15:755–766. 146. El-Omar EM, Oien K, El-Nujumi A, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 1997; 113:15–24. 147. Kemppainen H, Raiha I, Kujari H, Sourander L. Characteristics of Helicobacter pylori-negative and -positive peptic ulcer disease. Age Ageing 1998; 27:427–431. 148. Rauws EA, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GN. Campylobacter pyloridis-associated chronic active antral gastritis A prospective study of its prevalence and the effects of antibacterial and antiulcer treatment. Gastroenterology 1988; 94:33–40. 149. Lin JT. Helicobacter pylori infection in children—the role of intrafamilial clustering. Can J Gastroenterol 2000; 14:772–774. 150. Al-Knawy BA, Ahmed ME, Mirdad S, ElMekki A, Al-Ammari O. Intrafamilial clustering of Helicobacter pylori infection in Saudi Arabia. Can J Gastroenterol 2000; 14:772–774.

365

151. Drumm B, Perez-Perez GI, Blaser MJ, Sherman PM. Intrafamilial clustering of Helicobacter pylori infection. N Engl J Med 1990; 322:359–363. 152. Dooley CP, Cohen H, Fitzgibbons PL, et al. Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons. N Engl J Med 1989; 321:1562–1566. 153. Greenberg PD, Koch J, Cello JP. Clinical utility and cost effectiveness of Helicobacter pylori testing for patients with duodenal and gastric ulcers. Am J Gastroenterol 1996; 91:228–232. 154. Ford A, Delaney B, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev 2004:CD003840. 155. Nakamura S, Matsumoto T, Suekane H, et al. Long-term clinical outcome of Helicobacter pylori eradication for gastric mucosa-associated lymphoid tissue lymphoma with a reference to second-line treatment. Cancer 2005; 104(3):532–540. 156. Sullen DJE, Collins BJ, Christiansen KJ, Epis J, Warren JR, Cullen KJ. Long term risk of peptic ulcer disease in people with H. pylori infection—a community based study. Gastroenterology 1993; 104:A60. 157. Sipponen P, Varis K, Fraki O, Korri UM, Seppala K, Siurala M. Cumulative 10-year risk of symptomatic duodenal and gastric ulcer in patients with or without chronic gastritis. A clinical follow-up study of 454 outpatients. Scand J Gastroenterol 1990; 25:966–973. 158. Befrits R, Sjostedt S, Tour R, Leijonmarck CE, Hedenborg L, Backman M. Long-term effects of eradication of Helicobacter pylori on relapse and histology in gastric ulcer patients: a twoyear follow-up study. Scand J Gastroenterol 2004; 39:1066–1072. 159. Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med 1992; 116:705–708. 160. Wilhelmsen I, Berstad A. Quality of life and relapse of duodenal ulcer before and after eradication of Helicobacter pylori. Scand J Gastroenterol 1994; 29:874–879. 161. Ford AC, Delaney BC, Forman D, Moayyedi P. Eradication therapy in Helicobacter pylori positive peptic ulcer disease: systematic review and economic analysis. Am J Gastroenterol 2004; 99:1833–1855. 162. Miehlke S, Bayerdorffer E, Lehn N, et al. Two-year follow-up of duodenal ulcer patients treated with omeprazole and amoxicillin. Digestion 1995; 56:187–193. 163. Logan RP, Bardhan KD, Celestin LR, et al. Eradication of Helicobacter pylori and prevention of recurrence of duodenal ulcer: a randomized, double-blind, multi-centre trial of omeprazole with or without clarithromycin. Aliment Pharmacol Ther 1995; 9:417–423. 164. Parente F, Bargiggia S, Bollani S, Colombo E, Porro GB. Continuous maintenance with low-dose lansoprazole versus Helicobacter pylori eradication in the prevention of duodenal ulcer recurrence. Hepatogastroenterology 1998; 45:990–993. 165. Wong BC, Lam SK, Lai KC, et al. Triple therapy for Helicobacter pylori eradication is more effective than long-term maintenance antisecretory treatment in the prevention of recurrence of duodenal ulcer: a prospective long-term follow-up study. Aliment Pharmacol Ther 1999; 13:303–309. 166. Sharma VK, Sahai AV, Corder FA, Howden CW. Helicobacter pylori eradication is superior to ulcer healing with or without maintenance therapy to prevent further ulcer haemorrhage. Aliment Pharmacol Ther 2001; 15:1939–1947. 167. Gisbert JP, Khorrami S, Carballo F, Calvet X, Gene E, DominguezMunoz JE. H. pylori eradication therapy versus antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst Rev 2004:CD004062. 168. Somerville K, Faulkner G, Langman M. Non-steroidal antiinflammatory drugs and bleeding peptic ulcer. Lancet 1986; 1:462–464. 169. Kurata JH, Abbey DE. The effect of chronic aspirin use on duodenal and gastric ulcer hospitalizations. J Clin Gastroenterol 1990; 12:260–266.

medwedi.ru

366

Part Two: The Alimentary Tract—Esophagus and Stomach

170. Fries JF, Miller SR, Spitz PW, Williams CA, Hubert HB, Bloch DA. Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use. Gastroenterology 1989; 96:647–655. 171. Lam SK. Pathogenesis and pathophysiology of duodenal ulcer. Clin Gastroenterol 1984; 13:447–472. 172. Cox A. Stomach size and its relation to chronic peptic ulcer. Arch Pathol 1952; 54:407–422. 173. Gelfand DW, Dale WJ, Ott DJ. The location and size of gastric ulcers: radiologic and endoscopic evaluation. Am J Roentgenol 1984; 143:755–758. 174. Thompson G, Stevenson GW, Somers S. Distribution of gastric ulcers by double contrast barium meal with endoscopic correlation. J Can Assoc Radiol 1983; 34:296–297. 175. Hirschowitz BI. Pathobiology and management of hypergastrinemia and the Zollinger–Ellison syndrome. Yale J Biol Med 1992; 65:659–676; discussion 689–692. 176. Berg CL, Wolfe MM. Zollinger-Ellison syndrome. Med Clin North Am 1991; 75:903–921. 177. Weber HC, Orbuch M, Jensen RT. Diagnosis and management of Zollinger-Ellison syndrome. Semin Gastrointest Dis 1995; 6:79–89. 178. Hirschl AM, Rathbone BJ, Wyatt JI, Berger J, Rotter ML. Comparison of ELISA antigen preparations alone or in combination for serodiagnosing Helicobacter pylori infections. J Clin Pathol 1990; 43:511–513. 179. Marchildon P, Balaban DH, Sue M, et al. Usefulness of serological IgG antibody determinations for confirming eradication of Helicobacter pylori infection. Am J Gastroenterol 1999; 94:2105–2108. 180. Bergey B, Marchildon P, Peacock J, Megraud F. What is the role of serology in assessing Helicobacter pylori eradication? Aliment Pharmacol Ther 2003; 18:635–639. 181. Gomollon F, Ducons JA, Santolaria S, et al. Breath test is very reliable for diagnosis of Helicobacter pylori infection in real clinical practice. Dig Liver Dis 2003; 35:612–618. 182. Klein PD, Malaty HM, Martin RF, Graham KS, Genta RM, Graham DY. Noninvasive detection of Helicobacter pylori infection in clinical practice: the 13C urea breath test. Am J Gastroenterol 1996; 91:690–694. 183. Yousfi MM, El-Zimaity HM, Cole RA, Genta RM, Graham DY. Comparison of agar gel (CLO test) or reagent strip (PyloriTek) rapid urease tests for detection of Helicobacter pylori infection. Am J Gastroenterol 1997; 92:997–999. 184. Puetz T, Vakil N, Phadnis S, Dunn B, Robinson J. The Pyloritek test and the CLO test: accuracy and incremental cost analysis. Am J Gastroenterol 1997; 92:254–257. 185. Viiala CH, Windsor HM, Forbes GM, Chairman SO, Marshall BJ, Mollison LC. Evaluation of a new formulation CLO test. J Gastroenterol Hepatol 2002; 17:127–130. 186. Bachmann K, Sullivan TJ, Jauregui L. A controlled comparison of continuous ranitidine and intermittent famotidine infusions on gastric pH. J Clin Pharmacol 1993; 33:1219–1224. 187. Dawson J, Jain S, Cockel R. Effect of ranitidine and cimetidine on gastric ulcer healing and recurrence. Scand J Gastroenterol 1984; 19:665–668. 188. McCullough AJ. A multicenter, randomized, double-blind study comparing famotidine with ranitidine in the treatment of active duodenal ulcer disease. Am J Med 1986; 81:17–24. 189. Gitlin N, McCullough AJ, Smith JL, Mantell G, Berman R. A multicenter, double-blind, randomized, placebo-controlled comparison of nocturnal and twice-a-day famotidine in the treatment of active duodenal ulcer disease. Gastroenterology 1987; 92:48–53. 190. Dobrilla G, De Pretis G, Piazzi L, et al. Comparison of oncedaily bedtime administration of famotidine and ranitidine in the short-term treatment of duodenal ulcer. A multicenter, double-blind, controlled study. Scand J Gastroenterol Suppl 1987; 134:21–28. 191. Rodrigo L, Viver J, Conchillo F, et al. A multicenter, randomized, double-blind study comparing famotidine with cimetidine in the treatment of active duodenal ulcer disease. Digestion 1989; 42:86–92.

192. Palmer RH, Frank WO, Karlstadt R. Maintenance therapy of duodenal ulcer with H2-receptor antagonists—a meta-analysis. Aliment Pharmacol Ther 1990; 4:283–294. 193. Der G. An overview of proton pump inhibitors. Gastroenterol Nurs 2003; 26:182–190. 194. Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2003; 63:2739–2754. 195. Bamberg P, Caswell CM, Frame MH, Lam SK, Wong EC. A meta-analysis comparing the efficacy of omeprazole with H2-receptor antagonists for acute treatment of duodenal ulcer in Asian patients. J Gastroenterol Hepatol 1992; 7:577–585. 196. Eriksson S, Langstrom G, Rikner L, Carlsson R, Naesdal J. Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis. Eur J Gastroenterol Hepatol 1995; 7:467–475. 197. Poynard T, Lemaire M, Agostini H. Meta-analysis of randomized clinical trials comparing lansoprazole with ranitidine or famotidine in the treatment of acute duodenal ulcer. Eur J Gastroenterol Hepatol 1995; 7:661–665. 198. Rey JF, Legras B, Verdier A, Vicari F, Gorget C. Comparative study of sucralfate versus cimetidine in the treatment of acute gastroduodenal ulcer. Randomized trial with 667 patients. Am J Med 1989; 86:116–121. 199. Pop P, Nikkels RE, Thys O, Dorrestein GC. Comparison of sucralfate and cimetidine in the treatment of duodenal and gastric ulcers. A multicenter study. Scand J Gastroenterol Suppl 1983; 83:43–47. 200. Summary of the NIH consensus. Helicobacter pylori in peptic ulcer disease. Md Med J 1994; 43:923–924. 201. Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ 2004; 329:948. 202. Rostom A, Dube C, Wells G, et al. Prevention of NSAIDinduced gastroduodenal ulcers. Cochrane Database Syst Rev 2002:CD002296. 203. Dragstedt LR. Gastric vagotomy in the treatment of peptic ulcer. Postgrad Med 1951; 10:482–490. 204. Chan VM, Reznick RK, O’Rourke K, Kitchens JM, Lossing AG, Detsky AS. Meta-analysis of highly selective vagotomy versus truncal vagotomy and pyloroplasty in the surgical treatment of uncomplicated duodenal ulcer. Can J Surg 1994; 37: 457–464. 205. Ihasz M, Batorfi J, Balint A, et al. Long-term clinical results of highly selective vagotomy performed between 1980 and 1990. Surg Today 1996; 26:546–551. 206. Enskog L, Rydberg B, Adami HO, Enander LK, Ingvar C. Clinical results 1–10 years after highly selective vagotomy in 306 patients with prepyloric and duodenal ulcer disease. Br J Surg 1986; 73:357–360. 207. Popiela T, Turczynowski W, Karcz D, Legutko J, Zajac A. Longterm results of highly selective vagotomy in the treatment of duodenal ulcer patients using the intra-operative endoscopic congo red test to identify the parietal cell antrum-corpus borderline. Hepatogastroenterology 1993; 40:267–271. 208. Adami HO, Enander LK, Enskog L, Ingvar C, Rydberg B. Recurrences 1 to 10 years after highly selective vagotomy in prepyloric and duodenal ulcer disease. Frequency, pattern, and predictors. Ann Surg 1984; 199:393–399. 209. Hubert JP Jr, Kiernan PD, Beahrs OH, ReMine WH. Truncal vagotomy and resection in the treatment of duodenal ulcer. Mayo Clin Proc 1980; 55:19–24. 210. Koo J, Lam SK, Chan P, et al. Proximal gastric vagotomy, truncal vagotomy with drainage, and truncal vagotomy with antrectomy for chronic duodenal ulcer. A prospective, randomized controlled trial. Ann Surg 1983; 197:265–271. 211. Siu WT, Leong HT, Law BK, et al. Laparoscopic repair for perforated peptic ulcer: a randomized controlled trial. Ann Surg 2002; 235:313–319. 212. Donahue PE, Bombeck CT, Condon RE, Nyhus LM. Proximal gastric vagotomy versus selective vagotomy with antrectomy:

Chapter 15: Gastric Physiology and Acid-Peptic Disorders

213.

214. 215.

216.

217. 218.

results of a prospective, randomized clinical trial after four to twelve years. Surgery 1984; 96:585–591. Emas S, Eriksson B. Twelve-year follow-up of a prospective, randomized trial of selective vagotomy with pyloroplasty and selective proximal vagotomy with and without pyloroplasty for the treatment of duodenal, pyloric, and prepyloric ulcers. Am J Surg 1992; 164:4–12. Saik RP, Greenburg AG, Peskin GW. Pros and cons of parietal cell versus truncal vagotomy. Am J Surg 1984; 148:93–98. Taylor TV, Gunn AA, Macleod DA, MacLennan I. Anterior lesser curve seromyotomy and posterior truncal vagotomy in the treatment of chronic duodenal ulcer. Lancet 1982; 2:846–849. Taylor TV, Lythgoe JP, McFarland JB, Gilmore IT, Thomas PE, Ferguson GH. Anterior lesser curve seromyotomy and posterior truncal vagotomy versus truncal vagotomy and pyloroplasty in the treatment of chronic duodenal ulcer. Br J Surg 1990; 77:1007–1009. Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med 1994; 331:717–727. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with

219.

220.

221. 222.

223.

224.

367

rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123:241–249. Stabile BE. Redefining the role of surgery for perforated duodenal ulcer in the Helicobacter pylori era. Ann Surg 2000; 231:159–160. Crofts TJ, Park KG, Steele RJ, Chung SS, Li AK. A randomized trial of nonoperative treatment for perforated peptic ulcer. N Engl J Med 1989; 320:970–973. Berne TV, Donovan AJ. Nonoperative treatment of perforated duodenal ulcer. Arch Surg 1989; 124:830–832. Csendes A, Maluenda F, Braghetto I, Schutte H, Burdiles P, Diaz JC. Prospective randomized study comparing three surgical techniques for the treatment of gastric outlet obstruction secondary to duodenal ulcer. Am J Surg 1993; 166:45–49. Lau JY, Chung SC, Sung JJ, et al. Through-the-scope balloon dilation for pyloric stenosis: long-term results. Gastrointest Endosc 1996; 43:98–101. Aoki T. Current status of and problems in the treatment of gastric and duodenal ulcer disease: introduction. World J Surg 2000; 24:249.

medwedi.ru

SMALL AND LARGE INTESTINE

16 Physiology of Digestion and Absorption Bobby S. Glickman and Jon S. Thompson

INTRODUCTION The gastrointestinal (GI) tract has the sole responsibility for extracting fuel from the environment along with the physical building blocks and chemicals necessary to build and run the machinery of the body. The normal human diet comprises approximately 2 L of water admixed with 400 g of carbohydrate, 100 g of protein, and 60 to 100 g of fat. The digestive process proceeds in the stomach by mechanical, acid, and enzymatic activity resulting in chyme production. The resultant slurry is introduced to the duodenum under the control of hormones sensitive to volume, osmolality, and acidity. The role of the small intestine, then, is to absorb ingested water, electrolytes, and nutrients as well as to absorb the additional water, electrolytes, and enzymes secreted by the intestinal tract for the digestive process. This occurs sequentially along the small intestine involving intraluminal, mucosal, and intracellular processes and differs significantly for the various nutrients. Assimilation of nutrients is a complex process that we are better appreciating at the molecular level through ongoing investigation. The physicochemical steps of digestion have been well characterized along with much of the membrane events resulting in absorption. Secretion and motility are intimately related to digestion and absorption with regulation via the intrinsic and extrinsic innervation of the GI tract and interdependence of the mesenteric vasculature, lymphatics, and regulatory polypeptides. Despite the complexity, digestion and absorption are very efficient processes that result in the delivery of 1 L of effluent containing less than 5% of ingested nutrient to the large intestine. Still, many states of dysregulation are poorly understood along with overall governing mechanisms coordinating the elements of normal digestion and absorption. While some technical triumphs such as intestinal transplantation have become a reality, other processes as ubiquitous as postoperative ileus remain incompletely understood and with few treatment options. This chapter presents the current understanding of the digestion and absorption of dietary contents.

FLUID AND ELECTROLYTE SECRETION AND ABSORPTION The average adult produces approximately 100 to 200 mL of stool water per day. Considering that the gut normally handles 10 L of fluid daily (1–2 L exogenous intake and the rest endogenous secretions), this organ exhibits a highly efficient mechanism for conserving salt and water. Changes in intestinal absorption and secretion of fluid and electrolytes may result in increased stool water and hence diarrhea.

There are important regional differences in fluid and electrolyte absorption in the gut. These are related to gradients in mucosal resistance, absorptive mechanisms, and cellular transporters. The jejunum absorbs water isosmotically secondary to Na-coupled nutrient absorption. The ileum absorbs NaCl and secretes bicarbonate, also isosmotically. Generally the small bowel absorbs large volumes of fluid along with nutrient solutes, but does not concentrate the intestinal luminal contents. The colon is capable of absorbing sodium against a concentration gradient resulting in the formation of a compact stool. Interestingly, just as fluid fluxes (secretion and absorption) vary along the length of the gut, there is also variation within the microscopic realm of the individual villi and crypts. Enterocytes, similar to other transport epithelia, have distinct apical (luminal) and basolateral (serosal) membranes, tight intercellular junctions, a sodium pump in the basolateral membrane, and a negative intracellular potential difference. As enterocytes mature and migrate from the crypt base to the villus tip, they express proteins favoring absorption versus secretion. Transport molecules such as sodium channels, sodium nutrient carriers, and sodium– hydrogen exchange (NHE) -3 have a greater density in villus cells, whereas the cystic fibrosis transmembrane regulator (CFTR), which is responsible for Cl secretion, is more dense at the base of the crypt. Thus, in general, net absorption occurs in the villi, while net secretion occurs in the crypts. As a consequence, intestinal diseases, which primarily affect the villi shift the balance of fluid transport in favor of secretory diarrhea (1). To be absorbed, solutes first must traverse the unstirred layer of water and mucous adjacent to the epithelium. The depth of the unstirred layer varies along the length of the gut and will influence the rate at which particularly large lipid-soluble molecules are absorbed. The depth of the layer is influenced by luminal contents and peristalsis. Two major routes for absorption of fluids and electrolytes across the epithelium of the intestine exist. One route is between the enterocytes, despite the ‘‘relatively’’ tight junctions, and the other is directly across the lipid bilayer membrane of the enterocytes via diffusion, carriers, or channels. The relative importance of these two pathways and others is currently being reevaluated. Paracellular permeability is a dynamic mechanism influenced by, primarily, the apical zona occludens, which can be altered by various agonists and cellular characteristics such as the volume. Water, low-molecular-weight solutes, and ions use this pathway, flowing passively along electrochemical and osmotic gradients. The paracellular route lacks directional specificity, and movement may occur into or out of the lumen depending on relative concentrations as long as the pathways are open. The tight junctions are

medwedi.ru 369

370

Part Two: The Alimentary Tract—Small and Large Intestine

‘‘tighter’’ in moving distally from jejunum to colon allowing Na and water absorption against a gradient. Water movement occurs in response to osmotic gradients. Sodium is the principal ion driving absorptive flows, whereas active chloride secretion promotes the movement of water into the intestinal lumen. Nutrients have a crucial role in determining water transport. Carbohydrate malabsorption causes luminal retention of considerable osmotic force, while absorption of sugars and amino acids enhances water absorption. Sodium transport in the enterocyte is not only a major determinant of water flux but is also coupled to nutrient absorption through specific carriers (Fig. 1). The enterocyte actively pumps large amounts of sodium [using adenosine triphosphate (ATP) as energy] out of its own cytoplasm and into the underlying mucosal interstitium to be cleared away in equilibrium with the bloodstream. The pumps responsible for this process are located on the basal and lateral portions of the columnar enterocytes. This creates a relatively low concentration of cytosolic Na, so that the apical (i.e., brush border or luminal) portion of the enterocyte membrane can absorb Na along a favorable (‘‘downhill’’) electrochemical and diffusion gradient. Within this paradigm

are three basic mechanisms of Na entry across the apical membrane: (i) solute-coupled Na transport (e.g., to drive the uptake of amino acids and glucose), (ii) Cl-coupled Na transport (analogous to other solutes but for accumulation of intracellular Cl), and (iii) electrogenic sodium absorption independent of other solutes but facilitating water absorption. In all cases, the Na absorbed across the apical membrane is extruded across the basolateral membrane by the ATP-powered Na pump (1). Solute-coupled Na absorption allows for the accumulation of nutrients such as amino acids and glucose against a concentration gradient through linkage to ‘‘downhill’’ Na movement. This mechanism is influenced by luminal paracrine and systemic factors. A variety of transmembrane proteins act as carriers to shuttle the sodium ion, along with the cotransported molecule and surrounding water molecules, into the cellular space. The most prominent of these is labeled SGLT1. This 664 amino acid protein on the apical membrane is found exclusively in the small intestine, primarily in villus tip enterocytes. This transporter is responsible for half of the daily water reuptake in the intestine (2). Solute-coupled Na absorption is the mechanism of oral rehydration therapy used worldwide for cholera and related

Figure 1 Schematic depiction of Na-coupled nutrient and water transport across the intestinal brush border epithelium. Small open circles depict water molecules surrounding solutes. These water molecules are cotransported with the corresponding solute. The engine is the basolateral adenosine triphosphate–dependent Na pump, which expels Na from the cell and produces adenosine diphosphate as the spent fuel. Source: Illustration by Dr. Thompson.

Chapter 16: Physiology of Digestion and Absorption

endemics. The administration of oral solutions of dilute glucose or amino acids in combination with sodium allows water to be reclaimed as it follows these solutes across the membranes and between the ‘‘tight’’ junctions leaving the lumen (3). For every molecule of glucose absorbed, two molecules of Na and 225 molecules of water are absorbed as well (4,5). In fact, tight junctions are dilated by intraluminal glucose (6). The Cl-coupled Na absorption is more complex than the other solute-coupled transport systems. In fact, two distinct transporters work in concert to accomplish the task. One transporter exchanges Na for H (NHE), while the other exchanges Cl for HCO3. The net effect is the uptake of NaCl and export of a proton and HCO3, which effectively combine to form water and CO2 in the lumen (7,8). pH responses likely coordinate the two activities. Several NHEs have been identified. NHE-1 is localized to the basolateral membrane and regulates cell volume and pH. NHE-3 is an apical transporter found in villus cells, upregulated by glucocorticoids, and linked to growth factors. Na absorption that is not coupled to a solute or chloride is electrogenic because it involves net transfer of positive charge. Unlike the coupled transport systems that involve specialized protein carriers, this type of Na transport occurs through selective channels in the membrane that allow the passage of Na, but exclude other cations and anions. This absorptive pathway is most readily apparent in the distal colon and can be stimulated by mineralocorticoids and blocked by the diuretic amiloride. This mechanism accounts for the majority of sodium absorption between meals. Cl, the principal ion governing secretion, accumulates within intestinal cells above its electrochemical equilibrium. The permeability (conductance) of the apical membrane for Cl determines the rate of the anion’s movement across this membrane. The Cl conductance is controlled by several intracellular mediators: cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositol triphosphate, and calcium. Stimuli (e.g., cholera toxin, which raises cAMP or Escherichia coli, which raises cGMP) that increase any of these factors cause active Cl secretion and, secondarily, movement of water into the intestinal lumen. In addition to increasing the Cl conductance of the apical membrane, these mediators also block the Na–Cl cotransport system. This antiabsorptive effect favors fluid accumulation within the intestinal lumen and an increase in diarrhea. However, these agents have no effect on Na absorption coupled to solutes such as sugars or amino acids. The therapeutic implications of this observation have led to oral rehydration therapy. Defective Cl secretion can produce the opposite problem. The protein product of the cystic fibrosis (CF) gene, cystic fibrosis transmembrane conductance regulator (CFTR), is an apical transmembrane protein found in many tissues, notably respiratory and intestinal epithelia (9). CFTR is activated by intracellular cAMP and protein kinase A to open and allow Cl to move down its concentration gradient into the intestinal lumen; Na and water follow. In CF, a missense mutation leads to defective Cl secretion and consequently dehydrated secretions. In the GI tract, this may lead to obstruction of the intestinal lumen or pancreatic duct (10). In addition to the complex array of solute and nutrient transporters, which carry water to and fro across the brush border, water movement may be facilitated by specialized proteins known as aquaporins, which function as water channels (11). However, despite much recent attention, no direct

371

evidence has shown a significant role for an aquaporin in intestinal transport of water or solutes in human physiology.

OVERVIEW OF DIGESTION Fundamentals The digestive process is both mechanical and chemical. Mastication occurs in the mouth along with the introduction of salivary amylase and lipase. After transport by deglutition and muscular propulsion through the esophagus, mechanical mixing and churning continue in the acidic environment of the stomach. Pepsin contributes to early protein breakdown within the stomach. The duodenum receives the acidic chyme via the pylorus, and pancreatic bicarbonate neutralizes the contents. Pancreatic enzymes continue the digestion of fats, carbohydrates, and proteins as described below. Bile salts are introduced simultaneously and potentiate lipid digestion and transport across the unstirred water layer. Absorption at various levels is schematically shown in Table 1. As transit continues through the small bowel, large volumes of fluid are exchanged, and brush border enzymes complement the luminal pancreatic enzymes and bile salts to complete digestion. The colon has some absorptive capacity but primarily processes the fecal waste into a convenient form.

Pancreatic Enzymes Detailed discussion of the exocrine pancreas is covered in chapter by Joehl on pancreas. For the purpose of understanding digestion of the nutrients in our food, a brief survey of the relevant enzymes is helpful. As in the salivary glands, the pancreas produces amylase in great abundance, which will cleave dietary starch (amylopectin) into three types of small subunits, which undergo final digestion by nonpancreatic enzymes attached to the intestinal brush border. The pancreas also secretes numerous proteases including trypsin, chymotrypsin, elastase, and carboxypeptidase. These enzymes cleave proteins into much smaller subunits of individual amino acids as well as dipeptides and tripeptides. These forms then undergo direct absorption or further cleavage at the brush border. Finally, dietary fat is digested under the influence of three additional pancreatic enzymes and a coenzyme: lipase (and colipase), phospholipase A2 and cholesterol esterase. Naturally, the acid-buffering Table 1 Nutrient Absorption Specificity at Different Sites in the Intestine Duodenum Carbohydrate Fat Protein Bile salts Minerals Copper Iron Calcium Magnesium Phosphorus Sodium Zinc Vitamins A, D, E, K B1 B12

medwedi.ru

þþ þþ þþ

Jejunum þþþ þþþ þþþ

Ileum

Terminal ileum

þ þ þ þþþ

þþ þþþ þþ þ þ þ

þ þþ þþþ þþþ þþþ þþþ þþ

þ þþ þþ þþ þþþ

þ þ

þþþ þþþ

þ þþ þþþ

372

Part Two: The Alimentary Tract—Small and Large Intestine

bicarbonate secretion from the pancreas also facilitates efficient function of these enzymes.

Biliary Secretions and Enterohepatic Circulation The products of enzymatic digestion of dietary fat remain relatively water insoluble. Bile salts provide the mechanism for bringing cholesterol, monoglycerides, fatty acids, and phospholipids into solution by forming micelles. The structure of bile salts is similar to cholesterol and, in fact, results from cholesterol modification. In addition to several alterations in stereochemistry, saturation, and side groups in the ring, the tail of the molecule is carboxylated to an acid form. This acid form is then conjugated with glycine or taurine to form the final bile salt. Conjugation prevents undesired reabsorption of the bile salt until it encounters specific receptors in the terminal ileum and increases its solubility. It is through this ileal reabsorption that bile salts are transported back to the liver, a process known as enterohepatic circulation (see below). Bile salts are detergents; like all detergents they are amphophiles, possessing both hydrophilic and hydrophobic regions. Placed in an aqueous solution, bile salts spontaneously form into a particular three-dimensional arrangement called a micelle, in which the hydrophilic regions of the molecules are directed outward and the hydrophobic regions inward, thereby shielded from the aqueous environment. Diglycerides and triglycerides are too bulky to be packaged in these micelles and must await lipase hydrolysis. Fat-soluble vitamins are also included in micelles. A bile salt pool of 2 g cycles through the enterohepatic circulation six times daily. Only 0.5 g is lost in the stool daily to be replaced by synthesis. There are two different mechanisms of bile acid absorption. Passive diffusion occurs throughout, while active carrier-mediated transport is limited to the terminal ileum. The ileal bile acid transport system comprises the active mechanism for reclaiming bile salts. The system has four key components. First, a basolateral Na-K ATPase generates a sodium gradient across the cell membrane. Second, this Na gradient drives a Na-coupled bile acid symporter, which carries the bile acid into the terminal ileal enterocyte. Third, a bile acid–binding protein within the cytoplasm reduces the activity of the bile acid to prevent injury to the cell and its organelles. Finally, a basolateral anion exchanger exports the conserved bile acid for portal circulation and eventual reuptake and excretion by the liver (12). Disruption of the enterohepatic circulation may result in malabsorption and/or diarrhea. Ileal resection or dysfunction (e.g., Crohn’s disease) blocks the reabsorption of bile acids. Even with small resections of the ileum ( < 100 cm), the passage of bile acids into the colon is increased. The dihydroxy bile acids are potent cathartics; they alter intestinal permeability and stimulate active electrolyte secretion (13). Because there is considerable hepatic synthetic reserve, the increased fecal loss is compensated for by increased production. Therefore steatorrhea is mild, and the diarrhea that occurs is caused by the secretory effect of bile salts on the colon. With larger ileal resections ( > 100 cm), the liver can no longer produce enough bile acid to compensate for the fecal loss. Bile salt secretion drops significantly, and the steatorrhea becomes more severe ( > 20 g/day of fat) because of inadequate micelle formation in the small bowel. Diarrhea results in this setting from the increase in colonic long-chain fatty acids, which like bile salts, stimulate secretion. The enterohepatic circulation may be significantly altered by medications or in certain specific clinical settings. Cholestyramine, for example, functions as a binding resin

and sequesters bile acids. Thus, diarrhea associated with unabsorbed bile acids can be treated. Ursodeoxycholic acid, naturally occurring in bear bile and used in cholestatic diseases and for prophylaxis of cholelithiasis, is itself a hydrophilic bile acid. Oral administration of ursodeoxycholic acid competitively inhibits the ileal absorption of endogenous hydrophobic bile acids such as chenodeoxycholic and deoxycholic acid. Ursodeoxycholate becomes the major component of the bile salt pool. The consequences are diverse, including resolution of cholestasis. Ursodeoxycholic acid is unlikely to cause diarrhea because it has only one alpha-hydroxyl group. Bacterial overgrowth may impact the enterohepatic circulation by causing deconjugation of bile acids. The resultant unconjugated bile acid forms are less soluble, and fat absorption may be impaired by limited micellar formation.

PROTEIN ABSORPTION Dietary protein accounts for 10% to 15% of calories and 70% of intestinal protein load; the remainder consists of secreted enzymes and sloughed cells. Protein digestion begins with denaturation by gastric acid. Pepsinogen, secreted by gastric chief cells, is converted to pepsin in this same acidic environment. Pepsin begins the breakdown of denatured proteins into polypeptide subunits. However, pepsin is not essential for normal protein digestion or absorption. Individuals who do not synthesize pepsin (e.g., because of pernicious anemia or gastrectomy) still absorb protein efficiently (14,15). The presence of amino acids in the duodenal lumen liberates cholecystokinin, which then stimulates the release of pancreatic enzymes. Most protein digestion occurs in the upper small bowel by the action of pancreatic proteases (Fig. 2). These proteases are secreted as proenzymes from the pancreas and are activated in the duodenum by the mucosal enzyme enterokinase and pancreatic trypsin. Protein is digested, by the secreted pancreatic endopeptidases and exopeptidases, to amino acids and small peptides. The endopeptidases (trypsin, chymotrypsin, and elastase) hydrolyze bonds in the interior of polypeptides. The resulting polypeptides of varying lengths are further digested by the exopeptidases. The pancreatic carboxypeptidases hydrolyze terminal amino acids from the carboxyl end of peptides, whereas aminopeptidases produced by intestinal cells hydrolyze the terminal amino acids from the amino end of peptides. Finally, dipeptidases on the epithelial brush border liberate individual amino acids from their substrate. Following enzymatic digestion, one-third of amino acids are absorbed as free amino acids, while the majority is absorbed in the form of dipeptides and tripeptides. These oligopeptides then undergo breakdown to free amino acids within the enterocyte. This intracellular hydrolysis occurs for 90% of absorbed oligopeptides. The transporter responsible for this uptake of small peptides, hPEPT1, two or three amino acids in length, has been identified. It works by cotransporting a proton along a favorable electrochemical gradient in concert with the peptide absorption (Fig. 3). The electrochemical gradient is generated by a separate but related antiport exchanger (NHE3), which expels hydrogen and allows entry of sodium (along its favorable gradient). Many medications taken orally (e.g., beta-lactams and angiotensin-converting enzymeinhibitors) also mimic these forms and are absorbed by the same mechanisms. Bacterial enterotoxins (e.g., E. coli) or medications (e.g., the potassium sparing diuretic amiloride) can

Chapter 16: Physiology of Digestion and Absorption

373

Sequence of protein digestion Proteins

Polypeptides

Oligopeptides > FAAs

FAAs> Oligopeptides

FAAs

H S

S S

H S

Apical FAA transporters Oligopeptide transporters Brush border peptidases

Basolateral FAA transporters

Figure 2 Intraluminal and mucosal processing of peptides and amino acids. The sequence of protein digestion and peptide transport across the intestinal epithelium is shown. Many proteins contain several polypeptide subunits that associate closely by both noncovalent forces and covalent disulfide bonds. Disulfide bonds are broken allowing separation of peptide subunits in concert with denaturation to permit access for peptidases. Oligopeptides are transported by hPEPT1. The details of hPEPT1 function are seen in Figure 3. Free amino acids are transported by a variety of luminal and basolateral carriers. These are detailed in Tables 2 and 3. Source: Illustration by Dr. Thompson.

Na NHE3

Intact Oligopeptide H h Pep T1 oligopeptide

Free Amonia Acids Di and tri pepticlasses

Figure 3 Schematic function of the oligopeptide transporter hPEPT1. Most absorbed oligopeptides are subject to intracellular hydrolysis to free amino acids prior to metabolism or export. Source: Illustration by Dr. Thompson.

medwedi.ru

374

Part Two: The Alimentary Tract—Small and Large Intestine

inhibit NHE3, with resultant potential for decreased transport of peptides or peptidomimetic medications (16). Oligopeptides are primarily absorbed in the jejunum. Oligopeptide absorption by hPEPT1 is more robust and efficient than free amino acid absorption. Recognition of the oligopeptide transport pathway is essential for rational design of enteral feeding formulas. For example, an elemental type diet rich in di and tripeptides is more readily absorbed than one biased toward free amino acids. Consequently, the optimal formula for elemental nutrition will contain mostly oligopeptides instead of free amino acids. Free amino acids are generally absorbed in the ileum. Free amino acid transport across both the luminal and the basolateral membranes is quite complex. Each of these membranes utilizes transport proteins, which carry distinct or overlapping groups of free amino acids. The two membranes utilize distinct groups of carrier proteins. The luminal membrane harbors at least seven classes of transport proteins. Five of these transporters are dependent on the transmembrane Na gradient and two are independent. Table 2 lists the transporters and their substrates. Similarly, the basolateral membrane harbors at least five transporters of free amino acids. These are listed in Table 3. Amino acids (particularly glutamine) are also a significant energy source for enterocytes. About 10% of absorbed amino acids are utilized this way. Glutamine has been extensively studied for a possible therapeutic effect in many intestinal diseases as well as sepsis with multiorgan failure. Unfortunately there is limited evidence to support this role.

CARBOHYDRATE ABSORPTION Carbohydrate consumption accounts for the predominant form of caloric intake in most diets. Starch is a polysaccharide or complex carbohydrate and accounts for about one-third of total calories (two-thirds of carbohydrate calories) in a western diet. Amylopectin is the predominant form of starch followed by amylose. Disaccharides account for most of the remaining dietary carbohydrate. Sucrose (glucose–fructose), or table sugar, and lactose (glucose– galactose) from milk products are the main dietary disaccharides. Sucrose and lactose account for about 30% and 10% of dietary carbohydrate, respectively. Carbohydrates are absorbed as simple monosaccharides, following the necessary enzymatic degradation within the intestinal lumen and at the brush border cell surface. Glycogen is a

Table 3 Free Amino Acid Transporters Localized to the Basolateral Membrane of the Intestinal Epithelium Transporter Na gradient dependent . . . A ASC Na gradient independent . . . asc L yþ

Substrate Dipolar a-amino acids, imino acids Alanine, serine, cystine Alanine, serine, cystine Alanine, serine, glutamine, cystine Basic amino acids (lysine, arginine, ornithine)

minor component of the diet, but is the body’s major form of carbohydrate storage. Dietary fiber is a nondigestible polymeric form of glucose such as cellulose, hemicellulose, and pectin as well as oligosaccharide forms (raffinose and stachyose) found in legumes such as beans and lentils. Human beings lack the enzyme necessary for the hydrolysis of the particular linkages between the individual monosaccharide subunits. Unabsorbed dietary fiber not only increases fecal bulk, but also influences absorption of other nutrients. Fiber delays absorption of sugars and fat reducing the insulin response to a meal and lowers cholesterol levels by binding bile salts. Starch, the major form of dietary carbohydrate, is a polymer of glucose with a molecular weight of 100,000 or greater; i.e., one molecule of starch usually has more than 500 glucose subunits. The linkage between the glucose moieties determines the type of starch and its enzymatic degradation. Such types are classified by the spatial configuration of the glucosidic bond (alpha and beta) and the carbon atoms involved in the linkage (1,4 or 1,6). Amylose is a straight chain of alpha-1,4–linked glucoses. The most common form of dietary starch is the branched starch amylopectin, which consists of alpha-1,4 chains and branch points created by alpha-1,6 linkages at every 20 to 25 residues (Fig. 4). Glycogen is a branched starch like amylopectin, but it has a greater frequency of alpha-1,6 linkages. Digestion of starch begins in the mouth with the help of salivary amylase, but comes to a rapid halt in the acid environment of the stomach. Carbohydrate digestion is completed in the upper small bowel (primarily jejunum) and consists of two phases: intraluminal breakdown of starch and brush border hydrolysis of oligosaccharides

Table 2 Free Amino Acid Transporters Localized to the Luminal Surface of the Intestinal Epithelium Transporter Na gradient dependent . . . B B0,þ IMINO B XAG Na gradient independent . . . b0,þ yþ

Substrate Dipolar a-amino acids Dipolar a-amino acids, basic amino acids, cystine Imino acids (proline, hydroxyproline) B-amino acids Acidic amino acids (aspartate, glutamate) Dipolar a-amino acids, basic amino acids, cystine Basic amino acids

Figure 4 Alpha-amylopectin and its final hydrolytic products are shown with glucose molecules (circles) joined by alpha-1,4 (horizontal) links or alpha-1,6 (vertical) links. Source: From Ref. 17.

Chapter 16: Physiology of Digestion and Absorption

(Fig. 5). Unlike oligopeptides, oligosaccharides require digestion to sugars for absorption. Pancreatic alpha-amylase is primarily responsible for intraluminal digestion of starch. Because it is secreted in great excess, clinically significant amylase deficiency is extremely rare, even in cases of severe pancreatic insufficiency. Alpha-amylase is active only at the interior alpha-1,4 bonds of starch. It cannot hydrolyze 1,6 links, 1,4 links next to branch points, or the terminal glucose–glucose links. Therefore the final products of amylase digestion are the disaccharide maltose, the trisaccharide maltotriose, and alpha-limit dextrins (i.e., larger oligosaccharides of 5–10 glucose units containing the branch points). Human amylase is inactive against beta-links; therefore cellulose, which is made up entirely of beta-1,4 links, is not digested. Maltose, maltotriose, and alpha-limit dextrins, along with dietary disaccharides, are broken down into simple sugars (monosaccharides) by specific brush border enzymes (18). These include the enzymes beta-galactosidase (lactase), glycoamylase, sucrase, isomaltase, and alpha-dextrinase (19). The sucrase and isomaltase subunits are cleaved from a single larger proenzyme by trypsin or elastin after transport to the brush border (20). The concentration of these brush border enzymes is greatest in the villus cells of the jejunum and upper ileum (21,22). The enzymatic function is present in abundance, and the absorption of the monosaccharides (glucose, galactose, and fructose) is the limiting factor. These sugars can accumulate in the lumen and inhibit the corresponding disaccharidase. The hydrolytic capacity of the brush border enzymes provides an excess of monosaccharides for the transport carrier. The exception to this is lactose absorption, where the hydrolytic capacity of lactase is rate limiting. In many parts of the world, lactase-phylorizin hydrolase activity declines early in life. Genetically programmed downregulation of the lactase gene is detectable in children from the second year of life independent of dietary content. When clinically symptomatic, lactase deficiency may be treated by dietary modification or lactase enzyme supplementation. A complex regulatory mechanism appears to coordinate the activity of the brush border enzymes and the corresponding transport proteins (23). Glucose and galactose are transported across the luminal membrane of the cell by a family of carrier proteins that couple the movement of sugar to sodium, SGLT1 (24). This transport mechanism is similar to Na-coupled amino acid absorption. In the later stages of absorption, intraluminal concentrations of sugars may decrease; however, because of the Na coupling, active transport of sugars against a concentration gradient can occur. A mutation in the sodium–glucose cotransporter gene (SGLT1) is an

375

autosomal recessive trait producing severe diarrhea in newborn infants. A prompt clinical response is seen with treatment by elimination of lactose, glucose, and galactose from the diet (25). In contrast to the Na-coupled SGLT1, transport of glucose and galactose across the brush border, a group of carriers called GLUT (GLUT, glucose transport), mediates nonactive transport of substrates by facilitative diffusion. There are six GLUT species. Originally named for ‘‘glucose transporter,’’ this designation is somewhat misleading because fructose and galactose may be carried by certain species. Fructose absorption into the cell occurs by facilitated diffusion through GLUT 5. Although usually absorbed completely, fructose absorption capacity is limited. Because it is not concentrated against a gradient, unabsorbed fructose may serve as an osmotic load-drawing fluid into the isosmotic jejunum. This nutrient, present in soda, candy, fruit, and fruit juices as a sweetener, may result in bloating, abdominal pain, and diarrhea or excess flatulence. Analogous to lactose or sorbitol intolerance, fructose intolerance may explain these symptoms in susceptible individuals (26). The overall design of carbohydrate absorption is to deliver maximal amounts of calories while introducing the least possible osmotic force into the duodenum and jejunum, where carbohydrates are primarily absorbed. A molecule of starch and a molecule of glucose have the same osmotic effect but vastly different caloric value. Intraluminal digestion of starch stops at the oligosaccharide stage, limiting the osmotic effect. The rapid absorption of monosaccharides into the intestine after action by brush border enzymes minimizes the potential for drawing fluid into the jejunum and duodenum. Under normal conditions this system is extremely effective; when disrupted, malabsorption may be compounded by osmotic diarrhea. The enterocyte is not only responsible for nutrient uptake across its brush border but also delivery of the nutrient across the basolateral membrane to be available for systemic distribution. Once delivered into the cytosol, glucose can exit the cell across the basolateral membrane by two distinct mechanisms. Facilitated diffusion by glucose transporters (e.g., GLUT2) had long been thought to be the only significant pathway for glucose egress from the enterocyte; however, recent evidence demonstrates a second pathway of significant capacity. This route involves exocytosis of glucose packaged in vesicles (27). This newly recognized pathway may have significance in the genetic disease Fanconi–Bickel syndrome where mutant GLUT2 transporters result in glycogen storage and transport derangements (28). Fructose and galactose are exported from the enterocyte primarily by GLUT2 as well.

Figure 5 Carbohydrate digestion and absorption. The principal intraluminal event is starch digestion by amylase (left side of figure). The resulting maltose, maltotriose, and alpha-limit dextrins are broken down further by brush border enzymes, as are the disaccharides (crosshatched area). Specific active transport systems, coupled to Na, exist for glucose and galactose. Fructose is absorbed by facilitated diffusion. Source: Courtesy of G. Roddey, MD and J. H. Sellin, MD, from Chapter 18 of the Second Edition.

medwedi.ru

376

Part Two: The Alimentary Tract—Small and Large Intestine

FAT ABSORPTION Fat accounts for about 40% of caloric intake. Most fat (90%) is in the form of triglycerides, which consist of a glycerol backbone (three carbons long) and three fatty acids protruding like spokes. The fatty acids occur in varying lengths (i.e., number of consecutive carbon groups), and those of medium chain length (6–10 carbon units) are absorbed differently from the longer chains after enzymatic separation from the glycerol backbone. The next most common moiety in the diet is phospholipid, which is similar to triglycerides but one of the carbons on the glycerol backbone is linked to a polar phosphate moiety instead of a nonpolar fatty acid. Phospholipids are primarily present as the fundamental building block of cellular membranes (lipid bilayer). The strategy of lipid absorption essentially is designed to overcome the insolubility of nonpolar compounds in an aqueous medium. Absorption of a typical triglyceride containing longchain fatty acid branches is complex, requiring several steps (Fig. 6). Two of the side branches must be cleaved by the intraluminal enzymes, lipase and colipase. This leaves two free long-chain fatty acids and a long chain monoglyceride (one of the fatty acid branches still attached to the glycerol backbone). These subunits are then solubilized by bile salt micelles. The micelles facilitate delivery of the lipid products across the unstirred water layer and then the lipid bilayer of the enterocyte brush border. The micelle probably dissociates at the apical membrane during absorption. The bile salts and some cholesterol from any given micelle generally returns to the luminal phase for another round of emulsification after securing transport for the previous fatty acid cargo into the cell. Meanwhile, fatty acids, cholesterol, and monoglycerides can then permeate through the lipid regions of the apical membrane into the cell interior. In the absence of adequate bile salts, small droplets of hydrolyzed lipid products may permeate the unstirred water layer to reach the absorptive brush border. Diffusion into the cell by this route is favored chemically by the acidic microenvironment of the unstirred layer, which enhances solubility of the lipid molecules as they cross the bilayer cell membrane. Short- and medium-chain fatty acids traverse the brush border mainly by simple diffusion, while long-chain fatty acids enjoy dedicated carriers (FATP, fatty acid transport proteins). FATP 4 appears to be the major transporter (29–31). This molecule may be a target for antiobesity drug development. Once inside the enterocyte, fatty acid–binding proteins (FABPs) mediate transport to the endoplasmic reticulum for resynthesis of triglycerides. These FABPs prevent

their cargo from straying and joining unintended membranes and organelles prior to processing (32–34). Most of the fat in the diet is absorbed in the duodenum and proximal jejunum. Cells at the villus tip are primarily involved. The bile acids are recovered downstream in the terminal ileum after their emulsifying duties are complete. Unlike amino acids and sugars, lipids do not require a specific transmembrane carrier protein. Interestingly, once inside the epithelial cell, the lipid subunits are reassembled into triglycerides and cholesterol esters. Through a series of enzymatic steps in the endoplasmic reticulum, triglycerides are reformed and then accumulate within the Golgi apparatus. However, before exiting across the basolateral membrane of the cell, the triglycerides must be suitably packaged for transport in lymph. This process is chylomicron formation. Chylomicrons are large spheres (1000–5000 A) with a core of hydrophobic lipids, primarily triglycerides, which also include cholesterol, cholesterol esters, fat-soluble vitamins, and trace fats. The surface is covered by phospholipids and specialized apolipoproteins. Although these apolipoproteins cover less than a quarter of the surface and account for about 1% of the mass, they are essential for chylomicron formation and transport. These proteins are made in the intestine; their rate of synthesis appears to be stimulated by fat absorption. Congenital absence of a certain apolipoprotein (abetalipoproteinemia) prevents the exit step of chylomicrons across the basolateral membrane of the cell (35). Once in the subepithelial space, chylomicrons enter the central lacteal of the villus and the intestinal lymphatic system. Because of their size, they cannot pass through the relatively tight junctions of the capillaries and are therefore excluded from the portal system. The function of colipase is to expose the triglyceride target by displacing bile acids, while the lipase enzyme executes the hydrolytic cleavage reaction liberating the subunits as described. Without colipase, lipase function would be inhibited (36). Lipase has two sources: lingual (which is acid resistant) and pancreatic (which is present in great excess). Phospholipid digestion occurs similarly, but the pancreatic enzyme responsible is phospholipase A2. All of these processes are pH dependent, and thus pancreatic exocrine function is critical for the absorption of fat from the perspective of bicarbonate and enzyme secretion. Orlistat is an inhibitor of pancreatic and other lipases. It may be used in obesity to limit intestinal fat absorption (37,38). Cholesterol esterase is an enzyme responsible for cholesterol hydrolysis. This enzyme cleaves the esterified cholesterol molecule into its free lipophilic form, which then incorporates into the core of a micelle. One dietary source of fat comes replete with its

Figure 6 Fat digestion and absorption. Dietary fats, TG, and CE are emulsified to form fat droplets within the intestinal lumen. These droplets undergo a physiochemical transformation into a viscous isotrophic phase. At this stage, the TG is digested by pancreatic lipase. The resultant FFA and monoglyceride (MG), along with cholesterol (C), form mixed micelles with bile salts. The micelle then diffuses to the apical membrane. There are no brush border enzymes or specific membrane transport systems for fat absorption. Abbreviations: TG, triglycerides; CE, cholesterol esters; FFA, free fatty acids; MG, monoglyceride. Source: Courtesy of G. Roddey, MD and J. H. Sellin, MD, from Chapter 18 of the Second Edition.

Chapter 16: Physiology of Digestion and Absorption

own digestive enzyme. Human, but not bovine, milk contains a nonspecific lipase that is acid resistant, and therefore serves as an intestinal lipase for breast-fed infants with immature endogenous lipase production. Medium-chain triglycerides can be absorbed intact by the portal venous circulation. Alternatively, these same medium-chain triglycerides are readily hydrolyzed by lipase, and the fatty acid subunits are also absorbed directly into the portal circulation rather than the lymphatics. Consequently, medium-chain triglycerides can be theoretically used to advantage in the management of chylous ascites or chylothorax by supplying lipids via a route not dependent on lymph transport. Medium-chain triglycerides may also be absorbed more efficiently than other lipids in malabsorptive disorders. Short-chain fatty acids are produced during bacterial degradation of complex carbohydrates and proteins in the colon. These acids are absorbed similarly, and intracellular pH is balanced by the Na–H exchanger. Short-chain fatty acid uptake may provide an additional caloric source in patients with the short bowel syndrome (39).

VITAMINS AND MINERALS The fat-soluble vitamins (i.e., A, D, E, and K) are hydrolyzed, dissolved, and absorbed via bile salt dissolution similar to dietary fat. Both vitamin A (retinol) and beta carotene, the major dietary precursor of vitamin A, are absorbed by passive diffusion, as is vitamin D. Vitamin D (actually a precursor of the active metabolite forms) is derived primarily not only from endogenous sources through a sterol precursor but also from dietary sources. Vitamin E is ingested as alpha-tocopherol acetate prior to hydrolysis and micellar absorption. It is absorbed by passive diffusion in the small intestine. Dietary vitamin K is absorbed analogously, but is also formed endogenously in the colon as a bacterial product where it can be absorbed by colonocytes. Dietary (vegetable derived) vitamin K1 is absorbed through a carrier-mediated process in the small intestine facilitated by bile salts. Endogenous (bacteria derived) vitamin K2 is absorbed passively in the ileum and colon (40,41). The water-soluble B vitamins are absorbed by a variety of mechanisms. The smaller vitamins such as pyridoxine are absorbed by passive diffusion. Specific sodium-dependent active transport processes occur for thiamine, riboflavin, pantothenic acid, and biotin. Thiamine and riboflavin require energy-dependent phosphorylation and active transport. Vitamin B12 requires initial binding to salivary R proteins following liberation from foodstuff by gastric acid. Next the cobalamin is again liberated in the duodenum by pancreatic enzymes before its binding to intrinsic factor. Intrinsic factor is secreted by gastric parietal cells. Intrinsic factor protects the cobalamin molecule from degradation, and facilitates uptake by specific receptors in the terminal ileum. Cobalamin is a biologically precious molecule primarily extracted from meat. Human beings store enough reserve for several years, but deficiency ultimately results in megaloblastic anemia and neuropathy. Gastric or ileal resection or disease, gastric bypass, dietary insufficiency (vegetarian), or pancreatic insufficiency may each result in depletion of vitamin B12. After enterocyte uptake in the terminal ileum, cobalamin is complexed with transcobalamin for circulatory distribution. Vitamin C is best absorbed in the ileum, but its overall efficiency is low as a result of easy saturation of receptors. The receptors are active transport proteins that couple vitamin C absorption to Na gradients analogous to protein

377

and carbohydrate uptake. Because of the easy saturation of its receptors, large doses of vitamin C are poorly absorbed. Folic acid consists of a pteroic acid moiety linked to l-glutamate. Most dietary folate is in a conjugated form, with a chain of several glutamates (polyglutamate folates). Absorption of folate depends on hydrolysis of the glutamic acid chain and subsequent transfer of the monoglutamyl product across the intestinal epithelium. The glutamic acid chain appears to be resistant to pancreatic digestive enzymes and is most likely broken down by brush border enzymes, which liberate free folic acid and amino acids. Polyglutamate folate, as such, is not absorbed (42). The rate-limiting step in folate absorption is entry across the apical membrane of the enterocyte. At low luminal concentrations of folate, a saturable, anion-exchange mechanism of facilitated diffusion exists. At high-luminal concentrations, passive diffusion becomes evident. Alterations in pH affect the rate of intestinal uptake of folate; the optimum is pH 6.5. The epithelial cells reduce methylate folate, releasing methyltetrahydrofolate into the portal blood. In addition to small bowel folate absorption, the colon has receptors for folate transport at the luminal level as well as the basolateral membrane to facilitate uptake and passage into the systemic circulation (43). A common transmembrane protein transporter has been identified in the absorption of many divalent cations including iron, zinc, manganese, cobalt, cadmium, copper, nickel, and lead. It has been named divalent cation transporter 1 and is richly expressed in the duodenum (44). Iron levels modulate expression of this transporter. Zinc appears to be both absorbed and secreted in the small intestine with only 5% to 10% of ingested zinc being absorbed. There is enterohepatic circulation with maximal absorption in the ileum. The rare condition acrodermatitis enteropathica results from a defect in the absorption of zinc caused by a mutation in the brush border zinc transport protein (45). Copper absorption occurs primarily in the stomach and duodenum by a receptor-mediated saturable process. Copper is secreted in bile. Magnesium appears to be absorbed passively in the distal small intestine. Phosphate is absorbed throughout the small intestine by active and passive mechanisms (46). Most dietary iron is complexed in the organic heme molecules of hemoglobin and myoglobin. Iron salts are less readily absorbed than these organic moieties. Ferric iron (Fe2þ) is more readily absorbed than ferrous iron (Fe3þ); thus, in the intestine, ferric iron is reduced to ferrous iron by ferrireductase or gastric acid, ascorbic acid, and certain amino acids. Phosphates and fiber may reduce iron availability. Hereditary hemochromatosis is an autosomal recessive trait characterized by hyperabsorption of iron. Mechanisms for iron excretion from the body are limited (i.e., iron is hard to get rid of once absorbed); so homeostasis is achieved by regulating the uptake to closely match requirements. Hemochromatosis is excessive uptake relative to the iron stores. A mutation in the causative gene, HFE, disturbs the enterocyte’s ability to limit absorption of luminal iron based on body stores, possibly reflected by transferring saturation (47,48). Calcium is absorbed actively in the duodenum by a transporter protein as well as passively by paracellular diffusion throughout the small intestine. Calbindin, a member of the calmodulin superfamily, is a protein that buffers the intracellular space from calcium flux. This prevents intracellular calcium from inappropriately triggering the vast machinery of kinases that are stimulated by free calcium. Calbindin also may function as a calcium sensor to regulate absorption in the intestine (49). Vitamin D enhances this

medwedi.ru

378

Part Two: The Alimentary Tract—Small and Large Intestine

process, when stores are low, by upregulating calbindin, basolateral calcium (ATP dependent) pumps, and brush border permeability (50–53). Calcium is primarily absorbed in the small intestine as detailed, but colonocytes also have the capacity for carrier-mediated uptake. The absorbed calcium is subsequently exchanged for Na at the basolateral membrane to facilitate exit from the cell and systemic distribution (43).

REGULATION Regulation of the GI tract is very complex and includes influences from peptide hormones, neurotransmitters from an intrinsic and extrinsic autonomic nervous system, lymphatics, and circulation. The mucosa of the GI tract produces numerous hormones. Although their functions in GI regulation are only partly understood, Table 4 lists their known effects (54–56). In addition to those listed, two newer peptides have been described including orphanin in the colon and xenin in the duodenum with their effects being investigated (57). Furthermore, ubiquitous substances including acetycholine, serotonin, histamine, and nitric oxide all have complex and varied effects on intestinal regulation with regard to motility, secretion and permeability, and blood flow. They are produced throughout the GI tract, and their effects are site specific and a subject of active investigation (57). Motility of the GI tract accomplishes distal propulsion of contents as well as segmentation and mixing. The wall of the GI tract is home to an extrinsic neuronal complex (parasympathetic and sympathetic) and an intrinsic network of modified smooth muscle cells that function as a syncitium analogous to the cardiac Purkinge cell–conducting system. These interstitial cells of Cajal are responsible for the migrating motor complex (MC) which sweeps the GI tract free of debris periodically between meals. These cells have been described as the pacesetters of the intestine.

Intestinal lymphatics perform a dual function in reticuloendothelial processing and lipid absorption. The GI tract comprises the largest reservoir of lymphocytes in the body, which not only reflects an important immune and barrier function, but also a mechanism for pathophysiology in disease states. Enterocytes may participate in antigen presentation to these lymphocytes. This may be a mechanism of the phenomenon of oral tolerance in which rejection of antigens is downregulated following their oral administration. Circulatory derangements including ischemia or portal hypertension may disrupt normal performance of the gut. Portal hypertension can be viewed as a dysregulation of intestinohepatic blood flow resulting froma combinationof obstructed outflow and (counterintuitively) increased splanchnic inflow. Disturbances in motility and bacterial overgrowth in the small intestine may occur in cirrhotic patients (58).

DIARRHEA AND MALABSORPTION Alterations in the normal physiology of digestion and absorption can be manifest by the clinical findings of malabsorption and diarrhea. Malabsorption means that a nutrient in the diet is passing through the GI tract incompletely absorbed such that clinical features of weight loss, steatorrhea, flatulence, or a specific nutritional deficiency state results. Diarrhea is the abnormal passage of loose or liquid stool more frequently than three times daily or greater than 200 mL in volume. Diarrhea may be a prominent feature of malabsorption, but malabsorption may be present without diarrhea. Alternatively, diarrhea may be present in the absence of malabsorption (59). Malabsorption may be described mechanistically by the level of digestive derangement: luminal, mucosal, or removal. Luminal malabsorption includes failure of the digestive enzymes or their associated media to hydrolyze or otherwise prepare the ingested nutrients for transport

Table 4 Gastrointestinal Hormones and Intestinal Physiology Polypeptide Bombesin (gastrin releasing peptide) CCK

Ghrelin Glucagon-like peptide 1 Glucagon-like peptide 2 Gastric inhibitory peptide Gastrin

Motilin Neurotensin Pancreatic polypeptide Peptide YY Secretin Somatostatin Vasoactive intestinal peptide

Effects Universal ‘‘on’’ switch; stimulates release of acid and all GI hormones except secretin Stimulates intestinal motility, pancreatic enzyme secretion, gallbladder contraction, sphincter of Oddi relaxation; delays gastric emptying Stimulates growth hormone release, appetite Stimulates insulin release; inhibits intestinal motility, glucagon release, and gastric acid Enterotrophic Inhibits gastrin release; pepsinogen; stimulates insulin release Gastric acid, pepsinogen and pancreatic secretion; gastric mucosal growth; intestinal motility; decreased intestinal fluid absorption Stimulates interdigestive motility and possibly MMC Inhibits gastric secretion, promotes pancreatic and intestinal secretion and motility; enterotrophic Inhibits pancreatic secretion; stimulates GI motility Inhibits GI motility, secretion, appetite Stimulates bile flow, pancreatic water and bicarbonate secretion; inhibits gastrin and GI transit Universal ‘‘off’’ switch; inhibits GI motility, secretion, hormonal release Vasodilator; promotes pancreatic and intestinal secretion; inhibits gastric acid

Abbreviations: CCK, cholecystokinin; GI, gastrointestinal; MMC, migrating motor complex.

Stimulants

Source

Vagus nerve

Small bowel

Lumenal amino acids and lipids

Duodenum, jejunum

Starvation, hypoglycemia Lumenal glucose and fat

Stomach Ileum (L cells)

Nutrient ingestion Lumenal nutrients

Ileum and colon (L cells) Duodenum, jejunum (K cells) Antrum, duodenum (G cells)

Peptides, amino acids, antral distention, bombesin vagal and adrenergic stimulation Fasting, gastric distention, fat Lumenal fat Protein Lumenal fat, CCK Lumenal acid, fat, and bile Lumenal nutrients, CCK Vagus nerve

Duodenum, jejunum Ileum (N cells) Pancreas Ileum, colon Duodenum, jejunum (S cells) Duodenum, jejunum (I cells) Intestinal neurons

Chapter 16: Physiology of Digestion and Absorption

across the brush border. The differential diagnosis includes gastrectomy, Zollinger–Ellison syndrome, pancreatic insufficiency, bacterial overgrowth, and bile acid insufficiency. Mucosal malabsorption indicates a loss of the mucosal surface area or inadequacy of the mucosal surface in the terminal stage of digestion or transport of ingested nutrients. Potential diagnoses include short bowel syndrome, radiation enteritis, lactose deficiency, and celiac sprue. Malabsorption at the removal phase occurs with failure to export nutrients from the enterocyte effectively for distribution by the portal venous or lacteal routes. Causative disorders may include mesenteric vascular insufficiency and lymphatic obstruction. Evaluation for malabsorption includes confirmation of malabsorbed nutrients, determining the potential mechanism as described above, and then making a specific diagnosis. Broadly, malabsorption can be investigated by evaluation of the stool for the malabsorbed nutrient or its metabolite or by breath tests to detect the bacterial degradation of the malabsorbed nutrient. Fecal fat, rather than carbohydrate or protein, is used as a sensitive indicator of malabsorption for two fundamental reasons: successful fat absorption requires the pancreas, biliary system, and intestinal mucosa and therefore reflects the normal functioning of all three components. Additionally, a correlation exists between unabsorbed dietary fat and fecal fat, whereas unabsorbed carbohydrate and protein are rapidly degraded by bacteria. Once a mechanism and specific diagnosis are determined, appropriate treatment is instituted. Nutritional support may be required during the evaluation period. Diarrhea can be classified by following mechanisms: osmotic, secretory, exudative, and hypermotility. Multiple mechanisms may be contributory in a single patient (17). Fecal incontinence or urgency can be mistaken for diarrhea. Osmotic diarrhea is primarily seen in malabsorption, where the malabsorbed nutrient or its degradation products contribute to luminal fluid retention. Magnesium-containing laxatives work in the same way. Dietary restrictions may be necessary. Secretory diarrhea is produced by the action of toxic or irritating substances on the intestinal mucosa. Increased electrolyte loss is seen and oral rehydration therapy may be employed. Cholera toxin has multiple effects, but most prominently, secretory diarrhea. Bile acid dysregulation following cholecystectomy may irritate the colonic mucosa. Though rare, neuroendocrine tumors such as VIPoma, gastrinoma, and carcinoid should be considered. Exudative diarrhea results from the loss of blood protein or mucous from inflammation and ulceration or infection of the mucosa. Causes include Clostridium difficile, bacterial enterocolitis, radiation proctitis, chemotherapeutics, colorectal neoplasm, and inflammatory bowel disease. Immunocompromised hosts may suffer diarrhea related to opportunistic infections or the underlying cause such as HIV. Treatment is determined by the specific cause. Increased motility alone with decreased intestinal transit time may also produce diarrhea. Vagotomy may produce this disturbance. However, the other types of diarrhea mentioned above are often associated with rapid transit, so that this is a common contributor to all types of diarrhea.

SUMMARY The efficient absorption and digestion of nutrients require the integration of a series of complex events occuring within

379

the intestinal lumen, at the epithelial border and within the enterocyte. Fat absorption requires emulsification and solubilization by micelles within the intestinal lumen before absorption across the epithelium. Products of carbohydrate and protein digestion require specific transport carriers at the apical border of the intestinal epithelium. The absorption of water occurs secondary to the active transport of ions. Sodium is the major ion determining osmotic gradients favorable for water absorption while chloride is the driving force for secretion. All of these processes are regulated under the influence of peptide hormones, neurotransmitters, lymphatics, and the circulation. Diarrhea and malabsorption are the major clinical manifestations of impaired digestion and absorption. Clinical management requires a symptomatic approach to clarify the cause of diarrhea or malabsorption, which then can be managed appropriately. While many of the basic physiologic processes involved in digestion and absorption have been known for almost a century, we continue to make further advances in our understanding, which should improve our clinical management.

REFERENCES 1. Sellin J. Intestinal electrolyte absorption and secretion. In: Sleisenger M, Fordtran JS, eds. Gastrointestinal Disease. 6th. Philadelphia: WB Saunders, 1998:1451–1471. 2. Meinild AK, Klaerke D, Loo DD, Wright EM, Zeuthen T. The human Naþ/glucose cotransporter is a molecular water pump. J Physiol 1998; 508:15–21. 3. Leiper JB. Intestinal water absorption—implications for the formulation of rehydration solutions. Int J Sports Med 1998; 19(suppl 2):S129–S132. 4. Loo DDF, Zeuthen T, Chandy G, et al. Cotransport of water by the Naþ/glucose transporter. Proc Natl Acad Sci USA 1996; 93:13367–13370. 5. Madara JL, Pappenheimer JR. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J Membr Biol 1987; 100:149–164. 6. Pappenheimer JR. Physiological regulation of transepithelial impedance in the intestinal mucosa of rats and hamsters. J Membr Biol 1987; 100:137–148. 7. Fordtran JS, Rector FC, Carter NW. Mechanisms of sodium absorption in the human small intestine. J Clin Invest 1968; 47:884. 8. Liedtke CM, Hopfer U. Mechanism of Cl translocation across small intestinal brush border membrane. Am J Physiol 1982; 243:G263. 9. Anderson MP, Sheppard DN, Berger HA, Welsh MJ. Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia. (Part 1). Am J Physiol 1992; 263:L1–L14. 10. Fuller CM, Benos DJ. CFTR! (Part 1). Am J Physiol 1992; 263:C267–C286. 11. King LS, Agre P. Pathophysiology of the aquaporin water channels. Annu Rev Physiol 1996; 58:619–648. 12. Hofmann AF. Intestinal absorption of bile acids and biliary constituents. In: Johnson RL, ed. Physiology of the Gastrointestinal Tract. 3rd ed. New York: Raven Press, 1994:1850. 13. Heubi JE. Bile acid-induced diarrhea. In: Lebenthal E, Duffey M, eds. A Textbook of Secretory Diarrhea. New York: Raven Press, 1990. 14. Matthews DM, Adibi SA. Peptide absorption. Gastroenterology 1976; 71:151. 15. Sleisenger MH, Kim YS. Protein digestion and absorption. N Engl J Med 1979; 300:659. 16. Thwaites DT, Kennedy DJ, Raldua D, et al. H/dipeptide absorption across the human intestinal epithelium is controlled indirectly via a functional Na/H exchanger. Gastroentrology 2002; 122:1322–1333.

medwedi.ru

380

Part Two: The Alimentary Tract—Small and Large Intestine

17. Gray GM. Carbohydrate digestion and absorption. N Engl J Med 1975; 292:1225. 18. Alpers DH, Seetharam B. Physiology of diseases involving intestinal brush-border proteins. N Engl J Med 1977; 296:1047. 19. Takenoshita M, Yabune M, Katsura H, et al. Low sucrase activity in the small intestine of a senesence-accelerated strain of mouse, SAMP1. Biosci Biotechnol Biochem 1998; 62: 965–969. 20. Brasitus TA, Stirin MD. Absorption and cellular actions of vitamin D. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 3rd ed. New York: Raven Press, 1994:1935. 21. Triadrou N, Bataille J, Schmitz J. Longitudinal study of the human intestinal brush border membrane proteins. Gastroenterology 1983; 85:1326. 22. Rosensweig NS, Herman RH. Control of jejunal sucrase and maltase activity by dietary sucrose or fructose in man. J Clin Invest 1967; 46:186. 23. Kimmich GA, Randles J. Evidence for an intestinal Naþ: sugar transport coupling stoichiometry of 2.0. Biochim Biophys Acta 1980; 596:439. 24. Wright EM, Turk E, Martin MG. Molecular basis for glucosegalactose malabsorption. Cell Biochem Biophys 2002; 36: 115–121. 25. Choi YK, Johlin FC Jr, Summers RW, Jackson M, Rao SS. Fructose intolerance: an under-recognized problem. Am J Gastroenterol 2003; 98:1348–1353. 26. Santer R, Hillebrand G, Steinmann B, Schaub J. Intestinal glucose transport: evidence for a membrane traffic-based pathway in humans. Gastroenterology 2003; 124:34–39. 27. Santer R, Groth S, Kinner M, et al. The mutation spectrum of the facilitative glucose transporter gene SLCA2 (GLUT2) in patients with Fanconi-Bickel syndrome. Hum Genet 2002; 110:21–29. 28. Hirsch D, Stahl A, Lodish HF. A family of fatty acid transporters conserved from mycobacterium to man. Proc Natl Acad Sci USA 1998; 95:8625–8629. 29. Schaffer JE, Lodish HF. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein (see comments). Cell 1994; 79:427–436. 30. Stahl A, Hirsch DJ, Gimeno RE, et al. Identification of the major intestinal fatty acid transport protein. Mol Cell 1999; 4:299–308. 31. Kaikaus RM, Bass NM, Ockner RK. Functions of fatty acid binding proteins. Experientia 1990; 46:617–630. 32. Luxon BA. Inhibition of binding to fatty acid binding protein reduces the intracellular transport of fatty acids. Am J Physiol 1996; 271:G113–G120. 33. Luxon BA, Milliano MT. Cytoplasmic transport of fatty acids in rat enterocytes: role of binding to fatty acid-binding protein. Am J Physiol 1999; 277:G361–G366. 34. Tso P. Intestinal lipid absorption. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 3rd ed. New York: Raven Press, 1999:1867–1907. 35. Gaskin KJ, Durie PR, Hill RE, Lee LM, Forstner GG. Colipase and maximally activated pancreatic lipase in normal subjects and patients with steatorrhea. J Clin Invest 1982; 69:427. 36. Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 1998; 21:1288–1294. 37. McNeely W, Benfield P. Orlistat. Drugs 1998; 56:241–249. 38. Gonda T, Maouyo D, Rees SE, Montrose MH. Regulation of intracellular pH gradients by identified Na/H exchanger

39. 40.

41. 42.

43.

44.

45.

46. 47.

48.

49.

50. 51. 52.

53.

54.

55. 56. 57.

58.

59.

isoforms and a short-chain fatty acid. Am J Physiol 1999; 276:G259–G270. Hollander D. Vitamin K1 absorption by everted intestinal sacs of the rat. Am J Physiol 1973; 225:360–364. Hollander D, Rim E, Ruble PE Jr. Vitamin K2 colonic and ileal in vivo absorption: bile, fatty acids, and pH effects on transport. Am J Physiol 1977; 233:E124–E129. Rosenberg IH. Folate absorption: clinical questions and metabolic answers. Am J Clin Nutr 1990; 51:531–534. Saksena S, Ammar MS, Tyagi S, et al. Mechanisms of calcium transport in human colonic basolateral membrane vesicles. Dig Dis Sci 2002; 47:2306–2315. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388:482–488. Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 2002; 71:66–73. Borowitz SM, Ghishan SM. Phosphate transport in human jejunal brush border membrane vessicles. Gastroenterology 1989; 96:4. Ajioka RS, Kushner JP. Hereditary hemochromatosis. Semin Hematol 2002; 39:235–241. Zhang AS, Davies PS, Carlson HL, Enns CA. Mechanisms of HFE-induced regulation of iron homeostasis: insights from the W81A HFE mutation. Proc Natl Acad Sci USA 2003; 100:9500–9505. Berggard T, Miron S, Onnerfjord P, et al. Calbindin D28k exhibits properties characteristic of a Ca2þ sensor. J Biol Chem 2002; 277:16662–16672. Karbach U. Segmental heterogeneity of cellular and paracellular calcium transport across the rat duodenum and jejunum. Gastroenterology 1991; 100:47–58. Madara JL. Loosening tight junctions: lessons from the intestine. J Clin Invest 1989; 83:1089–1094. Feher JJ. Facilitated calcium diffusion by intestinal calcium binding protein. Am J Physiol 1983; 244:C303–C307. Walters JR, Weiser MM. Calcium transport by rat duodenal villus and crypt basolateral membranes. Am J Physiol 1987; 252:G170–G177. Date Y, Murakami N, Toshinai K, et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 2002; 123:1120– 1128. Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003; 349:941–948. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002; 122:531–544. Hansen MB. Neurohumoral control of gastrointestinal motility. Physiol Res 2003; 52:1–30. Gunnarsdottir SA, Sadik R, Shev S, et al. Small intestinal motility disturbances and bacterial overgrowth in patients with cirrhosis and portal hypertension. Am J Gastroenterol 2003; 98:1362–1370. Thomas PD, Forbes A, Green J, et al. Guidelines for the investigation of chronic diarrhoea. 2nd ed. Gut 2003; 52(suppl 5): v1–v15. Thomson AB, Keelan M, Thiesen A, Clandinin MT, Ropeleski M, Wild GE. Small bowel review: diseases of the small intestine. Dig Dis Sci 2001; 46:2555–2566.

17 Circulation and Vascular Disorders of the Splanchnic Vascular Bed Stuart I. Myers and Patricia A. Lowry

INTRODUCTION The blood vessels of the gastrointestinal (GI) system are part of a more extensive system called the splanchnic circulation. The splanchnic circulation includes the gut, pancreas, liver, and spleen. Splanchnic blood flow courses through the gut, spleen, and pancreas and then flows immediately into the hepatic circulation by way of the portal vein. Blood then flows through minute liver sinusoids and re-enters the systemic circulation via the hepatic veins. This complex secondary flow of blood allows the reticuloendothelial system of the sinusoids to remove harmful bacteria and other substances that could potentially enter the systemic circulation. Maintenance of an adequate blood supply to the intestines is important in insuring normal intestinal homeostasis. Splanchnic blood flow is influenced by several factors including the status of the normal systemic circulation, the degree of collateral blood flow, and the exposure to exogenous and endogenous neuro-humoral factors. Maintenance of normal splanchnic blood flow is important in preserving intestinal motility, absorption of nutrients, and immune function. This chapter will examine the anatomy and physiology of intestinal blood flow and will then examine the pathophysiology of the clinical disorders that result from altered intestinal blood flow.

NORMAL ANATOMY AND COLLATERAL CIRCULATION The intestines are supplied by a series of parallel circulations via the branches of the superior mesenteric artery (SMA) and the inferior mesenteric arteries. The collateral circulation is extensive and involves flow originating from the celiac axis as well (Fig. 1). On entering the wall of the gut, the arteries divide into branches that circle the gut in both directions, with the distal vessels meeting on the antimesenteric border of the intestine. Smaller arteries then penetrate the intestinal wall and supply the major distributing plexus within the submucosa (2). The intestinal arteries begin as first-order arterioles (1A). 1A vessels penetrate both muscle layers and course along the outer surface of the submucosa, giving rise to second-order arterioles (2A). Third-order arterioles (3A) pass from the submucosa directly into the tips of the mucosal villi. At the tip of the villi, they then divide into an arcade of vessels that feed the net-like subepithelial capillary system located on all sides of the villus (Fig. 2). Arterial flow and venous flow in the villus are in opposite direction and the vessels lie in close proximity. Because of this unusual ‘‘countercurrent vascular arrangement,’’ blood diffuses

directly out of the arteriole into the venule without being carried to the tips of the villi. Thus, as much as 80% of blood flow bypasses the tip of the villus in this manner and will not be available for metabolic functions of the villi (Fig. 3) (4). The celiac axis supplies the foregut structures primarily below the diaphragm (Fig. 4). The celiac axis originates from the anterior surface of the aorta at the level of T12. It is usually between 1 and 1.5 cm in length. After coursing through the crura of the diaphragm, it divides into the splenic, left gastric, and common hepatic arteries. The bifurcation of this major trunk occurs at the superior border of the pancreas. The SMA is the main supplier of intestinal blood flow from the duodenum–jejunum junction to the mid-transverse colon. The SMA originates from the anterior surface of the aorta 1.5 cm below the celiac axis. Its course is inferior to the pancreas where it divides into multiple branches that supply the lower portion of the pancreas, the small bowel, and the proximal two-thirds of the colon. The first three branches of the SMA are important from both a clinical and theoretical point of view. The inferior pancreaticoduodenal artery originates from the SMA and may be either a single trunk or a pair of vessels. If there is a single trunk, it divides very soon after its origin into an anterior and posterior branch. These supply the anterior and posterior inferior portions of the head of the pancreas. In addition, branches supply the third portion of the duodenum. These vessels course in a superior direction and anastomose directly, with their superior counterparts originating from the hepatic artery. The middle colic artery is the second branch of the SMA. The middle colic artery courses in the transverse mesocolon and sends branches to supply the transverse colon. There is, in addition, a branch that courses toward the left colon and anastomoses with the left colic artery. There are direct communications between the middle colic artery and the right colic artery via the marginal artery, which courses in the mesentery of the transverse and right colon. There is likewise a second anastomotic branch to the left colic complex via this marginal artery. The right colic artery is the third branch of the SMA and this courses in the right colonic mesentery, supplying the right colon with anastomotic branches via the marginal artery to both the middle colic artery and the ileocolic artery. The remainder of the SMA is virtually an end vessel with segmental branches going to the jejunum and ileum. The SMA terminates in the ileocolic branch, which supplies the terminal ileum, cecum, and appendix. It has a small communicating vessel, as just described, coursing along the marginal artery and anastomosing with the right colic artery (7,8). The inferior mesenteric artery (IMA) supplies the hindgut from mid-transverse colon to the rectum and is

medwedi.ru 381

382

Part Two: The Alimentary Tract—Small and Large Intestine

(A) CELIAC A.

SMA

LEFT COLIC A.

MIDDLE COLIC A. INF. MES. A.

COMMON ILIAC A.

SUP. HEMORRHOIDAL A.

DEEP CIRCUMFLEX A. INT. ILIAC A.

(B)

CELIAC A. SUP. MES. A.

INTERCOSTAL A.

INF. MES. A.

LUMBAR A. ILIO-LUMBAR A. CIRCUMFLEX ILIAC A.

COMMON ILIAC A. INT. ILIAC A.

EXT. ILIAC A.

INF. EPIGASTRIC A.

Figure 1 (A) Components of the viscerosystemic collateral circulation. This figure represents direction of flow through the splanchnic vascular bed to compensate for chronic occlusion of the infrarenal aorta. The arrows denote direction of flow. (B) Components of the systemic–systemic collateral flow. These are systemic collateral flow routes that may develop during chronic infrarenal aortic occlusion. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 1.

Figure 2 Outline of the intestinal microvasculature emphasizing blood supply with the inflow (A1), transitional (A2), and premucosal (A3) arteriolar structure, as well as outflow (V1) and transitional (V2) venules. Source: From Ref. 3.

Figure 3 Microvasculature of the villus, showing a countercurrent arrangement of blood flow in the arterioles and venules. Source: From Ref. 5.

the smallest of the three major vessels supplying the abdominal viscera. It originates from the anterior surface of the abdominal aorta 4 cm above the bifurcation. This vessel is very short, rarely exceeding 1 cm in length. The IMA divides into three branches, which supply the left colon, sigmoid colon, and superior portion of the rectum (Fig. 5). The left colic artery is the superior branch of the IMA. It courses upward along the descending colon and supplies it by segmental branches. It communicates with the marginal artery and, in addition, has a larger branch that connects directly with a branch of the middle colic artery in the mesentery of the colon. The sigmoidal arteries comprise the middle segmental distribution of the IMA, and there are usually three of them. They extend to the sigmoid colon and supply it in a segmental manner. These branches anastomose with the marginal artery along the colonic border. The superior rectal artery is the lower segment of the inferior mesenteric arterial system and supplies the superior portion of the rectum. It is the terminus of the IMA and anastomoses with the sigmoidal branches via the marginal artery. In addition, the superior rectal artery connects with the inferior and middle rectal arteries via a rich plexus in the wall of the rectum. The blood supply of the lower portion of the rectum originates from the internal iliac system. It comprises two paired vessels, the middle and inferior rectal arteries. The middle rectal arteries originate directly from the internal iliac arteries and course medially to the rectum through the lateral rectal attachments in the pelvis. They are very small vessels, measuring no more than 1 mm in diameter. They supply the middle portion of the rectum and anastomose with the superior rectal artery and inferior rectal

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

383

Figure 4 Artist’s conception of the surgical anatomy of the celiac axis and its three major branches. Some detail of collateral circulation and adjacent viscera is included. Source: From Ref. 6.

artery through the rich arterial plexus in the rectal wall. The inferior rectal artery is a terminal branch of the pudendal artery, which originates from the internal iliac artery. The pudendal artery passes through Alcock’s canal and extends into the perineal area. Here it gives off a branch to the rectum, which is a significant artery, usually measuring over 1 mm in diameter. This artery supplies the lower portion of the rectum and the anal canal. In addition, it may carry the bulk of the blood supply to the anal sphincter (Fig. 5) (7,8). There are four important anastomotic pathways that are constant and play a major role in the collateral circulation of the abdominal viscera: the left inferior phrenic artery,

the pancreaticoduodenal arcade, the left colic–middle colic arterial anastomosis, and the internal iliac artery system. The paired inferior phrenic arteries are the first parietal branches of the abdominal aorta. The inferior phrenic artery commonly originates between the diaphragmatic crura and courses the dome of the diaphragm where they divide into anterior and posterior branches. The posterior branches anastomose with intercostals arteries. The anterior branches anastomose with twigs of the contralateral artery, the musculophrenic artery, the pericardiophrenic artery, and the internal thoracic artery and can also communicate with the hepatic artery.

Figure 5 Artist’s conception representing the superior and inferior mesenteric arteries as well as the renal arteries, with adjacent viscera. Source: From Ref. 6.

medwedi.ru

384

Part Two: The Alimentary Tract—Small and Large Intestine

The pancreaticoduodenal arcade is a constant collateral channel joining the celiac axis and superior mesenteric arterial systems. Although the primary function of these vessels is to supply the pancreas and second and third portions of the duodenum, they can function as an anastomotic pathway between the two major upper abdominal vessels. It is interesting to note that the blood may run either cephalad or caudad in this system, depending upon the site of occlusion (Fig. 6). The left colic branch of the IMA sends a direct communicating branch to the the middle colic branch of the SMA. With occlusion of either the SMA or the IMA, this collateral channel will enlarge to carry the blood supply toward the area of occlusion. The internal iliac vessels supply the middle rectal and inferior rectal arteries. These anastomose by a rich arterial plexus within the wall of the rectum and anal area. The internal iliac arteries are particularly important at the time of abdominal aortic resection. The IMA is frequently sacrificed during aortic aneurysm repair. The internal iliac then becomes an important source of blood flow to the rectum and distal sigmoid colon (Figs. 7 and 8) (7,8). Additional collateral flow is provided to the gut via an extensive microscopic endogenous collateral network of vessels. As described above, small arteries penetrate the intestinal wall on the antimesenteric border, which divides into extensive submucosal vascular plexi, which provide a rich subepithelial capillary network within each villus at the cellular level. This plexus is much more extensive in the small bowel than in the colon, rendering the small intestine more resistant to ischemia. The physiologic control

Figure 7 Superior mesenteric–IMA anastomosis. An inferior mesenteric arteriogram demonstrates the anastomosis between the left colic artery (large closed arrow) and the middle colic branch (large open arrow) of the SMA. This is the arc of Riolan. The marginal artery of Drummond (small arrows) is seen adjacent to the mesenteric border of the descending colon. Abbreviations: IMA, inferior mesenteric artery; SMA, superior mesenteric artery. Source: From Ref. 10.

of microvascular intestinal blood flow is not unlike other vascular beds. The intestinal microvasculature is a circuit composed of a series of resistance arterioles, precapillary sphincters, capillaries, postcapillary sphincters, and the venous capacitance vessels. The most important determinant of blood flow control is the resistance arterioles (7,8). Venous blood collects in small venules, which form a system of venous arcades within the mesentery. These arcades join to form veins that correspond to the named arteries within the mesentery. These veins then drain into the inferior and superior mesenteric veins (SMVs) that join to form the portal vein. The extensive venous arcades within the mesentery provide an extensive venous collateral network for the small and large intestine (8).

PHYSIOLOGY OF INTESTINAL CIRCULATION

Figure 6 Celiac-SMA anastomosis. A superior mesenteric arteriogram of a patient with stenosis of the proximal hepatic artery demonstrates enlarged inferior pancreatoduodenal arcades (small arrow) filling the gastroduodenal (large arrows) and proper hepatic arteries. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 9.

Intestinal blood flow is affected by a variety of neurohumoral, local, and functional factors. Of prime importance is the sympathetic nervous system, which via a-adrenergic receptors maintains resting splanchnic arteriolar tone. The splanchnic bed receives up to 30% of the total cardiac output at rest, with 70% or more of the flow, which perfuses the mucosal–submucosal layers. Over the past several decades several hypotheses have evolved to describe three major areas of circulatory determinants for the regulation of intestinal blood flow. These include extrinsic factors (sympathetic and parasympathetic nervous system), intrinsic factors (local metabolic vs. myogenic), and humoral factors (circulating or

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

385

Table 1 Endogenous and Exogenous Vasoactive Mediators of the Splanchnic Circulation Constrictor Sympathetic tone (adrenergic) Parasympathetic tone (cholinergic) PO2 PCO2 pH Metabolites (Kþ, lactate, adenosine) Angiotensin I, II, III Activated complement (C5a) Antidiuretic hormone Calcium Endothelin-1 Epinephrine LTs Motilin Neuromedin U Neuropeptide Y Norepinephrine (high dose) Oxytocin PeptideYY PAF Prostaglandin B2, D2, F2a, H2 Serotonin TxA2 Vasopressin

Figure 8 Arteriogram of a patient with occlusion of the SMA. The prominent meandering artery shows that collateral channels have been present for some time and that the occlusion is not acute. The arrows show the direction of flow from the IMA to the SMA. Abbreviations: IMA, inferior mesenteric artery; SMA, superior mesenteric artery. Source: From Refs. 11, 11a.

local vasoactive or neurohumoral agents) (12–17). The reader should be reminded that the factors that contribute to the regulation of splanchnic blood flow are similar to those regulating other vascular beds. A list of potential vasoactive mediators of the splanchnic circulation is presented in Table 1.

Intrinsic Factors Regulating GI Blood Flow The splanchnic vascular bed, similar to other vascular beds, has the capacity for the return of normal blood flow over a wide variety of perfusion pressure to maintain adequate blood flow to the intestines. This autoregulation of blood flow implies that when the vascular bed is exposed to an increase in arterial blood pressure, the initial increase in blood flow to the vascular bed decreases to the normal level. The converse occurs with a decrease in arterial blood pressure. Two views have been proposed to explain this acute autoregulation mechanism: the metabolic theory and the myogenic theory.

Metabolic Theory The metabolic hypothesis of intrinsic regulation states that any pathologic situation that creates a negative imbalance between oxygen supply and demand raises the local concentrations of tissue metabolites, such as Hþ and Kþ, hyperosmolarity of the blood, the number of adenosine nucleotides, and the concentration of carbon dioxide,

Vasodilator Sympathetic tone Parasympathetic tone PO2 PCO2 pH Metabolites Acetylcholine Activated complement (C3a, C5a) Adenosine Adrenomedullin Bradykinin Calcitonin gene-related peptide Cholecystokinin Dopamine Gastric inhibitory peptide Gastrin Glucagon Glucocorticoids Glucose-dependent insulinotropic peptide Histamine Insulin Kalikrein Magnesium Neuromedin N Neurotensin NO Nitroglycerin Norepinephrine (low dose) Opiates Pituitary adenylate cyclase– activating Polypeptide Prostaglandin I2, E2 Secretin Serotonin (low dose) Sodium Substance P Thrombin Thyrotropin-releasing factor Uridine triphosphate VIP Xenin Xenopsin

Abbreviations: LTs, leukotrienes; PAF, platelet-activating factor; TxA2, thromboxane A2; NO, nitric oxide; VIP, vasoactive intestinal peptide.

causing local acidosis, which contributes to the control of local blood flow. Conversely, if excess blood flow occurs, excess metabolic nutrients will cause blood vessels to constrict, returning blood flow to normal. The metabolic theory therefore states that it is oxygen delivery, rather than blood flow, that regulates the intestinal circulation.

Myogenic Theory (15) The myogenic theory is based on the experimental observation that the stretch of a blood vessel will lead to smooth muscle cell contraction. Thus a high level of vessel stretch will cause a reactive vasoconstriction. Conversely at low pressures, the smooth muscle cells relax and blood flow thus increases. The myogenic theory thus assumes that vascular resistance is proportional to arteriolar transmural pressure, requiring the existence of arteriolar tension receptors. An

medwedi.ru

386

Part Two: The Alimentary Tract—Small and Large Intestine

acute decrease in perfusion pressure is compensated for by local regulatory mechanisms, so that flow reduction is proportionately less than the reduction in perfusion pressure, allowing maintenance of constant intestinal capillary pressure and transcapillary fluid exchange (15–17).

Mechanism for Dilating Large Upstream Arteries The myogenic and metabolic theories describe local mechanisms for preserving normal blood flow at the microvascular level. The endothelial cells of the larger arteries upstream from the microvascular vessels can synthesize several vasoactive substances that can affect contraction or vasodilation. One such substance is nitric oxide (NO). Rapid blood flow through a larger arteriole or artery causes shear stress and increases endothelial synthesis and release of NO, causing the artery to dilate and increase blood flow (12).

Intrinsic Paracrine Vasoactive Substances That Contribute to the Regulation of Splanchnic Blood Flow Endogenous NO has also been proposed to contribute to the regulation of microvascular blood flow in the GI tract. Evidence indicates that NO may be an important mediator of vascular tone in the GI tract, in particular gastric mucosal blood flow. Kubes et al. have shown that basal NO production is important in minimizing mucosal and microvascular barrier dysfunction following intestinal ischemia-reperfusion (IR) injury. Although the specific mechanisms are unknown, NO may be acting as an antioxidant and as an inhibitor of neutrophil adhesion to vascular endothelium and migration from blood vessels (18–22). Prostaglandins (PGs) have been shown to have both potent vasodilatory and vasoconstrictive actions in the splanchnic vascular bed. The major vasodilators are prostacyclin (PGI2) and PGE2, and the major vasoconstrictor (and agonist of platelet aggregation) is thromboxane A2 (TxA2). PGs have been shown to be synthesized throughout GI tract. Thus, the entire GI tract could serve as a source for locally vasoactive PGs. PG synthesis in the resting intestine favored the vasodilator PGs as cyclooxygenase (COX) inhibition decreased blood flow to the intestine. The importance of resting intestinal vasodilator PGs was further shown by experiments utilizing exogenous TxA2 to constrict the splanchnic vascular bed. In this study, splanchnic vascular vasoconstriction by exogenous TxA2 was potentiated by endogenous prostanoid inhibition by indomethacin [10 mg/kg intravenous (IV) inhibits endogenous vasodilators PGI2 and PGE2]. This finding suggested that synthesis of splanchnic vasodilator PGs is an important compensatory mechanism in the maintenance of blood flow (23–35). Leukotrienes (LTs) are another group of potent vasoactive metabolic products of arachidonic acid metabolism synthesized by the enzyme 5-lipoxygenase. The cysteinyl LTs [leukotriene C4 (LTC4), leukotriene D4(LTD4), and leukotriene E4(LTE4)] and the dehydroxylated LTB4 have been studied in normal and shock states. Injection of cysteinyl LTs caused systemic reactions that are similar to signs and symptoms associated with shock. These systemic effects are intense bronchoconstriction, increased vascular permeability, mucous formation, and coronary and splanchnic vasoconstriction (36–38).

Parasympathetic nerve stimulation leads to increasing blood flow to the stomach and lower colon (39). Activation of muscarinic receptors on the endothelium leads to a release of NO, which diffuses to the vascular smooth muscle and causes relaxation and vasodilation. In contrast, sympathetic nerve stimulation has a direct effect on the entire GI tract to cause vasoconstriction, primarily by activation of a-adrenergic receptors. Sympathetic fibers are distributed to all levels of the arteries except precapillary sphincters and the metarterioles (39). Thus, the greatest effect of sympathetic nerve stimulation is on the small arteries and arterioles. Stimulation of these fibers leads to the release of norepinephrine, vasoconstriction of the precapillary resistance vessels, and decreased blood flow. However, as seen elsewhere in the body, reduction of blood flow is associated with disproportionate vasoconstriction in the postcapillary capillary venous beds that make up the capacitance vessels. Within minutes of initial vasoconstriction, blood flow rises to nearly normal levels. The most reasonable explanation appears to be differential a and b adrenergic stimuli. A reactive hyperemic response generally follows the cessation of sympathetic stimulation, concluding this triphasic response to splanchnic sympathetic activity. Adrenergic stimuli also change intestinal motility, wall tension, and absorption and secretion, all of which have a profound effect on regional and local blood flow (39–41). Understanding the role of circulating GI hormones on the regulation of splanchnic blood flow continues to be a challenge. Most observations of the role of these hormones depend on the animal model used, experimental conditions, and the animal species utilized. Despite these challenges, some brief generalizations can be presented to the reader. Angiotensin II (AII) and vasopressin appear to be important physiological vasoconstrictors and redistribute flow from the muscle and mucosa to the submucosal layer (42). Cholecystokinin and secretin increase mucosal blood flow by activation of specific receptors on vascular smooth muscle cells. Enteroglucagon-like peptide, found in epithelial ‘‘L’’ type cells, is released following a meal and may contribute to the hyperemic response. Gastrin (or pentagastrin), in addition to increasing gastric acid secretion, increases gastric mucosal blood flow and has a questionable effect on proximal small-intestinal blood flow. Glucagon was shown to be a potent intestinal vasodilator in the cat (43). Somatostatin is a relatively selective vasoconstrictor of the upper GI circulation at pharmacologic doses. Substance P, a vasoactive intestinal peptide (VIP), and gastric inhibitory polypeptide all tend to be vasodilators at pharmacologic doses but not physiologic levels. Neurotensin is found in neuronal cells and its vasodilator effects are limited to the muscular layer. Motilin reduces mucosal blood flow. VIP, a neurocrine and paracrine mediator, is associated with the nerves supplying most of the intestinal vessels. These VIP-associated vessels are more pronounced in the mucosa and thus VIP is associated more with increase of blood flow to the mucosal layer. Peptide YY redistributes blood flow from the muscularis to the mucosa and submucosa Substance P is often associated with 5-HT and is located on nervous tissues. These fibers nervate layers of the vessel but Substance P appears to act most directly on the smooth muscle cells (44–47).

Extrinsic Factors That Regulate GI Blood Flow

REPERFUSION INJURY OF THE INTESTINE Clinical Relevance

The sympathetic and parasympathetic nervous systems make up the extrinsic component of intestinal blood flow.

There can be little doubt regarding the clinical relevance of ischemia and reperfusion injury to clinical medicine. The

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

reactivity of the splanchnic vascular bed to circulating and local paracrine vasoconstrictors and the sensitivity of the intestinal mucosa to reduced oxygen and nutrient delivery make it particularly susceptible to hypoperfusion with subsequent reperfusion injury. Intestinal reperfusion injury may occur following relief of arterial occlusion (e.g., during vascular surgical procedures or traumatic injury) or the restoration of systemic perfusion in patients suffering hypovolemic or cardiogenic shock (Fig. 9). The clinical manifestations of intestinal IR injury are dependent upon the duration and severity of the underlying ischemia. The mucosa is most susceptible to this injury and hence mucosal necrosis and sloughing with subsequent hemorrhage may be a manifestation of relatively early injury. In general, massive hemorrhage is a relatively uncommon presentation for this injury. Severe injury may be

387

associated with transmural necrosis of the intestinal wall, perforation, and peritonitis. More chronic ischemic states may be associated with the development of an ischemic stricture, with subsequent intestinal obstruction. Of interest, even relatively minimal periods of ischemia (e.g., one hour) may be associated with altered intestinal epithelial integrity (18). This has been postulated to be an important factor in the pathogenesis of the systemic inflammatory response syndrome and multiple organ failure in critically ill patients (49). A study by Paterson et al. suggested an association between skeletal muscle reperfusion and noncardiogenic pulmonary edema in patients undergoing repair of abdominal aortic aneurysms (AAAs) (50). Others have demonstrated that the most common cause of death following repair of AAAs is multiple organ failure syndrome (51).

Intestinal Morphology Clinically Important Causes of Intestinal Reperfusion Injury ................................... PRESPLANCHNIC HEART/CENTRAL CIRCULATORY SYSTEM (Nonocclusive mesenteric ischemia) Reduced Cardiac Output Hypovolemia Hemorrhage Cardiac tamponade Cardiac failure Dialysis Anesthesia Sepsis Hypoplastic left heart syndrome

The significance of reperfusion to tissue injury is evidenced by observations that the histologic injury and physiologic dysfunction of reperfused tissue is greater than that associated with an equivalent period of ischemia alone. This was demonstrated in the intestine by Parks and Granger in a study in which the histologic evidence of mucosal injury was significantly greater following three hours of ischemia and one hour of reperfusion than that associated with four hours of ischemia alone (52). As is shown in Figure 10, the principal morphologic site of intestinal reperfusion injury is the mucosa, with epithelial sloughing from the villi, mucosal edema, neutrophil infiltration, and hemorrhage into the lumen (52,54). This histologic picture has been well characterized with grading scales proposed by Mangino et al. and Chiu et al. (54,55).

Intestinal Pathophysiology SPLANCHNIC MACROVASCULAR OCCLUSION (Superior mesenteric artery) In situ thrombosis (atherosclerosis) Embolic disease Operative procedures Trauma Compression MICROVASCULAR OCCLUSION (Arteriolar, precapillary, postcapillary sphincters) Drugs Digitalis Cyclosporine Anesthetic agents Halothane Reperfusion injury Sympathetic nerve stimulation Norepinephrine POSTSPLANCHNIC MESENTERIC VENOUS THROMBOSIS Hypercoagulable syndromes Digitalis Cirrhosis Sympathetic nerve stimulation Norepinephrine

Figure 9 List of clinically important causes of intestinal reperfusion injury. Source: From Ref. 48.

Intestinal reperfusion injury is characterized by severely impaired splanchnic microvascular and epithelial function. Reperfusion-induced microvascular dysfunction has been characterized by the appearance of edema and hemorrhage within the mucosa, the extravasation of plasma proteins, and reduction of splanchnic blood flow. Altered microvascular permeability has been quantitated utilizing labeled plasma proteins (21) and determination of the osmotic reflection coefficient (56). Each of these parameters as well as the histologic findings has suggested an increased leakiness of the microvasculature for fluid and macromolecules upon reperfusion. Altered epithelial permeability has been quantitated by measuring the blood-to-lumen movement of 51Cr-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (18,20,21). Normally the IV administration of 51Cr-EDTA results in almost instantaneous equilibration across the vasculature into the interstitium; however, its movement across the epithelium is greatly restricted. After even a relatively brief period of ischemia (e.g., one hour), reperfusion has been shown to cause a sevenfold rise in the concentration of 51Cr-EDTA within the lumen of the bowel when compared with controls (18), a finding consistent with the morphologic picture of epithelial cell loss and villus injury. The effect of intestinal reperfusion on splanchnic blood flow has been examined using radiolabeled microspheres and flow probes in models of SMA occlusion (57) and hemorrhage and resuscitation (58). As early as 15 minutes following reperfusion, intestinal blood flow is severely reduced, a finding that persists throughout reperfusion

medwedi.ru

388

Part Two: The Alimentary Tract—Small and Large Intestine

Figure 10 (A) Representative photomicrograph of ileum from a sham-operated time-matched rat undergoing laparotomy, with isolation of the SMA without occlusion. Note that the villus epithelium is intact and there is no evidence of edema or neutrophil infiltration (hematoxylin-eosin X 100). (B) Representative photomicrograph of ileum of a rat undergoing 120 minutes of intestinal ischemia and 60 minutes of reperfusion. In this example the SMA was occluded with a microvascular clip; release of the clip allowed reperfusion. Mucosal injury is characterized by epithelial sloughing from the villi, mucosal edema, neutrophil infiltration, and hemorrhage into the lumen (hematoxylin-eosin X 100). Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 53.

(57,58). This progressive loss of tissue perfusion has also been demonstrated in models of skeletal muscle reperfusion (59) and has been termed the ‘‘no-reflow phenomenon’’ and likely relates to the generation of oxygen-derived free radicals (ODFRs), neutrophil sequestration, inhibition of prostacyclin, and, perhaps, NO release.

Mediators of Reperfusion-Induced Tissue Injury Reperfusion of ischemic intestine induces the release of a variety of proinflammatory mediators that exacerbate the local intestinal injury and lead to the generation of paracrine proinflammatory and vasoactive substances in remote organs. Many of these substances serve to direct, amplify, and disseminate the inflammatory response. For example, in addition to directly injuring tissue through the peroxidation of plasma membranes, ODFRs have been shown to be important chemotactic substances for neutrophils contributing to the activation of complement and are at least in part responsible for the impairment of the compensatory release of the potent vasodilator PGI2. These relationships highlight the redundancy in these proinflammatory systems [e.g., neutrophil chemotaxis may be related to local superoxide, TxA2 platelet-activating factor (PAF), and LTB4 release, and complement activation]. Several of the most important mediators are described below in detail.

Eicosanoids PGs are synthesized by the entire GI tract (26). Depending upon the specific mediator, prostanoids have been shown to have potent vasodilator (PGI2 and PGE2) and vasoconstrictor effects (TxA2) in the splanchnic vascular bed. Furthermore, these agents also appear to have important proinflammatory (TxA2) effects. PG synthesis in the resting intestine favors the vasodilator PGs, as evidenced by the observation that COX inhibition decreases blood flow to the intestine (28–30). Furthermore, cyclo-oxgenase inhibition was found in an isolated, perfused intestine preparation to significantly potentiate the vasoconstrictor effects of exogenous TxA2 administration (29). These studies suggest that

the paracrine release of the vasodilator PGs (PGE2 and PGI2) is an important autoregulatory mechanism in the maintenance of normal splanchnic blood flow. Humoral factors that have been shown to contribute to the regulation of splanchnic blood flow include angiotensin, norepinephrine, kinins, and eicosanoids. Using a swine cardiac tamponade model of hypovolemic shock, Bailey et al. (60) demonstrated that diminished perfusion of the splanchnic vascular bed was disproportionate to the reduction in cardiac output during hypovolemic shock. The exaggerated splanchnic hypoperfusion was related to the sensitivity of the splanchnic microvasculature to elevated circulating AII levels (60). Several investigators have demonstrated that AII and norepinephrine induce the release of PGI2 and PGE2 from the perfused rat splanchnic vasculature, suggesting that these potent vasodilators may antagonize the vasoconstrictor influences of AII, sympathetic nerve stimulation, and norepinephrine (24,61,62). These important studies suggested that splanchnic vasoconstriction might occur as a consequence of both increased exogenous factors, which cause vasoconstriction (AII, norepinephrine, sympathetic nerve stimulation), and the loss of endogenous splanchnic vasodilators. One must not totally exclude a role for vasoconstrictor eicosanoids in mediating splanchnic vasoconstriction. Exogenous LTC4 and TxA2 have been shown to be potent vasoconstrictors of the splanchnic vascular bed. Furthermore, Mangino et al. (53) demonstrated that following intestinal ischemia and reperfusion, LTC4 and TxA2 release was increased by more than 300%. The effect of vasoactive eicosanoids and inflammatory mediators on splanchnic blood flow during intestinal IR is outlined in Figure 11. A series of studies have shown that PGI2 is the predominant eicosanoid released by the in vitro perfused splanchnic vascular bed [termed the splanchnic vessel þ splanchnic intestine (SVþSI) preparation] and the in vitro perfused SVs (termed the SV preparation). Perfusing both preparations with a hypoxic Krebs–Henseleit buffer decreased in vitro SV þ SI PGI2 release but did not alter thromboxane B2 or PGE2 release or SV PGI2 release (31).

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

Figure 11 Postulated mechanism by which ODFRs are formed during intestinal IR injury. Events occurring during ischemia are indicated by dashed lines. Reported mechanisms by which ODFRs induce tissue injury are shown in the bottom right corner. Abbreviations: TxA2, thromboxane; LTB4, leukotriene; PAF, platelet activating factor; TNF, tumor necrosis factor; IL, interleukin; LTC4, leukotriene; ODFRs, oxygen-derived free radicals; IR, ischemia-reperfusion; LPS, lipopolysaccharide. Source: From Ref. 63.

These studies showed that there were two important sources of splanchnic PGI2 synthesis and release, the SVs and the intestine itself. The next group of studies was designed to specifically determine the role of exogenous AII during hypoxiainduced splanchnic vasoconstriction. Exogenous AII stimulated a dose-related increase in PGI2 release from both SV þ SI and SV preparations. Hypoxic perfusion significantly decreased SV and not (SV þ SI) PGI2 release (64). These studies further confirmed that both the SVs and the intestine were likely sources of both basal and AII-stimulated PG synthesis. Basal (not AII-stimulated) intestinal (SV þ SI) PGI2 synthesis was more vulnerable to hypoxia than that of the SV preparation (vessels). This is thought to be related to the sensitivity of the mucosa to the effects of hypoxia, particularly given the high metabolic activity and usually largest percentage of blood flow that is attributed to the mucosa (30,31,62). SV AII-stimulated PG synthesis was more sensitive to hypoxia than the SV þ SI. Decreased SV PGI2 release may thus be of importance in AII-mediated splanchnic vasoconstriction seen in shock. A series of studies examined the effects of acute hemorrhage on endogenous splanchnic PGI2 synthesis and release. Acute hemorrhage to a mean arterial pressure of 30 mmHg for 30 minutes (without reperfusion) severely reduces splanchnic blood flow (58) and induces a threefold increase in the release of PGI2 from the splanchnic vascular bed (31,64,65). It was postulated that the reduced PGI2 release seen following prolonged intestinal ischemia was due to a hypoxic environment similar to that seen during the perfusion of the isolated, perfused intestine with unoxygenated Krebs–Henseleit buffer (31,64,65). More recent studies have examined the enzymatic mechanisms by which hemorrhage induces the release of PGI2 from the splanchnic vascular bed. Inhibition of protein synthesis by administering cycloheximide to the isolated, perfused intestine of animals sustaining acute hemorrhage abolished the exaggerated PGI2 release associated with this

389

model (66). Western blot analysis of protein from the SMA, aorta and ileal mucosa, and muscularis/serosa for prostacyclin synthase (PS) and COX demonstrated a twofold increase in both of these enzymes within the ileal muscularis/serosa and a 50% increase in PS within the aorta and SMA (33). Together these data suggest that the increased release of PGI2 from the splanchnic bed following acute hemorrhage is dependent upon new protein synthesis and that the location of the increased enzyme content is the ileal muscularis/ serosa (COX and PS) and the aorta and SMA (PS). In contrast to animals sustaining acute hemorrhage alone, hemorrhage followed by reperfusion (the infusion of shed blood) was found to abolish the compensatory increased splanchnic release of PGI2 and hence worsen splanchnic hypoperfusion (34,35,67). Subsequent studies showed that the reperfusion-induced decrease in splanchnic PGI2 synthesis and SMA blood flow were restored to control levels by treatment with superoxide dismutase, a scavenger of ODFRs (67,68). These studies supported the notion that ODFRs were involved in the regulation of splanchnic PGI2 synthesis following acute hemorrhage and shock followed by reperfusion (SK þ R). These studies were the first to show that ODFRs contribute to the regulation of prostacyclin synthesis in the whole organ, supporting earlier studies by Egan et al. who demonstrated similar findings in cell-free systems (68,69). Recent studies have examined the effect of allopurinol and pentoxifylline on splanchnic PGI2 release following intestinal reperfusion injury (70). In these experiments, the SMA of rats was occluded for 20 minutes with a microvascular clip; release of the clip allowed reperfusion for 30 minutes. Treatment of the animals with pentoxifylline protected splanchnic PGI2 release whereas pretreatment with allopurinol, a xanthine oxidase inhibitor (71), had no demonstrable effect on the release of prostacyclin. Although this study did not specifically examine the mechanism of pentoxifylline protection of splanchnic PGI2 release following severe splanchnic IR injury, previous reports have shown that pentoxifylline increased tissue oxygenation, increased oxygen consumption, decreased leukocyte adhesiveness, and increased intestinal microvascular blood flow (72–75). Pentoxifylline has been proposed to improve intestinal microvascular blood flow by decreasing leukocyte ‘‘plugging’’ of microvasculature. This hypothesis was supported by in vitro studies demonstrating that pentoxifylline increased leukocyte deformability, decreased leukocyte adherence, enhanced chemotaxis, and blocked the action of inflammatory cytokines on leukocyte function (76–80). Several investigators have also demonstrated that pentoxifylline inhibits cytokine [tumor necrosis factor (TNF), interleukin-1]-induced neutrophil activation, thus preventing lysosomal degranulation, superoxide production and neutrophil adhesion to endothelium (80). Although the exact mechanism by which pentoxifylline protects endogenous splanchnic PGI2 release following intestinal IR injury is unknown, one can postulate that maintaining splanchnic microcirculatory flow during periods of ischemic or hemorrhagic shock is a worthy goal that, if achieved, may prevent intestinal barrier failure and its sequelae.

Oxygen-Derived Free Radicals Intestinal reperfusion injury has been associated with ODFRs (e.g., O2, H2O2, and OH) since the early 1980s (24,31). This work has been summarized by Granger et al. (81) and is illustrated in Figure 12. It is postulated that during ischemia, adenosine triphosphate (ATP) is catabolized to

medwedi.ru

ISCHEMIA

390

Part Two: The Alimentary Tract—Small and Large Intestine

ATP

AMP

Adenosine

Inosine

Xanthine Dehydrogenase Fe 2+ Fe3+

Hypoxanthine

Xanthine Oxidase

SOD Xanthine + O 2H2O2

OH-+ OH-

O2

REPERFUSION Peroxidation of membrane phospholipids DNA strand breakage Degradation of hyaluronic acid Altered intracellular metabolism reduced ATP production disrupted intracellular Ca homeostasis Neutrophil chemotaxis Complement activation Inhibition of Prostacyclin release Increase Thromboxane release Inactivation of constitutively released nitric oxide Formation of peroxy nitrite upon reaction with nitric oxide

hypoxanthine, which accumulates within the ischemic intestine. Simultaneously, xanthine dehydrogenase is converted to xanthine oxidase, which upon reperfusion (with the reintroduction of molecular oxygen) catalyzes the formation of xanthine from hypoxanthine. Superoxide anion (O2) is produced as a by-product of this reaction and may then be converted to hydrogen peroxide (H2O2) and hydroxyl radicals. The evidence supporting a role for xanthine oxidase– generated ODFRs in the local intestinal reperfusion injury has been summarized by Zimmerman et al. (83) and includes the following observations: (i) The intestinal mucosa is a rich source of xanthine oxidase. (ii) During intestinal ischemia, xanthine dehydrogenase is rapidly converted to xanthine oxidase (e.g., within the first hour of ischemia there is a six- to eightfold increase in xanthine oxidase). (iii) During intestinal ischemia there is a 10- to 20-fold increase in the concentration of hypoxanthine. (iv) Inhibitors of xanthine oxidase attenuate reperfusioninduced changes in intestinal microvascular permeability and mucosal injury. (v) Protease inhibitors, which prevent the conversion of xanthine dehydrogenase to xanthine oxidase, protect against reperfusion-induced intestinal injury. (vi) The intra-arterial infusion of hypoxanthine and xanthine oxidase increases vascular permeability in normal bowel to the same extent as observed in the postischemic intestine (an effect prevented by superoxide dismutase). (vii) Pretreatment with allopurinol (an inhibitor of xanthine oxidase) prevents the increased spontaneous chemiluminescence (an index of oxidant production) observed following reperfusion of the ischemic intestine. The mechanisms by which reperfusion-induced ODFR generation alter intestinal microvascular and epithelial integrity include the peroxidation of microvascular plasma membrane components

Figure 12 Hypothesis for events contributing to reduced splanchnic perfusion following intestinal IR injury. IR injury induces splanchnic vasoconstriction through two simultaneous actions, through the splanchnic vascular bed and through the systemic circulation. IR induces local splanchnic production of ODFRs, which originate from either the splanchnic bed or activated neutrophils. ODFRs downregulate endogenous splanchnic vasodilator synthesis (NO and PGI2). Neutrophils, activated by IR or potent circulating factors such as TxA2, LTB4, PAF, TNF, or a variety of cytokines, may contribute to splanchnic ischemia by microcirculatory plugging and release of potent vasoconstrictors such as TxA2 or LTC4. IR injury upregulates production of cytokines, PAF, etc., and activated complement. The net result is neutrophil activation, which contributes to production of ODFRs, and microcirculatory plugging, which can occur in the splanchnic bed or distal visceral beds such as the kidney, lung, heart, etc. Abbreviations: ATP, adenosine triphosphate; AMP, adenosine monophosphate; ODFRs, oxygenderived free radicals; IR, ischemia-reperfusion; PAF, platelet-activating factor; TxA2, thromboxane A2; TNF, tumor necrosis factor; LTB4, leukotriene B4; NO, nitric oxide; SOD, superoxide dismutase; PGI2, prosta cyclin I2. Source: From Ref. 82.

(84), degradation of hyaluronic acid (84), DNA strand breakage (85) and altered intracellular metabolism with reduced ATP production (86), and disrupted intracellular calcium homeostasis (87). These effects may alter microvascular integrity by impairing endothelial cell function and viability and disrupting the integrity of the interstitial matrix and capillary basement membrane (84–87). The role of endothelials cells, is likely to be particularly significant because they are considered to be an important endogenous source of ODFR production during IR injury (88). Furthermore, immunolocalization studies have demonstrated that hypoxia increases the activity of xanthine oxidase in cultured endothelial cells (88). In addition to directly mediating tissue injury, ODFRs may be particularly important in orchestrating the local inflammatory response. Granulocyte activation and adherence to the microvasculature is linked to the formation of reactive oxygen metabolites. Evidence for this includes the observation that scavengers of O2 and H2O2 inhibit reperfusion-induced splanchnic leukosequestration and neutrophil–endothelial cell adherence (83,89,90). The mechanism by which this occurs is unclear although O2–mediated inactivation of NO (the constitutive release of which acts as an important endothelium-derived antiadhesion molecule) has been postulated (22). Other potential mechanisms involve H2O2-mediated generation of PAF (91) and complement activation with the formation of the potent anaphylatoxins C3a and C5a (92,93). Reactive oxygen intermediates may also contribute to reperfusion injury by altering the function and integrity of normal autoregulatory mechanisms in the intestinal microvasculature. As alluded to previously, O2 may inactivate NO with subsequent vasoconstriction, neutrophil and platelet

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

adherence, and enhanced microvascular permeability (22,94,95). Furthermore, previous studies in our laboratory have demonstrated that the compensatory release of PGI2 by the ischemic intestine is inhibited by ODFRs upon reperfusion (35,67)—an event corresponding temporally to a marked reduction in splanchnic perfusion (35,57,58,67).

Neutrophils Within minutes of intestinal reperfusion, neutrophils are sequestered in the splanchnic, pulmonary, and hepatic microvascular beds. Activated neutrophils are thought to play an important role in the altered intestinal mucosal permeability (96) and microvascular dysfunction (56) associated with reperfusion injury. Evidence for this relationship has been derived from studies in which depletion of neutrophil numbers [with antineutrophil serum (56,96) or cytotoxic agents (58)] or inhibition of neutrophil–endothelial cell adherence [with specific monoclonal antibodies against adherence receptor glycoproteins (56,96)] was shown to protect the mucosal epithelium and microvascular membrane from reperfusion injury. These studies suggest that neutrophil infiltration is a cause, rather than an effect, of reperfusioninduced microvascular injury in the intestine (56). There are several mechanisms by which the sequestered neutrophils may mediate reperfusion-induced tissue injury. The large size and poor deformability of activated neutrophils, coupled with their ability to establish receptormediated adhesive interactions with the endothelium, may contribute to the capacity of these cells to obstruct the microcirculation during IR (59,97). Furthermore, previous studies have related neutrophils activated during hemorrhage resuscitation to inhibition of the release of the potent vasodilator PGI2 by the splanchnic bed (58). The activation of neutrophils and their emigration through the microvascular endothelium are also associated with the generation of a variety of cytotoxic substances including ODFRs, proteases, cationic proteins, and collagenase, which may disrupt microvascular barrier integrity. The mechanisms by which neutrophils are activated during IR have been examined by a variety of investigators. Reperfusion-induced neutrophil infiltration and tissue injury has been related to xanthine oxidase activation and the generation of O2, H2O2, and the hydroxyl radical (89,90,98). The activation of complement with the generation of the anaphylatoxins C3a and C5a (92,93), the local release of PAF (99), impaired endothelial NO release (22) and local generation of LTB4 and TxA2 (83) also likely contribute to neutrophil–endothelial cell interaction with subsequent emigration and neutrophil-mediated tissue injury.

Complement Intestinal reperfusion injury induces the activation of the alternate and classical complement cascades, with the generation of C3a and C5a (93,100). Complement activation has also been associated with other models of local tissue injury including skeletal muscle reperfusion (101) and thermal cutaneous injury (93). Hill et al. related the local intestinal reperfusion injury to the activation of complement in an experiment in which soluble complement receptor 1 was found to attenuate histologic evidence of the injury. One mechanism by which this appeared to occur was by inhibiting the sequestration of neutrophils into the intestine (100). Other potential mechanisms by which activated complement fragments may contribute to the local intestinal reperfusion injury include the formation of a membrane attack complex (C5b-9) with direct injury to the microvascular

391

endothelium and complement-mediated release of TxA2 and other proinflammatory vasoactive substances.

Nitric Oxide A variety of investigators have examined the role of NO in maintaining splanchnic microvascular function in normal and pathologic states (including intestinal reperfusion injury) (18,20,21). Studies by Kubes and coworkers have demonstrated in normal intestine that inhibition of the constitutive release of NO increases splanchnic vascular resistance, enhances microvascular permeability, and promotes neutrophil–endothelial cell interaction (22,94,95). Inhibition of the endothelial isoform of NO synthase [e.g., with NGnitro-L-arginine (L-NAME)] has been shown to markedly exacerbate reperfusion-induced intestinal microvascular permeability (20,21). In one series of studies, L-NAME caused a threefold increase in reperfusion-induced protein extravasation and a twofold increase in mucosal permeability over that associated with reperfusion injury alone (18,21). In this study, the infusion of exogenous sources of NO attenuated reperfusion-induced changes in microvascular and mucosal permeability but failed to significantly improve splanchnic blood flow, suggesting that the beneficial effect of NO in this model is not limited to its role as a potent vasodilator. As discussed earlier, the constitutive release of NO by the endothelium also has important effects on neutrophil– endothelial cell interaction (22,102), which may be of particular significance given the well-recognized effect of IR on neutrophil activation and recruitment (22,77). The nonselective inhibition of NO synthase with NG-monomethyl-Larginine or L-NAME has been shown to increase neutrophil adhesion to postcapillary venules more than 15-fold and neutrophil emigration more than threefold; an effect thought to be mediated through the leukocyte adhesion glycoprotein CD11/CD18 (95). Gaboury et al. suggested that the antiadhesive action of NO might be a result of its ability to inactivate the superoxide radical (22). This mechanism of action may be of particular importance in ODFR injury because the superoxide radical is thought to be involved in the neutrophil sequestration characteristic of this injury (89,90). Lastly, NO may directly affect microvascular permeability by an early (< 10 minutes) neutrophil-independent effect. Inhibition of NO release with L-NAME increases microvascular leakage of protein even prior to neutrophil adherence and emigration in the postcapillary venule (95). The mechanism by which this occurs appears to be complex, involving cyclic guanosine monophosphate, PAF, and alterations in the endothelial cell cytoskeleton (95). These data suggest that inhibition of the constitutive release of NO by L-NAME may directly enhance reperfusion-induced splanchnic microvascular permeability.

Remote Organ Injury Following Intestinal IR Intestinal IR incites a generalized inflammatory response characterized by the appearance of activated complement fragments, neutrophils, eicosanoids, endotoxin, and cytokines within the circulation (103–106). Many of these substances serve to direct, amplify, and disseminate the inflammatory response as is outlined in Table 1. This generalized inflammatory state culminates in injury to the lungs, liver, heart, and kidneys (103). An in-depth discussion of the pathophysiology of remote organ injury following intestinal IR is beyond the scope of this chapter and the reader is provided with references to examine this important area of pathophysiology (Fig. 11) (103–106).

medwedi.ru

392

Part Two: The Alimentary Tract—Small and Large Intestine

Clinical Syndromes That Provide Insight into Intestinal IR Injury There are a number of examples of clinical conditions associated with intestinal reperfusion injury, which provide clinical relevance for the many laboratory studies examining the local and remote consequences of this condition. Furthermore, examination of these clinical conditions allows greater insight into the pathophysiology of intestinal reperfusion injury, particularly because it relates to the balance between vasoactive paracrine and circulating mediators. This section will concentrate on presenting clinical conditions not commonly associated with intestinal IR. A comprehensive list of presplanchnic, splanchnic, and postsplanchnic causes of intestinal reperfusion injury is shown in Figure 9. The most common causes of mesenteric ischemia are presplanchnic in location and have been termed ‘‘nonocclusive mesenteric ischemia’’ (NOMI). The principal physiologic abnormality is reduced cardiac output, which may be the consequence of reduced preload, impaired contractility, or increased afterload. Hypovolemia due to hemorrhage, third-space fluid losses, diarrhea, vomiting, and hemodialysis is an extremely common cause of NOMI. Several studies have related hemodialysis to the development of NOMI. In one study, 9% of deaths of patients undergoing chronic hemodialysis deaths were due to NOMI. Furthermore, of those patients that developed NOMI, 75% died (107). The treatment of these patients includes prompt reversal of the hypotension, papaverine infusion, and subsequent avoidance of hypotension during dialysis (108). Another common cause of NOMI is impaired cardiac contractility that is associated with acute myocardial infarction, congestive heart failure, or cardiac arrest. Gaussorgues et al. related cardiac failure to mesenteric ischemia and altered intestinal integrity by documenting the presence of enteric bacteria within the bloodstream following cardiac arrest (109). In this study, 13 of 33 patients sustaining cardiac arrest (average duration 18 11 minutes) and undergoing cardiopulmonary resuscitation (average duration 6 4 minutes) were bacteremic within 12 hours of their cardiac arrest. In every case but one, the organism was a normal constituent of the enteric flora. Furthermore, all of these patients with enteric flora within their bloodstream died. This study provides further evidence supporting the hypothesis of bacterial translocation due to altered intestinal integrity following low flow states such as cardiac arrest (109). Lastly, Hebra et al. reported on 387 patients studied with hypoplastic left heart syndrome, of whom nearly 10% developed acute mesenteric ischemia at an average age of 17.5 5.4 weeks. Nearly 80% of these patients had documented low flow state with hypotension before the development of NOMI. The mortality rate for this group of patients was greater than 80% (110). This study provides clinical correlation for the experimental work previously described in pigs by Bulkely and coworkers (111,112). Several studies have demonstrated the importance of maintaining a balance of endogenous splanchnic vasodilators to counterbalance the normal constant adrenergic stimulus of norepinephrine release. Commonly used medications can alter this delicate balance either from normal usage or abuse. Petti et al. reported one case of a 19-year-old patient who presented with isolated NOMI following an overdose of the b-blocker propranolol. The splanchnic ischemia present in this patient was thought to be mediated by the unopposed a-adrenergic activity of the splanchnic adrenergic nervous system (113). Digitalis has also been shown to cause

splanchnic vasoconstriction with resultant increased splanchnic vascular resistance. The mode of action of digitalis in the splanchnic vascular bed is hypothesized to be mediated by increased vascular smooth muscle tone of splanchnic resistance and capacitance vessels and by increasing a-adrenergic tone (114). A study in normal volunteers showed that the decrease in splanchnic blood flow found following digitalis administration could be blocked by diltiazem, a calcium channel blocker (115). Calcium mediation of splanchnic vasoconstriction is not limited to digitalis. A more recent study in animals by Rego et al. showed a similar mechanism of action for cyclosporine-induced splanchnic vasoconstriction. Cyclosporine potentiation of isolated rat mesenteric arterial vasoconstriction was shown to be mediated by transmembrane calcium transport and exaggerated release of calcium, which could be blocked by use of calcium channel blockers (116).

Summary of Intestinal IR Injury From the material presented in the foregoing discussion, one can formulate a hypothesis encompassing intestinal IR injury. Intestinal IR injury (from any injury model) results in the local production of ODFRs that induce downregulation of endogenous splanchnic vasodilators and as a result, decreased splanchnic blood flow, loss of intestinal barrier function, and activation of neutrophils, complement, and other potent inflammatory mediators. The activated neutrophils, complement, and inflammatory mediators alter distant organ function by the interaction of the distant organ with neutrophil-mediated ODFR release, LTB4, or other neutrophil-derived factors. Circulating activated neutrophils interact with all distant organs (and the intestine) with varied effects on local autocrine factors, which contribute to altered organ function. The combination of microcirculation ‘‘plugging’’ by the activated neutrophils and the release of potent vasoactive compounds both contribute to organ dysfunction.

CLINICAL EVALUATION OF INTESTINAL BLOOD FLOW The diagnosis of acute mesenteric ischemia still relies on the clinician having a high index of suspicion for this disease. The incidence of acute mesenteric ischemia is 1% of admissions to tertiary medical centers but continues to rise due to increased awareness of this disease. The presentation of the patient with acute abdominal pain over the age of 50 and with cardiac arrhythmias, long-standing congestive heart failure, recent myocardial infarction, or hypotension should raise the awareness of the clinician. In all reported series, acute abdominal pain is the most common presenting symptom, which is usually out of proportion to the physical findings. Over the past several decades, various laboratory parameters have been examined with regard to specificity for acute mesenteric ischemia. Leukocytosis above 15,000 cells/mm3 is present in 75% of these patients. Approximately 50% of these patients present with a metabolic acidosis. The finding of an acid–base disturbance implies a serious systemic illness, and no study has proved that either an acidosis or a base deficit is a reliable predictor of intestinal ischemia. Elevated serum levels of amylase, alkaline phosphatase, lactate dehydrogenase, aspartate transferase, D-lactate, phosphate, and creatinine kinase and its isoenzymes have all proven to be nonspecific with regard to the diagnosis of acute mesenteric ischemia. All of these

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

laboratory tests when positive may be more of an indication of advanced disease or of other GI emergencies (117–123). Several techniques do hold promise in aiding the diagnosing of acute mesenteric ischemia. Analysis of peritoneal fluid and tonometric analysis of intraluminal pH of the different areas of the GI tract may in the future provide insight into the diagnosis of acute mesenteric ischemia. The limitation of these or any other tests used to diagnose acute mesenteric ischemia is the delay of time, which can adversely affect survival in these acutely ill patients (124–127). The use of Duplex scanning and Doppler flowmetry has been examined in these patients. Duplex sonography can aid in the diagnosis of acute mesenteric venous thrombosis of the SMV and portal veins. However Duplex scanning can only identify a lesion in the origin of major splanchnic arteries and cannot identify more distal mesenteric arterial pathology. The Duplex scan can therefore be used as a screening measure while the patients awaits transport to angiography suite or the operating room. Further description of the use of the Duplex scan and the radiologic evaluation of patients with acute mesenteric ischemia is described in the next section (13).

RADIOLOGIC EVALUATION OF PATIENTS WITH ACUTE MESENTERIC ISCHEMIA If the clinician suspects the diagnosis of acute mesenteric ischemia, rapid early arteriography is considered the next step. Arteriography is the only diagnostic modality that been shown to improve survival before infarction and prior to laparotomy if it can be performed without delay. Although the radiologic techniques listed below can be useful in the diagnosis of acute mesenteric syndromes, the clinician must consider the critical factor of time delay until definitive treatment is obtained with the potential of each modality to provide significant information to help in the diagnosis and treatment of these severely ill patients.

Plain Films The results of plain radiography are nonspecific and have a very low sensitivity in patients presenting with acute mesenteric ischemia (128,129). The most common finding is a nonspecific ileus pattern with dilated fluid-filled loops of bowel, but findings can also be minimal. Other findings that can be found on plain radiologic films include thickening of the bowel wall secondary to submucosal hemorrhage (thumbprinting) and separation of bowel loops caused by mucosal thickening, intramural gas, and mesenteric or portal venous gas. These findings when present usually indicate advanced disease (Fig. 13A) (129,131,132).

Ultrasound The findings identified by ultrasound are nonspecific for acute mesenteric ischemia. These include distended bowel loops, decreased peristalsis, ileus and peritoneal fluid collections. Flow abnormalities or the presence of thrombi within the origin of the mesenteric vessels increase the diagnostic accuracy (133,134). The presence of intramural gas and fluid collections are signs of necrosis of the intestinal wall (133). Ultrasound examination can demonstrate thrombosed mesenteric vessels that appear as tubular dilated structures filled with echogenic material. Duplex and color Doppler sonography can identify absence of flow and complete occlusion of the mesenteric vessels; however this technique cannot

393

reliably exclude peripherally located thromboemboli. Use of ultrasound has several major limitations that one must appreciate. These include the lack of patient cooperation, air-filled distended bowel loops, which can obscure the acoustic window, and the lack of skill and inexperience on the part of the person performing the ultrasound study (135). Ultrasound has also been shown to be a poor correlation between flow parameters and the severity of the intestinal ischemia (136,137). One must consider the added time delay of patients being evaluated with ultrasound with obtaining definitive diagnosis and treatment.

Angiography The use of angiography continues to be the most reliable method for diagnosing acute mesenteric ischemia. The main advantage of angiography over all other methods is twofold. First, one can make a rapid diagnosis of the origin of the acute mesenteric ischemia. The sensitivity of angiography for diagnosis of acute mesenteric ischemia approaches 90% (128,130). The findings of an abrupt cutoff of the vessel without evidence of collateral flow are considered diagnostic of an acute thromboembolic event. Second, angiography allows immediate therapy with either fibrinolytic agents or vasodilating agents. The disadvantages and risks of angiography include risk from the use of an invasive procedure (bleeding, femoral artery injury or occlusion, distal emboli, false aneurysm formation, arterial to venous fistula, etc.), nephrotoxicity of the dye, time delay from surgery treatment, and the cost. In the diagnosis of mesenteric thrombosis, the SMA origin is most commonly involved; but all three mesenteric vessels can be involved. Acute emboli typically lodge within several centimeters of the origin of the SMA. SMA emboli can also lodge at the orifice of the middle colic artery or at the origin of the right colic and ileocolic arteries. SMA emboli have a high association with other peripheral embolic events (Figs. 14 and 15) (13). The SMA is the most commonly symptomatic mesenteric vessel affected by NOMI. The angiographic findings associated with NOMI include segmental mesenteric arterial constriction, alternating areas of narrowing and dilatation of SMA branches, and spasm of the arcades. Both anteroposterior and lateral arteriographic views are necessary to adequately evaluate the arterial tree and accurately exclude mesenteric thrombosis. The selective infusion of vasodilating agents (0.5 to 1.0 mg/min papaverine) has been advocated to maintain intestinal perfusion in both the occlusive and nonocclusive forms of acute mesenteric ischemia. The selective infusion of vasodilators in patients diagnosed with NOMI prior to bowel infarction may relieve the arterial spasm and prevent the need for operative intervention (Figs. 16 and 17). Use of thrombolysis with and without angioplasty has been reported in several small series. In one series, over a threeyear period, 10 patients who presented with acute SMA emboli, normal abdominal examination, and normal abdominal plain films were treated with thrombolytic therapy. Seven of the 10 patients had successful clot lysis and did not require surgical treatment (141).

Barium Studies Barium studies should not be attempted in patients with acute mesenteric syndrome because the barium interferes with angiography and in the presence of bowel perforation can initiate an intense inflammatory reaction in the peritoneal cavity. Barium enema is occasionally performed in patients with atypical presentation of abdominal pain,

medwedi.ru

394

Part Two: The Alimentary Tract—Small and Large Intestine

Figure 13 A 60-year-old man with a history of mycoardial infarction, weakness, hypotension, fever, and acute abdominal pain. (A) Plain film of the abdomen shows distended loops of small bowel and some gas in the stomach and right colon. (B) An emergency superior mesenteric angiogram shows no evidence of vasoconstriction. The arcades in the right colon are prominent. (C and D) A barium enema shows extensive submucosal edema of the descending colon to the splenic flexure, manifested by thumbprinting; this is diagnostic of ischemic colitis. The patient resolved all symptoms over several days of conservative treatment and appropriate resuscitation. Follow-up barium enema showed no abnormality. Source: From Ref. 130.

when acute mesenteric ischemia is not suspected. Radiologic findings of acute ischemia include thumbprinting, bowel dilatation, thickened folds, ulceration, stasis of the barium, and effacement of the mucosal pattern (134,142). Upper GI tract barium studies in patients with acute mesenteric ischemia can demonstrate thickened folds, ulcerations, stasis of barium in the affected bowel, and stenosis (Fig. 13) (134,142–144).

Computed Tomography The early reports of computed tomography (CT) accuracy using first- and second-generation scanners were not favorable (41,134). The introduction of spiral CT and rapid bolus injection of contrast markedly improved the capability of CT to identify the bowel wall and and mesenteric vessels. CT sensitivity in the diagnosis of acute mesenteric ischemia

has ranged from 64% to 82% (128,134). CT finding specific for acute mesenteric ischemia includes splanchnic vascular occlusion, intramural gas, lack of bowel wall enhancement, and infarcts of the kidney, liver, and spleen (129,145). CT cannot detect early reversible mesenteric ischemia and cannot be used for treatment. Recent advances in CT development have resulted in the multidetector row CT, which combines multiple rows of detectors, faster gantry rotation, and narrow collimation (146). This technique can provide more detailed anatomic information about the intestine and mesenteric vessels. Use of three-dimensional (3D) volume rendering and maximum intensity projection imaging will be able to display the mesenteric vessels in a manner similar to conventional angiography (146). In a recent study, use of the biphasic CT with mesenteric CT angiography showed that the finding of any one of pneumatosis

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

395

Figure 14 Example of a SMA embolus. (A) Plain film shows no definite abnormality. There is normal distribution of gas in the stomach and small bowel. (B) A superior mesenteric arteriogram shows a filling defect in the main portion of the SMA; the arrow indicates the location of the embolus. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 138.

intestinalis, venous gas, SMA occlusion, celiac and IMA occlusion with distal SMA disease, or arterial embolism was 100% specific but only 73% sensitive in diagnosing acute mesenteric ischemia. A finding of bowel wall thickening in addition to focal lack of bowel wall enhancement, solid organ infarction, or venous thrombosis was 50% sensitive and 94% specific. Use of either of these criteria or the diagnosis showed a sensitivity of 96% and a specificity of 94% (147). Figure 18 depicts a CT scan performed for a patient with advanced intestinal ischemia with probable bowel wall necrosis.

Magnetic Resonance Angiography

Figure 15 Example of an acute SMA thrombosis. The lateral projection of the abdominal aortogram shows occlusion of the SMA (arrow) within the first centimeter of the origin. There is intense vasoconstriction of the celiac and renal arteries. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 138.

Magnetic resonance angiography (MRA), over the past decade, has evolved from a research tool to a clinical diagnostic modality. Because of the urgent need for treatment of acute mesenteric ischemia, MRA is only rarely utilized. Vascular visualization with MR has been greatly improved by the introduction of 3D gadolinium-enhanced MRA. MRA was shown in an experimental model to have similar sensitivity and specificity to digital subtraction angiography. MRA can show in situ thrombosis of the SMA, as well as visualization of collateral vessels. MRA is far less sensitive in identifying emboli that are more peripheral in the mesenteric bed. Dual-phase contrast-enhanced (CE) 3D MRA has been shown to be highly accurate in the diagnosis of SMV and portal vein thrombosis. MRA has as established role for chronic mesenteric ischemia (149). Despite the advances in CT and MRA, these modalities are of value in diagnosis but cannot, like conventional angiography, provide therapeutic benefit. Therefore conventional angiography remains the gold standard for the evaluation of acute mesenteric ischemia.

medwedi.ru

396

Part Two: The Alimentary Tract—Small and Large Intestine

Figure 16 NOMI with reversal. Seventy-four-yearold-man had congestive heart failure and pulmonary edema. Treatment with diuretics and digitalis. On the fourth day, the patient developed diffuse abdominal pain and abdominal distention. (A) Plain abdominal radiography shows pattern of nonspecific distention of the colon and small bowel, which is consistent with but not diagnostic of mesenteric ischemia. (B) Selective superior mesenteric angiogram, arterial phase, demonstrates diffuse abdominal spasm and impaired visualization of the intestinal arcade. (C) Selective SMA angiogram following a 16-hour therapeutic papaverine infusion demonstrates reversal of the vasoconstriction with the reappearance of the intestinal arcades. Abbreviations: NOMI, nonocclusive mesenteric ischemia; SMA, superior mesenteric artery. Source: From Ref. 139.

INTRAOPERATIVE ASSESSMENT OF INTESTINAL VIABILITY The intraoperative assessment of bowel viability is an important component of the operative treatment of acute mesenteric syndromes and is of importance in the immediate survival of the patients and ultimately the long-term outcome of those patients who survive the acute insult. The

three major techniques that are utilized for intraoperative assessment of bowel viability are clinical judgment, use of the pencil-like sterile Doppler ultrasonic flow probe, and use of fluorescein and inspection under Wood’s lamp. Other techniques (such as laser doppler flowmetry and pulse oximetry) have been used, but are not as well accepted (13). Clinical assessment of bowel viability includes detecting pulsation in the arcades, color of the bowel, peristalsis,

Figure 17 Diagrammatic representation of intestinal vasoconstriction before and after reversal as seen in Figure 16B and C. Source: From Ref. 140.

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

397

Figure 18 CT scan showing gas (arrow) in the portal veins (A) and gas (arrows) in the wall of the mesentery, and mesenteric vessels (B). Pneumatosis is a late sign of ischemic injury, connotes bowel necrosis, and mandates exploration. Abbreviation: CT, computed tomography. Source: From Ref. 148.

and bleeding from the cut edges. The clinical assessment of bowel viability depends on the experience of the surgeon and the obvious absence of these entities in the infarcted bowel. The surgeon first removes the infracted or necrotic bowel. Next, warmed, moist packs are applied to the bowel of questionable viability and adequate time (15–30 minutes) allowed to pass before further bowel resection is performed. For areas of continued questionable bowel viability secondlook procedures are performed 24 to 48 hours after the first laparotomy, followed by repeat laparotomy and further bowel resection, if needed. The downside to the second-look operation is the potential of exposing the patient to additional anesthetic and metabolic stress during the time prior to the second laparotomy. Clinical assessment is often complemented by the use of the pencil sterile Doppler probe. The small pencil-shaped probe is first tested on the larger vessels such as the abdominal aorta. The Doppler probe is gently applied to the antimesenteric border of the bowel wall and to discrete mesenteric flow. Obtaining a pulsatile arterial signal is an indication of blood flow to that particular bowel segment; however one must be aware that this technique only indicates presence or absence of flow and does not quantify the amount (150,151). This technique has scientific support based on several animal models and clinical series (152). One obvious limitation is the lack of sensitivity in small, patchy areas of questionable bowel viability in the presence of inadequate bowel wall blood flow (150–154). The second technique used in combination with clinical assessment to assess intraoperative bowel viability is the fluorescein dye technique. Fluorescein dye is an organic compound that enters viable intestine within minutes of IV injection. Fluorescein emits a gold-green fluorescence when it is exposed to ultraviolet light in the range of 3600 to 4000 nm. Two ampules (1000 mg) are injected over 60 seconds intravenously. The operating room lights are turned off and the bowel exposed to a Wood’s lamp (3600 nm). The gold-green fluorescence provides evidence of viable intestine whereas the absence of fluorescence demonstrates nonviable intestine. This technique has a 96% sensitivity and a 95% specificity for arterial ischemic syndromes (13,155–157). The dye itself can cause nausea and vomiting and, rarely, anaphylaxis (156). Unfortunately the dye presence has a long half-life and repeat use can only be done after 48 hours. Several series have described the sensitivity as 100% and the specificity to be 100% whereas the figures were 50% and 58%, respectively, for Doppler ultrasonography. In this study, clinical judgment had a sensitivity and specificity of 82% and 91% (154–158).

These data really support the combined use of clinical judgment and the use of the Doppler and/or the fluorescein techniques.

DISEASES THAT AFFECT THE VISCERAL VESSELS Occlusive disease of the visceral vessels can be divided into acute and chronic presentations and can affect either the arterial or the venous visceral vessels. Separate categories of disease will be presented, as well as descriptions of presentations following disease of each visceral artery. Acute visceral syndromes include acute emboli, in situ thrombosis of the visceral arteries, NOMI, and mesenteric venous thrombosis. A major difficulty with treatment of the acute visceral syndromes is the nonspecific presentation of the patients. The patients commonly present early in the disease with abdominal pain out of proportion to the abdominal examination. This presentation can occur in up to 90% of these patients, but not in all patients. The presentation of abdominal crisis, spontaneous bowel evacuation, and significant cardiac disease has been described as Bergan’s Triad for this disorder. Affected patients are often younger, with no prior intestinal angina symptoms (13,159–163). A majority of these patients who present with acute mesenteric disease are elderly and over 70% present over the age of 60. Nausea, vomiting, and diarrhea may be present but these are not consistent findings. Bowel sounds may be hyperactive in the early stages of the disease and disappear later following necrosis of the bowel. The patients’ temperature may be normal in the early stages of the disease to markedly elevated following bowel necrosis. Patients who present with acute mesenteric ischemia may present with melena or occult blood in up to 75% of patients. A pre-existing history of myocardial infarction and/or atrial fibrillation may indicate acute emboli as the etiology of mesenteric ischemia, whereas a preexisting history of chronic mesenteric ischemia can indicate the etiology as being in situ thrombosis. The most consistent laboratory finding is the immediate elevation of the white blood count. This elevation ranges from 16,000 to 35,000 cells/mm3. The presentation of the patients can range from severe abdominal pain to one of shock due to sepsis or volume depletion due to bowel perforation or necrosis. It should be emphasized that there are no consistent symptoms or physical findings in the presentation of patients with acute mesenteric ischemia. Development of peritoneal signs (abdominal tenderness, rebound, etc.) unfortunately usually indicates progression of the disease to bowel infarction and increased mortality. To minimize morbidity and

medwedi.ru

398

Part Two: The Alimentary Tract—Small and Large Intestine

mortality, the patients who present with acute mesenteric ischemia require rapid diagnosis, stabilization and correction of medical and metabolic problems, and use of invasive cardiovascular monitoring prior to and during definitive treatment of the underlying pathology (13,159–163).

Acute Diseases That Affect the Visceral Vessels Acute Embolus More than 95% of all emboli involving major abdominal visceral arteries originate from the heart and the aortic wall but unusual emboli include those from bronchogenic carcinoma, atrial myxoma, aortic or mitral valvular prostheses, and the proximal aortic wall (164). Paradoxical embolization in which the embolus arises in the peripheral venous system can occur but is quite rare. Acute mesenteric emboli can constitute up to 50% of all acute mesenteric syndromes (13,159–164). These patients normally do not have an antecedent history of chronic visceral angina but do have a history of preexisting cardiac disease such as atrial fibrillation (up to 70%), myocardial infarction, rheumatic heart disease arterial emboli. The majority of acute emboli to the mesenteric arteries affect the SMA, with a total of 5% of all peripheral arterial emboli affecting this vessel. This may be secondary to the acute angle of the SMA takeoff from the aorta, which allows easy entry of the embolus (Figs. 14 and 15). The celiac axis is not as affected by symptomatic acute emboli as the SMA. The may be due to either the right angle origin of the vessel from its takeoff from the aortic wall, or because of the excellent collateral flow of the celiac axis. An embolus to the celiac axis would most likely lodge at the trifurcation and allow adequate collateral flow from the SMA via the gastroduodenal branches to supply the entire distribution of the hepatic, left gastric, and splenic arteries. In contrast, emboli to the SMA usually comes to rest beyond the origin of the middle colic artery. Distal to the origin of the inferior pancreaticoduodenal arteries and the middle colic artery, the SMA narrows. At this area in the SMA there is little chance for collateral blood flow and the presentation of the patient will most likely be acute with small bowel necrosis. The distribution of emboli to the branches of the SMA are as follows: the middle colic artery (55%), right colic artery (16%), ileocolic artery (7%), or smaller peripheral branches (4%). Emboli involving the IMA are uncommon; however, they have been seen after manipulation of an atherosclerotic aorta. This may cause atherosclerotic debris to be broken off with subsequent embolization and infarction of the sigmoid colon (13,159–165).

Atherosclerosis Atherosclerosis may cause obliteration of the visceral arteries either secondary to aneurysmal formation or by simple occlusion secondary to the accumulation of atherosclerotic plaques. Derrick et al. (1959) accurately described the common distribution of atherosclerotic occlusive disease within the abdominal visceral arteries (166). They demonstrated that the common site of occlusion and plaque formation was within the first several centimeters from the origin of these vessels. The main channels beyond this point are most often spared from significant atherosclerotic deposition. Reiner et al. demonstrated that although uncommon, localized areas of bowel infarction can be due to areas of occlusive disease distal to the main arterial trunks (Figs. 7 and 8) (167) and, although uncommon, they may account for a localized area of infarction. In situ thrombosis of an underlying atherosclerotic plaque can occur in the SMA, celiac trunk, or IMA (in that

order of frequency). In situ thrombosis of an underlying atherosclerotic plaque comprises 44% to 82% of all acute mesenteric ischemic events. In contrast to patients who present with acute mesenteric embolic disease, from 50% to 70% patients with in situ thrombosis present with a history of weight loss, diarrhea, abdominal pain, or the diagnosis of an abdominal bruit. The overall mortality rate associated with acute in situ thromboses averages 80%, with some series having almost two-thirds of these patients undergoing laparotomy and or massive bowel resections because of extensive intestinal necrosis. The clinical presentation and amount of bowel resection required is determined by the site of in situ thrombosis and the extent of collateral flow. Complete atherosclerotic obstruction of the visceral vessels is not infrequently encountered in asymptomatic patients undergoing angiography for other pathology. The presence of collateral systems may allow more time before evolution of bowel necrosis or may contribute to a clinical presentation that is less severe than for embolus. Nevertheless, patients presenting with abdominal pain, again out of proportion to clinical findings, with a concomitant history of cardiovascular disease should alert the clinician to consider in situ thrombosis in the differential diagnosis (13,128,130,134,159–167).

Operative Interruption of Visceral Vessels Involvement of the SMA by neoplasm of the pancreas is one indication of nonoperability. Therefore, it seems unlikely that there would be justification for ligation of the SMA during resection of the pancreas. In the event that ligation should become necessary, the interruption must be proximal to the inferior pancreaticoduodenal branches to allow adequate collateral circulation from the celiac axis. Revascularization would seem prudent in the event that the SMA must be sacrificed. This could be done by reimplantation or with a bypass graft and would ensure adequate blood supply to the superior mesenteric distribution. During a 95% pancreatectomy for chronic relapsing pancreatitis, at least one branch of the pancreaticoduodenal arcade must be preserved in the course of extensive pancreatectomy (168). This must be done to ensure adequate blood supply to the duodenum. The blood supply to the duodenum and distal common bile duct originates as segmental branches from the pancreaticoduodenal arcade. Consequently, it is imperative at the time of a 95% pancreatectomy that one of these branches be preserved as it courses along the medial border of the duodenum in order to ensure adequate viability of the duodenum and distal common bile duct. Intestinal ischemia is an infrequent but serious complication of abdominal aortic surgery. The reported incidence of significant colon ischemia varies between 0.2% and 10%, with mortality rates averaging 50% to 75% (13,159–170). In a recent large clinical review of 2137 patients, the overall incidence of clinically significant ischemia was 1.1% (171). Intestinal ischemia is seen five times less frequently after surgery for occlusive disease versus AAA repair (13,159–172). In patients with aortic occlusive disease, the IMA is usually occluded with resulting rich collateral blood flow to the left colon. In aneurysmal disease, ischemia of the left colon may follow intraoperative ligation of the IMA if collateral circulation is compromised by coexistent SMA disease, by previous bowel resection, or by congenital interruption or absence of collateral routes. Congenital anatomy that predisposes to this problem include an aberrant takeoff of the middle colic artery (usually from the right colic artery) in 20% of cases andthe absence of the marginal artery of Drummond at the splenic flexure in 7%

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

(173). Other factors increasing risk of left colon ischemia following repair of AAAs include prolonged cross clamp time, reoperative graft procedures, ruptured aneurysms, the presence of hypoxemia, hypotension, arrhythmias and operative colonic trauma, and digitalis toxicity (13,171– 173). The internal iliac artery is another potential source of collateral flow to the left colon. The internal iliac artery can be diseased by an atherosclerotic or aneurysmal disease that can limit its capability of providing collateral flow to the IMA. An aortoiliac steal syndrome has been described after simultaneous aortic reconstructions and lumbar sympathectomies, resulting in a 40% to 70% decrease in IMA flow (13,171–174). Although infrequent, iatrogenic injury to the IMA can cause massive small bowel necrosis when it serves as the major collateral to the small bowel via the meandering mesenteric artery. If incomplete collateral flow to the IMA (little retrograde backflow) and left colon ischemia is suspected during aortic surgery, or if the IMA shows large ascending collateral vessels on preoperative angiographic examination, one can preserve antegrade IMA flow by end-to-side aortic anastomosis (Carrel button technique) or by use of an interposition vein graft (169,175). Postoperative patients who develop bloody diarrhea or watery guaiac-positive stools 48 to 72 hours after surgery should be suspected of developing intestinal ischemia. These patients can present with symptoms ranging from mild abdominal pain to septic shock. These patients should undergo immediate sigmoidoscopy. The presence of subclinical mucosal ischemia has been reported in 4% to 7% of patients (13,169–175). If sigmoidoscopy reveals hemorrhagic ulcerations and mucosal edema with friability, the patient will require resection of all compromised colon, and end-colostomy with distal Hartmann’s procedure. Patients with more benign findings on sigmoidoscopy can be conservatively followed with repeat sigmoidoscopy 24 to 48 hours later.

Nonocclusive Mesenteric Ischemia NOMI accounts for 20% to 50% of all mesenteric infarctions in which autopsy data are included (13,60,159–167, 176). NOMI has increased in incidence as our capability of treating increasing ill patients in the intensive care unit setting has evolved. NOMI almost always involves the distribution of the SMA and usually is the result of a redistribution of cardiac output combined with an SMA stenosis (one-third of patients). The decrease in mesenteric perfusion pressure is accompanied by splanchnic vasoconstriction initiated by myogenic mechanisms. The increased release of renal AII appears to be one of the mediators that contribute to the splanchnic vasoconstriction. The intense splanchnic vasoconstriction contributes to thrombus formation in the microvasculature with significant reduction in intestinal blood flow. In hypotensive patients, both endogenously released catecholamines and/or exogenous catecholamines further constrict the splanchnic microcirculation, with subsequent local thrombus formation, capillary sludging and hemoconcentration, and finally bowel ischemia and necrosis. Patients who are not treated in a timely manner suffer a mortality rate approaching 100% (13,60,159–167,176). Any pathologic condition that can lower the cardiac output can be associated with NOMI. These include congestive heart failure, arrhythmias, cardiopulmonary bypass, cardiogenic or septic shock, administration of vasopressors and IV calcium, major thermal injuries, and pancreatitis. In particular, one should be wary of patients treated with

399

digitalis, which is a potent in vitro contractor of arterial and venous smooth muscle in the gut, which simultaneously decreases splanchnic blood flow and oxygen consumption. As many as 83% of patients who present with NOMI are receiving digitalis at the time of diagnosis. The diagnosis is most commonly made in patients who are admitted to the hospital with the associated conditions listed above. The patients develop abdominal pain and evidence of a low cardiac output. The differential diagnosis includes acute cholecystitis, appendicitis, and bowel obstruction. The absence of abdominal pain in this condition is far more frequent than in occlusive mesenteric ischemia. Plain abdominal films often show only fluid-filled bowel loops. Emergent angiography is indicated and can distinguish NOMI from the occlusive syndromes and there may be a failure to visualize mesenteric vascular arcades or intramural vessels (Figs. 16 and 17). The initial treatment of this syndrome is the use of intra-arterial infusion of vasodilators (papaverine, glucagon, PGs, etc.) with concomitant aggressive attempts to normalize intravascular volume and cardiac hemodynamics. If the patients do not develop signs or symptoms of intestinal ischemia or necrosis, conservative therapy is warranted. Operative intervention and anesthesia only serve to further contribute to continued arterial spasm. Repeat angiography is then performed to document improvement or resolution of the arterial spasm. If the patient does not improve or deteriorates (suspect bowel necrosis) a laparotomy should be performed. Massive fluid replacement, cardiac support, and a continuous epidural block to decrease splanchnic vasoconstriction have been recommended after operation (13,60,159–167,176).

Mesenteric Venous Thrombosis Mesenteric venous thrombosis is the least common of the mesenteric ischemic syndromes, occurring in 5% or fewer of reported cases. Mesenteric venous thrombosis occurs in patients with predisposing conditions such as abdominal trauma, peritonitis, abdominal inflammation, abdominal trauma, portal hypertension, intra-abdominal tumors, adhesions, volvulus, decompression sickness, sickle-cell disease, polycythemia vera, coagulopathies (especially antithrombin in deficiencies and protein C and S deficiency), pregnancy, recent splenectomy, and the use of oral contraceptives. More than 40% of patients have had previous deep vein thrombophlebitis of the lower extremity. The reported age range is from 11 months to 89 years, but most series report an average age of approximately 50 years (13,159–167,177–179). Patients who present with acute mesenteric venous thrombosis have involvement of the major named veins, whereas patients with a less acute (or subacute presentation) more commonly have thrombosis of the of the smaller mesenteric veins. Patients with acute mesenteric venous thrombosis usually present with severe abdominal pain, tenderness, distention, positive fecal occult blood, and decreased bowel sounds. Experimental evidence shows that increasing venous pressure is associated with a myogenic cell–mediated reflex constriction of the arterioles, leading to more severe ischemia. The combination of increased venous pressure and arteriolar vasoconstriction contributes to massive bowel edema, cyanosis of the bowel wall, and eventually bowel necrosis. In contrast, patients presenting with subacute mesenteric venous thrombosis present with vague abdominal pain, nausea, and feelings of lassitude, which can last from days to weeks prior to examination. The pathology of the more subacute mesenteric venous

medwedi.ru

400

Part Two: The Alimentary Tract—Small and Large Intestine

thrombosis is thought to be thrombosis of small venules, which does not progress to involvement of the larger named veins. Progression of the venous thrombosis to involve the larger vein can lead to a progression of the symptoms as stated above (177–179). The laboratory analysis of patients with mesenteric venous thrombosis are quite nonspecific and include leukocytosis, hemoconcentration, and copious, bloody peritoneal transudate. Plain film examinations of patients with the subacute presentation are nonspecific. Findings of rigid, thickwalled segments of edematous bowel in which a small gas collection remains fixed in a straight or curved lumen on different radiographs usually implies infarcted intestine. As with acute arterial mesenteric ischemia, early selective angiography can be diagnostic, showing thrombus in the SMV, a delay in filling during the arterial phase, small artery spasm, poor emptying of arteries, failure of venous systems (including the portal vein) to opacify, reflux of contrast medium into the artery, and often opacification of thickened bowel wall as a result of transudation of contrast medium (128–131,133,134). In contrast to radiologic evaluation of patients with acute arterial mesenteric ischemia, other diagnostic modalities have been utilized with success in patients suspected of having mesenteric venous thrombosis [Ultrasound, CT, and magnetic resonance imaging (MRI)] (135– 137,141–147,149). A CE CT scan can establish a diagnosis in more than 90% of patients with mesenteric venous thrombosis and MRI has the advantage of avoiding exposure of the patient to ionizing radiation. Patients suspected of mesenteric venous thrombosis are the one group of mesenteric ischemic syndromes who benefit from early and aggressive anticoagulation and if presenting before bowel necrosis may benefit from a trial of thrombolytic therapy (13,128,134,160).

Management: The Preoperative, Operative and Postoperative Management Preoperative Management The patient at risk for acute mesenteric syndromes needs to be rapidly identified by history and presenting symptoms and signs. The patient is immediately treated with aggressive resuscitation to correct metabolic abnormalities and restore fluid volume. The resuscitation may require aggressive cardiovascular monitoring. Because of their constrictor effects on splanchnic blood flow, vasopressors and digitalis compounds should be avoided whenever possible. Antibiotic coverage is recommended when surgery is anticipated, and broad-spectrum coverage is the rule (13,159–167). Beside routine laboratory analysis, electrocardiograph (EKG), chest X-ray (CXR), and plain film of the abdomen should be obtained. This evaluation should be minimized in terms of time and the patient should, as rapidly as possible, undergo angiographic analysis of all three major splanchnic trunks to minimize bowel ischemia and necrosis. Some authorities recommend halving the usual dose of contrast medium because of these patients’ tenuous fluid balance and to avoid renal failure (128,134). Occlusion of the SMA or one of its branches with arterial spasm and a lack of collaterals (as seen with acute thrombosis) is frequently demonstrated. The splanchnic vasoconstriction seen with SMA embolization is well documented and its persistence after embolectomy may be a reason for the frequent inability to restore adequate blood flow and for the frequent late reocclusions of distal vessels. Because of this distal vasospasm, arterial vasodilators are selectively administered by

most radiologists (13,128,134,159–167). Tolazoline is used in an initial 25 mg bolus because of its rapid effect; further angiographic exposures are taken to ascertain this effect. If vasodilation is noted, a continuous intra-arterial infusion of papaverine is begun at 30 to 60 mg/hr. Glucagon at a rate of 1 g/kg/min has also been shown to improve blood flow when administered parenterally. Tolazoline is neither as safe nor as efficacious as papaverine for continuous infusion. The clinical and angiographic responses to vasodilator therapy determine the duration of the papaverine infusion, which is usually continued for 12 to 24 hours. Patients who demonstrate collateral flow and do not show signs or symptoms of severe bowel ischemia or necrosis may be candidates for thrombolytic therapy of emboli or in situ thrombotic clot and subsequent angioplasty of underlying atherosclerotic plaque. Differentiation between arterial thrombus and embolus can be difficult, and these patients should be treated for SMA embolus. The simultaneous obstruction of both celiac and superior mesenteric vessels by in situ thrombosis is usually ameliorated by restoring blood flow through just one of the involved vessels.

Interventional Management Embolus Following rapid resuscitation and demonstration of an SMA embolus by arteriography, the patient should be rapidly transported for operative management. The skin preparation in the operating room should include both legs in case autogenous vein graft or patch is required. Formal open exploratory laparotomy is performed. The bowel is rapidly assessed and arterial reconstruction is performed for any question of bowel viability. The SMA is identified by dissection through the base of the small bowel mesentery. The patient is given a bolus of heparin if it has not been started prior to arrival to the operating room. Following obtaining proximal and distal control of the SMA, a linear or transverse arteriotomy is made. The linear arteriotomy is preferred because this allows easy distal extension of the arteriotomy, if needed at the time of exploration. The formal embolectomy is performed with the use of the Fogarty catheters to remove all blood clots. Because of the small size of the SMA, a vein patch is preferred for closure of the arteriotomy. Successful removal of the clot and restoration of the SMA blood flow is confirmed by the presence of a palpable pulse and triphasic Doppler blood flow in the SMA distal to the embolectomy and the presence of arterial pulsations in the bowel mesentery. One must now observe the entire GI tract for 15 to 30 minutes to assess the need for bowel resection. The waiting period will allow the surgeon to more correctly assess which bowel requires resection and which bowel may reverse the ischemic process and be preserved. The bowel that presents with a dark or dusky appearance may be viable and be able to be preserved. Several adjunctive measures to observation are utilized to help the surgeon decide which areas of questionable viability can be preserved. These measures include fluorescein injection and Doppler ultrasonography, or a combination of the two can be used to help the surgeon decide which bowel is viable and can be preserved or which bowel is not viable and requires resection. The morbidity and mortality following treatment of acute mesenteric ischemia due to embolus is related to the amount of bowel resected, with resections of more than 50% approaching a 90% mortality. The bowel that continues to be questionable following treatment is further assessed with the use of a ‘‘second-look’’ operation within 24 hours. This decision is made at the time of the

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

original laprotomy. Patients may also require repeat angiography and/or postoperative continuation of intra-arterial papaverine to further minimize morbidity and mortality (13,159–165,180). One must weigh the relative risks of the continued use of anticoagulants in patients treated with acute mesenteric ischemia following SMA embolus. The use of systemic anticoagulation can lead to complications of intra-abdominal bleeding. However, the risk of postoperative thrombosis of the SMA and its branches remains a risk in patients not treated with systemic anticoagulation. The use of anticoagulation is thus dependent on the clinical picture and the experience of the treating surgeon. For example, one would not use systemic anticoagulation in patients who progress to multiple organ failure and disseminated intravascular coagulation. In general, to minimize bleeding risk yet decrease the incidence of late postoperative thromboses, most clinicians recommend some anticoagulation 48 hours after the operation. In patients awaiting a second-look procedure, low-molecular-weight dextran has been cited for both its plasma volumeexpansion qualities and its antithrombotic properties. The duration of anticoagulation varies widely among patients. Thrombolytic therapy should only be used in patients without evidence of bowel necrosis (13,159–165). The postoperative course of these patients is usually quite difficult. The patients can be exposed to shock-like syndromes due to sepsis, hypovolemia, or cardiogenic mechanisms. The patients can suffer from overt sepsis, GI bleeding, acute renal failure, pulmonary insufficiency, and myocardial dysfunction, all of which may progress to multiple organ dysfunction syndrome. The patient should be treated in an intensive care setting with use of invasive cardiovascular monitoring. Stable postoperative patients who develop unexplained acidosis, sepsis of unexplained origin, and refractory cardiovascular instability all suggest continuing bowel necrosis and may necessitate a second-look procedure. Treatment of patients who present with minor emboli is different than those presenting with major emboli and bowel necrosis. Minor SMA emboli are defined as those limited to the branches of the SMA or to the SMA distal to the origin of the ileocolic artery. Patients with minor emboli and without peritoneal signs are managed conservatively with papaverine infusion with or without anticoagulation and clinical observation. If patients develop evidence of bowel necrosis or peritoneal signs, prompt exploration is undertaken. Rarely patients who present with major emboli without peritoneal signs can be treated conservatively. These patients tend to have excellent collateral flow with perfusion distal to the embolus and are thus treated as patients who present with minor emboli (13,159–165). Acute Mesenteric Thrombosis The initial approach to operative treatment of patients with mesenteric thrombosis is similar to that of treatment of the patient with acute SMA embolus. The patient is treated with rapid resuscitation and is rapidly transported to the operating room. The skin preparation in the operating room should include both legs for harvesting vein for a graft. These patients present with thrombus formation in the presence of a stenotic atherosclerotic plaque. Restoration of blood flow to the mesenteric artery in question will require removal of the blood clot and treatment of the underlying atherosclerotic lesion. Antegrade bypass to the SMA or celiac artery is preferred with use of autologous vein graft in the presence of bowel necrosis and

401

infarction (13,159–165,181). Although successful thromboendarterectomy has been reported, most current authors favor venous graft or prosthetic bypass of the affected segment, with the aorta or right iliac artery as the inflow vessel (181–183). Reimplantation, if performed, is accomplished by transecting the artery distal to its disease and anastamosing directly to the aorta. The postoperative care is similar to that for acute mesenteric ischemia due to embolus. The postoperative course of these patients can be quite challenging. These patients have the added mortality and morbidity due to the systemic nature of the atherosclerotic disease, which can affect the coronary, cerebrovascular, renal, and extremity vascular beds. Because of the reperfusion of the acute intestinal ischemia, the patients can be exposed to shock-like syndromes due to sepsis, hypovolemia, or cardiogenic mechanisms. The patients can suffer individual visceral organ failure or progressive failure of multiple visceral organs. The patients are monitored closely in an intensive care setting with use of invasive cardiovascular monitoring. Unexplained acidosis, sepsis of unexplained origin, and refractory cardiovascular instability in stable postoperative patients all suggest continuing bowel necrosis and may necessitate a second-look procedure. Increasing numbers of patients who present with mesenteric thrombosis due to underlying atherosclerotic plaque have been treated with thrombolysis and percutaneous balloon angioplasties of the SMA or celiac arteries (128,134,141,184). This interventional approach may help decrease morbidity and mortality in the elderly complex patients but can only be performed in patients without evidence of bowel necrosis or infarction. Acute Mesenteric Ischemia After Aortic Surgery If incomplete collateral flow to the IMA (little retrograde backflow) and left colon ischemia is suspected during aortic surgery, or if the IMA shows large ascending collateral vessels on preoperative angiographic examination, one can preserve antegrade IMA flow by end-to-side aortic anastomosis (Carrel button technique) or by use of an interposition vein graft. Postoperative patients who develop bloody diarrhea or watery guaiac-positive stools 48 to 72 hours after surgery should be suspected of developing intestinal ischemia. These patients can present with symptoms ranging from mild abdominal pain to septic shock. These patients should undergo immediate sigmoidoscopy. The presence of subclinical mucosal ischemia has been reported in 4% to 7% of patients. If sigmoidoscopy reveals hemorrhagic ulcerations and mucosal edema with friability, the patient will require resection of all compromised colon, and end-colostomy with distal Hartmann’s procedure. Patients with more benign findings on sigmoidoscopy can be conservatively followed with repeat sigmoidoscopy 24 to 48 hours later. Small bowel ischemia is treated similarly in an aggressive fashion, although sigmoidoscopic findings may only reveal melena (13,159–165,169,175). Mesenteric Venous Thrombosis Patients suspected of mesenteric venous thrombosis are the one group with mesenteric ischemic syndromes who benefit with early and aggressive anticoagulation and if presenting before bowel necrosis may benefit from a trial of thrombolytic therapy and thrombolytic therapy. The majority of patients will require emergent surgery following an attempt to identify location and extent of venous clot (136). Immediately prior to abdominal exploration, the patients are treated with aggressive fluid resuscitation, anticoagulation with IV heparin, and systemic antibiotics.

medwedi.ru

402

Part Two: The Alimentary Tract—Small and Large Intestine

The surgeon removes all nonviable bowel and performs venous thrombectomy of the SMA to remove the thrombus. If the surgery is successful, the patients will require systemic oral anticoagulation with warfarin compounds for a minimum of six months after surgery. If the patient has an identified underlying coagulation disorder, then systemic oral anticoagulation is continued for life. Only the nonviable bowel needs to be resected because the combination of heparin therapy and second-look operations has been shown to limit the extent of bowel resection. Untreated, the mortality rate for acute mesenteric venous thrombosis is close to 100% whereas aggressive use of early exploration and anticoagulation has decreased the operative mortality rate below 15% with heparin therapy. Early and late rethrombosis is unfortunately common. Early rethrombosis is seen in about one-quarter of cases and carries a higher mortality rate of 60% to 80%. Some surgeons routinely advocate second-look procedures because of this high rethrombosis rate (13,159–165,177–179). Chronic Intestinal Ischemia The syndrome of chronic mesenteric ischemia was first described by Schnitzler in 1901 and Warburg in 1905 (185,186). Klein, in 1921, was the first to compare the pain of chronic mesenteric ischemia to the pain caused by intermittent claudication (187). In 1936, Dunphy was the first investigator to suggest that the symptoms of chronic mesenteric ischemia were a possible harbinger to the in situ thrombosis of one or more of the major visceral vessels, with subsequent development of intestinal gangrene (188). In Klein’s classic review, he described three possible outcomes to the gradual occlusion of the visceral arteries. The first possible outcome is the establishment of adequate collateral blood flow. The second possible outcome is intestinal infarction with a high incidence of mortality. The third possible outcome is obstruction of the visceral vessel without intestinal necrosis due to collateral blood flow that is adequate to meet minimal needs of intestinal viability but is not enough to meet the postprandial demands of increased blood flow, and the presentation of chronic intestinal ischemia (187). Patients who present with chronic intestinal angina are usually in the sixth decade of life and present with all the standard risk factors of systemic atherosclerosis. Most are heavy smokers, but unlike atherosclerotic syndromes, this has increased incidence in female patients (outnumber males in the ratio 3:1) (13,169,189–191). Patients with chronic mesenteric ischemia present with postprandial pain, weight loss, and diarrhea (13,169,189–191). The pain is usually generalized in the upper abdomen and may be referred to the back (182). Because the splanchnic bed has extensive collateral blood flow, most patients with chronic intestinal angina have involvement of at least two of the three major mesenteric vessels (188,189). The abdominal pain occurs from 15 minutes to 1 hour following a meal, is usually periumbilical, and can last up to three hours. Weight loss is usually significant as patients develop a fear of eating, diarrhea presents in one third of patients and these may have occult blood. Physical examination is nonspecific and an abdominal bruit may be present in 50% of these patients. The presentation of abdominal pain and weight loss may lead these patients to be evaluated for a variety of clinical diagnoses, especially for a GI neoplasm (13,189–192). Although not common, there are instances when involvement of one mesenteric vessel can cause symptoms of intestinal angina. Dunbar (193) and Rob (182,194)

described the clinical entity of celiac trunk compression in which patients present with postprandial upper abdominal pain and associated weight loss. Unlike patients with classic chronic mesenteric ischemia, patients with celiac compression usually do not have associated diarrhea; however they do readily restrict their food intake. Drapanas and Bron suggested that symptoms caused by celiac compression syndrome may be due a steal of blood from the SMA system to supply the distribution of the celiac axis (195). Reiner et al. suggested that occlusive disease in the pancreaticoduodenal arcade could prevent adequate collateral circulation to the celiac axis from the SMA system, thus providing another possible explanation for the symptoms due to celiac compression (167). Communications between the inferior and superior pancreaticoduodenal artery is uncommon, occurring in less than 1% of cadavers (196). Less frequently, the stenosis results from compression of the celiac axis by a celiac ganglion or arcuate ligament of the diaphragm, compression from an expanding or dissecting aortic aneurysm, or thromboangiitis obliterans or periarteritis nodosa. Duplex scan can be used as a screening tool to identify patients with significant occlusive disease at the origin of the celiac and superior mesenteric arteries (197–200). Over the past 15 years, numerous studies have shown that duplex ultrasound is an accurate screening test for proximal stenosis or occlusion of the celiac and superior mesenteric arteries. Moneta et al. have shown that a peak systolic velocity greater than 275 cm/sec is highly specific for significant SMA stenosis (198). Perko and Zwolak et al. have suggested that the use of end-diastolic velocity greater than 45 cm/sec is more accurate than use of peak systolic velocity (199,200). Gentile et al. have also reported blunting of the normal differences in peak systolic velocities between fasting and postprandial states (201). The duplex ultrasound thus has been shown to be accurate in both diagnosing proximal celiac and SMA stenosis and in assessing the physiologic significance of these stenoses. The reader should understand that the use of the duplex ultrasound in assessing the proximal celiac and superior mesenteric vessels is highly technician dependent. More recently, experience has been gained with MRA and CT angiography (197,202–209). CE MR has benefited from improved gradient technology, which allows ultrafast volume acquisitions with computer-assisted muliplane reformatting or volume rendering (202–204). This technique has been shown to correlate very well with conventional angiography and to be reproducible from observer to observer (202,205,206). An obvious advantage of MR compared to CT angiography is that it is safe for use in patients with compromised renal function. Spiral CT and more recent multidetector row CT produce better data on the abdominal aorta and all of its branches. The newer computer reconstruction techniques allow accurate measurement of arterial stenoses (197,207,208). Either Duplex ultrasound or MR or CT angiography should still be viewed as screening test to avoid unnecessary angiograms (197). If reconstruction is considered an arteriogram should be performed (Fig. 19). One must be sure that lateral as well as A–P views of the aorta are obtained to accurately assess the celiac artery and SMA arteries. Oblique views are necessary to evaluate the origin of the IMA. Routine selective catheterization of the visceral arteries provides information on the severity of the stenoses and the blood supply. Collateral vessels are usually best visualized on the anterioposterior projections. Select catheterization of the celiac artery can provide data on the length of SMA occlusions. The IMA should

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

403

Figure 19 Chronic mesenteric ischemia. A 61-year-old female patient with a five-year history of postprandial pain. (A) Mid-arterial phase aortogram shows a large, prominent IMA. (B) Late-phase arterial study shows the SMA (arrow) being filled in a retrograde fashion by collaterals from the IMA. It also shows late filling of the hepatic and splenic branches of the celiac artery. (C) Lateral view shows marked stenosis of the origin of the celiac artery (arrow). Abbreviations: IMA, inferior mesenteric artery; SMA, superior mesenteric artery. Source: From Ref. 210.

not undergo selective catheterization because this artery may be the sole arterial supply to the entire intestine and dissection of the IMA can lead to necrosis of the entire GI tract (197). The most common angiographic finding is significant stenoses of both the celiac artery and the SMA (85% of patients), in the presence of large collateral vessels (189,197,211). Patients who present with intestinal angina and weight loss and who demonstrate significant stenoses of the mesenteric vessels are considered for interventional repair. Intervention approach may either be by the use of angioplasty and stent or direct operative repair with either transaortic endarterectomy or bypass grafting. If celiac and SMA stenoses are found in an appropriately symptomatic patient, the literature favors revascularization of the SMA first by percutaneous angiography and then by stent placement. The celiac is a tortuous vessel that may require a staged approach (197). In cases of failed SMA percutaneous transluminal angioplasty, the celiac artery is approached. The use of thrombolytic agents has been suggested by several authors prior to passing a catheter across a symptomatic lesion (212,213). More recent reports have shown that stent placement in visceral arteries should be performed to both achieve successful recanalization of the artery and treat procedure-related dissection (197,212–215). Long-term prospective studies examining the use of angioplasty and stent technology in the treatment of chronic mesenteric ischemia will be required to determine long-term efficacy of this approach. Comparison to open operative surgical approaches will also require randomized study in the future to provide comparison of long-term efficacy and short- and long-term complications (197). Operative repair can be achieved either by bypass grafting or endarterectomy techniques (13,180,189,191,216–221).

There are advantages and disadvantages of either technique and the type of operative repair depends on the surgeon’s experience. Bypass grafting can utilize either autogenous greater saphenous vein or polyethylene terephthalate fabric (Dacron) grafts. Dacron grafts are preferred due to their resistance to kinking and better results. Use of autogenous greater saphenous vein is necessary in the presence of severe intestinal ischemia or spillage of bowel contents. Revascularization of more than one mesenteric vessel provides the best long-term result, with relief of pain (in 90% of patients), regaining of lost weight (75%), and improvement of malabsorption (13,191,216–221).

MISCELLANEOUS DISEASES THAT AFFECT THE VISCERA Occlusion or disruption of the blood supply to the abdominal viscera can occur by traumatic disruption, thrombosis secondary to trauma, external compression, or obliteration of the lumen.

Trauma Abdominal vascular injuries accounted for 2% of all vascular injuries during World War II, the Korean War, and the Vietnam War. Abdominal vascular injuries were highly lethal, with most patients dying before being treated. Those patients who survived long enough for implementation of treatment mostly had iliac artery injuries (222). In contrast, the civilian experience has greatly differed from the military experience. The incidence of abdominal vascular injuries due to penetrating trauma is approximately 10% to 20% and the incidence of abdominal vascular injuries due to

medwedi.ru

404

Part Two: The Alimentary Tract—Small and Large Intestine

blunt injury is approximately 5% to 10% (222–225). Several authors have suggested that the short time required for hospitalization and the lower wounding power of civilian handguns are responsible for the higher incidence of abdominal vascular trauma, in civilian practices (222–225). Zone I injuries involve the suprames colon, inframesocolon, suprarenal and infrarenal arteries, SMA and the celiac vessels. Zone II injuries involve the renal vessels. Zone III injuries involve the iliac vessels. These complex injuries require an excellent knowledge of anatomy, resuscitation, and prevention of hypothermia, use of intraoperative maneuvers suck as the Mattox maneuver, experience with vascular reconstruction, and appropriate use of different bypass graft materials. The reader is referred to several excellent reviews of this interesting, complex, and challenging area of diagnosis and treatment of complex abdominal vascular injuries (222–225).

External Compression Syndromes The celiac artery compression syndrome is an example of external compression of the celiac artery by the median arcuate ligament as described by Harjola and Dunbar et al. or compression by the celiac ganglia as described by Rob (182,193,194,226). Neoplasms may cause occlusion of major visceral arteries by either external compression or direct invasion. The celiac artery compression syndrome presents as postprandial pain and often as positional abdominal pain in the epigastrium associated with an epigastric bruit, nausea, and weight loss. The histopathologic findings of the celiac artery show a process of chronic celiac artery compression and significant intimal thickening (227). Younger women are often more affected than men (169,228). The variable anatomic positions of the celiac axis and median arcuate ligament may indeed lead to an anterior compression of the celiac axis, especially during expiration and various postural changes (Figs. 20 and 21). Duplex ultrasonography can be used to screen patients who are suspected of this celiac artery compression syndrome. Lateral aortic views obtained during angiographic analysis will show eccentric compression of the celiac trunk along its superior border, with caudal displacement confirming the clinical diagnosis. Despite confirming the clinical impression of celiac artery compression syndrome by arteriography, data from several reviews demonstrate that the diagnosis of celiac artery compression syndrome is quite controversial. In a series of 50 patients who were diagnosed with a symptomatic celiac artery compression syndrome, 24% were found to have at least a 50% stenosis of the celiac axis (231). Another review of 330 patients who were identified as having a symptomatic celiac artery compression syndrome by arteriography only demonstrated abdominal pain in 30% and weight loss in only 50% of these patients (228). Long-term follow-up following operative repair of symptomatic celiac artery compression syndrome reported recurrence rates of symptoms of over 50% (13,228,231– 234). Several authors have hypothesized that the symptoms related to celiac compression may be due in some cases to external pulsatile compression of the celiac plexus by the celiac artery. Several options are considered for surgical repair. For those patients whose syndrome is felt to be secondary to median arcuate ligament compression of the celiac artery, division of the ligament should be curative. For those patients whose symptoms are secondary to celiac compression from the celiac ganglion, ganglionectomy is indicated. For either etiology, bypass of the obstruction or patch angioplasty has been described (13,169,234).

Figure 20 Celiac artery compression. This is a lateral projection of an abdominal aortogram demonstrating extrinsic compression upon the superior aspect of the celiac axis. There is poststenotic dilatation distally. The SMA is normal. Abbreviation: SMA, superior mesenteric artery. Source: From Ref. 229.

A different type of external compression is one where the SMA compresses the duodenum. The symptoms are similar to chronic mesenteric ischemia but vomiting is obviously prominent due to the duodenal obstruction. The etiology of this syndrome is compression of the duodenum between the SMA (or major SMA branches) and the aorta and vertebral bodies. The SMA leaves the aorta at rather an acute angle under which lie the third and fourth portions of the duodenum. The syndrome is named after Wilkies, who described this entity in 1927. The majority of the patients are young females and commonly have other problems such as requiring complete bed rest and body cast, scoliosis, acute weight loss, and anorexia nervosa (13,235–238). Radiologic diagnosis is achieved using cineradiography, which classically demonstrates a ‘‘to-and-fro of the duodenal contents’’ proximal to the crossing of the SMA (236). A significant number of patients also have concomitant peptic ulcer disease (15%). Surgical treatment is limited to symptomatic patients with positive radiologic findings as described above. Surgical treatment consists of division of the ligament of Treitz; however duodenojejunostomy may be required in chronic cases.

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

405

Figure 21 Lateral aortogram in a patient with typical celiac compression syndrome. The degree of narrowing is increased markedly in full expiration. Source: From Ref. 230.

Inflammatory Lesions Inflammatory lesions that involve the splanchnic arteries are quite rare; however, a review of the more common lesions is important to provide the reader with data to develop an appropriate index of suspicion to diagnose patients who present with these diseases. Vasculitis can affect all levels of vessel in the splanchnic circulation, resulting in mesenteric ischemia, paralytic ileus, submucosal edema and hemorrhage, bowel stricture, or perforation. Vasculitis may involve primarily large vessels (Takayasu arteritis, giant cell arteritis, etc.), medium-sized vessels (polyarteritis nodosa, Kawasaki disease, primary granulomatous central nervous system vasculitis, etc.), or the small vessels (Henoch–Schonlein syndrome, systemic lupus erythematosis, rheumatoid vasculitis, Behcet syndrome, Wegener granulomatosis, Churg–Strauss syndrome). A reference for an excellent review of the radiologic findings of the mesenteric vasculitides is provided for the reader (239–241). The diseases that affect the larger vessels may present in a similar manner as acute emboli, thrombosis unless the patient has other systemic symptoms associated with the underlying vasculitis. Tuberculosis and collagen vascular diseases may produce an arteritis that causes secondary occlusive disease in the branches of the abdominal aorta. The lesions can involve the first several centimeters of the vessel at its origin from the aorta or involve the medium or small arterioles and thus may cause a variety of symptoms, including intestinal infarction. There is no adequate collateral blood supply to the small arterioles of the small intestine and involvement of these vessels almost invariably results in necrosis. Table 2 lists the collagen vascular diseases that most commonly affect the GI tract. The data presents the areas of major involvement and only those symptoms produced by involvement with the vessels supplying the GI tract. Thromboangiitis obliterans (Buerger’s disease) should be classified under inflammatory lesions but will be considered separately. This disease occurs in very young people

and is most often associated with the excessive use of tobacco. The usual site of this disease is the medium-sized arteries of the extremities. Figures 22 and 23 demonstrate typical changes found in patients undergoing angiography for Buerger’s disease. Fewer than a dozen verified cases of intestinal Buerger’s disease have been reported. Mesenteric vessel involvement by Buerger’s disease is unusual in that concomitant involvement of the peripheral vascular bed has not been reported. The site of involvement, similar to that of the collagen vascular diseases reported in Table 2, are the medium and small arteries of the splanchnic bed, which can result in small-intestinal perforation (40%), bowel necrosis, dysmotility and obstruction and death (40% mortality) (13,239,244–246).

Cocaine-Associated Mesenteric Ischemia In recent years, several publications have documented the association of cocaine abuse with acute and chronic mesenteric ischemia (247–250). The majority of patients of either sex present at less than 35 years of age and can present with intestinal ischemia that ranges from chronic visceral ischemia to bowel infarction. Myers et al. reported two cases of young women with a two-year IV cocaine abuse, who presented with severe chronic mesenteric ischemia. Both patients demonstrated celiac and SMA occlusions on diagnostic angiography and both were managed successfully with visceral revascularization (247). A subsequent follow-up study showed that the pathology in these two patients revealed total arterial obstruction by luminal thrombus with recanalization (250). The conclusion of these studies is that mesenteric ischemia should be considered in the differential diagnosis of acute and chronic abdominal pain in cocaine consumers (247–250). The use of crack cocaine during pregnancy exposes both the mother and the fetus to the potent vasoconstrictive actions of cocaine. Fetal activity of plasma cholinesterase, the enzyme responsible for detoxification of cocaine, is quite low (251). Therefore prolonged maternal cocaine abuse

medwedi.ru

406

Part Two: The Alimentary Tract—Small and Large Intestine

Table 2 GI Manifestations of Rheumatalogic Diseases Diagnosis

Pathology

Symptoms affecting mesenteric vessels

GI involvement

Antiphospholipid Antibody syndrome

Vasculitis

Small intestine, esophagus, colon

Behecet’s disease Churg–Strauss syndrome Cogan’s syndrome

Systemic vasculitis Necrotizing granulomatous vasculitis Aortitis, vasculitis

SMA vasculitis, SMA aneurysm SMA, small intestine Aorta, SMA

Giant cell arteritis Henoch–Schonlein purpura

Large vessel arteritis Immunoglobulin A-mediated immune Affecting small vessel

Aorta (10%), SMA Intestine, colon, esophagus, pancreas gallbladder

Inflammatory muscle disorders

Vasculopathy, small vessel involvement

Small intestine, esophagus

Kawasaki disease

Vasculitis

Coronary, SMA

Polyarteritis nodosa

Vasculitis of medium and small vessels

Small bowel

Rheumatoid arthritis

Small artery vasculitis

Ileum, colon, esophagus

Sjogren’s syndrome Systemic lupus erythmatosis

Mononuclear cell infiltration Deposition of pathogenic antibodies and immune complexes

Small intestine, colon Entire GI tract

Systemic sclerosis

Inflammatory vasculitis

Entire GI tract

Takayasu arteritis

Large vessel arteritis

Aorta, branches of aorta

Wegener’s granulomatosis

Necrotizing vasculitis granulomatous inflammation

Small intestine, colon

Vascular thromboses, thrombocytopenia, intestinal ischemia Intestinal ischemia and infarction Intestinal mucosal ischemia AAA, abdominal pain, nausea and vomiting after a meal Intestinal gangrene Abdominal pain, nonthrombocytopenic purpura, arthritis, ulceration of bowel mucosa, bowel infarction, gastric and bowel perforation, pancreatitis, appendicitis, cholecystitis, intususseption Abnormal GI peristalsis, reduced GI motility, hiatal hernia, intestinal ischemia, necrosis or perforation, 10% incidence of malignancy within 1 yr Abdominal pain, small bowel obstruction secondary to with stricture Abdominal pain, SI ischemia, perforation (5%), bowel infarction (1.4%), ulceration (6%) Ileal or colonic ischemia, diminished esophageal peristalsis, profuse diarrhea, flatulence, weight loss Jejunitis, sigmoiditis Esophageal ulceration and perforation, intestinal dysmotility, vasculitis and malabsorption, venous thrombosis and intestinal ischemia, aneurysmal disease Dysphagia, dyspepsia, small-intestinal dysmotility, pneumatosis intestinalis Abdominal pain, nausea, diarrhea, saccular aneurysms Intestinal perforation and ulceration

Abbreviations: AAA, abdominal aortic aneurysm; GI, gastrointestinal; SMA, superior mesenteric artery; SI, splanchnic intestine.

exposes the fetus to increased serum levels of cocaine. Fetal and neonatal exposure to cocaine can lead to prolonged ischemia of the intestine, integument, cardiovascular system, and the brain (252–255). Several case reports have described neonatal intestinal ischemia with bowel perforation secondary to maternal cocaine abuse (256–258).

SUMMARY The mesenteric vascular bed receives and distributes 10% to 15% of the cardiac output. GI functions of motility and digestion are dependent on adequate blood flow, which is distributed and regulated by both intrinsic and extrinsic mechanisms. Extrinsic control of mesenteric blood flow is due to the sympathetic and parasympathetic nervous system, circulating GI hormones, and vasoactive factors released from around the body. The intrinsic mechanisms regulating mesenteric blood flow are due to both myogenic

and metabolic regulatory systems. Pathophysiologic mechanisms that imbalance this complex interaction of extrinsic and intrinsic control of mesenteric blood flow produce a broad spectrum of disorders that can be difficult to diagnose and treat successfully. The diagnosis of acute mesenteric syndromes is dependent on the clinician having a high index of suspicion for this disease, which will then lead to rapid resuscitation and diagnosis. The use of diagnostic techniques of Duplex scan, Doppler flowmeter, and CT scan is only indicated when they do not add a time delay to transfer either to the angiography suite or to the operating suite. Angiography remains the gold standard in diagnosing acute mesenteric ischemia and can also be therapeutic in cases of NOMI or in those cases identified before bowel necrosis, which can be treated with lysis and angioplasty. The current data support the combined use of clinical judgment and the Doppler and/or the fluorescein techniques for intraoperative assessment of bowel viability. Aggressive

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

407

Figure 22 (A and B) Brachial angiogram shows a hypoplastic ulnar artery (white arrows), persistence of the interosseous artery (large black arrows), and occlusion of the distal radial artery at the level of the wrist (white arrow), with extensive but small collaterals (small black arrows). There is no reconstruction of the palmar arches. The arterial branches of the palm and fingers are severely narrowed. Source: From Ref. 242.

Figure 23 (A and B) Absence of both palmar arches, multiple areas of arterial narrowing (large white arrows), obstructions (black arrows), and pruning of the digital arteries (small white arrows). Source: From Ref. 243.

medwedi.ru

408

Part Two: The Alimentary Tract—Small and Large Intestine

diagnosis and treatment is the only means to reduce the high morbidity and mortality associated with each of these pathologic disorders of mesenteric blood flow. Identification of patients at risk for development of acute mesenteric ischemia (patients with chronic mesenteric ischemia, etc.) is one more means to try and decrease the high complication rates seen with acute mesenteric ischemia.

REFERENCES 1. Bron KM. Leriches syndrome: aoprioiliac ischemic disease. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1501. 2. Gannon BJ, Perry MA. Vascular organization of alimentary tract. In: Schultz SG, ed. Handbook of Physiology. The Gastrointestinal System. Bethesda: American Physiological Society, 1989:1301–1334. 3. Matheson PJ, Wilson MK, Garrison RN. Regulation of intestinal blood flow. J Surg Res 2000; 93:183. 4. Guyton AC, Hall JE. Overview of the circulation; medical physics of pressure, flow and resistance. In: Guyton AC, ed. Textbook of Medical Physiology. Tenth ed. WB Saunders Co., 2000:144–151. 5. Guyton AC, Hall JE. Overview of the circulation; medical physics of pressure, flow and resistance. In: Guyton AC, ed. Textbook of Medical Physiology. Tenth ed. WB Saunders Co., 2000:726. 6. Rich NM, Spencer FC. Injuries of miscellaneous intra()abdominal injuries. In: Rich NM, Spencer FC, eds. Vascular Trauma. WB Saunders Co., 1978:459. 7. Fry WJ. Arterial circulation of the small and large intestine. In: Strandness DE Jr, ed. Collateral Circulation in Clinical Surgery. Philadelphia, PA: WB Saunders Co., 1969:508–537. 8. Matheson PJ, Wilson MK, Garrison RN. Regulation of intestinal blood flow. J Surg Res 2000; 93:182–196. 9. Kaufman SL, Siegelman SS. Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1566. 10. Kaufman SL, Siegelman SS. Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1567. 11. Brandt LJ, Boley SJ. Intestinal ischemia. In: Feldman M, Friedman LS, Sleisenger MH, eds. Gastrointestinal and Liver Disease. 7th ed. Philadelphia: Saunders, 2002:2323. 11a. Boley SJ, Brandt LJ, Veith FJ. Ischemic disorders of the intestines. Curr Probl Surg 1978; 15:29. 12. Guyton AC, Hall JE. Overview of the circulation; medical physics of pressure, flow and resistance. In: Guyton AC, ed. Textbook of Medical Physiology. 10th ed. WB Saunders Co., 2000:175–183. 13. Brandt LJ, Boley SJ. Intestinal ischemia. In: Feldman M, Friedman LS, Sleisenger MH, eds. Gastrointestinal and Liver Disease. 7th ed. Philadelphia: Saunders, 2002:2321–2340. 14. Lanciault G, Jacobson ED. The gastrointestinal circulation. Gastroenterology 1976; 71:851–873. 15. Johnson PC. Myogenic nature of increase in intestinal vascular resistance with venous pressure elevation. Circ Res 1959; 6:992–999. 16. Folkow B. Regional adjustments of intestinal blood flow. Gastroenterology 1967; 52(2):423–432. 17. Granger DN, Rvietys PR. The splanchnic circulation: intrinsic regulation. Ann Rev Physiol 1981; 43:409–418. 18. Payne D, Kubes P. Nitric oxide donors reduce the rise in reperfusion-induced intestinal mucosal permeability. Am J Physiol 1993; 265:G189–G195. 19. Aoki N, Johnson G, Lefer AM. Beneficial effects of two forms of NO administration in feline splanchnic artery occlusion shock. Am J Physiol 1990; 258:G275–G281. 20. Kanwar S, Tepperman BL, Payne D, Sutherland LR, Kubes P. Time course of nitric oxide production and epithelial

21. 22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40. 41.

42.

dysfunction during ischemia/reperfusion of the feline small intestine. Circ Shock 1994; 42:135–140. Kubes P. Ischemia-reperfusion in feline small intestine: a role for nitric oxide. Am J Physiol 1993; 264(1 Pt 1):G143–G149. Gaboury J, Woodman RC, Granger DN, Reinhardt P, Kubes P. Nitric oxide prevents leukocyte adherence: role of superoxide. Am J Physiol 1993; 265:H862–H867. Gallavan RH, Chou CC. Prostaglandin synthesis inhibition and postprandial intestinal hyperemia. Am J Physiol 1982; 242(Gastrointest Physiol 5):G140–G146. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane and prostacyclin. Pharmacol Rev 1979; 30:293–331. Armstrong M, Lattimer N, Moncada S, et al. Comparison of vasopressor effects of prostacyclin and 6-oxo-PGF1? with those of prostaglandin E2 in rats and rabbits. Br J Pharmacol 1978; 62:125–130. LeDuc LE, Needleman P. Regional localization of prostacyclin and thromboxane synthesis in dog stomach and intestinal tract. J Pharmacol Exp Ther 1979; 211:181–188. Hawkey CJ, Rampton DS. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 1985; 89:1162–1168. Lipton HL, Chapnick BM, Hyman AL, et al. Inhibition of vasoconstrictor responses by prostacyclin (PGI2) in the feline mesenteric vascular bed. Arch Int Pharmacodyn 1979; 41:214–223. Coupar M, McLennan PL. The influence of prostaglandins on noradrenaline-induced vasoconstriction in isolated perfused mesenteric blood vessels of the rat. Br J Pharmacol 1978; 62:651–659. Dusting GJ, Moncada S, Vane JR. Vascular actions of arachidonic acid and metabolites in perfused mesenteric and femoral beds of the dog. Eur J Pharmacol 1978; 49:65–72. Reed MK, Taylor B, Myers SI. The effect of hypoxia on rat splanchnic prostanoid output. Prostaglandins 1989; 38: 599–608. Reed M, Taylor B, Myers S. The effect of hypoxia on Angiotensin-stimulated release of PGI2 from the splanchnic bed. J Trauma 1990; 30:993–999. Myers SI, Evans CT, Hernandez R, et al. Increased splanchnic prostacyclin synthase and cyclooxygenase content and activity during ischemia is due to new protein synthesis. Surgery 1994; 116:432–438. Myers SI, Taylor BJ, Stanislawska M. Reperfusion inhibits elevated splanchnic prostanoid production following hemorrhagic shock. Ann Surg 1991; 212:688–693. Myers SI, Hernandez R. Role of oxygen-derived free radicals on rat splanchnic eicosanoid production during acute hemorrhage. Prostaglandins 1992; 44:25–36. Feigen LP. Differential effects of leukotrienes C4, D4 and E4 in the canine renal and mesenteric vascular beds. J Pharm Exp Ther 1983; 225(3):682–687. Pawloski JR, Chapnick BM. Leukotrienes C4 and D4 are potent endothelium-dependent relaxing agents in canine splanchnic venous capacitance vessels. Circ Res 1993; 73(2):395–404. Chapnick BM. Divergent influences of leukotrienes C4, D4, and E4 on mesenteric and renal blood flow. Am J Physiol Heart Circ Physiol 1984; 246:H518–H524. Guyton AC, Hall JE. Nervous regulation of the circulation, and rapid control of arterial pressure. In: Guyton AC, ed. Textbook of Medical Physiology. 10th ed. WB Saunders Co., 2000:184–194. Surprenant A. Control of gastrointestinal tract by enteric nervous system. Ann Rev Physiol 1994; 56:117–140. Hwa JJ, Ghibaudi L, Williams P, Chatterjee M. Comparison of acetylcholine-dependent relaxation in large and small arteries of rat mesenteric vascular bed. Am J Physiol 1994; 35: H952–H958. Granger ND, Kvietys PR, Korthuis RJ, Premen AJ. Microcirculation of the intestinal mucsosa. In: Schultz SG, ed.

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed

43. 44.

45.

46.

47.

48.

49. 50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61. 62.

63.

Handbook of Physiology. The Gastrointestinal System. Bethesda: American Physiological Society, 1989:1405–1474. Zinner MJ et al. The hemodynamic effects of intravenous infusions of serotonin in conscious dogs. J Surg Res 1983; 34:171. Schmid PG, Fouad MS, Phillips MI. Peptides and blood vessels. In: Schultz SG, ed. Handbook of Physiology. The Cardivascular Sysytem. Bethesda: American Physiological Society, 1983:815–834. Jodal M, Lundgren O. Neurohormonal control of gastrointestinal blood flow. In: Schultz SG, ed. Handbook of Physiology. The Gastrointestinal System. Bethesda: American Physiological Society, 1989:1667–1711. Chou CC, Alemayehu A. Peptidergic regulation of gastrointestinal blood flow. In: Schultz SG, ed. Handbook of Physiology. The Gastrointestinal System. Bethesda: American Physiological Society, 1989:1325–342. Brandd ST, Schmidt WE. Gastrointestinal hormones. In: Yamada T, Alpers DR, Owyang C, Poswell DW, Silverstein FE, eds. Textbook of Gastroenterology. Philadelphia: JB Lippincott, 1995:25–71. Turnage RH, Myers SI. Pathophysiology. In: Longo WE, Peterson GJ, Jacobs DL, eds. Intestinal Ischemia Disorders. Quality Medical Publishing, 1999:40. Deitch EA. Multiple organ failure: pathophysiology and potential future therapy. Ann Surg 1992; 216:117–134. Paterson IS, Klausner JM. Non-cardiogenic pulmonary edema after abdominal aortic aneurysm surgery. Ann Surg 1989; 209:231. Huber TS, Harward TR, Flynn TC, Albright JL, Seeger JM. Operative mortality rates after elective infrarenal aortic reconstructions. J Vasc Surg 1995; 22:287–293. Parks DA, Granger DN. Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 1982; 250: G749–G753. Turnage RH, Myers SI. Pathophysiology. In: Longo WE, Peterson GJ, Jacobs DL, eds. Intestinal Ischemia Disorders. Quality Medical Publishing, 1999:20. Mangino MJ, Andeson CB, Murphy MK, Brunt E, Turk J. Mucosal arachidonate metabolism and intestinal ischemiareperfusion. Am J Physiol 1989; 257:G299–G307. Chiu CJ, McArdle AH, Brown R, Scott HJ, GurdFN. Intestinal mucosal lesion in low-flow states. I. A morphologic, hemodynamic, and metabolic reappraisal. Arch Surg 1970; 101: 478–483. Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Granger DN. Role of neutrophils in ischemia-reperfusioninduced microvascular injury. Am J Physiol 1987; 253: H699–H703. Turnage RH, Kadesky KM, Bartula L, Guice KS, Oldham KT, Myers SI. Splanchnic PGI2 release and reflow following intestinal reperfusion. J Surg Res 1995; 58:558–564. Turnage RH, Kadesky KM, Tom Rogers, Hernandez R, Bartula L, Myers SI. Neutrophil regulation of splanchnic blood flow after hemorrhagic shock. Ann Surg 1995; 222:66–72. Jerome SN, Smith CW, Korthuis RJ. CD18-dependent adherence reactions play an important role in the development of the no-reflow phenomenon. Am J Physiol 1993; 264: H479–H483. Bailey RW, Bulkley GB, Hamilton SR, Morris JB, Haglund UH. Protection of the small intestine from nonocclusive mesenteric ischemic injury due to cardiogenic shock. Am J Surg 1987; 153:108–1116. Mangino MJ, Chou CC. Arachidonic acid and postprandial intestinal ischemia. Am J Physiol 1984; 246:G521–G527. Chou CC, Kvietys PR. Physiological and pharmacological alterations in gastrointestinal blood flow (Chapter 27-Splanchnic blood flow overview). In: Bulkley GB, Granger DN, eds. The Measurement of Splanchnic Blood Flow. Baltimore, MD: Williams & Wilkens, 1981:477–509. Turnage RH, Myers SI. Pathophysiology. In: Longo WE, Peterson GJ, Jacobs DL, eds. Intestinal Ischemia Disorders. Quality Medical Publishing, 1999:30.

409

64. Myers SI, Reed MK, Taylor B, et al. Splanchnic prostanoid production: effect of hemorrhagic shock. J Surg Res 1990; 48:579–583. 65. Myers SI, Small J. Prolonged hemorrhagic shock decreased splanchnic prostacyclin synthesis. J Surg Res 1991; 50:417–420. 66. Myers SI, Hernandez R. Exaggerated splanchnic PGI2 release following acute hemorrhage is due to new protein synthesis. Prostaglandins Leukot Essent Fatty Acids 1993; 48:207–210. 67. Myers SI, Hernandez R. Oxygen free radical regulation of rat splanchnic blood flow. Surgery 1992; 112:347–354. 68. Egan RW, Gale PH, Kuehl FA Jr. Reduction in hydroperoxides in the prostaglandin biosynthetic pathway by a microsomal peroxidase. J Biol Chem 1979; 254:3295–3302. 69. Egan RW, Paxton J, Kuehl FA Jr. Mechanism for irreversible self-deactivation of prostaglandin synthetism. J Biol Chem 1976; 251:7329–7335. 70. Myers SI, Horton JW, Hernandez R, et al. Pentoxifylline protects splanchnic prostacyclin synthesis during mesenteric ischemia/reperfusion. Prostaglandins 1994; 47:137–150. 71. Itoh M, Guth PH. Role of oxygen-derived free radicals in hemorrhagic shock-induced gastric lesions in the rat. Gastroenterology 1985; 88(5):1162–1167. 72. Waxman K, Holness R, Tominaga G, et al. Pentoxifylline improves tissue oxygenation after hemorrhagic shock. Surgery 1987; 102:358–361. 73. Coccia MT, Waxman K, Soliman MH, et al. Pentoxifylline improves survival following hemorrhagic shock. Crit Care Med 1989; 17(1):36–38. 74. Waxman K, Clark L, Soliman MH, et al. Pentoxifylline in resuscitation of experimental hemorrhagic shock. Crit Care Med 1991; 19(5):728–731. 75. Flynn WJ, Cryer G, Garrison RN. Pentoxifylline but not saralasin restores hepatic blood flow after resuscitation from hemorrhagic shock. J Surg Res 1991; 50(6):616–621. 76. Currie MS, Murali K, Rao K, et al. Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, degranulation, and superoxide production. J Leuk Biol 1990; 47(3):244–250. 77. Bessler H, Gilgal R, Djaldetti M, et al. Effect of pentoxifylline on the phagocytic activity, CAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells. J Leuk Biol 1986; 40(6):747–754. 78. Hammerschmidt DE, Kotasek D, McCarthy T, et al. Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor. J Lab Clin Med 1988; 112(2):254–263. 79. Armstrong M Jr, Needham D, Hatchell DL, Nunn RS. Effect of pentoxifylline on the flow of polymorphonuclear leukocytes through a model capillary. Angiology 1990; 41(4): 253–262. 80. Sullivan GW, Carper HT, Novick WJ, et al. Inhibition of the inflammatory action of inteleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immun 1988; 56(7):1722–1729. 81. Granger DN, Hollwarth ME, Parks DA. Ischemia-reperfusion injury: role of oxygen-derived free radicals. Acta Physiol Scand 1986; 548:47–63. 82. Myers SI, Turnage RH. The role of eicosanoids and gut ischemia in distant organ dysfunction. In: Williams JG, ed. Multiple Organ Dysfunction Syndrome: Examining the Role of Eicosanoids and Procoagulants. RG Landes Co., 1996. 83. Zimmerman BJ, Grisham MB, Granger DN. Mechanisms of oxidant-mediated microvascular injury following reperfusion of the ischemic intestine. Basic Life Sci 1986; 49:881–886. 84. Fridovich I. The biology of oxygen radicals. Science 1978; 201:875–880. 85. Jackson J, Schraufstatter IU, Hyslop PA, et al. Role of oxidants in DAN damage: hydroxyl radical mediates the synergistic DNA damaging effects of asbestos and cigarette smoke. J Clin Invest 1987; 80:1090–1095. 86. Hyslop PA, Hinshaw DB, Halsey WA Jr, et al. Mechanisms of oxidant mediated cell injury: the glycolytic and mitochondrial

medwedi.ru

410

87.

88.

89.

90.

91.

92.

93.

94. 95.

96.

97.

98.

99. 100.

101.

102.

103.

104.

105.

106.

107.

Part Two: The Alimentary Tract—Small and Large Intestine pathways of ADP phosphorylation are major intracellular targets inactivated by hydrogen peroxide. J Biol Chem 1988; 263:1665–1675. Hyslop PA, Hinshaw DB, Schraufstatter IU, Sklar LA, Spragg RG, Cochrane CG. Intracellular calcium homeostasis during hydrogen peroxide injury to cultured P388D1 cells. J Cell Physiol 1986; 129:356–366. Zweier JL, Kuppusamy P, Lutty GA. Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues. Proc Natl Acad Sci 1992; 85:4046–4050. Suzuki M, Inauen W, Kvietys PR, et al. Superoxide mediates reperfusion-induced leukocyte-endothelial cell interactions. Am J Physiol 1989; 257:H1740–H1745. Zimmerman BJ, Grisham MB, Granger DN. Role of oxidants in ischemia/reperfusion-induced granulocyte infiltration. Am J Physiol 1990; 258:G185–G190. Lewis MS, Whatley RE, Cain P, Mclntyre TM, Prescott SM, Zimmerman GA. Hydrogen peroxide stimulates the synthesis of platelet activating factor by endothelium and induces endothelial cell-dependent neutrophil adhesion. J Clin Invest 1988; 82:2045–2055. Shingu M, Nonaka S, Nishimukai H, Nobunaga M, Kitamura H, Tomo-Oka K. Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils. Clin Exp Immunol 1992; 90:72–78. Turnage RH, Magee JC, Guice KS, Myers SI, Oldham KT. Complement activation by the hydroxyl radical during intestinal reperfusion. Shock 1994; 2:445–450. Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol 1992; 262:H611–H615. Kurose I, Kubes P, Wolf R, et al. Inhibition of nitric oxide production: mechanisms of vascular albumin leakage. Circ Res 1993; 73:164–171. Kurtel H, Fujimoto K, Zimmerman BJ, Granger DN, Tso P. Ischemia-reperfusion-induced mucosal dysfunction: role of neutrophils. Am J Physiol 1991; 261:G490–G496. Schmid-Schonbein G. Capillary plugging by granulocytes and the no-reflow phenomenon in the microcirculation. Federation Proc 1987; 46:2397–2401. Grisham MB, Hernandez LA, Granger DN. Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 1886; 251:G567–G574. Granger DN, Rutili G, McCord JM. Superoxide radicals in feline intestinal ischemia. Gastroenterology 1981; 81:22–29. Hill J, Lindsay TF, Ortiz F, Yeh CG, Hechtman HB, Moore FD Jr. Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat. J Immun 1992; 149:1723–1728. Lindsay TF, Hill J, Ortiz F, Rudolph A, Valeri CR, Hechtman HB, Moore FD Jr. Blockade of complement activation prevents local and pulmonary albumin leak after lower torso ischemiareperfusion. Ann Surg 1992; 216:677–682. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991; 88:4651–4655. Oldham KT, Guice KS, Turnage RH, et al. The systemic consequences of intestinal ischemia/reperfusion injury. J Vasc Surg 1993; 93:136–137. Schmeling DJ, Caty MG, Oldham KT, et al. Evidence for neutrophil-related acute lung injury after intestinal ischemia-reperfusion. Surgery 1989; 106:195–202. Poggetti RS, Moore FA, Moore EE, et al. Liver injury is reversible neutrophil-mediated event Mowing ischemia. Arch Surg 1992; 127:175–179. Kadeky KM, Turnage RH, Rogers TE, Inman L, Myers SI. In vitro evidence of neutrophil mediated lung injury after intestinal reperfusion. Shock 1995; 4:102–106. Diamond SM, Emmett M, Henrich WL. Bowel infarction as a cause of death in dialysis patients. JAMA 1986; 256: 2545–2547.

108. Valentine RJ, Whelan, TV, Meyers HF. Nonocclusive mesenteric ischemia in renal patients recognition and prevention of intestinal gangrene. Am J Kidney Dis 1990; 15:598–600. 109. Gaussorgues P, Gueugniaud PY, Vedrinne JM, Salord F, Mercatello A, Robert D. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med 1988; 4:575–577. 110. Hebra A, Brown MF, Hirschl RB, McGeehin K, O’Neill JA, Norwood WI, Ross AJ. Mesenteric ischemia in hypoplastic left heart syndrome. J Pediatr Surg 1993; 28:606–611. 111. Reilly PM, MacGowan S, Miyachi M, Schiller HJ, Vickers S, Bulkely GB. Mesenteric vasoconstriction in cardiogenic shock in pigs. Gastroenterology 1992; 102:1968–1979. 112. Reilly RM, Bulkely GB. Vasoactive mediators and splanchnic perfusion. Crit Care Med 1993; 21:555–568. 113. Pettei MJ, Levy J, Abramson S. Nonocclusive mesenteric ischemia associated with propranolol overdose: implications regarding splanchnic circulation. J Pediatr Gastroenterol Nutr 1990; 10:544–547. 114. Longhurst JC, Ross J. Extracardiac and coronary vascular effects of digitalis. J Am Col Cardiol 1985; 5:99A–105A. 115. Gasic S, Korn A, Eichler HG. Diltiazem counteracts digitalisdependent splanchnic vasoconstriction in man. Int J Clin Pharm Ther Toxicol 1987; 25:553–557. 116. Rego A, Vargas R, Suarez KR, Foegh ML, Ramwell PW. Mechanism of cyclosporinpotentiation of vasoconstriction of the isolated rat mesenteric arterial bed: role of extracelluar calcium. J Pharm Exp Ther 1990; 254:799–808. 117. Lamar W, Woodward L, Statland B. Clinical implications of creatine kinase BB isoenzyme [letter]. N Engl J Med 1978; 299:234. 118. Graeber G et al. Elevations of serum creatine phosphokinase in experimental mesenteric infarction. Surg Forum 1980; 31:148. 119. Graeber G et al. Changes in serum total creatine phosphokinase (CPK) and its isoenzymes caused by experimental ligation of the superior mesenteric artery. Am J Surg 1981; 193:499. 120. Doran G. Appearance of creatinine kinase BB isoenzyme in the serum of a patient suffering from infarction of the colon. Clin Chim Acta 1979; 92:415. 121. Jenson C, Smith G. A clinical study of 51 cases of mesenteric infarction. Surgery 1956; 40:930. 122. Ottinger L, Austen G. A study of 136 patients with mesenteric infarction. Surg Gynecol Obstet 1967; 124:251. 123. Brooks D, Carey L. Base deficit in superior mesenteric artery occlusion: an aid to early diagnosis. Ann Surg 1973; 177:352. 124. Kosloske A, Goldthorn J. Paracentesis as an aid to the diagnosis of intestinal gangrene: experience in 50 infants and children. Arch Surg 1982; 117:571. 125. Montgomery A et al. Intramucosal pH measurement with tonometers for detecting gastrointestinal ischemia in porcine hemorrhagic shock. Circ Shock 1989; 29:319. 126. Poole J, Sammartano R, Boley S. The use of tonometry in the early diagnosis of mesenteric ischemia. Curr Surg 1987; 44:21. 127. Maynard N et al. Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. JAMA 1993; 270:1203. 128. Klein HM, Lensing R, Klosterhalfen B, et al. Diagnostic imaging of mesenteric infarction. Radiology 1995; 197:79–92. 129. Smerud MJ, Johnson CD, Stephens DH. Diagnosis of bowel infarction: a comparison of plain films and CT scans in 23 cases. Am J Roentgenol 1990; 154:99–103. 130. Kaufman SL, Siegelman SS.Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1582. 131. Liebman PR et al. Hepatic-portal venous gas in adults: etiology, pathophysiology and clinical significance. Ann Surg 1978; 187:281. 132. Kaleya RN, Sammartano RJ, Boley SJ. Aggressive approach to mesenteric ischemia. Surg Clin North Am 1992; 72:157–181. 133. Feisher AC, Muhletaler CA, James AE. Sonographic assessment of the bowel wall. Am J Roentgenol 1981; 136:887–891.

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed 134. Kim A, Kwon H. Evaluation of suspected mesenteric ischemia. Efficacy of radiologic studies. Radiol Clin N Am 2003; 41:327–342. 135. Moneta GL, Yeager RA, Dalman R, et al. Duplex ultrasound criteria for diagnosis of splanchnic artery stenosis or occlusion. J Vasc Surg 1991; 14:511–520. 136. Moneta GL. Screening for mesenteric vascular insufficiency and follow-up of mesenteric artery bypass procedures. Semin Vasc Surg 2001; 14:186–192. 137. Roobottom CA, Dubbins PA. Significant disease of the celiac and mesenteric arteries in asymptomatic patients: predictive value of Doppler sonography. Am J Roentgenol 1993; 161: 985–988. 138. Kaufman SL, Siegelman SS. Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1577. 139. Kaufman SL, Siegelman SS. Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1578. 140. Kaufman SL, Siegelman SS. Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1579. 141. Simo G, Echenagusia AJ, Camunez F, Turegano F, Cabrera A, Urbano J. Superior mesenteric arterial embolism:local fibrinolytic treatment with Urokinase. Radiology 1997; 204(3): 775–779. 142. Joffe N, Goldman H, Antonioli DA. Barium studies in small bowel infarction. Radiology 1977; 123:303–309. 143. Iida M, Matsui T, Fuchigami T. Ischemic colitis: serial changes in double contrast barium enema examinations. Radiology 1986; 159(2):337–341. 144. Wittenberg J et al. Ischemic colitis: radiology and pathophysiology. Am J Roentgenol 1975; 123:287. 145. Taourel PG, Deneuville M, Pradel JA, et al. Acute mesenteric ischemia: diagnosis with contrast-enhanced CT. Radiology 1996; 199:632–636. 146. Rydberg J, Buckwalter KA, Caldemeyer, KS, et al. Multisection CT: scanning techniques and clinical applications. Radiographics 2000; 20(6):1787–1806. 147. Kirpatrick IDC, Kroeker MA, Greenberg HM. Biphasic CT with mesenteric CT angiography in the evaluation of acute mesenteric ischemia: initial experience. Radiology 2003; 92:91–98. 148. Brandt LJ, Boley SJ. Intestinal ischemia. In: Feldman M, Friedman LS, Sleisenger MH, eds. Gastrointestinal and Liver Disease. 7th ed. Philadelphia: Saunders, 2002:2325. 149. Hagspiel KD, Leung DA, Angle F, et al. MR angiography of the mesenteric vasculature. Radiol Clin North Am 2002; 40:867–886. 150. O’Donnell JA, Hobson RW. Operative confirmation of Doppler ultrasound in evaluation of intestinal viability. Surgery 1980; 87(1):109–112. 151. Wright GB, Hobson RW. Prediction of intestinal viability using Doppler ultrasound techniques. Am J Surg 1975; 129(6): 642–654. 152. Shah SD, Andersen CA. Prediction of small bowel viability using Doppler ultrasound. Ann Surg 1981; 194(1):97–99. 153. Redaelli CA, Schilling MK, Buchler MW. Intraoperative laser Doppler flowmetry: a predictor of ischemic injury in acute mesenteric infarction. Dig Surg 1998; 15(1):55–59. 154. Cooperman M, Martin EW, Carey LC. Evaluation of ischemic intestine by Doppler ultrasound. Am J Surg 1980; 139(1): 73–77. 155. Mann A, Fazio VW, Lucas FV. A comparative study of the use of fluorescein and the Doppler device in the determination of intestinal viability. Surg Gynecol Obstet 1982; 154(1): 53–55. 156. La Piana FG, Penner R. Anaphylactoid reaction to intravenously administered fluorescein. Arch Ophthalmol 1968; 79(2):161–162. 157. Marguggi RA, Greenspan M. Reliable intraoperative prediction of intestinal viability using a fluorescent indicator. Surg Gynecol Obstet 1981; 152(1):33–35.

411

158. Bulkley GB et al. Intraoperative determination of small intestinal viability following ischemic injury. Ann Surg 1981; 193(5):628–637. 159. Bergan JJ et al. Revascularization in treatment of mesenteric infarction. Ann Surg 1975; 187(4):430–438. 160. Endean ED, Barnes SL, Kwolek CJ, Minion DJ, Schwarcz TH, Mentzer RM Jr. Surgical management of thrombotic intestinal ischemia. Ann Surg 2001; 223(6):801–808. 161. Mansour MA. Management of Acute mesenteric ischemia. Arch Surg 1999; 134:328–330. 162. Tendler DA. Acute intestinal ischemia and infarction. Semin Gastrointest Dis 2003; 14(2):66–76. 163. Park WM, Gloviczki P, Cherry KJ, et al. Contemporary management of acute mesenteric ischemia: factors associated with survival. J Vasc Surg 2002; 35(3):445–452. 164. Williams LF. Vascular insufficiency of the intestines. Gastroenterology 1971; 61(5):757–777. 165. Crawford ES et al. Celiac axis, superior mesenteric artery, and inferior mesenteric arterial occlusion: surgical considerations. Surgery 1977; 82(6):856–866. 166. Derrick JR, Pollard HS, Moore RM. The pattern of arteriosclerotic narrowing of the celiac and superior mesenteric arteries. Ann Surg 1966; 164:1085–1088. 167. Reiner L, Rodriguez FL, Jimenez FA, Platt R. Injection studies on mesenteric arterial circulation. III. Occlusions without intestinal infarction. Arch Pathol 1962; 73:461–472. 168. Fry WJ, Child CG. Ninety-five percent distal pancreatectomy for chronic pancreatitis. Ann Surg 1965; 162:543–549. 169. Rogers DM et al. Mesenteric vascular problems: a 26 year experience. Ann Surg 1982; 195(5):554–565. 170. Johnson WC, Nasbeth DC. Visceral infarction following aortic surgery. Ann Surg 1974; 180(3):312–318. 171. Brewster DC, Franklin DP, Cambria RP. et al. Intestinal ischemia complicating abdominal aortic surgery. Surgery 1991; 109(4):447–454. 172. Redaelli CA, Carrel T, et al. Intestinal ischemia following replacement of the infrarenal aorta and aorto-iliac bifurcation. Helv Chir Acta 1992; 58(4):589–594. 173. Siddharth P, Smith NL. An anatomic basis to prevent ischemia of the colon during operations upon the aorta. Surg Gynecol Obstet 1981; 153(1):71–73. 174. Kountz SL, Taub DR, Connolly JE. Aortoiliac steal syndrome. Arch Surg 1966; 92(4):490–497. 175. Ernst CB et al. Inferior mesenteric artery stump pressure. Ann Surg 1978; 187(6):1–6. 176. Fogarty TJ, Fletcher WS. Genesis of nonocclusive mesenteric ischemia. Ann Surg 1961(6):239–252. 177. Abdu RA, Zakhour BJ, Dallis DJ. Mesenteric venous thrombosis-1911 to 1984. Surgery 1987; 101(4):383–388. 178. Khodadadi J et al. Mesenteric venous thrombosis: the importance of a second look operation. Arch Surg 1980; 115(3):315– 317. 179. Sack J, Aldret JS. Primary mesenteric venous thrombosis. Surg Gynecol Obstet 1982; 154:205. 180. Morris GC, Crawford ES, Cooley DA, DeBakey ME. Revascularization of the celiac and superior mesenteric arteries. Arch Surg 1962; 84:95–107. 181. Stoney RJ, Cunningham CG. Acute mesenteric ischemia. Surgery 1993; 114(3):489–490. 182. Rob C. Surgical diseases of the celiac and mesenteric arteries. Arch Surg 1966; 93(1):21–32. 183. Shaw RS, Rutledge RH. Superior mesenteric artery embolectomy in the treatment of massive mesenteric infarction. N Engl J Med 1957; 257(13):595–598. 184. Becker GH, Katzen BT, Dake MD. Noncoronary angioplasty. Radiology 1989; 170:921–940. 185. Schnitzler F. Zur Symptomatik des Darmarterienverschlusses. Wien Med Wschr 1901; 12:506. 186. Warburg E. Uber Dysragia intermittens angiosclerotica intestinalis. Munchen Med Wschr 1905; 52:1174. 187. Klein E. Embolism and thrombosis of the superior mesenteric artery. Surg Gynec Obstec 1921; 33:385–405.

medwedi.ru

412

Part Two: The Alimentary Tract—Small and Large Intestine

188. Dunphy JE. Abdominal pain of vascular origin. Am J Med Sci 1936; 192:109–113. 189. Stoney RJ, Meacham PW. Chronic intestinal ischemia caused by visceral atherosclerosis. In: Cameron JL, ed. Current Surgical Therapy. St. Louis: Mosby, 1984:1984–1985. 190. Moawad J, Gewertz BL. Chronic mesenteric ischemia. Clinical presentation and diagnosis. Surg Clin North Am 1997; 77: 357–369. 191. Cho J, Carr JA, Jacobsen G, Shepard AD, Nypaver TJ, Reddy DJ. Long-term outcome after mesenteric artery reconstruction: A 37 year experience. J Vasc Surg 2002; 35(3): 453–460. 192. Gluecklich B et al. Chronic mesenteric ischemia masquerading as cancer. Surg Gynecol Obstet 1979; 148(1):49–56. 193. Dunbar JD, Molnar W, Berman FF, Marble SA. Comparison of the celiac trunk and abdominal angina. Am J Roentgenol 1965; 95:731–744. 194. Rob C. Diseases of the celiac and mesenteric arteries. Surg Gynec Obstret 1967; 124:118–119. 195. Drapanas T, Bron KM. Stenosis of the celiac artery. Ann Surg 1966; 164:1085–1088. 196. Woodburne RT, Olsen LL. The arteries of the pancreas. Anal Rec 1951; 111:255–270. 197. Cognet F, Ben Sale D, Dranssart M, et al. Chronic mesenteric ischemia: imaging and percutaneous treatment. Radiographics 2002; 22:863–879. 198. Moneta GL, Lee RW, Yeager RA, Taylor LM, Porter JM. Mesenteric duplex scanning: a blinded prospective study. J Vasc Surg 1993; 17:79–84. 199. Perko MJ. Duplex ultrasound for assessment of superior mesenteric artery blood flow. Eur J Vasc Endovasc Surg 2001; 21:106–117. 200. Zwolak RM, Fillinger MF, Walsh DB, et al. Mesenteric and celiac duplex scanning: a validation study. J Vasc Surg 1998; 27:1078–1087. 201. Gentile AT, Moneta GL, Lee RW, Masser PA, Taylor LM, Porter JM. Usefulness of fasting and postprandial duplex ultrasound examinations for predicting high-grade superior mesenteric artery stenosis. Am J Surg 1995; 169:476–479. 202. Carlos RC, Stanley JC, Stafford-Johnson D, Prince MR. Interoberver variability in the evaluation of chronic mesenteric ischemia with gadolinium-enhanced MR angiography. Acad Radiol 2001; 8(9):879–887. 203. Shirkhoda A, Konez O, Shetty AN, Bis KG, Elwood RA, Kirsh MJ. Contrast-enhanced MR angiography of me mesenteric circulation: a pictorial essay. Radiographics 1998; 18: 851–861. 204. Gilfeather M, Holland GA, Siegelman ES, et al. Gadoliniumenhanced ultrafast three-dimensional spoiled gradientecho MR imaging of the abdominal aorta and visceral and iliac vessels. Radiographics 1997; 17:423–432. 205. Ernst O, Asnar V, Sergent G, et al. Comparing contrastenhanced breath hold MR angiography and conventional angiography in the evaluation of mesenteric circulation. Am J Roentgenol 2000; 174:433–439. 206. Meaney JF, Prince MR, Nostrant TT, Stanley JC. Gadoliniumenhanced MR angiography of visceral arteries in patients with suspected chronic mesenteric ischemia. J Magn Reson Imaging 1997; 7:171–176. 207. Cikrit DF, Harris VJ, Hernmer CG, et al. Comparison of spiral CT scan and arteriography for evaluation of renal and visceral arteries. Ann Vasc Surg 1996; 10:109–116. 208. Horton KM, Fishman EK. 3D CT angiography of the celiac and superior mesenteric artyeries with multidetector CT data sets: preliminary observations. Abdom Imaging 2000; 25:523–525. 209. Konen E, Amitai M, Apter S, et al. CT angiography of superior mesenteric artery syndrome. Am J Roentgenol 1998; 171: 1279–1281. 210. Kaufman SL, Siegelman SS. Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1570.

211. McShane MD, Proctor A, Spencer P, Cumberlane DC, Welsh CL. Mesenteric angiography for chronic intestinal ischemia. Eur J Vasc Surg 1992; 6:333–336. 212. Tytle TL, Prati RC. Percuataneous recanalization in chronic occlusion of the superior mesenteric artery. J Vasc Interv Radiol 1995; 6:133–136. 213. Maleux G, Wilms G, Stockx L, Vancleemput J, Baert AL. Percutaneous recanalization and stent placement in chronic proximal superior mesenteric artery occlusion. Eur Radiol 1997; 7:1228–1230. 214. Sheeran S, Murphy T, Khioaja A, Sussinan S, Hallisey M. Stent placement for treatment of mesenteric artery stenoses or occlusions. J Vasc Radiol 1999; 10:861–867. 215. Waybill PN, Enea NA. Use of a Palmaz stent deployed in the superior mesenteric artery for chronic mesenteric ischemia. J Vasc Interv Radiol 1997; 8:1069–1071. 216. Stoney RJ, Ehrenfeld WK, Wylie EJ. Revascularization methods in chronic visceral ischemia caused by atherosclerosis. Ann Surg 1977; 186:468–476. 217. Cunningham CG, Reilly LM, Rapp JH, Schneider PA, Stoney RJ. Chronic visceral ischemia. Three decades of progress. Ann Surg 1991; 214:276–287. 218. Rapp JH, Reilly LM, Qvarfordt PG, Goldstone J, Ehrenfeld WK, Stoney RJ. Durability of endarterectomy and antegrade grafts in the treatment of chroniuc visceral ischemia. J Vasc Surg 1986; 3:799–806. 219. Johnston KW, Lindsay TF, Walker PM, Kalman PG. Mesenteric arterial bypass grafts: early and late results and suggested surgical approach for chroniuc and acute mesenteric ischemia. Surgery 1995; 118:1–7. 220. Mateo RB, O’Hara PJ, Hertzer NR, Mascba EJ, Beven EG, Krajewski LP. Elective surgical treatment of symptomatic chronic mesenteric occlusive disease: early results and late outcomes. J Vasc Surg 1999; 29:821–832. 221. Moawad J, McKinsey JF, Wyble CW, Bassiouny HS, Schwartz LB, Gewertz BL. Current results of surgical therapy for chroniuc mesenteric ischemia. Arch Surg 1997; 132:613–619. 222. Feliciano DM, Burch JM, Graham JM. Abdominal Vascular Injury. In Mattox KL, Moore EE, Felicano DV, eds. Trauma. Norwalk, CT: Appleton and Lange, 1988:519–536. 223. Feliciano DM, Burch JM, Spjut-Patrinely V, Mattox KL, Jordan GL Jr. Abdominal gunshot wouinds. An Urban center’s experience with 300 consecutive patients. Ann Surg 1988; 208:362–370. 224. Asensio JA et al. Abdominal vascular injuries to the aorta. Surg Clin Noth Am 2001; 81(6):1395–1416. 225. Asensio JA et al. Operative management and outcome of 302 abdominal vascular injuries. Am J Surg 2000; 180(6):528–533. 226. Harjola PT. A rare obstruction of the celiac axis. Ann Chir Gynaecol Fenn 1963; 52:547–550. 227. Bech F, Loessberg A, Rosenblum J, Glagov S, Gewertz BL. Median arcuate ligament compression syndrome in monozygotic twins. J Vasc Surg 1994; 19(5):934–938. 228. Brandt LJ, Boley SJ. Celiac axis compression syndrome: a critical review. Dig Dis 1978; 23:633. 229. Kaufman SL, Siegelman SS. Visceral ischemic syndromes. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1571. 230. Wylie EJ, Stoney RJ, Ehrenfeld WK, Effeney DJ. Visceral artery compression syndromes. In: Wylie EJ, Stoney RJ, Ehrenfeld WK, Effeney DJ, eds. Manual of Vascular Surgery. SpringerVerlag, 1986:212. 231. Levin DC, Baltaxe HA. High incidence of celiac axis narrowing in asymptomatic individuals. Am J Roentgenol 1972; 46:426. 232. Evans WE. Long-term evaluation of the celiac band syndrome. Surgery 1974; 76(6):867–871. 233. Plate G, Eklof B, Vang J. The celiac compression syndrome: myth or reality? Acta Chir Scand 1981; 147:201–203. 234. Stanley JC, Fry WJ. Median arcuate ligament syndrome. Arch Surg 1971; 103(2):252–258. 235. Wilkie DPD. Chronic duodenal ileus. Am J Med Sci 1927; 173:643.

Chapter 17: Circulation and Vascular Disorders of the Splanchnic Vascular Bed 236. Akin JT, Gray SW, Skandalakis JE. Vascular compression of the duodenum: presentations of ten cases and review of the literature. Surgery 1976; 79(5):515–522. 237. Pentlow BD, Dent RG. Acute vascular compression of the duodenum in anorexia nervosa. Br J Surg 1981; 68(9): 665–666. 238. Price P, Clark CG. Wilkie’s syndrome. J R Coll Surg Edinb 1979; 24(5):280–281. 239. Ha HK, Lee SH, Rha SE, et al. Radiologic features of vasculitis involving the gastrointestinal tract. Radiographics 2000; 20: 779–794. 240. Hagspiel KD, Angle JF, Spinosa DJ, Matsumoto AH. Case 13: polyarteritis nodosa-systematic necrotizing vasculitis with involvement of hepatic and superior mesenteric arteries. Radiology 1999; 212:359–364. 241. Aglaki EA. Gastrointestinal manifestations of rheumatologic disorders. Shiraz-E Med J 2003; 3:1–23. 242. Castaneda-Zuniga WR, Amplatz K. Buerger’s disease. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1554. 243. Castaneda-Zuniga WR, Amplatz K. Buerger’s disease. In: Tepleck JG, Haskin ME, eds. Surgical Radiology. WB Saunders Co., 1981:1555. 244. Buerger L. Thromboangiitis obliterans: a story of the vascular lesions leading to presenile spontaneous gangrene. Am J Med Sci 1908; 136:567. 245. Deitch EA, Sikkema WW. Intestinal manifestations of Buerger’s disease. Am J Surg 1981; 47:326. 246. Broide E, Scapa E, Peer A, Abramowich D, Eshchar J. Buerger’s disease presenting as acute small bowel ischemia. Gastroenterology 1993; 104(4):1192–1195. 247. Myers SI, Clagett GP, Valentine ME, Anand A, Chervu A. Chronic intestinal ischemia caused by intravenous cocaine use: report of two cases and review of the literature. J Vasc Surg 1996; 23:724–729.

413

248. Sudhakar CB, Al-Hakeem M, MacArthur JD, Sumpio BE. Mesenteric ischemia secondary to cocaine abuse: case reports and literature review. Am J Gastroenterol 1997; 92(6):1053–1054. 249. Osorio J, Farreras N, Ortiz DZ, Bachs E. Cocaine-induced mesenteric ischemia. Dig Surg 2000; 17(6):648–651. 250. Hoang MP, Lee EL, Anand A. Histologic spectrum of arterial and arteriolar lesions in acute and chronic cocaine-induced mesenteric ischemia: report of three cases and literature review. Am J Path 1998; 22(11):1404–1410. 251. Stewart D, Inaba J, Lucassen M, Kalow W. Cocaine metabolism: cocaine and norcocaine hydrolysis by liver and serum esterases. Clin Pharmacol Ther 1979; 25:464–468. 252. Dixon SD, Bejar R. Echoencephalographic findings in neonates associated with maternal cocaine and methamphetamine use: incidence and clinical correlates. J Pediatr 1989; 115:770–778. 253. Lipshultz SE, Frassica JJ, Orav EJ. Cardiovascular abnormalities in infants prenatally exposed to cocaine. J Pediatr 1991; 118:44–51. 254. Dominquez R, Vila-Coro AA, Slopis JM, Bohan TP. Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child 1991; 145: 688–695. 255. Rosenak D, Diamant YZ, Yaffe H, Hornstein E. Cocaine: maternal use during pregnancy and its effect on the mother, the fetus, and the infant. Obstet Gynecol Surv 1990; 45:348–359. 256. Endress C, King GA. Cocaine-induced small bowel perforation [letter]. Am J Roentgenol 1990; 154:1346–1347. 257. Lee HS, Lamaute HR, Pizzi WF, Piccard DL, Luks FL. Acute gastroduodenal perforations associated with the use of crack. Ann Surg 1990; 211:15–17. 258. Hall TR, Zaninovic A, Lewin D, Barret C, Boechat MI. Neonatal intestinal ischemia with bowel perforation: an in utero complication of maternal cocaine abuse. Am J Roentgenol 1992; 158:1303–1304.

medwedi.ru

18 Inflammatory Disorders of the Small Bowel and Colon Douglas J. Turner and Barbara L. Bass

INTRODUCTION The intestinal tract is the site of a number of inflammatory disorders that vary considerably in underlying pathogenesis, pattern of presentation, and severity. This chapter summarizes the more important inflammatory processes involving the small bowel and colon, emphasizing the underlying physiologic dysfunction associated with each, and the means by which physiologic function may be restored or improved through surgical intervention.

pathogenesis of CD, the NOD variants seem to account for less than 20% of all cases. The evidence of a genetic predisposition is less strong for UC than for CD. However, there is evidence of association with some DR2 alleles of the human leukocyte antigen region as well as some areas on chromosomes 3, 7, and 12. Specific genetic factors also impact on the severity of the disease in UC, as well as its response to steroids and its extraintestinal manifestations (4,5).

Infection INFLAMMATORY BOWEL DISEASE Inflammatory bowel disease (IBD) encompasses a broad spectrum of idiopathic relapsing inflammatory conditions affecting the intestinal tract; the two most common are Crohn’s disease (CD) and ulcerative colitis (UC). The prevalence for each of these conditions ranges from 5 to 100 cases/100,000 population. The incidence of CD is gradually increasing, whereas that of UC has been stable over the last three decades. Both of these diseases show a bimodal peak in the age of onset, with peaks in the third and seventh decades of life. Despite substantial expansion of our understanding of these conditions over the past 20 years, the exact pathogenesis of these entities remains uncertain.

Pathogenesis Genetics A role of genetic predisposition in IBD is supported by heritable patterns of disease. Genetic factors appear to be more important in CD than UC. Monozygotic twins are more likely to have IBD than dizygotic twins, and about 15% of all IBD patients have a first degree relative with confirmed diagnosis of IBD. Epidemiological studies of race and ethnicity have shown certain populations (e.g., Ashkenazic Jews and whites) to have high prevalence rates of IBD. Environmental factors are clearly operative as well, as demonstrated by the decreased risk of developing IBD after immigration to different countries. Recently, a specific genetic susceptibility locus has been mapped for CD to the IBD1 site on chromosome 16 (1). Further, recent genome scans of affected pairs have yielded multiple areas on several chromosomes (6, 12, and 14 among others) that are possible loci for disease association (2). One relevant gene, the NOD2 gene, has been described in association with CD (3), and appears to encode for a protein that both associates with bacterial lipopolysaccharide and is involved in apoptotic cell death (1). Although this protein appears to play a major role in the

Because of the clinical and pathologic similarities to chronic dysentery, infectious agents have been suspected in IBD since the earliest reports. There is frequently a temporal relationship between the onset of IBD and antecedent enteric infection. There are also striking similarities in histologic appearance between CD and tuberculus enteritis, as noted initially by Crohn when describing the disease in 1932 (6). Accordingly, Mycobacterium paratuberculosis has been the object of much recent interest as a causative agent. This agent has been cultured from several patients with CD, and some CD patients have antibody titers against mycobacterial antigens (7,8). DNA polymerase chain reaction studies have identified mycobacterial antigens in intestinal mucosa; however it has not been found to be specific for CD (7). An alternative hypothesis, prompted by the discovery of viral antigens in the mucosa of CD patients, suggests that chronic measles (paramyxovirus) infection may lead to a chronic vasculitis that leads to repeated mucosal injury (9). This has not been confirmed by other investigators, as has been the case with myriad other pathogenic microbes that have been proposed as etiologic agents of IBD. Clinical experience argues against infection per se, as IBD does not respond to antibiotic therapy (except for management of infections complications), whereas it does improve with immunosuppressive medications. However, intestinal microflora may be a factor in IBD either through an, as yet, undiscovered pathogen or also through antigenic stimuli. Certain bacterial proteins have shown cross-reactivity with host proteins, suggesting that this mimicry may induce an autoimmune response (10). In experimental models, administration of bacterial products has also been shown to initiate colitis. The amelioration of IBD activity following diversion of the fecal stream may be due, in part, to the removal of bacterial infections or antigenic stimuli (11).

Host Defenses A number of immunologic abnormalities have been detected in IBD (Table 1) (12). The number of factors, the multiple effects ascribed to each, and the counter-regulatory relationships that exist among them make isolating a single

medwedi.ru 415

416

Part Two: The Alimentary Tract—Small and Large Intestine

Table 1 Immunologic Abnormalities in IBD Factors increased Serum IgA1 Mucosal IgG, IgG:IgA ratio pANCA (UC) Major histocompatibility complex class II antigen expression by enterocytes Mucosal IL-1, IL-6, IL-8 Serum IL-2, IL-6, IL-10 Soluble IL-2 receptor Mucosal CD8þ (cytotoxic) T-cells TNF-a CD14þ macrophages CD44v3 and v6 colonocyte surface antigen (UC) Mucosal substance P (UC) LP T-cell response to IL-2 LP T-cells (CD) Mucosal PGE2 and LTB4 Serum intercellular adhesion molecule-1 Tropomyosin Mucosal permeability (CD) IL-2 receptor Transferrin receptor 4F2 antigen

Factors decreased Dimeric, secretory IgA T-cell response to IL-2 Mucosal IL-2, IL-4, interferon-g Monocyte IL-4 responsiveness Mucosal mucin (UC) Mucosal CD4þ (helper) T-cells Mucosal vasoactive intestinal peptide (UC) Mucosal substance P (CD)

Abbreviations: IBD, inflammatory bowel disease; Ig, immunoglobin; IL, interleukin; LP, lamina propria; pANCA, perinuclear antineutrophil cytoplasmic antibody; PGE2, prostaglandin E2; LTB4, leukotrieae B4; UC, ulcerative colitis; CD, Crohn’s disease; TNF, tumor necrosis factor.

element as the causative factor in IBD a daunting task. Indeed, the vast number of irregularities identified, to date, is not unexpected for IBD, but rather predictable given the ongoing inflammation characteristic of IBD. Nevertheless, a number of factors suggest a central role for the mucosal immune system in IBD pathophysiology. In UC, enterocytes have been shown to inappropriately express class II major histocompatibility antigens that regulate T-cell activity. Recent attention in UC has focused on autoantibodies targeted against a 40 kDa antigen on the colonic epithelial cells, which appears to be related to tropomyosin, as well as against perinuclear antineutrophil cytoplasmic antibody (pANCA) (10). In some reports, as many as 70% of patients with UC express pANCAs (13). Although evidence confirming a specific role for pANCA has not been found, it has recently allowed identification of a subgroup of CD patients who demonstrate increased colonic disease activity (14), as well as a subgroup of UC patients more likely to demonstrate biliary manifestations of IBD (13). Cross-reactivity with pANCA has allowed the identification of ocular and biliary antigens that may play a role in extraintestinal manifestations of IBD (15). CD has repeatedly been shown to be associated with proliferation of helper T-cells (8). Both UC and CD show increased expression of B-cells, T-cells, and several cytokines as shown in Table 1. One clear mediator in human CD is tumor necrosis factor (TNF)-a, and several clinical trials have demonstrated chimeric anti–TNF-a to be an effective agent, leading to its use in the clinical setting (16).

Dietary and Environmental Factors Diet has been implicated as a possible etiologic factor because of its importance in determining the local environment of

the gastrointestinal tract. The ‘‘Western’’ diet (or its deficiencies) is also implicated, due to the striking increase of IBD seen in the Western industrialized world. No specific food item including caffeine, cow’s milk, eggs, refined sugars, and wheat, among the many suspected, has been proven responsible. Psychological factors inducing stress and depression have been shown to associate with IBD (17). Of the many environmental factors proposed to play a role, only tobacco has proved significant. Smoking appears to have a protective effect on UC, while it appears to serve as a risk factor for CD; in patients with CD, smoking rates are twice the rate of the general population (18).

Clinical Presentation UC can often be differentiated from CD on the basis of the history and physical examination. UC is best characterized by the acute onset of abdominal pain, diarrhea, hematochezia, and tenesmus. The severity of symptoms corresponds to the extent of the disease. The abdominal examination may be unremarkable in the patient with UC unless toxic megacolon is present. In contrast, the clinical manifestations of CD may be highly variable due to the potential for diffuse and sporadic involvement of any area of the gastrointestinal tract. The disease typically presents in an insidious manner, often coming to medical attention only after a complication has developed. Chronic abdominal pain, nonbloody diarrhea, and signs of systemic toxicity such as fever, malaise, and cachexia are its cardinal features. Signs of obstruction or an inflammatory mass may be present in addition to perianal disease. Both forms of IBD may be associated with extraintestinal manifestations, more commonly UC. The pathologic features that have been used to distinguish the two forms of IBD are shown in Figure 1. Approximately 10% to 15% of patients, specifically those with severe colitis, have conditions that cannot be characterized at presentation as a specific form of IBD. Such ‘‘indeterminate’’ colitis eventually defines itself on long-term follow-up, based on patterns of disease progression. For all

Figure 1 Pathologic features of IBD. Abbreviation: IBD, inflammatory bowel disease.

Chapter 18: Inflammatory Disorders of the Small Bowel and Colon

417

conditions, exclusion of infectious enteritis by a thorough travel and exposure history, as well as with stool and serologic studies, is of critical importance at initial diagnosis. Other laboratory studies are not specific for IBD, but may help identify correctable electrolyte or hematologic abnormalities. Acute-phase factors (C-reactive protein, sedimentation rate, etc.) are frequently monitored despite the lack of correlation with clinically or endoscopically determined disease severity. Monitoring of visceral protein levels (albumin, prealbumin, transferrin, etc.) in these chronically ill patients allows the assessment of nutritional status. Colonoscopy can generally differentiate the two processes and rule out other causes of colitis, although examination and biopsy specimen interpretations are more accurate in the healing or quiescent stage. Once the diagnosis has been established, endoscopy should be employed cautiously, especially during flare-ups, when the risk of complication is high. Because the small bowel is less accessible to endoscopy, the diagnosis of small bowel CD is dependent on small bowel radiographic contrast studies, which can best demonstrate mucosal lesions as well as delineate the number, location, and degree of stricturing and fistulization (Figs. 2–5). Computed tomography (CT) is particularly useful in cases with abscess formation but may also reveal inflammatory masses and luminal obstruction.

Management Medical Therapy Anti-inflammatory therapy, beginning in the 1930s with sulfasalazine (SASP), has been the mainstay of medical management (8). The SASP molecule links 5-aminosalicyclic acid (5-ASA), responsible for the drug’s therapeutic effects, with sulfapyridine, which was initially thought to act as an antibiotic but which is now known to serve essentially as a carrier. SASP’s use is limited by allergic and dosedependent side effects, attributed to the sulfa component, and by limited efficacy in severe UC and small intestinal CD. The exact mechanism of action is unknown, but the drug has been shown to inhibit a number of proinflammatory processes active in IBD, including release of interleukin (IL)-1 and other cytokines, mucosal antibody synthesis,

Figure 2 Crohn’s ileitis. Characteristic transmural inflammation of the terminal ileum with fibrosis of the intestinal wall. Note the abrupt cessation of the disease at the ileocecal valve and completely normal appearance of the cecal mucosa and wall. Source: From Ref. 19.

Figure 3 Crohn’s ileitis. Upper gastrointestinal and small bowel followthrough contrast study showing multiple long strictures distributed through many feet of small bowel, the characteristic pattern of skip lesions seen in this disease. Surgical management of skip lesions is dependent on their proximity and localization to a single region of the small bowel. Clusters of strictures are best managed by segmental resection, whereas diffuse skip-lesion strictures are optimally managed with stricturoplasty. Source: From Ref. 20.

arachidonic acid metabolism, and oxygen radical production. An intriguing recent report suggests that long-term 5-ASA use may be protective against the development of cancer (22). Mesalamine, the unbound 5-ASA moiety, and

Figure 4 Photomicrograph of biopsy specimen from a patient with UC. Moderate dysplasia with loss of polarity and proliferation of epithelial cells is noted (original magnification 260). Abbreviation: UC, ulcerative colitis. Source: From Ref. 21.

medwedi.ru

418

Part Two: The Alimentary Tract—Small and Large Intestine

Figure 5 UC. Barium enema of a patient with panulcerative colitis, revealing the cobblestone texture of the colonic mucosa and loss of haustral markings that give rise to the ‘‘lead pipe’’ appearance of the colon. Abbreviation: UC, ulcerative colitis. Source: From Ref. 20.

olasalazine, a 5-ASA dimer, are newer, costlier formulations; they have fewer side effects than SASP, but their efficacy is probably only equivalent. Because patients are able to tolerate higher doses, and because the bioavailability of 5-ASA is higher in the small bowel, mesalamine appears particularly well suited to management of small intestinal CD. Additionally, although there has been no demonstrated benefit of maintenance therapy with SASP in CD after resection, a number of trials have shown reduced recurrence with high-dose mesalamine (23). Moderate to severe exacerbations of IBD are treated with systemic glucocorticoids, which exert their therapeutic effects through nonspecific inhibition of inflammation and immune function. Enema preparations (for both 5-ASA and steroids) can be used effectively as topical agents in distal UC. Until the advent of small intestine–active 5-ASA agents, symptomatic small bowel CD necessitated the use of systemic steroids. There is no benefit to continued maintenance therapy with steroids after remission has been induced or after surgical resection. Steroid dependence warrants consideration of either alternative modes of therapy or surgical intervention because of the severe dose- and duration-related side effects associated with long-term steroid use. The need for alternatives to glucocorticoids for severe disease has led to the use of immunosuppressant therapy for IBD, adapted from the organ transplant experience. Two purine analogs, azathioprine and its metabolite 6-mercaptopurine, have been the most extensively and successfully used (24). Their mechanism of action in IBD has not been determined, but it is likely that their specific inhibition of T-cell and natural killer cell function and proliferation plays an important part. Their major benefit in

IBD management has been their steroid-sparing effect and their ability to maintain remission. They have also been shown to be effective in the therapy of perianal and fistulous CD. One drawback is their delayed onset of activity, often requiring three to six months for improvement to become apparent. Neutropenia is the major dose-limiting side effect, and close monitoring of the complete blood count is essential. Although controversial, recent data implies that IBD patients on azathioprine are not at increased risk of lymphoma as are patients on long-term immunosuppression with solid organ transplants (25). The folate inhibitor, methotrexate, has been used extensively as an anti-inflammatory agent in rheumatoid diseases, and has been used to maintain long-term remission and steroid-sparing effects particularly for CD. Toxicities upon the bone marrow, liver, and lungs limit its usage. Cyclosporine, a selective inhibitor of IL-2 synthesis, has also shown some benefit for select patients with severe disease, although the data is conflicting and the potential toxicities (especially nephrotoxicity) are severe. There is little role for antibiotics in UC except for the perioperative period. On the other hand, patients with CD often require antibiotics for perforating disease (phlegmons and abscesses). Metronidazole and ciprofloxacin have both been shown to be effective in moderate CD, particularly those with an active colonic component (26,27). Newer agents include a variety of therapies that target TNF. The most widely utilized medication in this category is infliximab (Remicade), a human–murine chimeric monoclonal antibody against TNF-a. Infusion of infliximab in initial reports showed that a single infusion generated as high as an 81% response rate and 48% remission rate (28). Further trials of this agent have demonstrated its safety; side effects include acute infusion reactions in approximately 20% of patients, most commonly in patients who have had prior infusions and developed antichimeric antibodies (1,29). Both CD and UC patients are at increased risk for the development of adenocarcinoma; although the far greater risk is for colorectal adenocarcinoma in patients with UC. Although the same predisposing genetic alterations necessary for the progression from normal to adenomatous to malignant cell phenotype that has been shown to take place in sporadic colorectal cancer have been confirmed in UC, the cause of the increased risk and more rapid progression is unknown (30). Cancer screening for patients with UC presupposes that colonoscopy can identify premalignant areas of dysplasia. Most protocols call for patients with long-standing (longer than seven years) pancolitis to undergo colonoscopy every other year. Multiple biopsy samples are obtained to identify dysplastic mucosa. The benefit of such surveillance programs has been questioned from a cost-analysis perspective because of the extraordinary number of colonoscopies and biopsies required to identify the 12% of patients with UC who are likely to have cancer develop. Others have criticized programs for their shortcomings, noting that as many as 42% of patients are found to have an invasive cancer when colectomy is carried out for dysplasia and as many as a third of these cancers are locally advanced or metastatic at the time of surgery (31). Nevertheless, with the lack of alternatives, surveillance represents the best option for most patients.

Surgical Therapy Surgical management of IBD is often viewed as a last resort. In UC, this tendency is largely a result of cultural aversion to ileostomy, which was at one time the only alternative to continued medical management. Delayed surgical

Chapter 18: Inflammatory Disorders of the Small Bowel and Colon

intervention in CD is probably a reaction to the aggressive resectional approaches common in the past, which were based on the misguided notion that the disease could be eradicated and all too frequently created short bowel syndrome and parenteral nutrition dependency. The evolution of the ileoanal pouch procedure into an acceptable alternative to ileostomy for UC and the development of more deliberate bowel preserving surgical approaches to CD have radically altered current management and improved outcomes. Surgical removal of the diseased colonic mucosa cures UC and eliminates the risk of carcinoma. Nevertheless, because the disease runs a variable course, surgery is reserved for the more aggressive patterns of UC. In order of frequency, the indications for surgery in UC are intractability, steroid dependence or intolerance, cancer prophylaxis (for patients with mucosal dysplasia) or cancer resection, fulminant presentation (toxic megacolon), perforation, and hemorrhage. An operation is required during the first year after diagnosis in as many as 30% of patients with severe colitis. The overall rates of colectomy vary widely, between 25% and 80%, at 25 years follow-up (32). The need for colectomy varies according to extent and severity of the disease. The likelihood of requiring surgery is six times greater for patients with pancolitis than for those with isolated proctitis, but approximately 15% to 20% of patients with initially limited distal disease have eventually progressed to more extensive colitis. Early operation is usually necessary because of the aggressive nature of the disease. Patients come to surgery later in the course of the disease either for intractable, recurrent disease or because of the risk for development or actual presence of cancer. The choice of reconstructive method for UC is dictated by the clinical setting. Use of partial colon resection in any situation, other than an emergency, has been largely abandoned, on grounds that it leaves diseased tissue behind. When sepsis, hemorrhage, or toxic megacolon is present, or the possibility of advanced cancer exists, an abdominal colectomy and end-ileostomy with either a Hartmann pouch or a mucous fistula are performed. This strategy allows a restorative procedure at a later time. In the elective case, patient choice, moderated by consideration of age and body habitus, plays a large role. Many opt for restorative proctocolectomy, with removal of the distal rectal mucosa and the creation of an ileal reservoir with an ileoanal anastomosis. Some surgeons opt to render the pouch nonfunctional with the use of a temporary diverting ileostomy, to avoid early postoperative septic and anastomotic complications, although single-stage procedures with no diverting ileostomy can be safely performed in carefully selected patients (33,34). The morbidity of the pouch procedure (in its numerous configurations) compares favorably with that associated with proctocolectomy and ileostomy, although the requirement for multiple surgical procedures is clear. Idiopathic pouch inflammation, known as pouchitis, occurs in 20% to 30% of patients following restorative proctocolectomy (35,36). Pouchitis is unrelated to misdiagnosed CD and is rarely observed in patients undergoing pouch creation for familial polyposis. This syndrome provides further evidence of an underlying disorder in the regulatory mechanisms of inflammation in these patients. Many patients with pouchitis harbor pANCAs. In a small minority of patients, pouchitis is aggressive, necessitating long-term medical therapy or even pouch excision. Most cases, however, respond to short courses of metronidazole or quinolones and nonsteroidal anti-inflammatory drugs.

419

Operation does not affect the natural history of CD; indeed, asymptomatic microscopic recurrence is found in 70% to 80% of patients at one year (37). For this reason, surgical therapy is directed toward correcting complications and removing gross disease, not attaining negative microscopic margins of resection. Obstructing strictures, symptomatic internal fistulas, external fistulas, abscess formation from perforation, and persistent perianal disease are usual indications. Surgery should not be deferred indefinitely during multiple trials of ineffective medical therapy. This strategy risks worsening the nutritional condition of these patients and may lead to life-threatening complications from medical therapies. Surgery should be considered for chronic, unremitting symptoms when medical therapy has not affected prompt or durable remission. Preoperative definition of the intestinal anatomy is essential to identify concurrent areas of disease, particularly with respect to strictures. Equally important is the radiographic definition of fistulous connections, which are generally but not exclusively found proximal to strictures. A major advance in the management of these patients has been the development of radiologically directed percutaneous drainage techniques. Used as temporizing measures to relieve the septic complications of abscess formation, these techniques allow nutritional optimization by parenteral route in these ill patients in preparation for definitive surgical intervention. Endoscopy may be necessary when enterocolonic fistulas are identified, to rule out colonic CD and the need for more extensive resection. Limiting resection to grossly normal margins at dominant stricture sites or at points of fistulization, rather than to microscopically normal margins, has been shown to be safe and preserves functional tissue (38,39). To avoid excessive resection and risk of short bowel syndrome, simple or multiple ‘‘strictureplasties’’ may be used to release stenotic regions when multiple areas of small bowel are involved (40). Experience with strictureplasty in ileocolonic anastomotic strictures and colonic strictures is largely anecdotal and requires further evaluation. Resection remains the primary mode of treatment for colonic disease, and the benefits of proctocolectomy with ileostomy versus ileorectal anastomosis continue to be debated.

APPENDICITIS Inflammation of the appendix is the most common acute surgical disease in North America. Long recognized as a potentially lethal entity, early reports of right lower quadrant disease refer to ‘‘perityphlitis,’’ a process ascribed to acute pathology of the appendix in a classic article by Fitz in 1886 (41). Appendicitis may occur at any age, but has a peak incidence in the 10- to 19-year-old age group, which corresponds to the increased lymphoid tissue found in appendices of patients in this age group. During the last half century, the rate of appendicitis appears to be declining (42). The vermiform appendix is a worm-like appendage of the cecum found at the confluence of the three taeniae coli. The appendiceal artery, a branch of the ileocolic artery, provides the arterial blood supply to the appendix, which courses through its distinct mesentery. The narrow orifice of the appendix predisposes the lumen to obstruction from either luminal or mural processes, both of which are causally linked to appendiceal inflammation. Although obstruction of the appendiceal lumen as the primary etiology of appendicitis has been debated, research starting with that of Wangensteen and Bowers (43) in the 1930s

medwedi.ru

420

Part Two: The Alimentary Tract—Small and Large Intestine

provides experimental and clinical support for this pathophysiologic mechanism. The most common cause of obstruction is a fecalith, a concretion of luminal contents impacted at the orifice of the appendiceal lumen. Fecaliths are common, being present in approximately 30% of patients without appendicitis. They are nonetheless, likely involved in the pathogenesis of appendicitis for as many as 90% of cases of gangrenous appendicitis are found to have an associated fecalith (44). Less common causes of appendiceal obstruction include lymphoid hyperplasia, foreign bodies, intestinal worms, and neoplasms. The most common neoplasm of the appendix associated with appendicitis is the carcinoid tumor. Appendicitis associated with an adenocarcinoma or metastatic disease to the appendix has been reported rarely. Although the precise mechanism by which luminal obstruction can result in appendiceal inflammation has not been determined, the following sequence is frequently described. Continued secretion of mucus and fluid from the appendiceal mucosa after luminal obstruction causes mural distention. The increased wall distention and tension elicit visceral afferent nerve stimulation, which is clinically manifested as vague, periumbilical abdominal pain. As the distension continues, lymphatic and capillary obstruction ensues, and resident bacteria multiply, further worsening the hydrostatic pressure. As venous pressure is overcome, the mucosa becomes leaky, and inflammation progresses to the serosa, initiating somatic nerve stimulation and parietal pain sensation localized to the right lower quadrant. Left untreated, venous thrombosis and arterial thrombosis follow, with consequent ischemia, eventually leading to gangrene and perforation. The classic clinical presentation of appendicitis begins with vague periumbilical abdominal pain, which subsequently localizes to the right lower quadrant over the next 12 to 48 hours. Localization, however, may vary in cases where the tip of the appendix is retrocecal, intrapelvic, or elevated by the uterus during pregnancy. Anorexia, nausea, and vomiting are frequently reported, and altered bowel habits may be noted. Low-grade fever and mild leukocytosis, along with a urinalysis showing a few leukocytes and erythrocytes presumably due to inflammation of the adjacent right ureter, may be present. Physical examination typically reveals right lower quadrant tenderness with guarding, depending on the degree of inflammation present. If a mass is present, advanced disease associated with a large appendiceal phlegmon or abscess is likely. Unfortunately, clinical findings and the course of the disease are often variable and subtle. Delay in diagnosis and treatment is common, particularly in infants, young children, and elderly persons. Delay in appropriate treatment is associated with progression of appendicitis to gangrene and appendiceal abscess. Morbidity increases with delay of therapy. While mortality from appendicitis is rare, it does occur and is typically associated with a delay in diagnosis. Mortality risk is highest for elderly, immunecompromised, and infant patients. The variability in presentation of acute appendicitis, both in clinical course and physical findings, and the potentially dire consequences of misdiagnosis have prompted efforts to develop a more definitive laboratory test or management algorithm. Multiple studies have investigated the value of leukocyte counts, C-reactive protein, phospholipase A2, and sedimentation rate (45). Clinical algorithms that selectively use abdominal radiography, ultrasonography, or CT scan with or without gastrointestinal contrast studies

have also been investigated. Despite many such studies, no diagnostic algorithm has yet proved able to provide exceptional predictive value, and clinical assessment and judgment remain the diagnostic tools of choice. Diagnostic algorithms are often region or institution specific, based largely on the availability of emergency imaging and local emergency room physicians and surgical preferences (46). Prompt diagnosis and appendectomy remain the mainstay in treating appendicitis and preventing complications. As described by McBurney (47), a right lower quadrant incision with delivery of the appendix and amputation at its base is the standard of care for acute appendicitis (Fig. 6). If perforation is noted, adequate irrigation of the operative area and pelvis is added to the procedure, and wound closure is delayed. Laparoscopic appendectomy is an equally successful approach. Additionally, laparoscopy offers the opportunity to confirm the diagnosis and examine the lower abdomen and pelvis for other pathology, using a minimally invasive approach. This modality may have particular value when diagnostic uncertainty is heightened, particularly in female patients. Several reports have noted less postoperative pain, shorter hospitalizations, and superior cosmetic results with this modality. Although laparoscopic appendectomy is a safe procedure for uncomplicated appendicitis, its use in complicated appendicitis can be technically challenging (49). Perioperative antibiotics are indicated to decrease the incidence of wound infection in acute appendicitis.

Figure 6 Technique of appendectomy. (A) Common incisions for the open appendectomy technique. (B) Delivery of the appendix. (C) Ligation and division of the mesoappendix. (D) Ligation of the base of the appendix. (E) Residual stump without inversion. (F) Removal of the appendix with ligation. (G) Inversion of ligated stump. Source: From Ref. 48.

Chapter 18: Inflammatory Disorders of the Small Bowel and Colon

Therapeutic antibiotics are required for right lower quadrant peritonitis secondary to appendiceal perforation. Infrequently, patients may present with ‘‘missed appendicitis,’’ with the primary manifestation of a right lower quadrant abscess. Such abscesses can be managed with percutaneous drainage followed by interval appendectomy two to three months later (47).

MECKEL’S DIVERTICULUM ‘‘Meckel’s diverticulum is frequently suspected, often looked for and seldom found.’’ So stated Mayo (50) regarding this congenital abnormality of the small intestine. A true diverticulum, a Meckel’s diverticulum, involves all layers of the small intestine, and is the result of a remnant of the omphalomesenteric duct. In utero, this duct connects the primitive gut to the yolk sac and normally obliterates by seven to eight weeks of gestation. Failure of obliteration can result either in an ileoumbilical fistula, a cystic remnant along the duct, a fibrous band, or, most commonly, a Meckel’s diverticulum. These diverticuli are usually found within 90 cm of the ileocecal value; however, at least 180 cm of bowel proximal to the ileocecal value should be evaluated prior to excluding a Meckel’s diverticulum (51). The blood supply to the diverticulum is from a remnant of the vitelline artery, which arises from the superior mesenteric artery and may or may not have its own mesentery. There is about a 2% (range 0.14–2.45%) incidence of this anomaly in the general population. Asymptomatic lesions are equally described in both sexes; however, symptomatic cases are described three times as frequently in men. There is an association between Meckel’s diverticulum and certain congenital anomalies, including cleft palate, bicornuate uterus, and annular pancreas. There is also an increased incidence in CD (6–18%), but the explanation for this is unknown (52). As many as 50% of Meckel’s diverticuli contain ectopic gastrointestinal mucosal tissue. Parietal cell–rich acid-secreting mucosa is most commonly present, but less frequently pancreatic tissue, Brunner’s glands, colonic mucosa, or hepatobiliary tissue is identified. Inflammatory conditions may arise from acid secretion and ulceration of the adjacent ileal mucosa, which may lead to gastrointestinal hemorrhage. Obstruction of the orifice of the diverticulum by fecal matter, foreign bodies, or neoplastic tissue may elicit an inflammatory cycle similar to appendicitis. Carcinoids and adenocarcinomas have been rarely found in diverticuli. In adults, the most common complication of Meckel’s diverticulum is mechanical small bowel obstruction. Multiple patterns of obstruction have been described, including intussusception into the terminal ileum and right colon, volvulus of the attached small bowel around the fibrous mesenteric band, and internal herniation. Local inflammatory changes, with peptic ulceration and scarring, can also progress to lesions that cause obstruction. Incarceration of a Meckel’s diverticulum in an abdominal hernia has been described and is referred to as a Littre’s hernia. Although first described for incarceration within a femoral hernia, this term is now generally applied to any hernia with an incarceratedMeckel’sdiverticulum.Thecomplicationsassociatedwith Meckel’s diverticulum vary with the age of the patient. The pediatric population most commonly has painless hematochezia, whereas the adult population is more likely to show symptoms referable to diverticular inflammation or bowel obstruction. Because this anomaly is relatively rare, accurate diagnosis is often not established until laparotomy.

421

The presence of ectopic gastric mucosa in some Meckel’s diverticuli has allowed the development of a noninvasive imaging procedure. Diverticuli containing functional gastric mucosa selectively take up 99m(Tc) pertechnetate after intravenous injection. This gamma-emitting isotope can then be detected with external cameras. At least 1.8 cm2 of ectopic gastric mucosa must be present to be detected with this scan. The accuracy of the scan in children approaches 90%; in the adult population, however, sensitivity is 62.5% and specificity is only 9% (53). Surgical management of symptomatic Meckel’s diverticulum requires surgical segmental small bowel resection to remove all ectopic tissue and adjacent inflamed or ulcerated areas. The incidental finding of Meckel’s diverticulum presents less clear indications for excision. Lesions with a narrow orifice, an associated palpable mass, a fibrous band, or a vitelline vessel without a mesentery should be resected. The incidental Meckel’s diverticulum with any of these features that is free of signs of inflammation or scarring can be safely managed with simple excision from the antimesenteric surface of the small bowel, without segmental small bowel resection. This simplified approach is easily accomplished with a gastrointestinal stapling device. The risk of morbidity after elective, incidental excision has been reported to be 2%, compared with a 7% risk of morbidity after operation for symptomatic lesions. Meckel’s diverticuli without these findings should likely be left undisturbed (54).

JEJUNOILEAL DIVERTICULI Diverticuli of the jejunum and ileum are rarely associated with clinical manifestations. Although such diverticuli are noted in 4.6% of the population at autopsy, they are described on only 0.5% to 2.3% of small bowel contrast studies (55,56). These pseudodiverticuli are formed by herniation of the small bowel mucosa into the mesenteric fat at the sites where the vasa recta penetrate the bowel wall. The diverticuli, often multiple, are more frequently found in the proximal jejunum, probably because of the larger size of the vasa recta in this area of the small bowel, and are often not apparent on routine abdominal exploration, because they are concealed within the mesenteric fat. They are thought to be acquired diverticuli; it is theorized that increased intraluminal pressure, possibly associated with abnormal peristaltic action, may be responsible for their development. Although these diverticuli are frequently clinically silent, clinical syndromes that may be associated with small bowel diverticuli include malabsorption, hemorrhage, inflammation, and obstruction. Extensive regions of small bowel diverticulosis may be associated with abnormal small bowel motility, with consequent stasis and bacterial overgrowth. A secondary malabsorption syndrome characterized by crampy abdominal pain, anemia, and diarrhea may ensue. Hemorrhage is rarely associated with these lesions, but they have been described as a cause of recurrent occult gastrointestinal hemorrhage. Obstruction of the orifice of the diverticulum with inspissated luminal material can result in acute inflammation, which may progress to peritonitis and perforation. Asymptomatic lesions, or those identified incidentally on upper gastrointestinal tract small bowel follow-through series, do not require surgical intervention. Lesions associated with acute inflammation or hemorrhage require emergency operation with segmental small bowel resection.

medwedi.ru

422

Part Two: The Alimentary Tract—Small and Large Intestine

COLONIC DIVERTICULAR DISEASE Colonic diverticulosis is a common acquired structural disorder of the colon. Although it was first described in the 18th century, the pathologic significance of this disorder was not fully appreciated until the early 20th century. This condition has increased in frequency during the last 80 years in conjunction with an aging population; autopsy prevalence rates of 5% were noted in the early 1900s, while prevalent rates of 50% are now reported. Approximately 30% of all persons older than 45 years have diverticulosis, and as many as 70% of people older than 85 years have this condition. The condition is manifested equally among men and women. The pathogenesis of colonic diverticuli remains unclear, although two factors seem to be operative in their development: weakness in the colonic wall and intraluminal pressure gradients. Intraluminal pressure recordings demonstrate a process termed segmentation, which allows small segments of the bowel to develop relatively high pressures. Patients with diverticulosis have similar resting pressures, but generate markedly increased pressures with contraction. Diverticuli are most frequently identified in the sigmoid colon, the region where the highest pressures are generated (Fig. 7). The structural feature that is predisposed to diverticular development is the point where the vasa recta enter the bowel through the muscular wall. These perforating vessels cause weakness in the colon wall and are the sites where diverticuli form. The association of diverticular disease with increasing age may be explained by the decreased collagen synthesis and increased elastin content of the submucosa of the colon in elderly persons. Muscular thickening of the colonic wall, a condition termed myochosis, is present in younger people of the Western population at risk for disease. This muscular abnormality constricts the lumen of the colon and leads to higher intraluminal pressures; it is thought to be the precursor of diverticulosis (58). A low-residue diet typical of Western populations is associated with the risk of diverticulosis (59). Diverticulosis is not present in African populations, where a high-residue

Figure 7 Diverticulosis of the colon. Cross section of the colon depicting the sites where diverticuli form. Note that the antimesenteric portion is spared. Diverticuli originate at the site where the blood vessel penetrates the colonic wall. Source: From Ref. 57.

diet is the norm. Population-shift studies have shown that Japanese immigrants, who have a low incidence of diverticulosis before immigration, acquire the same risk as the native U.S. population after adopting the low-residue regional diet of their new environment. As many as 25% of patients with diverticulosis develop a complication of this condition. Acute diverticulitis is the most common manifestation. Diverticulitis is caused by the obstruction of the orifice of the diverticulum by fecal material, with consequent bacterial overgrowth, inflammation, and eventual transmural inflammation and peritonitis. Advanced complications may be manifested by free or localized perforation, abscess formation, fistulization to adjacent viscera or the skin, and acute colonic obstruction. Bleeding is rarely associated with acute diverticulitis, although it is a well-described complication of diverticulosis. Acute diverticulitis is characterized by the gradual onset of crampy left lower quadrant pain. Altered bowel habits, including diarrhea or constipation, may be reported. More advanced disease is associated with fever, leukocytosis, and distinct left lower quadrant peritonitis. An abdominal CT scan to identify pericolonic inflammation and mesenteric streaking, with or without associated abscess, is the most sensitive radiographic study to identify acute diverticulitis. Contrast enemas and sigmoidoscopy are contraindicated, and plain abdominal films are of value only to rule out free perforation. Mild cases of diverticulitis, not associated with paralytic ileus, can be treated with oral antibiotics on an outpatient basis. However, patients with fever, leukocytosis, or left lower quadrant peritonitis require hospitalization for intravenous antibiotic administration. Prompt evaluation with CT scan allows percutaneous drainage of localized abscess cavities preparatory to delayed elective segmental colonic resection. Patients with diffuse peritonitis and those for whom initial nonoperative therapeutic measures fail should proceed to urgent laparotomy. Surgical management is dictated by the operative findings (60). If preoperative mechanical bowel preparation is possible, a one-stage procedure with resection and primary anastomosis is indicated. All involved bowel should be resected, particularly including the entire sigmoid colon. The distal margin of resection should be defined by the region in the upper rectum, where the taeniae coli splay apart to become a confluent muscular layer. Patients with acute perforation, localized undrained abscess, or peritonitis should be treated with a two-stage procedure, with initial segmental resection of the inflamed bowel, descending colostomy, and a Hartman’s rectal pouch. Rarely, the inflammatory process in the sigmoid colon is so severe as to warrant the older three-stage approach to this disease, in which a transverse colostomy to divert fecal stream is performed at the initial setting, prior to subsequent sigmoid resection after the acute inflammatory process resolves and later closure of the colostomy. Elective surgical resection is generally recommended for patients younger than 40 years who have had one attack of diverticulitis severe enough to warrant hospitalization. Judgment regarding elective surgical management for older patients is based on medical comorbidities and suitability of the patient for elective colonic resection. Patients who have had a single attack of diverticulitis have a risk of recurrent disease exceeding 50%. For surgeons experienced with the technique, laparoscopic or hand-assisted minimally invasive approaches are appropriate options for patients undergoing sigmoid resection for diverticulitis.

Chapter 18: Inflammatory Disorders of the Small Bowel and Colon

CLOSTRIDIUM DIFFICILE COLITIS With the advent of broad-spectrum antibiotics and their frequent use, the incidence of pseudomembranous colitis caused by C. difficile infection is increasing. C. difficile colitis is characterized by diarrhea and colorectal mucosal inflammation. Original descriptions of this clinical scenario date to the 19th century in patients undergoing intestinal surgery for obstruction or ischemia; this observation, combined with occasional contemporary reports of C. difficile colitis in immunocompromised patients, attests to the possibility that the condition may develop in the absence of antibiotic use. Nevertheless, the disease today is closely associated with antibiotic therapy (61,62). Enteral medications appear to be slightly more likely to lead to disease than parenteral antibiotics, although frequency of use of parenteral agents in surgery makes them a common cause in this subset of patients. Agents most frequently implicated are cephalosporins, clindamycin, and lincomycin, but associations have been made with nearly all antibiotics except aminoglycosides, nitroimidazols, and monobactams. Prolonged antibiotic use is most often involved, but a single dose of systemic therapy can lead to C. difficile colitis. C. difficile is most likely a minor component of the normal flora, although it is rarely cultured in individuals without symptoms. The organism can be transmitted from patient to patient by health care carriers and instruments, and nosocomial epidemics are well documented (63). Once the organism is present, antibiotic-induced alterations in the normal colonic microflora may give C. difficile the proliferative advantage that leads to clinical disease. Of the various products that the bacterium secretes, two are toxins. Toxin A is weakly cytotoxic but elicits an inflammatory response characterized by vasodilation and hemorrhage (64). Toxin B is released from the cell membrane on lysis and is the basis for commercially available cytotoxic assays. Both toxins are necessary for clinical disease. C. difficile colitis represents one of the more common and costly nosocomial infections in surgical patients. A high index of suspicion is critical to allow a prompt therapeutic response. Watery diarrhea is the hallmark of the disease. Blood may be present in the stool but is rare. Abdominal pain and low-grade fevers are characteristic but not specific in patients after abdominal operations. Mortality as great as 40% is documented for untreated patients; it drops to less than 10% with recognition and institution of appropriate measures. Stool cultures for the organism and stool assay for the C. difficile cytotoxin (toxin B) are diagnostic and readily available in most institutions. Although culture is the most sensitive test, cytotoxin assay is more specific (65). The presence of leukocytes in the stool can be a more rapid, if less sensitive and specific, diagnostic aid. When the diagnosis is uncertain, endoscopy can be helpful. The rectum and left colon are involved in 75% of patients, with the right colon affected infrequently. Endoscopy reveals scattered patches of white plaque (the pseudomembranes) interspersed between normal appearing mucosa. Histologically, plaques are made up of fibrin, mucus, sloughed epithelial cells, and neutrophils. In the absence of pseudomembranes, the microscopic appearance can be difficult to differentiate from that of ischemic colitis. Most patients show clinical improvement when the offending antibiotic is removed, although diarrhea may persist for more than a month. Relapses occur and carriers without symptoms pose a risk to the community. Therefore, even mild cases should be treated. Treatment consists of

423

institution of C. difficile-specific therapy; the agents of choice are oral vancomycin and metronidazole. Although vancomycin may have a slight therapeutic advantage, its greater cost and the recent development of vancomycin resistant Enterococcus species mandate that its use be reserved for severe cases or metronidazole-resistant C. difficile colitis. Parenteral metronidazole can be used in patients unable to take oral medication; higher therapeutic doses are needed, however, and therapeutic failures are more common. If continued antibiotic treatment is essential for treatment of concomitant disease, antibiotics not commonly linked to C. difficile colitis, such as penicillin, ampicillin, aminoglycosides, erythromycin, or tetracycline, should be used if possible. Surgery may be required in fulminant cases associated with toxic megacolon or perforation. C. difficile colitis is most likely to progress to megacolon and systemic sepsis in immune-compromised patients, particularly those with solid organ transplants. Marked systemic sepsis, extreme leukocytosis, and colonic distention and ileus are the hallmarks of toxic megacolon. Prompt surgical resection of the total abdominal colon with ileostomy and Hartman’s pouch is appropriate. At the time of exploration, transmural necrosis may not be evident on gross external examination of the colon, nonetheless total abdominal colectomy should be performed (66).

RADIATION ENTERITIS The beneficial effects of radiation on tumors became evident shortly after Roentgen invented his X-ray device 100 years ago. The harmful effects on normal tissue were reported soon thereafter, but it was not until the development of megavoltage external-beam radiation in the 1950s, which expanded the therapeutic role of irradiation, that intestinal damage began to be widely reported (67). Despite efforts to limit injury by minimizing the radiation field and optimizing the dose administered, an increased incidence of gastrointestinal complications has been reported (68). The increase is probably caused by the increased use of this modality for pelvic malignancies as well as improved long-term patient survival. The synchronous administration of chemotherapy during radiation therapy to enhance radiosensitivity of the tumor may also lead to an increase in the incidence of radiation enteritis. The acute effects of radiation are defined in experimental in vivo models (69,70). Radiation energy induces its tumoricidal effects by denaturing DNA and forming oxygen free radicals. The sensitivity of normal tissue varies according to the proliferative rate of the cellular components. The alimentary tract, particularly the small bowel, is exquisitely sensitive to radiation because of the high rate of proliferation found throughout the intestinal epithelium. Mitotic activity in the crypts of the small intestine stops within hours after radiation exposure to single radiation doses of 500 to 1000 cGy (rads). Cell necrosis peaks at six to eight hours. Conventional understanding proposed a proliferative burst during the next 24 hours by the remaining viable crypt cells. However, it is more likely that initial repair occurs by restitution, with flattening of the villi as residual cells spread out to cover the denuded areas of the epithelium. A leukocyte infiltrate is often present. The changes are associated with nausea, vomiting, and diarrhea. The diarrhea results in part from malabsorption of nutrients and bile salts and can be ameliorated by cholestyramine (71). Restitution from a single small-dose injury is complete

medwedi.ru

424

Part Two: The Alimentary Tract—Small and Large Intestine

by day 3, whereas after a course of treatment, histologic recovery requires two weeks. Symptomatic recovery may take as long as six months. With larger doses (1500 cGy) and a proportionately larger cell kill, the re-epithelialization process is incomplete, the intestinal barrier function is lost, and septic death often results. Clinically, acute radiation enteritis is usually self-limited and responds to symptomatic therapy and conservative management. Whereas acute injury is limited to the mucosa, chronic radiation enteritis involves the full thickness of the intestinal wall. It is seen six months to many years after exposure, generally correlates with the severity of the acute injury, and occurs through unknown mechanisms (72). The most prominent and consistent histologic feature is obliterative sclerosis and intimal hyperplasia of the submucosal arterioles. This obstruction to blood flow likely results in ischemia and is responsible for the mucosal ulceration and atrophy typically associated with it. Inflammatory cells infiltrate the lamina propria, and the muscularis mucosa is hyperplastic and fibrotic. The normal appearance of the muscularis propria is preserved. Serositis, with infiltration by fibroblasts and inflammatory cells, is universally present. These changes are generally progressive. Patients with chronic injury generally show acute signs of partial bowel obstruction superimposed on a history of chronic diarrhea and malabsorption. Because many have a prior history of abdominal surgery, cancer, or both, differentiating between radiation enteritis and tumor recurrence or adhesions may be difficult. Contrast upper and lower gastrointestinal tract series may be helpful, although findings must be differentiated clinically from other processes, primarily CD and ischemia. Such series also help define the location and extent of fistulous tracts and strictures, thereby guiding the operative approach. Most cases respond, at least initially, to conservative management with institution of bowel rest followed by a low-residue diet. As many as 40% of patients receiving radiation treatments have symptoms severe enough to require medical intervention at some point, and 2% to 5% require operative management. Fistula and stricture are the major indications for operation. Surgical intervention is hampered by the extensive serositis and dense vascular adhesions commonly encountered. Conservative measures such as proximal enterostomy and enteroenteral bypasses may be the most appropriate approach. Resection with reanastomosis can be safely carried out when the segment involved can be mobilized and the ends to be anastomosed are grossly normal in appearance. Because of the progressive nature and difficult management once the disease is established, prevention is the key. Careful targeting of the radiation field, optimization of the dose, and distension of the bladder during treatments minimize the risk of intestinal injury, although a relationship between amount of bowel exposed in the radiation field and surgical complications is not always evident (73). A number of intraoperative techniques have been suggested to prevent small bowel from dropping into the pelvis after such radical procedures as hysterectomy, exenteration, and abdominoperineal resection. These include reperitonealization of the pelvis, placement of omental, and absorbable mesh slings across the pelvic brim, and insertion of salineor silicone-filled pouches in the pelvic space. The efficacy of these measures remains unproven. Numerous pharmacologic agents have been shown to ameliorate acute experimental radiation injury, including elemental diets, prostaglandins, epidermal growth factor, glutamine, and sucralfate, but proof of clinical benefit is lacking for all

but the last, and none have been shown to alter the course of chronic radiation enteritis.

SUMMARY A large number of inflammatory disorders may adversely influence the normal physiology of the small bowel and colon. The inflammatory disorders of surgical significance include appendicitis, Meckel’s diverticulitis, diverticular disease of the colon (and on occasion jejunum and ileum), CD, and UC. Other diseases that may require surgical intervention in selected situations include C. difficile colitis and radiation enteritis. The impact that these disease processes have on intestinal function varies considerably in terms of disability and long-term sequelae. An understanding of the physiologic derangements associated with each inflammatory disorder forms the basis for correction and for those surgical procedures that must be used to restore intestinal function to normal.

REFERENCES 1. Su C, Lichtenstein GR. Recent developments in inflammatory bowel disease. Med Clin N Am 2002; 86:1497–1523. 2. Barmada MM, Brant SR, Nicolae DL, et al. A genome scan in 260 inflammatory bowel disease-affected relative pairs. Inflamm Bowel Dis 2003; 10:15–22. 3. Hugot JP, Chamaillard M, et al. Association of NOD2 leucinerich repeat variants with susceptibility to Cohn’s disease. Nature 2001; 379:821–823. 4. Ardizzone S, Bianchi-Porro G. Inflammatory bowel disease: new insights into pathogenesis and treatment. J Intern Med 2002; 252:475–496. 5. Farrell RJ, Murphy A, Long A. High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy. Gastroenterology 2000; 118: 279–288. 6. Crohn BB, Ginzburg L, Oppenheimer GD. Regional enteritis: a pathological and clinical entity. JAMA 1932; 99:1323–1329. 7. Hubbard J, Surawicz CM. Etiological role of mycobacterium in Crohn’s disease: an assessment of the literature. Dig Dis 1999; 17:6–13. 8. Hendrickson BA, Gokhale R, Cho JH. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev 2002; 15:79–94. 9. Wakefield AJ, Montgomery SM, Pounder RE. Crohn’s disease: the case for measles virus. J Gastroenterol Hepatol 1999; 31:247–254. 10. Farrell RJ, Peppercorn MA. Ulcerative colitis. Lancet 2002; 359:331–340. 11. Mitsuyama K, Toyonaga A, Sata M. Intestinal microflora as a therapeutic target in inflammatory bowel disease. J Gastroenterol 2002; 37(suppl 14):73–77. 12. Schreiber S, et al. The role of the mucosal immune system in inflammatory bowel disease. Gastroenterol Clin N Am 1992; 21:451. 13. Saxon A, Shanahan F, Landers C, et al. A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol 1990; 86:202–210. 14. Vasiliauskas EA, Plevy SE, Landers CJ, et al. Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn’s disease define a clinical subgroup. Gastroenterology 1996; 110:1810–1819. 15. Gordon LK, Eggena M, Targan SR, Braun J. Definition of ocular antigens in ciliary body and retinal ganglion cells by the marker antibody pANCA. Invest Ophthalmol Vis Sci 1999; 40:1250–1255. 16. van Deventer SJ. New biological therapies in inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2003; 17:119–130.

Chapter 18: Inflammatory Disorders of the Small Bowel and Colon 17. Levenstein S, Prantera C, Varvo V, et al. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol 2000; 95:1213–1220. 18. Thomas GA, Rhodes J, Green JT, Richardson C. Role of smoking in inflammatory bowel disease: implications for therapy. Postgrad Med J 2000; 76:273–279. 19. Corman ML. Colon and Rectal Surgery. 2nd ed. Philadelphia: JB Lippincott, 1989. 20. Kirsner JB, Shorter RG. Inflammatory Bowel Disease. 4th ed. Baltimore: Williams and Wilkins, 1995. 21. Corman ML. Colon and Rectal Surgery. 3rd ed. Philadelphia: JB Lippincott, 1993. 22. Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000; 14(2):145–153. 23. McLeod RS, Wolff BG, Steinhart AH, et al. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology 1995; 109:404–413. 24. Pearson DC, May GR, Fick GH, et al. Azathioprine and 6mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med 1995; 123:132–142. 25. Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn’s disease: benefits outweigh the risk of lymphoma. Gastroenterology 2000; 118(6):1018–1024. 26. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995; 108(6):1617–1621. 27. Colombel JF, Lemann M, Cassagnou M, et al. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease. Am J Gastroenterol 1999; 94(3):674–678. 28. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 1997; 337(15):1029–1035. 29. Blam ME, Stein RB, Lichtenstein GR. Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: current and future perspectives. Am J Gastroenterol 2001; 96:1977–1997. 30. Kern SE, Redston M, Seymour AB, et al. Molecular genetic profiles of colitis-associated neoplasms. Gastroenterology 1994; 107(2):420–428. 31. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994; 343:71. 32. Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis. A long term follow-up of 1116 patients. Dig Dis Sci 1993; 38:1137. 33. Mowschenson PM, Critchlow JF. Outcome of early surgical complications following ileoanal pouch operation without diverting ileostomy. Am J Surg 1995; 169(1):143–145. 34. Mowschenson PM, Critchlow JF, Peppercorn MA. Ileoanal pouch operation: long-term outcome with or without diverting ileostomy. Arch Surg 2000; 135(4):463–466. 35. Hulten L. Proctocolectomy and ileostomy to pouch surgery for ulcerative colitis. World J Surg 1998; 22:335–341. 36. Sandborn WJ. Pouchitis following ileal pouch-anal anastomosis: definition, pathogenesis, and treatment. Gastroenterology 1994; 107:1856. 37. Rutgeerts P, Geboes K, van Trappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990; 99:956–963. 38. Kotangi H, Kramer K, Fazio VW, Petras R. Do microscopic abnormalities at resection margins correlate with increased anastomotic recurrence in Crohn’s disease? Retrospective analysis of 100 cases. Dis Colon Rectum 1991; 34:909–916. 39. Fazio VW, Marchette F, et al. Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled trial. Ann Surg 1996; 224:563–571. 40. Fazio VW, et al. Long-term follow-up of strictureplasty in Crohn’s disease. Dis Colon Rectm 1993; 36:355.

425

41. Fitz RH. Perforating inflammation of the vermiform appendix: with special reference to its early diagnosis and treatment. Trans Assoc Am Physicians 1886; 1:107. 42. Addiss DG, et al. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol 1990; 132:910. 43. Wangensteen OH, Bowers WF. Significance of the obstructive factor in the genesis of acute appendicitis. Arch Surg 1937; 34:496. 44. Jones BA, et al. The prevalence of appendiceal fecaliths in patients with and without appendicitis. A comparative study from Canada and South Africa. Ann Surg 1985; 202:80. 45. Dueholme S, Bagi P, Bud M. Laboratory aid in the diagnosis of acute appendicitis. A blinded, prospective trial concerning diagnostic value of leukocyte count, neutrophil differential count, and C-reactive protein. Dis Colon Rectum 1989; 32:855. 46. Kieran JA, Curet MJ, Schermer CR. Institutional variations in the management of patients with acute appendicitis. J Gastrointest Surg 2003; 7(4):523–528. 47. McBurney C. Experience with early operative interference in the cases of disease of the veriform appendix. NY Med J 1889; 50:676. 48. Sabiston DC Jr, ed. Essentials of Surgery. Philadelphia: WB Saunders, 1987. 49. Vargas HI, Averbook A, Stamos MJ. Appendiceal mass: conservative therapy followed by interval laparoscopic appendectomy. Am Surg 1994; 60:753. 50. Mayo CW. Meckel’s diverticulum. Mayo Clin Proc 1933; 8:230. 51. DiGiacomo JC, Cottone FJ. Surgical treatment of Meckel’s diverticulum. South Med J 1993; 86:671. 52. Turgeon DK, Barnett JL. Meckel’s diverticulum. Am J Gastroenterol 1990; 85:777. 53. Cooney DR, et al. The abdominal technetium scan (a decade of experience). J Pediatr Surg 1982; 17:611. 54. Cullen JJ, et al. Surgical management of Meckel’s diverticulum an epidemiologic, population based study. Ann Surg 1994; 220:564. 55. Longo WE, Vernava AM III. Clinical implications of jejunoileal diverticular disease. Dis Colon Rectum 1992; 35:381. 56. Tsiotos GG, Farnell MB, Ilstrup DM. Non-Meckelian jejunal or ileal diverticulosis: an analysis of 112 cases. Surgery 1994; 116:726. 57. Way LW, ed. Current Surgical Diagnosis and Treatment. 7th edn. Los Altos, CA: Lange Medical Books, 1985. 58. Watters DA, Smith AN. Strength of the colon wall in diverticular disease. Br J Surg 1990; 77:257. 59. Burkitt DP, Walker AR, Painter NS. Effect of dietary fibre on stools and the transit-times, and its role in the causation of disease. Lancet 1972; 2:1408. 60. Roberts PL, Veidenheimer MC. Current management of diverticulitis. Adv Surg 1994; 27:189. 61. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difficile colitis. JAMA 1993; 269:71. 62. Kelly CP, Pothoulakis C, La Mont JT. Clostridium difficile colitis. N Engl J Med 1994; 330:257. 63. McFarland LV, et al. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989; 320:204. 64. Burakoff R, et al. Effects of purified Clostridium difficile toxin A on rabbit distal colon. Gastroenterology 1995; 109:348. 65. Gerding DN, Brazier JS. Optimal methods for identifying Clostridium difficile infections. Clin Infect Dis 1993; 16(suppl 4):S439. 66. Lipsett PA, et al. Pseudomembranous colitis: a surgical disease? Surgery 1994; 116:491. 67. Walsh D. Deep tissue traumatism from Roentgen ray exposure. BMJ 1897; 2:272. 68. Allen-Mersh TG, et al. Has the incidence of radiation-induced bowel damage following treatment of uterine carcinoma changed in the last 20 years? J R Soc Med 1986; 79:387.

medwedi.ru

426

Part Two: The Alimentary Tract—Small and Large Intestine

69. Kinsella TJ, Bloomer WD. Tolerance of the intestine to radiation therapy. Surg Gynecol Obstet 1980; 151:273. 70. Yeoh EK, Horowitz M. Radiation enteritis. Surg Gynecol Obstet 1987; 165:373. 71. Yeoh E, et al. Effect of pelvic irradiation on gastrointestinal function: a prospective longitudinal study. Am J Med 1993; 95:397.

72. Coia LR, Myerson RJ, Tepper JE. Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Bio Phys 1995; 31:1213. 73. Letschert JG, et al. The volume effect in radiation-related late small bowel complications: results of a clinical study of the EORTC Radiotherapy Cooperative Group. Radiother Oncol 1994; 32:116.

LIVER, BILIARY TRACT, PANCREAS, AND SPLEEN

19 Hepatic Physiology Jose M. Prince and Timothy R. Billiar

INTRODUCTION From the earliest times of recorded history, the liver has enjoyed special attention and fascination. In ancient Mesopotamia, the cradle of civilization, sorcerers and physicians would perform divination rituals in order to discover the sin committed by a person, which rendered them ill. This was often accomplished by hepatascopy in which the liver of a sacrified animal, such as a sheep, would be carefully examined in an effort to determine the tribute demanded by the gods for the transgression. The underlying idea was that the liver was the collecting point of blood and therefore the seat of life (1). By carefully examining its topical anatomy, the intentions of the gods could be discerned. According to the world’s oldest medical record, a Sumerian clay tablet dating from 2150 B.C., the responsibilities of the treating physicians were to wash wounds, make poultices, and apply bandages; the physicians in ancient Babylon may have been the first to be regulated by law because a description in the Hammurabic code describing their pay scale and obligations stated, ‘‘if a physician performs a major operation on a lord . . . and has caused the lord’s death . . . they shall cut off his hand’’ (2). Such penalties were derived from divination rituals using hepatoscopy. It is little wonder that the liver has enjoyed a high place of preeminence down through the centuries. Even today, it is associated with continuing mystery. How does it regenerate itself when large portions are resected? When many other organs are expendable why are its functions so crucial that life itself depends on its health? While many of its mysteries have been unraveled, the liver continues to be an unusual organ demanding great respect. This chapter attempts to explain its complex anatomy and physiology and why it is so important if homeostasis is to be insured for the entire human organism.

EMBRYOLOGY Accounting for 5% of the body weight of a newborn infant, it is not surprising that the liver develops into the most massive organ in the fetus. In fact, the liver produces most of the prominence of the newborn abdomen (3,4). A careful understanding of the process by which the liver forms, known as hepatogenesis, provides the operating surgeon with the functional understanding necessary to fully grasp the surgical anatomy of this organ. For this to be fully appreciated, one must have a thorough knowledge of the birth of this organ. Over the last several decades, great advances have been made in identifying the important genes whose expression dictates the initiation of cellular differentiation into the complex 3-D structure of the liver. It all commences

when the liver primordium emerges from the ventral aspect of the distal foregut at approximately 18 days. By week 16, the architectural organization of the liver is well developed (5). Hepatogenesis proceeds from two anlages, the hepatic diverticulum and the septum transversum. The septum transversum is the mesenchymal plate that partially divides the embryonic thoracic and abdominal cavities. The development of the hepatic diverticulum at the future duodenum requires the formation of the definitive endoderm during gastrulation. Endodermal patterning yields a population of liver progenitor cells called hepatoblasts (Fig. 1) (6,7). Arising cranially from the hepatic diverticulum, the hepatoblasts form sheets and cords within the septum transversum, which are arranged along the vitelline veins as they enter from the yolk sac. Ultimately, the vitelline veins fuse to form the portal vein. The hepatoblasts differentiate into hepatocytes and cholangiocytes (8). The caudal development of the hepatic diverticulum forms the extrahepatic biliary system, including the gall bladder. As hepatogenesis progresses, the enlarging liver makes contact with the superior and inferior coverings that delimit the septum transversum and begins to split them apart. The inferior serosal membrane covers almost the entire surface of the liver as the visceral peritoneum; however, at the superior pole, the liver makes direct contact with the developing central tendon of the diaphragm, avoiding the peritoneal investiture and is identified surgically as the bare area of the liver. The margins of the bare area are surrounded by the reflection, or fold, of the peritoneum from the inferior surface of the diaphragm onto the surface of the liver, forming the coronary ligament (encircling the bare area like a crown). Of note, the direct contact between the liver and the diaphragm in the bare area permits the formation of vascular anastomoses between hepatic portal vessels and the systemic veins of the diaphragm. Surgical mobilization of the liver during operation is based on identifying and dividing the ligamentous attachments of the liver formed during development. A narrow ventral mesentery attaches the liver to the ventral body wall and differentiates into the membranous falciform ligament. The umbilical vein is carried within the free caudal margin of this membrane. The ventral mesentery also gives rise to the lesser omentum, a translucent membrane between the liver and the stomach, which may be identified as having two principal components: the hepatoduodenal ligament and the hepatogastric ligament. The hepatoduodenal ligament consists of the caudal border of the lesser omentum, which connects the liver to the developing stomach. Within the hepatoduodenal ligament are contained the portal vein, the proper hepatic artery, and the extrahepatic biliary ducts (hepatic, cystic, and common bile ducts).

medwedi.ru 427

428

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

(A) Competence

(B) Specification

(C) Morphogenesis

ventral foregut endoderm

Pre-cardiac mesodem

cardiac mesodem

hepatic genes activated

vascularized liver

septum transversum mesenchyme

As its name implies, the hepatogastric ligament is the region of the lesser omentum between the liver and the stomach. During the sixth week, the abdominal foregut rotates to the right, directing the liver to its adult anatomic location in the right upper quadrant of the abdomen. As a result of this rotation, the lesser omentum reduces the communication between the lesser and greater sacs of the peritoneal cavity to a narrow canal, the epiploic foramen of Winslow (9).

Circulatory System Hepatogenesis is carefully coordinated with vascular development. Angioblasts, the precursors to endothelial cells, are found between the thickening hepatic endoderm and the surrounding septum transversum mesenchyme prior to hepatocyte invasion of the septum transversum. These early endothelial cells intermingle with the hepatoblasts as they form into a liver bud and provide crucial growth stimulus to the hepatic bud (10). During the 5th week of gestation, initial advances into the hepatic cords form channels originating from the vitelline veins to form primitive sinusoids, a dense network of anatomizing venous spaces. In the adult liver, these sinusoids will be lined with a fenestrated endothelium that exposes the hepatocytes to the contents of the blood as it flows from the portal vein and hepatic artery to the hepatic veins. The primitive embryonic venous system is divided into three bilaterally symmetrical drainage systems of which two play critical roles in the development of the hepatic vasculature. The vitelline system collects deoxygenated blood from the gastrointestinal tract; whereas, the umbilical system carries oxygenated blood from the placenta. The right and left vitelline veins emerge from the yolk sac; however, by the third month, the left vitelline vein has completely disappeared and united with the right vitelline vein to form the portal vein. The portal vein enters the enlarging hepatic mass through the porta hepatis, or hilum of the liver, establishing the pathways for the portal tracts and intrahepatic branching of portal veins with associated mesenchymal tissue (11). The superior portion of the right vitelline vein ultimately becomes the terminal segment of the inferior vena cava (IVC). Within the growing liver, a single oblique channel amongst the sinusoids, the ductus venosus, becomes dominant and drains into the IVC. During fetal life, the ductus venosus receives the oxygenated blood from the umbilical system and shunts it directly to the heart (9). In contrast to the vitelline veins, the right umbilical vein will disappear with the left umbilical vein persisting. The hepatic artery is derived from the celiac axis, and arterial sprouts grow into the liver from the hilum along the portal tracts.

Figure 1 Phases of hepatogenesis. Endodermal patterning results in the activation of hepatic genes with subsequent liver differentiation into the septum transversum mesenchyme. Source: From Ref. 7.

Proper development of the complex sinusoidal vasculature during hepatogenesis is essential for the liver to perform its role as a site for hematopoiesis by midgestation. During fetal life, the liver is the prominent site of hematopoiesis and up to 60% of the liver mass consists of blood cells (12). As early as the 4th week, foci of hematopoietic cells derived from the mesenchyme of the septum transversum begin to produce blood cells. This intense and diffuse production of blood between hepatoblasts and within the portal tracts continues until 24 weeks of gestation. After 25 to 28 weeks, the hematopoetic cells begin to form islands, and by the 36th week, hematopoeisis exists only as scattered islands in the parenchyma as other sites in the body increasingly bear the burden of hematopoeisis.

Biliary System At the same time as the liver parenchyma develops, both the intrahepatic and extrahepatic biliary ducts form. By week 7, a double layer of cells develops around the portal tract. Peripheral biliary tubular structures form between these two layers of cells. Over the next several weeks, these structures remodel to form terminal bile ducts by week 11. From this point onwards, the maturation of the intrahepatic biliary tree occurs from the hilum outwards and continues past birth for several months. Bile acid synthesis begins at 5 to 9 weeks, with bile secretion identified by 12 weeks (13). The extrahepatic and intrahepatic biliary tree maintain patency and continuity throughout gestation, ensuring a passage to the alimentary canal for the bile (5).

HISTOLOGY The microarchitectural determination of what constitutes the functional liver unit has been debated since 1833. Classically, the liver comprises 1 to 2 mm diameter hexagonal hepatic lobules oriented around the terminal tributaries of the hepatic vein or central veins. Hepatocytes radiate as cords of cells from the central vein, with hepatocytes abutting the portal tract referred to as the limiting plate. Upon microscopic evaluation, hepatocytes tend to be uninucleate, diploid cells with minimal variation in overall cellular dimensions, though the nuclei may vary in size, number, and ploidy. Between the cords of hepatocytes are vascular sinusoids that bathe the cells on two sides with well-mixed portal venous and hepatic arterial blood, representing 25% of the cardiac output of the body. The terminology developed to discuss hepatic lobular anatomy persists in the practice of liver pathology, with pathologists describing injury patterns by location as being centrilobular, mid-zonal, or periportal (14).

Chapter 19: Hepatic Physiology

Alternatively, the hepatic acinar structure of the liver has been advanced by some authors as a more accurate depiction of the ‘‘metabolic lobule.’’ Triangular in shape, the acinus has at its base the terminal branches of the hepatic artery and the portal vein, with the terminal hepatic venule (i.e., the central vein) occupying the apex of the acinus (Fig. 2). The parenchyma of the hepatic acinus is divided into three zones based upon distance from the blood supply. The concept of zonal distribution accurately represents a lobular gradient of hepatic enzymes, oxygen concentration, and metabolic substrates, which corresponds with many forms of hepatic injury (16). In addition to the parenchymal hepatocytes, a number of nonparenchymal cells constitute key populations of cells that are essential to proper functioning of the liver as an organ. Endothelial cells lining the suinusoids define an extrasinusoidal space of Disse, into which the microvilli of the liver protrude. The large pores, or fenestrations (almost 1 mm), present between the endothelial cells permit substances in the plasma, including large proteins such as albumin, to move freely into the space of Disse. Within the space of Disse, hepatic stellate cells (formerly called Ito cells) can be found. They contribute to the storage and metabolism of vitamin A and to collagen production in the normal and fibrotic liver. They are an important source of the key hepatocyte mitogen, hepatocyte growth factor (HGF) (17). Scattered Kupffer cells of the monocyte–phagocyte system populate the luminal face of the endothelial cells, accounting for 31% of sinusoidal cells. These Kupffer cells provide a rich source of cytokines for signaling within the liver after injury and, as will be discuss later, play a critical role in fighting infections (18).

429

beneath the armor provided by the right lower ribs and their cartilage, though the liver may abut the abdominal wall in the epigastrium of a healthy person. Beneath the ribs, the upper extent of the liver should be considered to be as high as the 5th rib at the level of the nipple line. The normal inferior extent of the liver can often be palpated along the costal margin in the thin upright patient, though patients with hepatic congestion and enlargement may present with a liver palpable all the way to the right lower quadrant. When supine, the liver gravitates backwards; whereas, with deep inspiration, the diaphragm forces descent of the liver below the costal margin. The gallbladder fundus projects toward the lateral aspect of the right rectus muscle at the level of the 9th rib (19–21).

Internal Surface Anatomy The spongy, reddish brown liver is surrounded by a capsule of strong connective tissue, called Glisson’s capsule. The liver has a soft consistency that is easily friable. The liver is divided into right and left lobes by a line that extends from the gallbadder fossa to the IVC, called Cantlie’s line. The left lobe of the liver is further divided into lateral and medial segments by the falciform ligament. As described above, the embryologic development of the liver determines the topographic anatomy of the liver, which is defined on initial surgical exploration principally by its five ligamentous attachments. Additionally, adjacent organs leave their impression on the liver surface, including the stomach, the right kidney, the transverse colon, and the diaphragm. There are no visible surface markings that define the hepatic segmental anatomy described below.

Functional Anatomy ANATOMY As the largest abdominal organ and the largest gland in the body, the liver accounts for about 2% of the body weight in adults (about 1.5 kg). During routine physical examination or in the rapid evaluation of a trauma patient, it is important for the surgeon to understand the location of the liver relative to patient position and external anatomy. On physical examination, the majority of the liver is protected

Figure 2 Diagram comparing the hepatic acinus with zones 1, 2, and 3 to the hepatic lobule (dotted line). Portal tract contains portal venule (v), hepatic arteriole (a), and hepatic duct (d), terminal hepatic venule (t). Source: From Ref. 15.

Since 1954, Couinaud’s liver segment classification has become the standard basis for liver surgery (Fig. 3). In this system, autonomously functioning units of the liver are defined by avascular planes based upon the interface of the portal venous anatomy with the hepatic veins (23). Segments 1 through 4 represent the classic left lobe of the liver; whereas, segments 5 through 8 correspond to the right lobe of the liver. The middle hepatic vein separates the right and left lobes of the liver as it passes in the interlobar fissure. Segment 1, the caudate lobe, lies anterior and to the left of the IVC. Segments 2 and 3, the left lateral segments, and segment 4 constitute the remainder of the classical left lobe. The right hepatic vein, the longest vein in the liver, runs in the right intersegmental fissure and divides the right lobe of the liver into anterior (segments 5 and 8) and posterior (segments 6 and 7) components. The portal elements further divide the anterior and posterior components into their respective segments (Fig. 4) (24). Based on this segmental anatomy of the liver, complex hepatic resections have been developed to a degree of sophistication that forms the basis of living related donor transplantation (26). In dealing with malignancy in the liver, the cardinal rules of hepatic resection mandate that all tumor be resected with sufficient hepatic parenchyma preserved to sustain life without disrupting the vascular, venous, and biliary drainage of the remaining liver (27).

Vascular Anatomy The portal venous, hepatic arterial, and biliary systems run together within the intrasegmental parts of the hepatic parenchyma. The portal venous system provides approximately 75% of the hepatic inflow, with the remaining 25%

medwedi.ru

430

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Figure 3 The functional division of the liver and of the liver segments according to Couinaud’s nomenclature: (A) as seen in the patient; (B) in the ex vivo position. Source: From Ref. 22.

supplied by the hepatic artery; however, the hepatic arterial flow provides about 50% to 75% of the oxygen to the liver. Commonly arising from the celiac artery, the common hepatic artery provides systemic arterial blood to the liver.

Figure 4 Schematic representation of the functional anatomy of the liver. There are three main hepatic veins lying within the liver scissurae and dividing the liver into four sectors, each receiving a portal pedicle. The hepatic veins and portal pedicles are intertwined as are the fingers of two hands. Source: From Ref. 25.

Occasionally, the common hepatic artery may arise from the superior mesenteric artery. The common hepatic artery divides into left and right branches, but the origins of these arteries can vary frequently. In the most common variations, the left hepatic branch originates from the left gastric artery (25%) or the right hepatic branch arises from the superior mesentery artery (17%). The division between left and right hepatic arteries generally occurs to the left of the hepatic hilum. As it courses laterally, the right hepatic artery crosses behind the common hepatic duct in 80% of people. Variations in the hepatic arterial system are almost as common as the ‘‘normal’’ condition that is found in only 55% of the population (28). The portal vein is hidden in the hepatoduodenal ligament behind the extrahepatic bile ducts and hepatic artery. The portal vein divides at the hepatic hilum into the left and the shorter right branch. The right branch divides anteriorly to supply segments 5 and 8 via ascending and descending branches, respectively. The right portal vein posterior branch curves posterolaterally and divides for segments 6 and 7. The left portal vein courses transversely for 3 to 5 cm in the hilum and then curves left and anteriorly to the base of the umbilical fissure. The left portal venous system anatomy is rather constant, with segment 2 provided with a solitary vein and segment 3 having up to three veins (29). Variations in the portal vein tend to involve the right portal vein system with a trifurcation found in 10% to 15% of livers or a right anterior portal vein originating from the left portal vein. Rarely, the entire left portal vein may be absent (30). The portal venous system is valveless, permitting retrograde diversion of flow in the setting of obstruction resulting in portal hypertension. Portal hypertension may be categorized as suprahepatic, intrahepatic, or prehepatic. In the setting of suprahepatic and intrahepatic portal hypertension, ascites formation may be precipitated by the increased sinusoidal pressure that leads to increased passage of fluid into the space of Disse. Ultimately, hepatic lymph drainage capacity is exceeded and in combination with a low oncotic pressure, the patient develops ascites (31). For example, hepatic venous obstruction, as occurs with heart failure or hepatic vein thrombosis, results in increased pressure in the sinusoids causing portal venous system hypertension. Blood flow may even be reversed in acute settings in the portal veins. The absence of valves, which permits this flow reversal, allows surgeons to cannulate smaller omental or mesenteric vessels to measure portal vein pressure intraoperatively. In chronic conditions resulting in portal hypertension, the augmentation of the extrahepatic communications between the portal venous system and the systemic venous system provides an important alternate flow of blood for the portal blood to the right side of the heart. Four principal sites of portosystemic anastamoses are (i) distal esophagus/proximal stomach, (ii) umbilical/ periumbilical veins, (iii) superior/inferior and middle hemorrhoidal veins, and (iv) retroperitoneal veins (32). The venous drainage of the liver consists of three main hepatic veins that drain into the suprahepatic IVC and a variety of accessory hepatic veins that drain into the retrohepatic vena cava. The main hepatic veins flow in the interlobar or intersegmentar fissures. The right hepatic vein is single in 94% of cases and drains segments 5, 6, and 7. Following Cantlie’s line, the middle hepatic vein forms a common trunk with the left hepatic vein in 85% of people and drains the central liver (segments 4, 5, and 8) (33). The left hepatic vein drains segments 2 and 3 (sometimes 4) and generally joins the middle hepatic vein prior to

Chapter 19: Hepatic Physiology

arriving at the IVC. The caudate lobe is drained mainly on the left by a single vein in half of all livers.

Biliary Anatomy Understanding the variations in the biliary anatomy is critical to proceeding safely with liver and gallbladder surgery. The gallbladder can vary in size and position, sometimes being buried deep within the liver parenchyma. It can be double or septated, or can have its own mesenterium. The delicate blood supply of the extrahepatic bile ducts is provided by as many as seven arteries that may form distinct anastamotic patterns around the ducts. Typically, the distal, or retroduodenal, bile duct is supplied by the posterior superior pancreaticoduodenal artery, and the right hepatic artery provides the blood supply to the middle part. The gallbladder and cystic duct have a rich network, but the right and left hepatic ducts have a sparse network. Most commonly, the cystic artery is a single artery originating from the right hepatic artery. At times, two cystic arteries may be present. Venous drainage of the gallbladder is into the portal system of adjacent liver segments 4 and 5, with important implications for the spread of gallbladder pathology into the liver parenchyma (30).

HEPATIC FUNCTIONS (TABLE 1) Blood Reservoir Large quantities of blood can be stored in the liver. The liver is an expandable organ in which the normal blood volume of about 450 mL (10% of total body blood volume) can be increased to hold up to an additional 1 L of blood. Cardiac failure is a common clinical scenario requiring this adaptive response by the liver. In the setting of acute hemorrhage, the liver may provide as much as 300 mL of blood to compensate for the bleeding (34).

431

systemic circulation as a result of the ruthless efficiency of the Kupffer cells in phagocytosing the foreign intruders. A 90% hepatectomy, however, results in bacteremia within two hours in rats. Kupffer cells, macrophages derived from blood mononuclear cells, inhabit the hepatic sinusoids and comprise between 70% and 90% of the reticuoendothelial system (35). The Kupffer cells also prevent endotoxins from entering the systemic circulation (36). In addition to their role in filtering the blood, the Kupffer cells play an important role in intercellular signaling and cytokine release in response to various forms of hepatic injury and disease (37).

Hemostasis The liver parenchyma produces almost all of the enzymes necessary for the coagulation cascade (38). Fibrinogen, prothrombin, Factor V, and Factor VII are amongst the important factors produced by the liver. In addition to the parenchyma, the endothelial cells and macrophages found in the liver produce some of the coagulation factors. Macrophages produce Factor VIII:C and plasminogen activator inhibitor-2, whereas, endothelial cells generate tissue plasminogen activator, von Willebrand factor, and thrombomodulin. The liver produces all the vitamin K–dependent coagulation factors, which include prothrombin and Factors VII, IX, and X. Vitamin K is a fat-soluble vitamin absorbed from the small intestine through the action of bile (39). Inadequate biliary production and excretion from liver disease can result in vitamin K insufficiency, which results in a coagulopathic state. In fact, liver disease in general is associated with a hemorrhagic diathesis caused by a number of factors including impaired synthesis of the coagulation factors (Table 2) (40).

Toxin Elimination

Blood that passes through the intestinal capillaries picks up a large number of bacteria from the intestines. In fact, blood cultures performed on portal venous samples will often grow colonic bacilli; whereas, systemic blood samples will rarely grow bacterial colonies. Less than 1% of the bacteria that arrive at the liver via the portal vein will enter

In addition to cleansing the blood of macroscopic bacteria, the liver filters the blood and chemically modifies a variety of toxins, drugs, and hormones. These biotransformation and detoxification reactions are numerous. Many tend to involve the P-450–dependent microsomal mixed function oxidase system (42). In principle, the liver attempts to modify endogenous or exogenous substances to either inactivate the substance directly or render it more suitable for elimination from the body by biliary or urinary excretion. Liver diseases may manifest a failure of this hepatic function

Table 1 Hepatic Functions

Table 2 Effect of Liver Disease on Hemostasis

Filtration (Kupffer cell of reticuloendothelial system) Capture and process incoming substrates and bacteria Maintenance of metabolic homeostasis Fundamental mechanisms Capture Intracellular metabolism Storage Release Modulation of metabolic substrates Carbohydrates: glucose, fructose, galactose Lipids: fatty acids, glycerol, cholesterol Amino acids: protein synthesis and degradation Specific protein synthesis Secretory proteins: albumin, acute phase reactants, carrier proteins Coagulation proteins: clotting proteins, anticoagulants, proteins, fibrinolytic proteins Lipid phase metabolism Drug metabolism Bile formation

Decreased synthesis of proteins Coagulation: Factors XII, IX, VII, V, and II; fibrinogen, prekallikrein, kininogen Anticoagulant: proteins C and S, antithrombin III Profibrinolytic: plasminogen Antifibrinolytic: 2–antiplasmin, Cl–inhibitor, 2–macro–globulin, histidine-rich glycoprotein Synthesis of abnormal proteins Vitamin K–dependent factors Factor VIII and von Willebrand’s factor Fibrinogen Decreased clearance function Activated coagulation factors Plasminogen activators Thrombin antithrombin III complexes Abnormalities of platelets Disseminated intravascular coagulation Lipoproteins

Blood Cleansing

Source: From Ref. 41.

medwedi.ru

432

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

as an increased sensitivity to certain drugs such as sedatives or opiates or may enhance the biologic action of endogenous hormones, evidenced by the feminizing effects of chronic liver disease. Unfortunately, a healthy liver can suffer injury as a result of a drug reaction. In fact this accounts for 50% of the cases of acute liver failure in the United States, 75% of which result in liver transplantation or death (43). Acetaminophen, the most common agent responsible for acute liver failure, causes hepatocyte injury in a dose-related manner. Therapy with N-acetylcysteine repletes glutathione levels and may prevent injury if started within the first 24 hours after ingestion (44). One particularly important hepatic detoxification pathway is that involving the elimination of the ammonium ion (Fig. 5). Utlilizing the Krebs–Henseleit cycle, the ammonium ion is converted to urea via a series of intermediates in a process that involves both the mitochondria and the cytosol of the hepatocytes (46). This pathway of ammonium fixation is irreversible. Glutamate, formed from ammonium ion and alpha-ketoglutarate, serves as the principal NH2 donor. Carbamoyl-phosphate synthetase I represents the ratecontrolling step in urea synthesis (47). Two-thirds of the ammonia entering the portal vein is converted to urea and the remainder into glutamine. Unlike urea synthesis, glutamine synthesis for detoxification is a reversible process.

Iron Storage The normal iron content of the body is about 4 g including about 1 g of storage iron kept mostly in the liver (48). Iron absorbed from the small intestine is transported in the plasma as transferrin. Transferrin may release its iron to any tissue, but hepatocytes in particular accept excess iron present in the blood. In the cytoplasm of the hepatocytes, iron binds with apoferritin to form ferritin, the storage form of iron. Individuals with hereditary hemochromatosis

Figure 5 The urea cycle. Source: From Ref. 45.

suffer from a chronic iron overload syndrome that results in excessive iron storage in the liver and subsequent hepatic injury and fibrosis (49).

METABOLIC HOMEOSTASIS The liver functions as a complex chemical factory organizing, conducting, and regulating a multitude of chemical reactions that sustain our lives. Throughout their productive life, the hepatic cells maintain a high rate of metabolism in which they share substrates and energy from one metabolic system to another. We shall focus our discussion on the key metabolic processes that are especially important in understanding the integrated physiology of the surgical patient.

Carbohydrate Metabolism In carbohydrate metabolism, the liver plays an important role in maintaining a normal blood glucose concentration by changing glucose production, altering glycogen storage, and converting galactose and fructose to glucose. With key components of the body, such as brain tissue and red blood corpuscles being obligate consumers of glucose, production of glucose must be maintained, despite iatrogenic, physiologic, or pathologic challenges. The liver produces glucose as a result of two main processes, gluconeogenesis and glycogenolysis (Fig. 6). Hepatic glucose production and utilization involves the movement of substrates through a series of major cycles involving a sequence of intricate reactions, each catalyzed by an enzyme. Ultimately, all of the reactions result in glucose transport into or out of the hepatocyte. In the fed state or when hormonal conditions (i.e., high insulin, low glucagon) favor hepatocyte glucose uptake, glucose enters hepatocytes as a result of facilitated diffusion through constitutively active glucose transporters, primarily GLUT-2 (51). Conversely, when the hormonal conditions that favor gluconeogenesis exist (i.e., low insulin, high glucagon, and fasting state), hepatocytes release glucose into the extracellular space. The ability of hepatocytes to respond in these two manners depends upon regulation of the enzyme glucokinase (hexokinase IV), which rapidly phosphorylates intracellular glucose (52). This keeps glucose levels from building up inside the hepatocyte and maintains a concentration gradient across the cell membrane. Diabetes, in which hepatocyte glucose utilization is unbalanced and glucose is released from the cells as a result of unrestrained gluconeogenesis, serves as a good example (53). In this setting, glucokinase mRNA levels are very low and the glucokinase gene is inactive. As a result, glucokinase activity is reduced, a low rate of glucose phosphorylation exists, intracellular glucose accumulates, and glucose is exported by facilitated diffusion. Injection of insulin in the diabetic state increases glucokinase gene transcription and mRNA levels within 30 to 60 minutes, leading to increased glucokinase activity (54,55). The insulinmediated increase in glucokinase activity results in increased glucose phosphorylation, decreasing the intracellular glucose pool and favoring glucose entry into the hepatocyte along a downhill gradient. Although insulin regulates glucokinase activity in hepatocytes, insulin plays almost no role in glucose transport into hepatocytes. By contrast, in peripheral tissues such as muscle, insulin signaling leads to increased glucose transporter levels (GLUT-4) in the cell membrane and increased glucose uptake (56). Independent of the glucose concentration, glucagon inhibits

Chapter 19: Hepatic Physiology

Figure 6 Glycolysis–gluconeogenesis. These reactions are entirely cytoplasmic and, in response to mass action, readily reversible. Reversibility permits glycolysis and gluconeogenesis in the same cellular compartment. Mass action is determined by importation of substrate under the influence of insulin (glycolysis and glycogen synthesis), facilitated exit from the pathway (pyruvate entry into mitochondria for the Krebs cycle), or the entry of products (lactate or amino acids) that promote gluconeogenesis, an event also regulated by glucagon. The location of the rate-limiting enzymatic pathways for both glycolysis and gluconeogenesis are identified. Source: Adapted from Ref. 50.

433

for only 12 hours, with the peripheral tissues requiring 180 g/day (120 g for the brain). During fasting and starvation, the liver coordinates a complex process of metabolic adaptation. During the initial phase of fasting, the liver produces glucose from its glycogen stores by the process of glycogenolysis. As hepatic glycogen stores become exhausted in the first 24 hours, gluconeogenesis becomes increasingly more important and alternative substrates begin to replace glucose as the source of fuel throughout the body. During the initial 48 hours, serum glucagon levels increase while insulin levels decrease to about half their normal level. This increase in the plasma glucagon/insulin ratio stimulates hepatic gluconeogenesis, glycogenolysis, synthesis of ketone bodies, and free fatty acid (FFA) mobilization from adipose tissue (59,61). The liver then turns to other sources outside of itself to provide the necessary substrates for gluconeogenesis. The main gluconeogenic precursors are amino acids released from muscle, lactate, and glycerol (62). In the fasting state, lactate accounts for 50% of the gluconeogenic substrates and an even greater component during exercise. At baseline, lactate is produced by the anaerobic glycolysis of red blood cells, platelets, and the renal medulla; however, tissues in which pyruvate oxidation capacity is exceeded (e.g., exercising muscle) by a high rate of glycolysis produce lactate. In the Cori cycle, when the muscle metabolizes glucose only to lactate, the liver converts this lactate to glucose, which the muscle can once again convert to lactate for energy (63). The adaptation to starvation can be so successful that obese individuals have been treated clinically for over 200 days of total fasting without serious complications (64). Additional sources of glucose include the digestion of sucrose and lactose in the small intestine to yield glucose, fructose, and galactose. Both the fructose and galactose enter the portal system where the majority is removed by the first passage of blood through the liver. In the hepatocytes, fructose and galactose are metabolized into substrates for glycolysis or glycogen synthesis. Fructose utilization is not insulin dependent.

Lipid Metabolism glucokinase and overrides the stimulatory effect of insulin (55). Additonally, glucokinase activity may be modulated by a glucokinase regulatory protein that competitively inhibits glucose binding (57). Intracellular signaling by second messenger cascades initiated by these hormones results in altered levels of cyclic adenosine monophosphate, calcium, and phospatidylinositol 3-kinase (58). Ultimately, the overall flow of metabolites depends upon the underlying hormonal state of the patient, which regulates the key hepatic enzymes that alter the balance, resulting in glucose uptake or release by the hepatocytes. The process of hepatocyte glucose metabolism is regulated by a variety of acute and chronic regulatory mechanisms (59). After a meal in response to the increase in blood glucose concentration, hepatocytes convert glucose to glycogen for storage. Glycogen synthase catalyzes the key step of glycogen synthesis. The activity of glycogen synthase is regulated by its phosphorylation state and by phosphorylated glucose levels (56). The total hepatic glycogen stores may be as much as 80 g. By contrast, the muscles contain 400 g of glycogen but unlike the liver, the muscle cells are unable to secrete glucose (60). The 80 g of hepatic glycogen stores are sufficient to supply the fuel needs of the body

There are three major classes of complex lipids: triglycerides, cholesterol, and phospholipids. The largest energy reservoir in the human body is stored as triglyceride in adipose tissue. These triglyceride stores are hydrolyzed to FFAs and glycerol by a hormone-sensitive lipase (65). The FFAs enter the circulation where they associate with albumin during transport. The FFAs can then be oxidized to water and carbon dioxide through the citric acid cycle and generate tremendous amounts of energy. Although some lipid metabolism can occur in all cells of the body, certain aspects of lipid metabolism occur principally in the liver. The liver has a high capacity to remove FFAs from the circulation. Once in the hepatocytes, the liver has the capacity to maintain a high rate of FFA oxidation to supply energy above and beyond its need, which can be utilized by the other organs in the body. Unlike in other organs, FFAs can be esterified back into tryglycerides or be oxidized to ketone bodies (e.g., acetoacetate and b-hydroxybutyrate) in the liver. During periods of starvation, the brain and muscle can utilize these ketone bodies as an additional source of energy. During fed periods when insulin levels are high and glucagon is low, the liver synthesizes fat from carbohydrates and proteins, which is then transported by lipoproteins to adipose tissue for storage.

medwedi.ru

434

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

The liver is a principal site for lipoprotein formation. These lipoproteins are water-soluble macromolecular complexes of lipids and one or more specific proteins, called apoproteins. These complexes form pseudomicelles with the nonpolar lipids in the center of the complex and the more polar lipids and apoproteins forming the external surface. The apoprotein component of the lipoproteins targets the complex for delivery to specific tissues in the body. In general, the lipoproteins contain cholesterol, triglycerides, phospholipids, cholesteryl esters, and apoproteins. In humans, six major classes of plasma lipoproteins are commonly defined by their density, particle size, apoprotein content, and electrophoretic mobility (66). Chylomicrons are generated by the small intestine to carry dietary triglycerides and cholesterol. Endothelial cells of the vascular system enrich the cholesterol content of these chylomicrons by hydrolyzing the triglycerides with lipoprotein lipase (LPL). These chylomicron remnants are then rapidly cleared by the liver. The liver in turn synthesizes very low-density lipoproteins (VLDLs) to export the cholesterol and triglycerides generated by the liver. The VLDL is then subjected to hydrolysis of its triglyceride content by LPL and a distinct hepatic LPL to yield intermediate-density lipoproteins and low-density lipoproteins (LDLs) (67). The LDLs serve as the major cholesterol transport carriers in the plasma. Finally, the liver, in addition to other sources, generates high-density lipoproteins (HDLs), which associate with much of the cholesteryl esters as a result of the action of lecithin-cholesterol acytransferase. In reverse cholesterol transport, HDLs acquire cholesterol from the peripheral tissues and transfer them back to the liver as cholesteryl esters for excretion. Almost 80% of the cholesterol synthesized by the liver is converted to bile salts and secreted into the bile. Both the cholesterol and phospholipids carried by the lipoproteins are used by the cells of the body for a variety of uses including the formation of cellular membranes and intracellular structures (68).

Protein Metabolism Without a liver, the body might be able to adjust carbohydrate and fat metabolism and still survive; however, without the liver performing its critical role in protein metabolism, the patient cannot survive more than a few days at best. Proteins obtained from our diet are utilized by the liver for the synthesis of nonessential amino acids, purines, pyrmidines, and other nitrogen-containing compounds. The most significant functions of the liver in protein metabolism include (i) deamination of amino acids, (ii) urea formation for ammonia removal, (iii) synthesis of plasma proteins, and (iv) interconversions between the amino acids and other important metabolic compounds (Fig. 7). The vast majority of deamination, a necessary step in the processing of amino acids for energy, occurs in the liver. In carbohydrate and fat metabolism, complete oxidation results in the by-products of carbon dioxide and water, which are eliminated by respiration and urination. By contrast, protein metabolism results in the hydrolysis of proteins into bipolar amino acids whose oxidation results in HCO3 and NH4þ (ammonium). The nitrogenous waste may be cleared by a variety of mechanisms. The liver removes the waste product of this deamination, ammonia, from the body by forming urea through the urea cycle as previously described. Furthermore, additional ammonia produced by enteric bacteria and by the intestines is processed into urea by the liver. Although carbamoyl-phosphate synthetase is the rate-controlling enzyme of the urea cycle, the liver glutaminase in the periportal hepatocytes has the unique characteristic of being activated by its product, which results in a feed-forward effect on hepatic urea synthesis (70). Glutamine synthesis is the most important alternative pathway for ammonia detoxification and can be carried out in a number of tissues including perivenous hepatocytes. In fact, glutamine constitutes 50% of the free amino acid pool in the body (71). Normally, ammonia levels are maintained in a narrow range by hepatic ureagenesis and muscle glutamine synthesis.

Figure 7 Amino acid interconversion relies on cytoplasmic transamination, whereas metabolism of the carbon skeleton of the amino acid proceeds in the mitochondria. Most intermediates of the Krebs cycle can readily diffuse from the double convoluted membrane of the mitochondrion to participate in cytoplasmic intermediary metabolism. Source: From Ref. 69.

Chapter 19: Hepatic Physiology

Without hepatic urea generation in liver failure, the rising plasma concentration of ammonia reflects the presence of hepatic encephalopathy, which may result in hepatic coma and death (72). In cirrhosis, portosystemic shunts can greatly decrease blood flow to the liver, limiting the plasma exposed to the liver for ammonia elimination, resulting in increased systemic ammonia levels (73,74). These shunts can account for up to 50% of the portal flow (75). Perhaps as important as ammonia metabolism is the fact that the bicarbonate produced by oxidation of proteins must be eliminated to regulate systemic pH. Thus, urea synthesis removes not only toxic ammonium ions, but also equimolar amounts of bicarbonate. Adjustments in hepatic urea synthesis are important in pH homeostasis, highlighting another important interrelated function of the liver (76). After a meal rich in protein, the liver extracts the vast majority of the amino acids entering into the portal circulation. An important exception to note involves the branched-chain amino acids (BCAA), leucine, isoleucine, and valine. These BCAA are used primarily by the skeletal muscle (74). Because they do not require hepatic processing, attempts have been made to evaluate the use of BCAA in hepatic failure to reduce hepatic encephalopathy (77–79). Insulin release after a protein-rich meal facilitates the uptake of amino acids into muscle and fat and inhibits protein breakdown. Both the liver and muscle interconvert amino acids and release them into the circulation. The nonessential amino acids are oxidized in the liver and muscle, but the essential amino acids are primarily consumed in the liver. Excess dietary amino acids cannot be stored in the body. Some of the amino acids are used for gluconeogenesis, others for nonessential amino acid synthesis or protein synthesis. Except for the imunoglobulins, the vast majority of the major plasma proteins are produced by the liver. Serum albumin, the most abundant serum protein, is produced exclusively in the liver (80). Albumin production can account for up to 15% of all the total hepatic proteins synthesized. In addition to housekeeping protein production, the liver constantly responds to the needs of the body. Activation of the systemic inflammatory response results in a burst of protein synthesis, such as that of C-reactive protein and fibrinogen, in response to signaling by interleukin (IL)-6. These acute phase proteins generally serve to limit tissue damage and facilitate microbial clearance by inhibiting protesases, opsonizing bacteria, binding heavy metals, and modifying the immune response (81,82). The production of each of the proteins synthesized by the liver is controlled by specific regulatory mechanisms. In general, the plasma concentrations of specific proteins after acute liver injury depends upon the kinetics of synthesis and the turnover rate of the particular protein. For example, clotting factors (plasma half-time of hours to days) are more likely to be depressed initially by acute liver injury, than longer-lived proteins such as albumin (3 weeks).

435

breakdown of heme. The rate-limiting step for bilirubin formation is the conversion of heme to biliverdin. Biliverdin, a nontoxic, water-soluble compound, is then converted to water-insoluble, nonpolar bilirubin. This unconjugated bilirubin diffuses across biologic membranes, crossing the blood–brain barrier, the placenta, and the gallbladder epithelium. As a result, unconjugated bilirubin is excreted in bile in only trace amounts. Unconjugated bilirubin is transported in the circulation reversibly bound to albumin until delivery to the liver, where it is esterified with glucuronic acid, increasing the water solubility of the compound. The conjugated bilirubin glucuronides are then secreted by an energy-dependent process into the bile canaliculi for transport to the gallbladder and intestines. Within the terminal ileum and colon, the conjugated bilirubin is converted once again to an unconjugated bilirubin. This time, the unconjugated bilirubin is modified into urobilinogens and related products. A small portion is oxidized to urobilin, providing some of the brown pigment that gives stool its normal color. In normal adults, 95% of circulating bilirubin is unconjugated. Unconjugated bilirubin exposed to light causes the formation of photoisomers and lumirubin, which can be excreted by the liver without conjugation. This process provides the physiologic foundation for the treatment of neonatal hyperbilirubinemia with phototherapy (84).

PATHOPHYSIOLOGY Understanding the clinical manifestations and diagnostic approaches to treating patients with deranged liver function is critical to the preoperative assessment that in many cases predetermines the successful outcome of surgical intervention in liver diseases. Patients with liver disease are burdened with a greater risk for surgical and anesthesia complications (85). A careful history and physical examination prior to surgery should be performed to screen patients for liver disease (Table 3). Risk factors to inquire about include prior blood transfusions, tattoos, intravenous illicit drug use, alcohol consumption, sexually transmitted diseases, family history of liver disease, and current medications. Physical examination should evaluate the patient for the presence of jaundice, ascites or increased abdominal girth, gynecomastia, spider telangiectasias, palmar erythema, splenomegaly, or testicular atrophy. Should liver disease be identified or known preoperatively, an assessment of the surgical risk must be made by the surgeon and discussed with the patient. This assessment must consider the nature and urgency of the procedure, the severity of the liver disease, and the presence of comorbid medical conditions. Many studies have identified a variety of risk factors with the type of surgery perhaps being the Table 3 Preoperative Surgical Evaluation of Patients Should Include Screening for Some of These Common Findings Identifiable by a Careful History and Physical Examination

Biliary Metabolism The formation of bile by the liver and the function of the bile salts in the digestive system are discussed in other sections of this book. We will briefly review the basic aspects of bile formation important in understanding liver physiology. Red blood corpuscles have a life span averaging 120 days (83). Senescent erythrocytes are degraded by the mononuclear phagocytic cells of the liver, spleen, and bone marrow. The heme moiety from the hemoglobin within these corpuscles accounts for about 70% of the bilirubin formed by the

History Blood transfusions Tattoos Intravenous illegal drug use Alcohol consumption Sexually transmitted diseases Family history of liver disease Current medications

medwedi.ru

Physical examination Jaundice Ascites or increased abdominal girth Spider telangiectasias Palmar erythema Splenomegaly Gynecomastia Testicular atrophy

436

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

most important (86). Emergency surgery carries a higher morbidity and mortality than elective procedures. When comparing different surgical sites, abdominal surgery reduces hepatic arterial blood flow to a greater degree than extraabdominal procedures through a reflex systemic hypotension from dilation of capacitance vessels when traction is applied to the viscera (87). Within the abdomen, cholecystectomy, gastric operations, and colectomy have traditionally been associated with a greater mortality in patients with decompensated cirrhosis (88–92). With the advances in minimally invasive surgery over the last decade, a laparoscopic approach may be feasible in the setting of compensated cirrhosis and may improve outcomes in the future (93,94). In general, cardiac surgery in the face of cirrhosis presents the patient with a high risk of death (95). As we have discussed in this chapter, the liver performs a great number of critical functions for the body; thus it is not surprising that a malfunctioning or failing liver should expose patients to a greater risk of death and complications with surgery. A very useful system for assessing the risk of surgery in patients with chronic liver disease is the Child–Pugh classification schema (Table 4). A number of retrospective studies demonstrate that perioperative morbidity and mortality correlate well with this classification of cirrhosis (98,99). Each component of the system evaluates a different aspect of hepatic function. Albumin and prothrombin measure the synthetic function of the liver. Bilirubin levels reflect the capacity of the liver to process metabolities. Ascites accumulation reflects the presence of portal venous hypertension and the alterations in plasma oncotic pressure. Lastly, the presence of hepatic encephalopathy heralds an inability of the liver to clear toxins from the circulation. Patients with significant hepatic dysfunction, undergoing abdominal surgery, can have mortality rates as high as 82% for Child C (100). Other classification systems that utilize different parameters have been evaluated and are used at some centers. The Acute Physiology and Chronic Health Evaluation III score has been shown to predict survival in cirrhotic patients admitted to an intensive care unit (101). Recently, the model for end-stage liver disease scale, MELD, has replaced the Child–Pugh classification for liver transplant allocation (102). Hepatic encephalopathy befalls patients with both chronic and acute liver failure. In acute liver failure, patients suffer from a rapid decline in mentation with increased intracranial pressure, which may lead to death. Chronic liver disease results in impaired memory, poor reaction times, sensory Table 4 Pugh’s Modification of Child’s Classification Clinical and biochemical measurements Encephalopathy (96) Ascites Bilirubin (mg/100 mL) Albumin (g/L) PT (second prolonged) Child’s A ¼ 5–6 points (mortality ¼ 3–10%) Child’s B ¼ 7–9 points (mortality ¼ 10–30%) Child’s C ¼ 10–15 points (mortality ¼ 50–80%)

Points scored for increasing abnormality 1

2

3

None Absent 1–2 >35 1–4

1 and 2 Slight 2–3 28–35 4–6

3 and 4 Moderate >3 <28 >6

Abbreviation: PT, prothrombin time. Source: From Ref. 97.

and motor dysfunction, and maybe even coma. These changes are fully reversible with the improvement of liver function. The precise pathogenesis remains unclear. Since 1893, when members of Pavlov’s group described ‘‘the meat intoxication syndrome,’’ ammonia has been judged an important factor in the development of hepatic encephalopathy. Ammonia and other toxins are not metabolized properly by the liver in patients with hepatic encephalopathy, resulting in alterations in the blood–brain barrier, cerebral neurotransmission, and cerebral energy metabolism (103,104).

DIAGNOSTIC TESTING Clinical evaluation of the patient with liver disease normally includes a variety of assays to assist the surgeon with making the initial diagnosis, following patient progress, and determining prognosis. Not surprisingly, with the liver performing such a complex variety of tasks for the body, laboratory tests of liver function and disease may not accurately reflect the actual state of the organ. Thus, the surgeon must combine a variety of tests performed over a range of time and interpret the test results within the context of each individual patient. As we discussed in the prior section, assessing the extent of liver disease remains invaluable in planning the operation, ensuring sufficient hepatic reserves, and counseling the patient. We will briefly review the most common tests performed in clinical practice, often called the liver function tests (105). This nomenclature is misleading, because most of these tests do not actually measure how the liver is functioning. In considering these laboratory assays, they can best be divided into two broad categories: (i) true hepatic function assays and (ii) screening tests of hepatobiliary disease.

Hepatic Function Tests Synthesis Albumin The critical role of protein synthesis of the liver can be evaluated by determining the serum level of proteins synthesized by the liver. For this reason, serum albumin levels may provide insight into the protein synthetic capacity of the liver over a period of several weeks. The half-life of albumin in the serum is approximately 21 days, with 4% of the total albumin pool being degraded daily. The liver synthesizes about 200 mg/kg of albumin daily in a healthy person. The serum albumin level reflects a balance between synthesis and loss (80). Hypoalbuminemia is not specific for the functional state of the liver because low albumin levels might represent a decreased synthetic capacity by the liver, protein malnutrition, increased extracellular volume, or increased protein loss as occurs in the nephrotic renal syndrome. This example emphasizes an important aspect of the clinical decision, which surgeons face when evaluating patients with hepatic disease, namely a single test result that is often uninterpretable in isolation of other results in the context of the individual patient. Surgical patients often have depressed albumin synthesis as a result of the inflammatory signaling mediated by inhibitory substances such as tumor necrosis factor and IL-1 (106,107). Prothrombin Time Another important tests of hepatic synthesis is the measurement of the prothrombin time (PT). As previously discussed, the liver is the major site for generation of the coagulation proteins. The PT measures the rate at which

Chapter 19: Hepatic Physiology

prothrombin in titrated plasma is converted to thrombin. This test depends not only on the plasma levels of prothrombin, but also on the proteins involved in the extrinsic pathway of the coagulation cascade, such as fibrinogen and Factors V, VII, and IX. The plasma half-life of these factors is usually less than one day, causing a rapid change in the PT with changes in hepatic synthetic function. A prolonged PT is not specific for liver disease, but may correlate with prognosis in some hepatic conditions when congenital and acquired coagulopathies have been eliminated from the differential diagnosis. In general, when the PT is prolonged due to vitamin K deficiency, the parenteral adminstration of vitamin K will rapidly rectify the situation. In the setting of parenchymal liver disease, vitamin K supplementation is ineffective. The degree of prolongation of the prothromin time correlates with prognosis in some conditions. In acute viral, toxic, or alcoholic hepatitis, a prolongation of more than five seconds may signal a more fulminant course of disease. A PT greater than 100 seconds may be an indication for liver transplantation (108,109).

Screening Tests Hepatocyte Cellular Injury Hepatocytes contain thousands of enzymes within their toolbox to perform the tasks assigned to the liver by the body. These enzymes are normally intracellular, but are released when the hepatocytes are injured. The most commonly assayed enzymes are the aminotransferases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). AST and ALT catalyze the transfer of alpha-amino groups from aspartate and alanine, respectively, to ketoglutarate, yielding pyruvate and oxaloacetate. Neither enzyme is exclusively found in the liver, though ALT is present in highest concentration in the liver and is more specific for liver disease than AST. ALT is localized to the cytoplasm; whereas, AST is found within the cytoplasm and the mitochondria of the cells. AST is cleared more rapidly than ALT. The highest elevations occur in conditions associated with extensive hepatocellular necrosis, such as viral hepatitis, ischemic shock, and acute toxic injury; however, the extent of liver cell necrosis correlates poorly with the magnitude of elevation. Furthermore, the absolute elevation offers little prognostic value. In caring for patients with alcoholic hepatitis, the transaminase levels will rarely go over 200 to 300 IU/L (110–112). In addition to AST and ALT, a variety of hepatic enzymes have been evaluated for diagnostic purposes and have been found to be inferior to the aminotransferases. Lactose dehydrogenase, isocitrate dehydrogenase, and sorbitol dehydrogenase are cytoplasmic enzymes found in hepatocytes and in a number of tissues throughout the body (113,114). They have limited diagnostic usefulness. Glutamate dehydrogenase is a mitochondrial enzyme with a high concentration in centrilobular hepatocytes; however, measurement is rarely performed clinically (115).

Biliary Injury Alkaline phosphatases (ALP) are present in many tissues in the body, but the serum levels usually reflect the hepatic and bone isozymes. ALP catalyzes the release of orthophosphate from ester substrates at alkaline pH. Although a variety of nonhepatic conditions may cause an elevation in ALP levels, the source may be easily identified based upon the clinical picture. If necessary, further laboratory tests can be performed to differentiate the isoenzyme; however, the more common clinical practice involves the addition of a second

437

confirmatory assay such as 5’-nuleotidase, leucine aminopeptidase, or gamma-glutamyl transpeptidase (GGTP). Of these tests, GGTP has become the most common adjunctive assay because the GGTP level is not elevated in bone disease. Thus, an elevated ALP in the setting of an elevated GGTP suggests a hepatobiliary origin for the ALP. Large elevations of ALP of 3 to 10 times normal usually indicate obstruction of bile flow in the biliary tree, with the highest elevations generally seen with extrahepatic obstruction. The ALP may be the only clinically identified alteration seen in patients with bile duct strictures or lesions obstructing only one lobe or segment, and for this reason it is a fairly sensitive screening test for hepatic malignancy. Of course, the ALP assay is not a perfect screening test because one-third of the patients with isolated ALP elevations have no evidence of hepatobiliary disease (105).

Metabolite and Drug Clearance This group of tests measures the capacity of the liver to clear exogenous and endogenous substances from the circulation. As described previously, the metabolism of hemoglobin results in the production of bilirubin, which is processed by the liver for excretion into the gut. Hepatic injury may result in a decreased capacity of the liver to conjugate bile and other drugs, resulting in hyperbilirubinemia. Hyperbilirubinemia may result from a variety of other causes including excessive hemolysis, genetic defects in bilirubin processing, or excretory dysfunction. Although, bilirubin measurements, both conjugated and unconjugated fractions, are the most commonly assessed endogenous marker of metabolite and drug clearance, other assays have been developed, which rely upon the capacity of the liver to clear an exogenous drug or dye. The use of indocyanine green and bromsulphalein dyes, galactose and lidocaine administration, and various breath tests (aminopyrine/caffeine) have all been evaluated, but they have seen little general clinical use (116–118).

Immunologic Tests A number of specific tests have been developed to identify infectious and inflammatory conditions that affect the liver. Viral hepatitis caused by hepatitis A, B, C, D, or E viruses can be assayed in the serum. Other infectious causes can be pursued, such as cytomegalovirus, Epstein–Barr virus, or amebic infections (119,120). In the setting of autoimmune disorders, the presence of antimitochondrial (primary biliary cirrhosis), smooth muscle (sclerosing cholangitis), or antinuclear antibody can be determined (121). Alpha fetoprotein and carcinoembryonic antigen levels may prove useful in evaluating patients with neoplasms.

Liver Biopsy Liver biopsy is the gold standard diagnostic test in alcoholic liver disease and cirrhosis, short of explanting the entire liver. Liver biopsy may be performed via a blind percutaneous approach, transjugular, ultrasound or radiographically directed, or a laparoscopic biopsy (122). In the setting of acute hepatitis or acute cholestatic jaundice, the histologic changes are nonspecific and the biopsy is mainly for prognostic purposes. With cirrhosis, the liver biopsy may demonstrate not only the presence of cirrhosis, but perhaps the etiology as well, such as hereditary hemochromatosis, alpha-1 antitrypsin deficiency, or Wilson’s disease. Although the risk of death from a liver biopsy is low (0.04%), a significant concern associated with the procedure is the possibility of sampling

medwedi.ru

438

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

error in which the histology of the biopsy may not be a true representation of the current state of the pathology (123).

Radiographic Evaluation A complete review of all the radiologic tests available to assess the liver is beyond the scope of this chapter. Ultrasound provides a useful noninvasive method of evaluating the parenchyma, the biliary system, and the vascular supply of the liver; however, ultrasound evaluation is hampered by operator variability and lower accuracy in hepatic lesion detection (124). Intraoperative ultrasound facilitates the identification of lesions that might not be palpable or visualized during a laparoscopic procedure. Increasing speed and quality of computed tomography (CT) scanning has continued to improve the anatomic picture and utility of this study in the preoperative evaluation of patients for hepatic resection. Lesions less than 5 mm in diameter can now be identified and, in some cases, characterized. Liver CT evaluation can be performed using dual or triple phase imaging. Because most tumors of the liver have only a hepatic arterial blood supply, the hepatic arterial phase of the CT detects hypervascular lesions (such as hepatocellular carcinoma). Improved detection of liver lesions can be obtained by angiographically assisted CT scans. In the setting of trauma, CT scanning has become the gold standard modality for detecting solid organ injury in the hemodynamically stable patient and has demonstrated a high sensitivity and specificity for liver lacerations. In addition to CT scanning, magnetic resonance imaging (MRI) of the liver has proved very specific for both focal and diffuse liver diseases (125,126). Many of the advances in both CT and MRI scanning are based on significant improvements in the computer hardware and software available to enhance and manipulate the radiographic images (127,128).

REGENERATION Incorporated into the tale of Prometheus in Greek mythology, hepatic regeneration remains a fascinating area of active scientific exploration. In the myth, Prometheus is punished by the gods for giving men the knowledge of fire by having him chained to a stone. Daily a great bird eats his liver, only to have it regrow overnight to be ready for another meal. In actuality, the regenerative process does not happen overnight, but instead involves a complex process of self-renewal. Most organs in the adult human are unable to increase cell numbers after injury, but instead some are able to respond with cellular hypertrophy (129). The liver does not actually regenerate in the true sense as depicted in the legend of Prometheus. A new lobe does not regrow after partial hepatectomy. Partial hepatectomy results in the initiation of DNA synthesis in the remaining liver cells and a return by the liver to its optimal mass relative to the body (130). This capacity is unlimited, occurring after multiple resections. There are three phases in liver regeneration: (i) initiation, (ii) proliferation, and (iii) termination. The liver initiates regeneration three days after a resection and returns to its original size after about six months. Liver function has usually returned to normal two to three weeks after partial hepatectomy (129). Many advances have been made in identifying the genetic and molecular signals that regulate the growth factors and cytokines important in liver regeneration, many of which are elaborated by the Kupffer cells and hepatic stellate cells

(131). In particular, HGF plays an important role in the signaling responsible for regeneration (132). Epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) are also strong mitogens for primary hepatocytes (129). Hepatic oval ‘‘stem’’ cells are increasingly identified as participants in some forms of hepatic regeneration. These small cells have an oval nucleus and are bipotential cells with the capacity to differentiate into both hepatocytes and bile ductular cells. The oval cells are believed to reside in the canals of Hering and in extrahepatic sites, in particular the bone marrow (133). Oval cells express receptors for HGF, EGF, and TGF-alpha. The mechanisms by which these cells are activated and differentiate to participate in hepatic regeneration are not well understood and are the subject of intense investigation (134).

FUTURE Only 40 years ago, patients with end-stage liver disease had no surgical therapy available to them. Organ transplantation, once the stuff of science fiction, has become almost routine. With the advent of the orthotopic liver transplant, the possibility of surviving once unsurvivable conditions has become a reality. The one-year survival is almost 90% and a threeyear survival of 80% can be achieved at many leading medical centers. Despite increasing utilization of marginal donors and living related donor transplantation, waiting lists persist in the United States, with more than 1500 patients dying while awaiting transplant in 2003 (Based on OPTN data as on January 1, 2005). A variety of new approaches and some new twists on old approaches continue to be pioneered. Split liver transplantation allows for the right lobe of the liver to be transplanted into an adult while the left lobe is given to a pediatric recipient. Unfortunately, this technique results in increased graft failure and biliary complications. Domino transplantation has also been used to increase the organ pool by transplanting the explanted liver from a recipient with familial amyloidosis to a second recipient. Living donor transplantation has significantly increased the pool of donors, with 500 adult-to-adult transplants performed in the United States in 2001. In addition to whole organ transplants, isolated hepatocyte transplantation has been used as a bridge to transplantation in patients with fulminant hepatic failure and to treat inherited metabolic disorders (135). For similar indications, extracorporeal liver perfusion has been attempted over the last four decades using human, pig, baboon, and cow livers (136). At present, a number of institutions are in the process of developing artificial bioreactors within which to grow hepatocytes to perform a version of hemodialysis as a bridge to transplant for patients in fulminant hepatic failure. Finally, modifications in the porcine genome continue to be pursued in hopes of lowering the immunologic barriers to xenotransplantation. Ultimately, finding an adequate long-term nonbiologic replacement for the liver remains inconceivable given the more than 5000 functions performed by the organ.

SUMMARY Among the many organs required for human existence, the liver is especially unique not only because it is critical to life itself, but also because of its unusual ability to heal and regenerate itself when injured. It is the only organ in the

Chapter 19: Hepatic Physiology

body where protein, lipid, and carbohydrate metabolism come together for metabolic coordination and homeostasis; if it fails in carrying out these responsibilities eventual death is the end result from complications resulting from its failure to carry out its life-giving functions. In contrast to the kidney in which absent organ function can be substituted by hemodialysis, it is unlikely that a mechanical device will ever be developed, which can successfully take over the literally thousands of intrinsic functions carried out by the liver. Thus, as reverenced by the ancients of old, the liver truly is an organ of wonder and fascination.

REFERENCES 1. Medicine: An Illustrated History. New York: Abrams, 1987. 2. A History of Medicine: From Prehistory to the Year 2020. New York: Barnes and Noble Books, 1992. 3. Lawson EE, Grand RJ, Neff RK, Cohen LF. Clinical estimation of liver span in infants and children. Am J Dis Child 1978; 132:474–476. 4. Clark JH, Wood RP. Modern Surgical Care: Physiologic Foundations and Clinical Applications. 2nd ed. St. Louis: Quality Medical Publishing, 1998:491–512. 5. Ali A, Crawford MJ. Developmental biology: an array of new possibilities. Biotechnol Adv 2002; 20:363–378. 6. Zaret KS. Regulatory phases of early liver development: paradigms of organogenesis. Nat Rev Genet 2002; 3:499–512. 7. Zaret KS. Liver specification and early morphogenesis. Mech Dev 2000; 92:83–88. 8. Duncan SA. Transcriptional regulation of liver development. Dev Dyn 2000; 219:131–142. 9. Human Embryology. 3rd ed. New York: Churchill Livingstone, 2001. 10. Matsumoto K, Yoshitomi H, Rossant J, Zaret KS. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 2001; 294:559–563. 11. Nakanuma Y, Hoso M, Sanzen T, Sasaki M. Microstructure and development of the normal and pathologic biliary tract in humans, including blood supply. Microsc Res Tech 1997; 38:552–570. 12. Hunter JA, Paul J. Haemoglobins of the foetal and adult rat: sites of synthesis and the effects of erythropoietin. J Embryol Exp Morphol 1969; 21:361–368. 13. Suchy FJ, Bucuvalas JC, Novak DA. Determinants of bile formation during development: ontogeny of hepatic bile acid metabolism and transport. Semin Liver Dis 1987; 7:77–84. 14. Feldmann G, Scoazec JY, Racine L, Bernuau D. Functional hepatocellular heterogeneity for the production of plasma proteins. Enzyme 1992; 46:139–154. 15. Thung SN, Gerber MA. Liver. In: Sternberg SS, ed. Histology for Pathologists. New York: Raven Press, 1992:625. 16. Rappaport AM. The microcirculatory hepatic unit. Microvasc Res 1973; 6:212–228. 17. Schumacher P, Geerts A, Pietrangelo A, Dienes HP, Rogler CE. Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver but not myofibroblast-like cells derived from fat-storing cells. Hepatology 1992; 15:5–11. 18. Billiar TR, Curran RD. Kupffer cell and hepatocyte interactions: a brief overview. J Parenter Enteral Nutr 1990; 14:175S–180S. 19. Gray H. Anatomy of the Human Body. 20th ed. Philadelphia: Lea & Febiger, 1918. 20. Zoli M, Magalotti D, Grimaldi M, Gueli C, Marchesini G, Pisi E. Physical examination of the liver: is it still worth it? Am J Gastroenterol 1995; 90:1428–1432. 21. Naylor CD. The rational clinical examination. Physical examination of the liver. JAMA 1994; 271:1859–1865. 22. Bismouth H, Aldridge MC, Kuntslinger F. Macroscopic anatomy of the liver. In: Mclntyre N, et al., eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press, 1991:4.

439

23. Lamade W, Vetter M, Hassenpflug P, Thorn M, Meinzer HP, Herfarth C. Navigation and image-guided HBP surgery: a review and preview. J Hepatobiliary Pancreat Surg 2002; 9:592–599. 24. Couinaud C. Liver anatomy: portal (and suprahepatic) or biliary segmentation. Dig Surg 1999; 16:459–467. 25. Bismouth, H, Aldridge MC, Kuntslinger F. Macroscopic anatomy of the liver. In: Mclntyre N, et al., eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press, 1991:5. 26. Houssin D, Boillot O, Soubrane O, et al. Controlled liver splitting for transplantation in two recipients: technique, results and perspectives. Br J Surg 1993; 80:75–80. 27. Jung G, Krahe T, Krug B, Hahn U, Raab M. Delineation of segmental liver anatomy. Comparison of ultrasonography, spiral CT and MR imaging for preoperative localization of focal liver lesions to specific hepatic segments. Acta Radiol 1996; 37:691–695. 28. Deshpande RR, Heaton ND, Rela M. Surgical anatomy of segmental liver transplantation. Br J Surg 2002; 89:1078–1088. 29. Ger R. Surgical anatomy of the liver. Surg Clin North Am 1989; 69:179–192. 30. Gadzijev EM. Surgical anatomy of hepatoduodenal ligament and hepatic hilus. J Hepatobiliary Pancreat Surg 2002; 9:531–533. 31. Witte MH, Witte CL, Dumont AE. Estimated net transcapillary water and protein flux in the liver and intestine of patients with portal hypertension from hepatic cirrhosis. Gastroenterology 1981; 80:265–272. 32. Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol 2003; 38(suppl 1):S54–S68. 33. Nakamura S, Tsuzuki T. Surgical anatomy of the hepatic veins and the inferior vena cava. Surg Gynecol Obstet 1981; 152:43–50. 34. Textbook of Medical Physiology. 9th ed. Philadelphia: W.B. Saunders Company, 1996. 35. Katz S, Jimenez MA, Lehmkuhler WE, Grosfeld JL. Liver bacterial clearance following hepatic artery ligation and portacaval shunt. J Surg Res 1991; 51:267–270. 36. Mathison JC, Ulevitch RJ. The clearance, tissue distribution, and cellular localization of intravenously injected lipopolysaccharide in rabbits. J Immunol 1979; 123:2133–2143. 37. Hepatocyte and Kupffer Cell Interactions. Boca Raton: CRC Press, 1992. 38. Hambleton J, Leung LL, Levi M. Coagulation: consultative hemostasis. Hematology. Am Soc Hematol Educ Program 2002:335–352. 39. Nelsestuen GL, Zytkovicz TH, Howard JB. The mode of action of vitamin K. Identification of gamma-carboxyglutamicacid as a component of prothrombin. J Biol Chem 1974; 249:6347–6350. 40. Mammen EF. Coagulation defects in liver disease. Med Clin North Am 1994; 78:545–554. 41. Hoffman AL, et al. Hepatic regeneration: current concepts and clinical, implications. Semin Liver Dis 1994; 14(2):191. 42. Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 2001; 14:611–650. 43. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947–954. 44. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349:474–485. 45. Herrmann R, Mclntyre N. Amino-acid metabolism, urea production; and pH regulation. In: Mclntyre N, et al., eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press, 1991:168. 46. Krebs HA. Metabolism of amino acids. III. Deamination of amino acids. Biochem J 2004; 29:1620–1644. 47. Cohen NS, Kyan FS, Kyan SS, Cheung CW, Raijman L. The apparent Km of ammonia for carbamoyl phosphate synthetase (ammonia) in situ. Biochem J 1985; 229:205–211. 48. Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003; 101:3359–3364. 49. Smith LH Jr. Overview of hemochromatosis. West J Med 1990; 153:296–308.

medwedi.ru

440

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

50. Merrell RC. Hepatic physiology. In: Miller TA, ed. Physiologic Basis of Modern Surgical Care. St. Louis: CV Mosby, 1988:407. 51. Bell GI, Burant CF, Takeda J, Gould GW. Structure and function of mammalian facilitative sugar transporters. J Biol Chem 1993; 268:19161–19164. 52. Iynedjian PB. Mammalian glucokinase and its gene. Biochem J 1993; 293(Pt 1):1–13. 53. Cline GW, Rothman DL, Magnusson I, Katz LD, Shulman GI. 13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus. J Clin Invest 1994; 94:2369–2376. 54. Iynedjian PB, Gjinovci A, Renold AE. Stimulation by insulin of glucokinase gene transcription in liver of diabetic rats. J Biol Chem 1988; 263:740–744. 55. Iynedjian PB, Jotterand D, Nouspikel T, Asfari M, Pilot PR. Transcriptional induction of glucokinase gene by insulin in cultured liver cells and its repression by the glucagon-cAMP system. J Biol Chem 1989; 264:21824–21829. 56. Ferrer JC, Favre C, Gomis RR, et al. Control of glycogen deposition. FEBS Lett 2003; 546:127–132. 57. van Schaftingen E, Veiga-da-Cunha M, Niculescu L. The regulatory protein of glucokinase. Biochem Soc Trans 1997; 25:136–140. 58. Barthel A, Schmoll D. Novel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2003; 285:E685–E692. 59. Granner D, Pilkis S. The genes of hepatic glucose metabolism. J Biol Chem 1990; 265:10173–10176. 60. Cahill GF Jr. Starvation in man. N Engl J Med 1970; 282: 668–675. 61. Marliss EB, Aoki TT, Unger RH, Soeldner JS, Cahill GF Jr. Glucagon levels and metabolic effects in fasting man. J Clin Invest 1970; 49:2256–2270. 62. Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol 1992; 54:885–909. 63. Katz J, Tayek JA. Recycling of glucose and determination of the Cori cycle and gluconeogenesis. Am J Physiol 1999; 277:E401–E407. 64. Thomson TJ, Runcie J, Miller V. Treatment of obesity by total fasting for up to 249 days. Lancet 1966; 2:992–996. 65. Reshef L, Olswang Y, Cassuto H, et al. Glyceroneogenesis and the triglyceride/fatty acid cycle. J Biol Chem 2003; 278: 30413–30416. 66. Mahley RW. Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology. Circulation 1985; 72:943–948. 67. Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res 2002; 43:1997–2006. 68. von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vase Biol 2001; 21:13–27. 69. Merrell RC. Hepatic physiology. In: Miller TA, ed. Physiologic Basis of Modern Surgical Care. St. Louis: CV Mosby, 1988:410. 70. Haussinger D. Hepatocyte heterogeneity in glutamine and ammonia metabolism and the role of an intercellular glutamine cycle during ureogenesis in perfused rat liver. Eur J Biochem 1983; 133:269–275. 71. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990; 48:297–309. 72. Rudman D, DiFulco TJ, Galambos JT, Smith RB III, Salam AA, Warren WD. Maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects. J Clin Invest 1973; 52:2241–2249. 73. Zieve L. Pathogenesis of hepatic encephalopathy. Metab Brain Dis 1987; 2:147–165. 74. James JH. Branched chain amino acids in heptatic encephalopathy. Am J Surg 2002; 183:424–429. 75. Debatin JF, Zahner B, Meyenberger C, et al. Azygos blood flow: phase contrast quantitation in volunteers and patients

76.

77.

78.

79.

80. 81. 82. 83.

84.

85. 86. 87. 88. 89.

90.

91.

92. 93.

94.

95. 96. 97.

98.

99.

100.

101.

with portal hypertension pre- and postintrahepatic shunt placement. Hepatology 1996; 24:1109–1115. Haussinger D. Regulation of hepatic ammonia metabolism: the intercellular glutamine cycle. Adv Enzyme Regul 1986; 25:159–180. Berlin JA, Chalmers TC. Meta-analysis of branched-chain amino acids in hepatic encephalopathy. Gastroenterology 1989; 97:1043–1045. Vilstrup H, Gluud C, Hardt F, et al. Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis. J Hepatol 1990; 10:291–296. Marchesini G, Bianchi G, Rossi B, Brizi M, Melchionda N. Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis. J Gastroenterol 2000; 35(suppl 12):7–12. Rothschild MA, Oratz M, Schreiber SS. Serum albumin. Hepatology 1988; 8:385–401. Ramadori G, Armbrust T. Cytokines in the liver. Eur J Gastroenterol Hepatol 2001; 13:777–784. Pannen BH, Robotham JL. The acute-phase response. New Horiz 1995; 3:183–197. Shibahara S, Kitamuro T, Takahashi K. Heme degradation and human disease: diversity is the soul of life. Antioxid Redox Signal 2002; 4:593–602. Hansen TW. Recent advances in the pharmacotherapy for hyperbilirubinaemia in the neonate. Expert Opin Pharmacother 2003; 4:1939–1948. Friedman LS. The risk of surgery in patients with liver disease. Hepatology 1999; 29:1617–1623. Friedman LS, Maddrey WC. Surgery in the patient with liver disease. Med Clin North Am 1987; 71:453–476. German SI. Disturbances in hepatic blood flow during anesthesia and surgery. Arch Surg 1976; 111:881–883. Pitt HA, Cameron JL, Postier RG, Gadacz TR. Factors affecting mortality in biliary tract surgery. Am J Surg 1981; 141:66–72. Bloch RS, Allaben RD, Walt AJ. Cholecystectomy in patients with cirrhosis. A surgical challenge. Arch Surg 1985; 120: 669–672. Aranha GV, Kruss D, Greenlee HB. Therapeutic options for biliary tract disease in advanced cirrhosis. Am J Surg 1988; 155:374–377. Metcalf AM, Dozois RR, Wolff BG, Beart RW Jr. The surgical risk of colectomy in patients with cirrhosis. Dis Colon Rectum 1987; 30:529–531. Lehnert T, Herfarth C. Peptic ulcer surgery in patients with liver cirrhosis. Ann Surg 1993; 217:338–346. Fernandes NF, Schwesinger WH, Hilsenbeck SG, et al. Laparoscopic cholecystectomy and cirrhosis: a case-control study of outcomes. Liver Transpl 2000; 6:340–344. Poggio JL, Rowland CM, Gores GJ, Nagomey DM, Donohue JH. A comparison of laparoscopic and open cholecystectomy in patients with compensated cirrhosis and symptomatic gallstone disease. Surgery 2000; 127:405–411. Klemperer JD, Ko W, Krieger KH, et al. Cardiac operations in patients with cirrhosis. Ann Thorac Surg 1998; 65:85–87. Trey, et al. N Engl J Med 1966; 274:473. Mclntyre N. Symptoms and signs of liver disease. In: Mclntyre N, et al, eds. Oxford Textbook of Clinical Hepatology. Oxford: Oxford University Press, 1991:273. Pugh RN, Murray-Lyon JM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646–649. Ziser A, Plevak DJ, Wiesner RH, Rakela J, Offord KP, Brown DL. Morbidity and mortality in cirrhotic patients undergoing anesthesia and surgery. Anesthesiology 1999; 90:42–53. Mansour A, Watson W, Shayani V, Pickleman J. Abdominal operations in patients with cirrhosis: still a major surgical challenge. Surgery 1997; 122:730–735. Zimmerman JE, Wagner DP, Seneff MG, Becker RB, Sun X, Knaus WA. Intensive care unit admissions with cirrhosis: risk-stratifying patient groups and predicting individual survival. Hepatology 1996; 23:1393–1401.

Chapter 19: Hepatic Physiology 102. Freeman RB Jr, Wiesheri RH, Harper A, et al. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl 2002; 8:851–858. 103. Jalan R, Hayes PC. Hepatic encephalopathy and ascites. Lancet 1997; 350:1309–1315. 104. Jalan R, Shawcross D, Davies N. The molecular pathogenesis of hepatic encephalopathy. Int J Biochem Cell Biol 2003; 35:1175–1181. 105. Limdi JK, Hyde GM. Evaluation of abnormal liver function tests. Postgrad Med J 2003; 79:307–312. 106. Dinarello CA. Interleukin-1 and the pathogenesis of the acutephase response. N Engl J Med 1984; 311:1413–1418. 107. Perlmutter DH, Dinarello CA, Punsal PI, Colten HR. Cachectin/tumor necrosis factor regulates hepatic acutephase gene expression. J Clin Invest 1986; 78:1349–1354. 108. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445. 109. Deitcher SR. Interpretation of the international normalised ratio in patients with liver disease. Lancet 2002; 359:47–48. 110. Dunn M, Martins J, Reissmann KR. The disappearance rate of glutamic oxalacetic transaminase from the circulation and its distribution in the body’s fluid compartments and secretions. J Lab Clin Med 1958; 51:259–265. 111. Zimmerman HJ, West M. Serum enzyme levels in the diagnosis of hepatic disease. Am J Gastroenterol 1963; 40: 387–404. 112. Rej R. Aspartate aminotransferase activity and isoenzyme proportions in human liver tissues. Clin Chem 1978; 24: 1971–1979. 113. Smit MJ, Duursma AM, Bouma JM, Gruber M. Receptormediated endocytosis of lactate dehydrogenase M4 by liver macrophages: a mechanism for elimination of enzymes from plasma. Evidence for competition by creatine kinase MM, adenylate kinase, malate, and alcohol dehydrogenase. J Biol Chem 1987; 262:13020–13026. 114. Bell JL, Shaldon S, Baron DN. Serum isocitrate dehydrogenase in liver disease and some other conditions. Clin Sci 1962; 23:57–66. 115. Van Waes L, Lieber CS. Glutamate dehydrogenase: a reliable marker of liver cell necrosis in the alcoholic. Br Med J 1977; 2:1508–1510. 116. Shani M, Gilon E, Ben Ezzer J, Sheba C. Sulfobromophthalein tolerance test in patients with Dubin–Johnson syndrome and their relatives. Gastroenterology 1970; 59:842–847. 117. Henderson JM, Kutner MH, Noe B. Galactose clearance and liver blood flow. Gastroenterology 1988; 95:1157–1158.

441

118. Tanaka E, Inomata S, Yasuhara H. The clinical importance of conventional and quantitative liver function tests in liver transplantation. J Clin Pharm Ther 2000; 25:411–419. 119. Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003; 20(362):2095–2100. 120. Harris KR, Dighe AS. Laboratory testing for viral hepatitis. Am J Clin Pathol 2002; 118(suppl):S18–S25. 121. Luxon BA. Autoimmune hepatitis. Making sense of all those antibodies. Postgrad Med 2003; 114:79–80. 122. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001; 344:495–500. 123. Phillips MG, Preedy VR, Hughes RD. Assessment of prognosis in alcoholic liver disease: can serum hyaluronate replace liver biopsy? Eur J Gastroenterol Hepatol 2003; 15:941–944. 124. Wernecke K, Rummeny E, Bongartz G, et al. Detection of hepatic masses in patients with carcinoma: comparative sensitivities of sonography, CT, and MR imaging. Am J Roentgenol 1991; 157:731–739. 125. Martin DR. Magnetic resonance imaging of diffuse liver diseases. Top Magn Reson Imaging 2002; 13:151–163. 126. Martin DR, Semelka RC. Imaging of benign and malignant focal liver lesions. Magn Reson Imaging Clin N Am 2001; 9:785-vii. 127. Rununeny EJ, Marchal G. Liver imaging. Clinical applications and future perspectives. Acta Radiol 1997; 38:626–630. 128. Poyanli A, Sencer S. Computed tomography scan of the liver. Eur J Radiol 1999; 32:15–20. 129. Court FG, Wemyss-Holden SA, Dennison AR, Maddem GJ. The mystery of liver regeneration. Br J Surg 2002; 89:1089–1095. 130. Higashiyama H, Yamaguchi T, Mori K, et al. Graft size assessment by preoperative computed tomography in living related partial liver transplantation. Br J Surg 1993; 80: 489–492. 131. Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol 2002; 13:425–431. 132. Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997; 276:60–66. 133. Theise ND, Krause DS. Bone marrow to liver: the blood of Prometheus. Semin Cell Dev Biol 2002; 13:411–417. 134. Petersen BE. Hepatic ‘‘stem’’ cells: coming full circle. Blood Cells Mol Dis 2001; 27:590–600. 135. Strom SC, Chowdhury JR, Fox IJ. Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis 1999; 19:39–48. 136. Pascher A, Sauer IM, Hammer C, Gerlach JC, Neuhaus P. Extracorporeal liver perfusion as hepatic assist in acute liver failure: a review of world experience. Xenotransplantation 2002; 9:309–324.

medwedi.ru

20 Portal Hypertension Alexander S. Rosemurgy and Emmanuel E. Zervos

INTRODUCTION Normal portal pressure is near 10 to 12 mmHg, with a gradient of near 0 to 4 mmHg between portal vein and the inferior vena cava (IVC). While the term ‘‘portal hypertension’’ denotes an increased pressure in the portal vein, it is generally reserved for occasions when the portal vein–IVC gradient is increased beyond 10 to 12 mmHg. There are a host of reasons why portal hypertension can develop. Some of the causes of portal hypertension are much more innocuous than others. For example, extrahepatic compression or obstruction of the portal vein can lead to portal hypertension, without concomitant hepatocellular dysfunction. Conversely, hepatic injury with subsequent fibrosis, as with cirrhosis, can lead to portal hypertension in the setting of impaired hepatic function. Therapies applied to portal hypertension will have varying outcomes depending on underlying liver function. Thus, knowing the cause of portal hypertension is essential in assigning risks of therapy and in predicting outcomes after therapy. Causes of portal hypertension are noted in Table 1. Particular note is made of the sinusoidal causes of portal hypertension, because they are notoriously associated with impaired hepatic function.

ANATOMY

pancreas. Conventionally, the common hepatic artery arises off the celiac axis, and, in short order, becomes the proper hepatic artery beyond the origin of the gastroduodenal artery, and then the left and right hepatic arteries. It is not uncommon to have an accessory or replaced right hepatic artery arising from the superior mesenteric artery, which travels to the liver anterior and lateral to the portal vein. Figure 1 shows normal portal anatomy.

VARICEAL HEMORRHAGE Presentation and Early Care There are several reasons why someone with portal hypertension will present for care. Portal hypertension may exist, but not be the cause of presentation. Rather, patients with portal hypertension might present because of impaired hepatic function, ascites, encephalopathy, or quality-of-life issues. Portal hypertension may result in gastrointestinal bleeding, which can be very sensational. As pressures in the portal system increase, small, otherwise nondescript, veins arising along the portal vein and its branches become low-resistance outflow collaterals. These veins become conduits through which portal blood flows out of and away from the hypertensive portal system toward the relatively lower-pressure central venous system. While much focus is on the area of the esophagus,

The liver has two sources of vascular inflow: hepatic arterial inflow and portal venous inflow. The majority (60% to 70%) of hepatic blood flow is from the portal venous system. Conversely, the majority (60–70%) of oxygen delivery to the liver comes from the hepatic artery, because the portal vein has relatively lower oxygen saturation. The portal venous system drains the spleen, the colon, the small bowel, the pancreas, the duodenum, and the gallbladder. Before entering the hepatoduodenal ligament, the portal vein travels along the undersurface of the

Table 1 Causes of Portal Hypertension

Splenic vein

Presinusoidal Extrahepatic Congenital Trauma Malignancy Hypercoagulable state Umbilical sepsis

Intrahepatic Schistosomaisis Congenital hepatic fibrosis Primary biliary cirrhosis

coronary vein portal vein

inferior mesenteric vein

Sinusoidal Cirrhosis

Postsinusoidal Budd Chiari Veno-occlusive disease

superior mesenteric vein

Figure 1 Normal portal anatomy.

medwedi.ru 443

444

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

esophagogastric junction, and stomach, collateralization of veins from the portal system occurs in clinically important forms in several locations (Table 2). Because of systemic– portal venous collateralization in patients with portal hypertension, varicose veins (i.e., varices) can and will arise, an example being the superior hemorrhoidal veins. Other sites where the interface between the portal system and the systemic venous system is particularly important are at enterostomy (e.g., ileostomy and colostomy) sites (Fig. 2). Most commonly, patients with portal hypertension, which presents as bleeding will present with bleeding arising from varices along the esophagus, esophagogastric junction, or stomach. Bleeding from varices can be slow or massive. Thereby, blood loss can be occult in patients presenting with anemia, or it can be massive and sensational, in patients vomiting blood and in extremis. For the purpose of this chapter, we will focus on rapid blood loss, though principles put forth in this chapter are applicable to all patients. When patients present with variceal bleeding, many activities important in care must occur at once. Airway management is of paramount importance, as patients undergo the ‘‘ABC’s of resuscitation.’’ If patients are not adequately oxygenating or ventilating, orotracheal intubation should be undertaken without delay. As well, if encephalopathy or other cause of depression of mentation exists, the airway should be protected by orotracheal intubation. Secure intravenous access must be obtained; central venous access is not a priority at this time. Resuscitation must be initiated immediately, with uncrossed matched blood given, if necessary. The immediate end point of resuscitation is stabilization of blood pressure. Subsequently, measures of organ perfusion, such as urinary output, become paramount and, later yet, concerns with over-resuscitation require attention. If patients are over-resuscitated, many adverse events can occur. Obviously, over-resuscitation can lead to acute pulmonary edema and other complications, but the issue in these patients is the impact of over-resuscitation on portal pressure. If a healthy patient without portal hypertension is over-resuscitated, then central venous pressure could be pushed to 20 mmHg. With this, and a portal vein–IVC pressure gradient of 6 mmHg, portal pressures are pushed to 26 mmHg. Generally, this has no sequela, because there are no varices. For a patient with portal hypertension, over-resuscitation, which elevates the central venous Table 2 Sites of Communication Between Portal Venous and Systemic Circulation Along the stomach, gastroesophageal junction, and esophagus In the cephalad retroperitoneum about the pancreas, duodenum, and root of the mesentery Retroperitoneal collaterals between the intestines and retroperitoneum, especially laterally, particularly involving the colon, particularly at the hepatic flexure and splenic flexure Between the superior (portal) and inferior (systemic) hemorrhoidal veins Veins about the bladder, especially anteriorly (space of Retzius) At the site of a colostomy, ileostomy, gastrostomy, or other stoma At the umbilicus, where the umbilical vein (which connects to the left branch of the portal vein) communicates with cutaneous veins (systemic venous system) leading to the appearance of caput medusa (large dilated superficial veins in the subcutaneous tissue on the abdominal wall) Between the spleen and the diaphragm In adhesions involving the intra-abdominal viscera and the retroperitoneum

Figure 2 Colostomy in a patient with portal hypertension (note varices around stoma).

pressure to 20 mmHg, has important implications. For this patient, with a portal vein–IVC gradient of 16 mmHg, portal pressures are raised to 36 mmHg and varices are distended, promoting ongoing bleeding. Promotion of ongoing bleeding can be the unfortunate and unintended consequence of over-resuscitation. Given that under-resuscitation is the concern with early therapy, central venous pressure monitoring is not necessary until later, after blood pressure has stabilized and time permits. Pharmacotherapy should be utilized as a first step after the ‘‘ABC’s of resuscitation.’’ Octreotide has become the drug of choice to reduce portal venous inflow and, thereby, portal pressures. If bleeding can be controlled with Octreotide, time would permit further evaluation and care. If bleeding continues out of control, further intervention must be undertaken immediately. Endoscopy can have major role in the diagnosis and treatment of major variceal bleeding. If bleeding continues despite Octreotide therapy, endoscopy should be undertaken to identify the source of bleeding, and, if possible, control it. Patients with cirrhosis and portal hypertension, and who experience gastrointestinal hemorrhage, have a high probability of bleeding from sites other than varices. High on the list of sites of nonvariceal bleeding is duodenal ulcer disease. Other potential sites of bleeding include sites of gastric ulcer disease, distal esophageal disease, including reflux esophagitis or Mallory–Weis tears, and esophagogastroduodenal malignancy. Endoscopy can identify sites of nonvariceal bleeding, unless bleeding is so rapid that the esophagus, stomach, and duodenum cannot be cleared of blood and blood clots. If profuse bleeding does not allow application of endoscopy, a balloon-tipped tube passed per os into the stomach should be utilized to control exsanguinating presumptive variceal hemorrhage. The Sengstaken–Blakemore (SB) tube is commonly utilized (Fig. 3). Before being used, a nasogastric-type tube should be tied to the SB tube proximal to the esophageal balloon. The application of the nasogastric-type tube will prevent accumulation of oropharyngeal secretions in the proximal esophagus.

Chapter 20:

Figure 3 SB tube in situ. Abbreviation: SB, Sengstaken–Blakemore.

The SB tube is passed per os into the stomach. If time permits, an X-ray is obtained to document position of the SB tube in the stomach. If time and circumstances do not permit, air should be pushed down the gastric lavage port. Auscultation of the abdominal wall over the stomach can confirm placement of the SB tube into stomach with some security. At this point, the gastric balloon is in place with 250 cc of air, and the SB tube is pulled back with one pound of pressure. To accomplish this, we use a 500 cc bag of crystalloid hoisted over a pulley on an orthopedic frame, which is always available in the emergency department or ICU. If bleeding continues, the esophageal balloon is inflated to 30 mmHg pressure. The SB tube can be left in place with balloons inflated for 48 hours. Beyond this, ulcerations brought on by the inflated balloons are an ever-increasing concern. Control of bleeding by the SB tube allows resuscitation to continue uncompromised by ongoing blood loss, correction of coagulopathy, treatment of comorbidities, support of drug/ alcohol dependency, purging of the gastrointestinal tract (GI) of blood, and attention to issues of general health. If, after the application of pharmacologic therapy, bleeding ameliorates and endoscopy can be undertaken, specific therapy for bleeding can be undertaken. Bleeding due to variceal sources can be addressed with endoscopic variceal sclerotherapy (EVS) or banding (EVB). While EVS and EVB are effective, their use is often determined by the endoscopist’s preference. In general, EVB is preferred for smaller, more isolated varices. Unfortunately, only varices limited to the esophagus or the first few centimeters of the proximal stomach are amenable to or candidates for EVS or EVB. Complications of EVS or EVB are thankfully uncommon. Ulcerations at sites of therapy are not uncommon, but uncommonly, the ulcers can bleed. Bleeding at sites of ulceration can be massive and will require site-specific care (endoscopic injection, thermal energy, or balloon tamponade) and possibly portal decompression. Late stricture formation is also possible, but uncommon. The biggest risk of EVS or EVB is failure to control variceal bleeding. Such a failure will require definitive therapy, to be discussed, possibly after temporary balloon tamponade. While successful endoscopic therapy will result in cessation of bleeding, ultimately the goal of endoscopic therapy

Portal Hypertension

445

is obliteration of esophageal and very proximal gastric varices. This may require several sessions of EVS or EVB even after cessation of bleeding. Longer-term, surveillance endoscopy will be required to ensure obliteration of varices. Failure of endoscopic therapy must be defined prior to initiation of EVS or EVB. Generally, failure of endoscopic therapy is defined as the inability to control variceal bleeding, finding varices most amenable to endoscopic therapy (e.g., gastric varices or portal gastropathy), or the inability to obliterate esophageal varices over time. Gastric varices require a special mention. While they may develop as venous outflow conduits from the portal vein confluence, along the wall of the stomach, they may not develop into vascular structures of any size. Conventionally, gastric varices are thought of as large tortuous vessels in the gastric wall. They may, however, develop as small extensive venous channels in the gastric wall, giving the stomach lining the appearance of velvet saturated with blood. This latter appearance of gastric varices is often referred to as ‘‘portal gastropathy’’ or ‘‘gastritis’’ of portal hypertension. The former term denotes the appearance the stomach lining can acquire in portal hypertension, while the latter recognizes the impairment of gastric function, which can occur with portal hypertension. In general, the early evaluation and care of patients with portal hypertension is best defined by the axiom ‘‘hope for the best, but prepare for the worst.’’ Keep blood products on hand; keep an SB tube at the bedside. Utilize pharmacotherapy and endoscopic therapy early. Prepare for the possibility that more definitive therapy may be necessary.

Assessing Hepatic Function When patients present with variceal hemorrhage due to portal hypertension and cirrhosis, an important part of the evaluation process is assessment of liver function. This assessment is undertaken through many routes. Both clinical and laboratory assessment are important. At the bedside, much can be said about a patient’s liver function. Generally muscular wasting, though possibly due to lifestyle, is consistent with poor liver function. As well, ascites, cutaneous spider angiomas, a ‘‘ruddy’’ complexion, encephalopathy (to whatever degree), extensive bruising, and jaundice or icterus are manifestations of the extensive hepatic impairment that can be apparent clinically. Laboratory testing can also document hepatic impairment. Hepatic synthetic ability can be determined through serum cholesterol and albumin, though both are acute phase reactants and will decrease notably with stress. Prothrombin time (PT) is a measure of the intrinsic clotting mechanism and is dependent upon hepatic synthesis. Bleeding can notably impact PT through consumption and loss. Hepatic detoxification can be measured through serum bilirubin levels. Elevated levels, particularly of the unconjugated form, of bilirubin are indicative of hepatic impairment. Impaired detoxification will impact drug metabolism, as with narcotics, numerous anesthetic agents, and Tylenol; but this will not aid in assessment of liver function. Platelet counts are depressed in patients with cirrhosis and portal hypertension, particularly with bleeding. High portal pressures and/or splenic vein occlusion will lead to splenic sequestration of platelets and, thereby, thrombocytopenia. Bleeding will add to this through platelet loss and consumption. Taken together, clinical and laboratory testing and assessment of liver function can be used to stratify hepatic reserve. Differences between hepatic function and

medwedi.ru

446

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 3 Child–Turcotte Hepatic Risk Classification A Bilirubin Albumin Encephalopathy Ascites Nutrition (muscle mass)

<2 >3.5 None None Normal

B 2–3 3–3.5 Controlled Controlled Fair

Table 4 Pugh Modification of Child’s Classification C >3 <3 Dense Refractory Poor

Points Bilirubin (mg/dL) Ascites PT (sec. prolonged) Encephalopathy Albumin (g/dL)

1 <2 None 1–3 None >3.5

2 2–3 Controlled 4–6 Controlled 2.8–3.5

3 >3 Refractory >6 Dense <2.8

Abbreviation: PT, prothrombin time. Source: From Ref. 1.

hepatic reserve are not always clear, but can be elucidated through this metaphor: hepatic function is akin to running, while hepatic reserve is akin to running as fast as possible, as if running for one’s life. While hepatic function, to a degree, is what we measure clinically or through laboratory testing, hepatic reserve is what we want to know. Hepatic reserve can be estimated by using Child’s classifications (also known as the Child–Turcotte classification) (Table 3) or a modification of it, the Child–Pugh Score (also called the Pugh Score) (Table 4). The Child–Pugh score was developed to expand on and, thereby, improve upon Child’s classification by including measurement of the PT and by noting if portal hypertension is caused by biliary cirrhosis. To establish a Child’s class, each stratifying factor is codified as being of the ‘‘A,’’ ‘‘B,’’ or ‘‘C’’ level. The class assigned is the same as the worst letter assigned any factor. A patient with four ‘‘As’’ and one ‘‘C,’’ is assigned Child’s class C, as is a person with five ‘‘Cs.’’ The Pugh Score is a number that ranges from 5 to 15. Each patient is assigned a number. The lower the number, the better. In general, a number of 5 or 6 is equivalent to a Child’s class A; 7 to 9 a Child’s class B; and 10 or more a Child’s class C. Patients with excellent hepatic function and estimated strong hepatic reserve (i.e., Child’s class A) will tolerate stress, bleeding, and/or invasive intervention better than patients with poor function/reserve (Child’s class C). Patients of Child’s class C have, generally speaking, finite survival, whereas patients of Child’s class A can have hopes of gender- and age-adjusted survival in the absence of progressive hepatic deterioration. Patients who are bleeding and of Child’s class C designation are generally considered, given adequate psychosocioeconomic support and resources, to be transplant candidates, whereas patients of Child’s class A and B are considered not to be in need of imminent transplantation. Further narrowing ‘‘imminent’’ is difficult, but generally, three to five years is considered to be beyond ‘‘imminent.’’

Liver transplantation is the only curative therapy for variceal bleeding due to portal hypertension. Success with liver transplantation is ever improving, with one-year graft survival and patient survival approaching 80% and 90%, respectively. Survival beyond three years generally approaches age- and gender-adjusted controls, though immunosuppression must be continued and recurrent viral hepatic disease is always a concern.

Definitive Therapy for Variceal Bleeding

Portasystemic Shunts

The options for definitive therapy for bleeding varices in patients with portal hypertension are several, and very different in their scope. They are as follows:

Two clinical developments have changed the landscape of the treatment of complicated portal hypertension in recent years: the maturation of liver transplantation and the widespread application of transjugular intraheptic portasystemic shunt (TIPS). The development of liver transplantation and TIPS has diminished the role of general surgeons in the treatment of patients with variceal hemorrhage. Today, it is probable that residents completing training in general surgery will have never undertaken a portasystemic shunt, nor will they have cared for a patient undergoing a portasystemic shunt. Therefore, considerations of surgical shunting and treating bleeding varices due to cirrhosis and portal hypertension is either invaluable information to general surgeons and general surgeons in training, or it is profoundly irrelevant. In our opinion, because surgeons are routinely called upon to offer treatment as a last resort for patients with upper GI hemorrhage, it is the former.

& & &

&

Endoscopic therapy with pharmacotherapy Liver transplantation Portasystemic shunts & Distal splenorenal shunts & Portacaval shunts & H-graft portacaval shunts (HGPCSs) & Mesocaval shunts & Large-diameter side-to-side portacaval shunts & Transjugular intrahepatic portasystemic shunt (TIPS) Devascularization procedures

Before assigning definitive therapy, several actions should be undertaken. A Child’s class or Pugh Score should

be assigned. If possible, some assessment of comorbidities should be undertaken. Portal vein patency, through colorflow Doppler ultrasound or venous phase visceral angiography, should be determined. Patients with poorest hepatic reserve (i.e., Child’s class C), particularly those with serious and irreparable comorbidities, will ideally be definitively treated with less invasive measures, such as medical and endoscopic therapy, whereas patients with best hepatic reserve (i.e., Child’s class A), especially if without serious comorbidity, will be treated with therapies, through possibly more invasive approaches, which will offer best chances of long-term relief of variceal bleeding.

Endoscopic Therapy Endoscopic therapy has already been discussed. In short, the goal of therapy is obliteration of esophageal varices. Patients with gastric varices are not candidates for endoscopic therapy because of risks of perforation and because long-term rates of success are poor. Pharmacotherapy, generally limited to beta-blockade with propanolol, is of limited help, but it is a worthwhile adjunct. Propranolol is dosed to see a 25% reduction in resting pulse or a pulse of 60 per minute. Propranolol will cause a reduction in exercise tolerance.

Liver Transplantation

Chapter 20:

A negative view of surgical shunting evolves from a host of perspectives. Patients with massive upper GI hemorrhage generally present at inconvenient times and they are difficult patients to care for. Often, the patients are admitted to nonsurgical services and ‘‘control’’ over the patients is lost by general surgeons. As well, there is tremendous misinformation regarding the efficacy of nonsurgical shunting such as TIPS. The role of TIPS continues to evolve, but it is strongly supported by nonsurgical health care providers. Furthermore, as noted earlier, general surgeons generally are unfamiliar with surgical shunting today, making the care of these patients a source of some discomfort and uncertainty. Surgical shunts are not definitive therapy; transplantation is. However, not everyone is eligible for hepatic transplantation. Strong social factors and health and medical factors contribute to restriction of transplantation (Table 5). Considerations for surgical shunting, however, should not detract from the efficacy and the applicability of transplantation. Hepatic transplantation is curative for patients with bleeding varices due to cirrhosis and portal hypertension. Hepatic transplantation is a major therapeutic modality that has evolved into a mainstay of therapy for patients of bleeding varices due to cirrhosis and portal hypertension. Hepatic transplantation is not to be discouraged or condemned, but, as mentioned, transplantation may be restricted for a host of reasons. Notably, not everyone needs a transplant. The key to deciding whether someone needs a transplant or should undergo surgical shunting is hepatic reserve. Unfortunately, hepatic reserve is very difficult to determine and nothing is better presently in determining such reserve than assigning a Child–Turcotte class (also known as a Child’s class) or a Child–Pugh score. Surgical shunting palliates bleeding varices due to cirrhosis and portal hypertension. Portal decompression achieved through surgical or radiological methods has been shown to be more effective than endoscopic and medical therapy through numerous, randomized controlled trials (1–15). Furthermore, as previously noted, not all patients are candidates for definitive endoscopic therapy. Lastly, surgical shunting has been documented to conserve resources relative to medical therapy with or without endoscopic therapy and has been shown to prolong survival and limit rebleeding (16). Surgical shunts come in many types and varieties. Some have been relegated to history. In short, there are two basic types: Central (nonselective) shunts and noncentral (selective) shunts. Best results with each shunt in common use today are noted by surgeons or groups that promote one shunt and primarily undertake one type of shunt. By intent, central shunts decompress the portal system. There, are many types of central and noncentral shunts

Portal Hypertension

Table 6 Types of Portasystemic Shunts Central (nonselective) End-to-side portacaval shunt Side-to-side portacaval shunt Mesocaval shunt Proximal splenorenal shunt Interposition portacaval shunt Interposition splenorenal shunt

Noncentral (selective) Distal splenorenal (Warren) Coronary caval shunt

(Table 6). An end-to-side portacaval shunt decompresses the portal system very well, but does not decompress the sinusoidal system within the liver. Furthermore, an end-to-side portacaval shunt diverts all portal flow away from the liver. Because of the high incidence of postshunt hepatic dysfunction, end-to-side portacaval shunts have been relegated to history. An end-to-side shunt is shown in Figure 4. Side-to-side portacaval shunts and variations of sideto-side portacaval shunts, such as prosthetic HGPCSs, continue to be used. Reports from many centers across the world purport excellent outcomes with impressive results with long follow-up. A side-to-side shunt is shown in Figure 5. Mesocaval shunts seem to be favored by some, because they do not violate the right upper quadrant and, thereby, do not add difficulty to subsequent hepatic transplantation, if undertaken. Their main role seems to be in decompressing the mesenteric system in patients with portal vein occlusion. A mesocaval shunt is shown in Figure 6. Proximal splenorenal shunts have largely the same role. Proximal splenorenal shunts are undertaken with a splenectomy and involve an anastomosis between the splenic vein near the splenic hilum and the renal vein. This shunt decompresses the portal system very well and is primarily undertaken for patients with portal vein occlusion that is distal to the superior mesenteric vein–splenic vein junction. A proximal splenorenal shunt is shown in Figure 7. Interposition splenorenal shunts are uncommonly undertaken. This

Table 5 Issues Limiting Application of Transplantation for Bleeding Varices Alcoholism Ilicit drugs Inadequate funding Psychosocial issues (reliability/compliance) Health Organ shortages Program accessibility Religious issues

447

Figure 4 End-to-side portacaval shunt.

medwedi.ru

448

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Figure 7 Proximal splenorenal shunt.

Figure 5 Side-to-side portacaval shunt.

shunt decompresses the gastroesophageal–variceal complex as well as the portal system. It is generally reserved for patients with portal vein occlusion that involves the splenic vein–superior mesenteric vein junction. This shunt will decompress the superior mesenteric vein indirectly through collaterals, but is primarily favored over a mesocaval shunt when the gastroesophageal variceal complex is the area of hemorrhage. An interposition shunt is shown in Figure 8. TIPS is functionally a side-to-side portacaval shunt (Fig. 9). Many favor it because it offers a nonsurgical approach to shunting. TIPS is placed by interventional radiologists, generally through a right internal jugular vein approach. A wire is placed across the hepatic parenchyma and subsequently an endovascular stent is placed, bridging the right branch of the portal vein to the right hepatic vein. Long-term issues with patency and occlusion remain a concern.

Figure 6 Mesocaval shunt.

The variety of noncentral shunts is much more limited. The distal splenorenal shunt is the only noncentral (i.e., selective) shunt widely undertaken. It has been utilized in a host of centers by a host of surgeons for many years, and its long-term results are outstanding. Unfortunately, its use is largely limited to patients of Child’s class A and in some circumstances of Child’s class B. Patients with hepatofugal flow (i.e., flow away from the liver) or ascites are generally not considered candidates for distal splenorenal shunts. A distal splenorenal shunt is shown in Figure 10. A great deal of study has dealt with small- versus large-diameter interposition prosthetic HGPCSs, which are both central shunts. Small-diameter shunts, relative to large-diameter shunts, maintain partial portal decompression. Large-diameter HGPCSs are more likely to promote equilibration of pressures between the portal system and the vena cava. Thereby, small-diameter shunts promote portal hepatic blood flow and reduce postshunt hepatic dysfunction. Through maintenance of partial portal decompression, it is thought that partial portal decompression provides optimal outcomes. Similarly, best results after distal splenorenal shunts are found in patients experiencing partial portal decompression. After distal splenorenal shunts, portal pressures may increase or decrease. Portal pressures after distal splenorenal shunts may increase because outflow collaterals from the portal system, such as the coronary vein and

Figure 8 Interposition splenorenal shunt.

Chapter 20:

Figure 9 TIPS. Abbreviation: TIPS, transjugular intrahepatic portasystemic shunt.

gastroepiploic veins, are aggressively ligated. After distal splenorenal shunts, portal pressure may fall because inflow to the portal system, for example from the splenic vein, is diverted. Actually, it is impossible to tell before shunting what will happen to portal pressures after distal splenorenal shunting. Nonetheless, what does happen has profound prognostic implications. If portal pressures increase following shunting, patients are likely to recollateralize to the gastroesophageal variceal complex, promoting recurrent variceal hemorrhage. As well, recollateralization to the gastroesophageal variceal complex and across the pancreas to the shunt will lead to loss of portal blood flow into the liver, and thereby hepatic dysfunction will be an increasing issue following shunting. Lastly, if portal pressures increase with shunting, ascites and/or portal vein thrombosis is more likely to occur. If portal pressures decrease following distal splenorenal shunt, ascites will be discouraged, recollateralization to the gastroesophageal variceal complex or through the pancreas to the distal splenorenal shunt will be less likely to occur, promoting ongoing portal hepatic perfusion (hepatopetal flow). In other words, best results after distal splenorenal shunts occur in patients who have partial portal decompression.

Figure 10 Distal splenorenal shunt (Warren).

Portal Hypertension

449

Partial portal decompression can be obtained directly, as opposed to indirectly through distal splenorenal shunt, by application of a small-diameter prosthetic HGPCS, mentioned previously. Our focus has been on small-diameter prosthetic HGPCSs to directly achieve partial portal decompression. An HGPCS is shown in situ in Figure 11. For us, the small-diameter prosthetic interposition HGPCS is not a technically demanding operation, with good outcomes noted by multiple authors across the world (17–26). Shunt thrombosis is uncommon, both early and late. There is a low incidence of rebleeding, postshunt ascites, postshunt encephalopathy, and/or hepatic dysfunction. The shunt does violate the right upper quadrant and the hepatoduodenal ligament. It does involve an anastomosis of the portal vein. Transplant surgeons have debated the impact of this across the world. Some note that this makes the operation more difficult, while others note that portal decompression at the time of transplantation is beneficial and the previous operation inconsequential (27,28). TIPS has received considerable attention over the course of the past several years for a host of reasons (Table 7). TIPS provide partial portal decompression to varying degrees, depending on stent size. Portal decompression is often less than hoped for because of the relatively long length that the shunt travels through the liver. Given the increased resistance to the length of the shunt, shunt diameter often needs to be larger (10–12 mm) than smaller (8 mm). As well, shunt stenosis is a particular problem. Because of problems with shunt stenosis and thrombosis, close follow-up is required. However, despite close followup, shunt stenosis and thrombosis with rebleeding all too frequently occurs. This impacts survival, and so makes TIPS an increasingly expensive endeavor with time (17,21,29–32). Notably, there is a tremendous body of medical literature about TIPS. Nonetheless, there is more experience than data, because excellent outcomes are often purported, inconsistent with published literature. As well, inconsistent terms of ‘‘success’’ and ‘‘failure’’ make discussion of outcomes difficult. For example, TIPS undertaken as definitive therapy for portal hypertension should include unexpected transplantations because outcome is variable. Nonetheless, transplantation following TIPS is often considered a successful outcome. In any other field of intervention, the unexpected need for subsequent therapy would be considered an outcome failure. Experience from around the world is consistent. TIPS shunt stenosis and thrombosis are remarkable problems, with rates of thrombosis, stenosis, or irreversible occlusion up to 50% at one year being quite common. We have compared TIPS to small-diameter prosthetic HGPCS through a randomized clinical trial (17–19,21). Shunt failure was defined prospectively as an inability to place shunt, unexpected transplantation, major vandal hemorrhage following shunting, irreversible shunt occlusion, or death. Transplantation was considered a failure because shunting was undertaken in each patient as definitive therapy. Transplantation was taken to avert progressive hepatic dysfunction and death, and was therefore considered a treatment failure. One hundred and thirty-two patients were randomized. Patients undergoing either shunt were similar in age, gender, presence of preoperative ascites, and Child’s class. A few more patients undergoing TIPS were of Child’s class A, while a few more patients undergoing smalldiameter prosthetic HGPCSs were of Child’s class C.

medwedi.ru

450

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

patients who are poor operative risks, such as patients with profound aortic stenosis and mitral valve regurgitation, chronic obstructive pulmonary disease, and other notable comorbidities. As well, TIPS is recommended for patients who have a ‘‘hostile’’ abdomen, as might occur after multiple previous abdominal operations or obesity. Small-diameter prosthetic HGPCSs have wide applicability for surgeons and patients. It is effective in salvage for patients who have failed medical and/or endoscopic therapy. It is encouraged for patients not requiring imminent transplantation. Similarly, the application of distal splenorenal shunts is encouraged for patients who do not require imminent transplantation. Unfortunately, distal splenorenal shunts are limited to patients with Child’s class A or B, better hepatic function, and hepatopetal flow.

Devascularization Procedures Figure 11 H-graft portacaval shunt.

Shunt failure was noted with relatively short followup (median three years) in 51 occurrences after TIPS and 24 occurrences after HGPCSs. Major variceal rehemorrhage and (unexpected) transplantation were statistically more frequent following TIPS than HGPCSs. In all, after TIPS, 49 interventions were undertaken in 19 patients to treat shunt stenosis or thrombosis. Seven interventions were required in six patients to treat shunt stenosis or thrombosis following small-diameter HGPCSs. Despite vigilance in shunt follow-up, TIPS provided less optimal outcomes than HGPCSs for patients with bleeding varices due to portal hypertension. Although both types of shunts provided partial portal decompression, TIPS was more commonly associated with stenosis, led to more interventions, was associated with more variceal rebleeding, was more frequently associated with liver failure, was more often associated with death, and was more often associated with shunt failure as defined prospectively. Survival at two years favored HGPCSs over TIPS by life-table analysis (21). In summary, there is no best surgical shunt. Accordingly, several questions should always be asked when considering shunting procedure. Does the patient need intervention? Does the patient need a transplant based on hepatic function? Can the patient have a liver transplant? When will the patient need a transplant, if ever? Which shunt to use and when? Our recommendation at this time is that TIPS be utilized as a bridge to imminent transplantation. ‘‘Imminent’’ transplantation is stressed. TIPS is also recommended for

When the previously discussed therapies for bleeding varices due to portal hypertension and cirrhosis are not successful or fail, devascularization may be the only approach possible. A gastric devascularization procedure is depicted in Figure 12. We have had discouraging results with these procedures, because quality of life following them seems poor and morbidity in undertaking them seems high. Furthermore, uniform descriptions of these procedures are lacking. Splenic vein obstruction or thrombosis can lead to a unique form of bleeding gastroesophageal varices, often without portal hypertension. This circumstance is often called ‘‘left-sided portal hypertension’’ or ‘‘sinisteral portal hypertension.’’ Splenic vein obstruction may leave the short gastric veins as the only venous outflow from the

Table 7 Perceived Advantages to Transjugular Intrahepatic Portasystemic Shunt Provides partial portal decompression Avoids abdominal surgery Thrombosis/obstruction can generally be corrected with an interventional radiologic procedure The procedure can be undertaken on ‘‘short order’’ Widely available Does not interfere with subsequent transplantation

Figure 12 Devascularization procedure (Sigiura).

Chapter 20:

451

management of patients with bleeding esophageal varices at our institution (Fig. 13). First, the patient presenting with upper gastrointestinal hemorrhage must undergo upper endoscopy to verify the source of bleeding. As mentioned, hemorrhage in such patients often arises from sources other than bleeding varices. If the bleeding is variceal in origin, banding or sclerotherapy are considered as treatment options first. If the patient responds to such treatment and this is the first episode of hemorrhage, then they are managed medically. If the variceal hemorrhage cannot be controlled with endoscopy, or if this is a recurrent episode of hemorrhage, definitive shunting or transplantation comes to the forefront as a treatment option. TIPS should be applied in patients who will realistically proceed for imminent transplant evaluation. Preoperative assessment for portal decompression should begin for patients who are not candidates for imminent transplantation. Absence of those factors enumerated earlier in this chapter would suggest that a patient will realistically proceed to transplantation (Table 5).

splenic hilum. In turn, this can lead to high venous flow from the spleen across the stomach, leading to gastric varices. Gastric varices due to splenic vein obstruction are effectively treated by splenectomy, a limited form of a devascularization procedure. Splenectomy should be preceded by assessment of liver function, portal vein patency, and portal hypertension, as well as vaccinations for pneumococcus (pneumovax vaccine) and Haemophilus influenza. If a patient has portal hypertension and splenic vein obstruction, splenectomy will not reliably decompress the gastric varices. Similarly, with portal vein obstruction, a more broad and encompassing devascularization procedure may be necessary. Assessment of liver function will be necessary to enable informed consent and realistic assignment of risk. As well, liver problems or other comorbidities may be alleviated with preoperative preparation.

Treatment Algorithm We have proposed a treatment algorithm encompassing the principles set forth in the preceding text to simplify the

Pharmacotherapy Banding Sclerotherapy

Portal Hypertension

Failed or not amenable to medical management?

no

yes

-Gastric devasc. -Interposition splenorenal shunt -Linton shunt

Candidate for imminent transplantation? no

yes

Portal vein patent ?

no

Ascites ?

yes

Splenectomy

no

Splenic vein Patent?

no

yes

TIPS

yes

Comorbities: Comorbidities: cardio/pulmonary contraindication to celiotomy "hostile" abdomen septic shock, dense,irreversible encephalopathy

Distal Splenorenal shunt (Warren)

no

Small diameter HGPCS

Figure 13 Treatment algorithm. Abbreviations: TIPS, transjugular intrahepatic portasystemic shunt; HGPCS, H-graft portacaval shunt.

medwedi.ru

452

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

First, patency of the splenic and portal vein must be confirmed through color-flow Doppler ultrasound. If ultrasound is uncertain or shows portal venous thrombosis, this should be followed up with mesenteric angiography to confirm the presence and determine the extent of the thrombosis. If the splenic vein is thrombosed, and the portal vein is patent, then the patient has sinistral or left-sided portal hypertension. In most cases, this is definitively managed with splenectomy only. If the splenic vein is patent, but the portal vein is thrombosed, both TIPS and HGPCS are not employed. If the patient has no ascites, the distal splenorenal shunt is a reasonable option. If ascites is present, only three treatment options exist: gastric devascularization, proximal splenorenal shunt (also called the Linton shunt), or partial splenic decompression through placement of an interposition graft between the splenic and left renal vein. This last option is potentially less ascitogenic than complete ligation of the splenic vein at the portal confluence. If both the splenic and portal veins are thrombosed, gastric devascularization is the only option. Patency of the portal vein in the presence or absence of ascites suggests feasibility of both TIPS and HGPCS. We prefer to apply H-graft prosthesis in these patients for the reasons indicated in the prior section. Circumstances under which we would consider TIPS over surgical shunts include those in which the patient will most certainly not survive a major abdominal operation. This may be the case in a patient with multiple previous operations in the right upper quadrant or patients with significant cardiopulmonary impairment, including severe mitral regurgitation and aortic stenosis that precludesceliotomy. Dense, irreversibleencephalopathy or sepsis requiring inotropic agents are strong relative contraindications to placement of the H-graft shunt.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

SUMMARY 15.

Although the management of portal hypertension and its complications has dramatically changed over the past two decades with the development of nonoperative treatment strategies, surgical intervention still may become necessary in a small subset of patients. Thus the surgeons who are called upon to consult with their medical colleagues on the most appropriate care to render to a particular patient with portal hypertension must be knowledgeable in all the treatment options currently available, how to adequately evaluate the patient in question, and when surgery may be indicated to manage a complication, in contrast to prolonged medical therapy. This chapter has attempted to provide an evidence-based summary of these considerations so that the surgeons can anchor their decision-making on a solid informational foundation.

REFERENCES 1. Garcia-Villarreal L, et al. Transjugular intrahepatic portosystemic shunt versusw endoscopic sclerotherapy for the prevention of variceal rebleeding after recent variceal hemorrhage. Hepatology 1999; 29(1):27–32. 2. Cabrera J, et al. Transjugular, intrahepatic portosystemic shunt versus sclerotherapy in the elective treatment of variceal hemorrhage. Gastroenterology 1996; 110(3):832–839. 3. Cello JP, et al. Endoscopic sclerotherapy compared with percutaneous transjugular intrahepatic portosystemic shunt after initial sclerotherapy in patients with acute variceal hemorrhage.

16.

17.

18.

19.

20.

21.

22.

23.

A randomized, controlled trial. Ann Intern Med 1997; 126(11): 858–865. Collins JC, et al. Partial portacaval shunt for variceal hemorrhage: longitudinal analysis of effectiveness. Arch Surg 1998; 133(6):590–592; discussion 592–594. Isaksson B, et al. Mesocaval shunt or repeated sclerotherapy: effects on rebleeding and encephalopathy—a randomized trial. Surgery 1995; 117(5): 498–504. Jalan R, et al. A randomized trial comparing transjugular intrahepatic portosystemic stent-shunt with variceal band ligation in the prevention of rebleeding from esophageal varices. Hepatology 1997; 26(5):1115–1122. Levine BA, Gaskill HV III, Sirinek KR. Portasystemic shunting remains the procedure of choice for control of variceal hemorrhage. Arch Surg 1985; 120(3):296–300. Orloff MJ, et al. Prospective randomized trial of emergency portacaval shunt and emergency medical therapy in unselected cirrhotic patients with bleeding varices. Hepatology 1994; 20(4 Pt 1):863–872. Papatheodoridis GV, et al. Transjugular intrahepatic portosystemic shunt-compared with endoscopic treatment for prevention of variceal rebleeding: a meta-analysis. Hepatology 1999; 30(3):612–622. Paquet KJ, et al. Mesocaval interposition shunt with small-diameter, polytetrafluoroethylene grafts in sclerotherapy failure. Br J Surg 1995; 82(2):199–203. Planas R, et al. Portacaval shunt versus endoscopic sclerotherapy in the elective treatment of variceal hemorrhage. Gastroenterology 1991; 100(4):1078–1086. Rikkers LF, et al. Shunt surgery versus endoscopic sclerotherapy for variceal hemorrhage: late results of a randomized trial. Am J Surg 1993; 165(1):27–32; discussion 32–33. Rossle M, et al. Randomised trial of transjugular-intrahepaticportosystemic shunt versus endoscopy plus propranolol for prevention of variceal rebleeding. Lancet 1997; 349(9058): 1043–1049. Sauer P, et al. Transjugular intrahepatic portosystemic stent shunt versus sclerotherapy plus propranolol for variceal rebleeding. Gastroenterology 1997; 113(5):1623–1631. Warren WD, et al. Distal splenorenal shunt versus endoscopic sclerotherapy for long-term management of variceal bleeding. Preliminary report of a prospective, randomized trial. Ann Surg 1986; 203(5):454–462. Rosemurgy AS, Zervos EE, Bloomston M, Durkin AJ, Clark WC, Gofft S. Post-shunt resource consumption favors small-diameter prosthetic H-graft portacaval shunt over TIPS for patients with poor hepatic reserve. Ann Surg 2003; 237(6):820–825. Rosemurgy AS II, et al. Transjugular intrahepatic portosystemic shunt versus H-graft portacaval shunt in the management of bleeding varices: a cost-benefit analysis. Surgery 1997; 122(4):794–799; discussion 799–800. Rosemurgy AS, et al. A prospective trial of transjugular intrahepatic portasystemic stent shunts versus small-diameter prosthetic H-graft portacaval shunts in the treatment of bleeding varices. Ann Surg 1996; 224(3):378–384; discussion 384–386. Rosemurgy AS, McAllister EW, Kearney RE. Prospective study of a prosthetic H-graft portacaval shunt. Am J Surg 1991; 161(1):159–163; discussion 163–164. Rosemurgy AS, et al. Small-diameter prosthetic H-graft portacaval shunt: definitive therapy for variceal bleeding. J Gastrointest Surg 1998; 2(6):585–591. Rosemurgy AS, et al. Transjugular intrahepatic portosystemic shunt vs. small-diameter prosthetic H-graft portacaval shunt: extended follow-up of an expanded randomized prospective trial. J Gastrointest Surg 2000; 4(6):589–597. Rypins EB, Milne N, Sarfeh IJ. Analysis of nutrient hepatic blood flow after 8-mm versus 16-mm portacaval H-grafts in a prospective randomized trial. Am J Surg 1995; 169(2):197–200; discussion 200–201. Rypins EB, Sarfeh IJ. Influence of portal hemodynamics on long-term survival of alcoholic cirrhotic patients after

Chapter 20:

24.

25. 26.

27.

small-diameter portacaval H grafts. Am J Surg 1988; 155(1): 152–158. Rypins EB, Sarfeh IJ. Small-diameter portacaval H-graft for variceal hemorrhage. Surg Clin North Am 1990; 70(2): 395–404. Sarfeh IJ. Comparative study of portacaval and mesocaval interposition shunts. Am J Surg 1981; 142(4):511–513. Sarfeh IJ, Rypins EB. Partial versus total portacaval shunt in alcoholic cirrhosis. Results of a prospective, randomized clinical trial. Ann Surg 1994; 219(4):353–361. Mazzaferro V, et al. Liver transplantation in patients with previous portasystemic shunt. Am J Surg 1990; 160(1):111–116.

Portal Hypertension

453

28. Brems JJ, et al. Effect of a prior portasystemic shunt on subsequent liver transplantation. Ann Surg 1989; 209(1):51–56. 29. Grace ND. TIPS: the long and short of it. Gastroenterology 1997; 112(3):1040–1043. 30. Helton WS, et al. Critical appraisal of the angiographic portacaval shunt (TIPS). Am J Surg 1993; 165(5):566–571. 31. Kerlan RK Jr, et al. Transjugular intrahepatic portosystemic shunts: current status. Am J Roentgenol 1995; 164(5): 1059–1066. 32. Martin M, et al. Transjugular intrahepatic portosystemic shunt in the management of variceal bleeding: indications and clinical results. Surgery 1993; 114(4):719–726; discussion 726–727.

medwedi.ru

21 Calculous Disease of the Gallbladder and Common Bile Duct Lillian S. Kao and Terrence H. Liu

INTRODUCTION Gallstone disease is one of the most common human afflictions and has been recognized since antiquity. Effective treatment of patients with gallstone-related complications became possible with the introduction of cholecystectomy by Langenbuch in 1882 (1), and in the early 1900s, the development of oral cholecystography made early diagnosis of gallstones possible, thus leading to the expansion of surgical treatment for gallstones. However, despite widespread clinical interest, gallstone pathogenesis remained largely obscure throughout the early 20th century. During the 1960s, many of the physical chemistry principles governing stone formation were elucidated. Shortly following these discoveries, oral dissolution therapy for cholesterol gallstones was introduced (2,3), and the subsequent availability of pharmacologic therapy led to a wave of investigational activities throughout the 1970s and 1980s, leading to the further elucidation of gallstone pathogenesis. These investigations identified multiple pathogenic factors and confirmed the limitations of gallstone dissolution therapy. The introduction of laparoscopic cholecystectomy in the late 1980s prompted the redirection of gallstone therapy toward the surgical removal of the gallbladder. As the management of gallstones continues to evolve in the new millennium, appreciation of bile physiology and gallstone pathogenesis remains vital for the future development of novel, noninvasive treatment strategies. Furthermore, familiarity with gallstone pathogenesis has practical relevance for the practicing physician in the promotion of disease prevention and patient education. The current chapter primarily focuses on the physiology of bile formation and its relationship to gallstone pathogenesis. With this backdrop, clinical aspects of gallstone disease management will also be discussed.

EPIDEMIOLOGY Gallstones are a common health problem, affecting approximately 12% or 30 million people and resulting in over 6 billion dollars spent in direct and indirect costs annually in the United States alone (4). Worldwide, the prevalence of gallstones varies widely with geography and ethnicity. The greatest prevalence of gallstones, based on ultrasonographic data, is found in the European and North American populations. In a review of worldwide studies, the mean prevalence of gallstones in Western Europe was 10.7% with a range of 5.9% to 21.0%. Studies on Asian populations demonstrated a much lower prevalence rate than in the Europeans, with a mean of 4%, while the lowest prevalence rate of gallstones was found in Africans (5). Within the United States, the age-standardized prevalence of gallstones differs by race as well as by gender.

American Indians have the highest prevalence of gallstones. Amongst the Pima Indians in Arizona, greater than 70% of women over the age of 25 were found to have gallstones, by oral cholecystography (6). In another study of 13 AmericanIndian tribes, the prevalence of gallbladder disease was noted to be 64.1% amongst women and 29.5% amongst men (7). Mexican Americans are another subpopulation with a high prevalence of gallstones. Using data from the Third National Health and Nutrition Examination Survey (NHANES III), the prevalence of gallstones was noted to be 26.7% amongst Mexican-American women compared to only 5.3% amongst non-Hispanic black men (8). Gallstones are classified as predominantly cholesterol, black pigment, and brown pigment stones. Predominantly cholesterol stones comprise 70% of gallstones in the United States. Pigment stones, which contain calcium bilirubinate, account for 30% of gallstones in the United States, but are more common in Asian populations. Black pigment stones are associated with cirrhosis and hemolytic states, and are described as tarry in appearance. They are located almost exclusively in the gallbladder and are sterile. In contrast, brown pigment stones are characterized as brown and earthy. They are associated with bacterial or parasitic infection of the biliary tree, which is where they commonly originate. The risk factors for gallstone formation are both genetic and environmental. Multiple studies have demonstrated an increased incidence of cholelithiasis in first-degree relatives of gallstone patients (9,10) and a greater concordance of gallstones among monozygotic than that among dizygotic twins (11). The genetic heritability of symptomatic gallstone disease is estimated to be at least 30% (12). Epidemiologic studies have consistently demonstrated that age, gender, obesity, and parity are risk factors for the development of gallstones (12). Other risk factors include: rapid weight loss, total parenteral nutrition, exogenous estrogens, hyperlipidemia, and ileal disease of the small bowel.

BILE PHYSIOLOGY Determinants of Bile Formation Bile is a complex fluid that is considered both a digestive secretion and an excretory fluid. The physiologic functions of bile include lipid digestion and absorption, cholesterol homeostasis, and excretion of heavy metals and lipid-soluble wastes. Insoluble lipids (cholesterol and lecithin) are the major components of bile, which are dependent on the detergent effects of bile acids to remain soluble in the aqueous medium. The formation of hepatic bile involves the secretion of osmotically active inorganic anions into the canalicular lumen, followed by passive water and solute movements. Bile produced from hepatocytes contains bile acids, cholesterol, phospholipids, water, electrolytes, and fat-soluble

medwedi.ru 455

456

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

metabolites, and the formation of hepatic bile is generally categorized as bile salt–dependent flow (BSDF) and bile salt–independent flow (BSIF) (13). During passage through the intrahepatic bile ducts, hepatic bile is modified with secretions derived from bile duct epithelial cells (cholangiocytes), where the quantity and quality of this secretion are largely regulated by hormonal and autonomic controls (14–17).

Table 1 Effectors and Second Messengers of Bile Secretion

Hepatocytes Glucagon, VIP, forskolin

cAMP

Hepatic Bile Formation

TNF-alpha, inflammation

Nitric oxide

Heme-metabolism PGD2, PGE2, PGF2 Vasopressin, ATP, UTP, catecholamines

Carbon monoxide Prostaglandins Protein kinase

Vasopressin, angiotensin, catecholamines, ATP, UTP bile acids

Ca2þ

Hepatic bile formation may be quantified with the administration of erythritol or mannitols, which are metabolically inert solutes that passively enter the bile at the level of biliary canaliculi. Based on the clearance of these inert compounds, the combined output of BSDF and BSIF may be determined. The volume of hepatic bile flow remains relatively constant, where the daily production is approximately 250 mL from each of the two components (18). The BSDF describes the process whereby energydependent movements of bile acids into the canalicular lumen lead to the movement of solutes and water into the canalicular lumen (19–23). One of the mechanisms whereby bile acid movement occurs is based on the Naþ, Kþ-ATPase activity at the basolateral membrane, which produces a net electrical potential across the cell membrane leading to the sinusoidal uptake of bile acids with their accompanying cation (predominantly Naþ). Following uptake at the sinusoidal membranes, bile acids are transported across hepatocytes by intracellular transporters to the canalicular surface for excretion. The transcellular passage of bile acids is a rapid event that often occurs within seconds to minutes. The intracellular transfer of bile acids is disbelieved to occur by diffusion; however, this process requires protein binding or vesicular transport to protect cells from the detergent effects of bile acids (24–26). The secretion of bile acids into the canalicular lumen has been identified as the rate-limiting step in bile formation (27–33). Several human canalicular bile acid transporters have been identified, including those responsible for the development of progressive familial intrahepatic cholestatic syndromes 1 to 3 and pregnancy-associated cholestasis (34–39). In contrast to BSDF, BSIF is bile flow that is attributable to active secretion of inorganic electrolytes and solutes. The secretion of glutathione (GSH) and other unidentified solutes by hepatocytes has been suggested to provide the driving forces for BSIF (40–42). The multidrug-resistant protein 2 is a transport protein identified as being responsible for canalicular transport of GSH, and the accumulation of GSH in the canalicular lumen generates an osmotic gradient whereby biliary solute movement occurs (43,44). Other forces for solute movement in BSIF include the Naþ-Hþ exchange mechanism on the hepatocyte basolateral membranes, which is responsible for generating the osmotic gradient for canalicular HCO3 secretion (45–47).

Site/activators

Second messengers

Cholangiocytes Secretin, adenosine

cAMP

Acetylcholine, ATP, UPT

cAMP, Ca2þ

Somatostatin

cAMP

Bile acids

Effects Stimulates BSDF, BSIF, vesicular transcytosis, canalicular exocytosis, lipid excretion Increase BSIF, canalicular oxidized glutathione (GGSG) excretion, and paracellular permeability Decreased BSDF Decreased BSDF Increased paracellular permeability, exocytosis; decreased BSIF and biliary lipid excretion Increased paracellular permeability, and canalicular contraction; decreased BSIF Stimulates exocytosis, chloride channel opening, insertion of membrane water channels Activates Ca2þ-gated Cl channels, potentiates cAMP production Inhibition of secretin and acetylcholinemediated chloride and water movements Increased secretin receptor expression

Abbreviations: VIP, vasoactive intestinal peptide; cAMP, cyclic adenosine monophosphate; BSDF, bile salt–dependent flow; BSIF, bile salt-independent flow. Source: From Ref. 55.

channels leading to chloride efflux. The formation of cAMP stimulates the insertion of water channels into the cholangiocyte cell membranes, resulting in water secretion. Stimulation of the acetylcholine receptors on the basolateral membranes of bile duct epithelial cells augments secretin-mediatedcAMP production, whereas, the stimulation of somatostatin receptors causes the inhibition of secretin-mediated cAMP production (55). (Table 1 contains a list of effectors and second messengers of bile secretion.)

Gallbladder Functions Bile Production by Cholangiocytes Once formed, the hepatic bile is modified by secretions derived from cholangiocytes lining the intrahepatic ducts prior to storage in the gallbladder. Many hormonal and autonomic stimuli have been found to influence cholangiocyte bile formation. Acidic pH, and the presence of fatty acids and bile salts in the duodenum have been found to stimulate secretin release into portal circulation (17,48–54). The binding of secretin to receptors on the basolateral membrane of cholangiocytes results in cyclic adenosine monophosplate (cAMP) formation, opening of the cystic fibrosis transmembrane conductance regulators, and opening of the chloride

Bile released from the liver is stored in the gallbladder until it is stimulated for release. The composition of bile within the gallbladder is further modified during storage, where gallbladder motility and a number of mucosal functions are recognized to affect gallbladder bile compositions. Effective bile release from the gallbladder requires gallbladder contraction with simultaneous relaxation of the sphincter of Oddi. A number of hormonal and autonomic factors are involved in the regulation of bile release, with cholecystokinin (CCK) being recognized as the most potent stimulus for gallbladder contraction. CCK release occurs as a physiologic response to food ingestion, and it has been

Chapter 21:

recognized that different food compositions are capable of stimulating variable levels of CCK release. In general, the presence of fat in the duodenal lumen is the most potent stimulus for CCK release, and long-chain fatty acids are associated with greater CCK release than short-chain fatty acids (56–60). Contraction of the gallbladder following meal ingestion is in part regulated by cholinergic stimulation, because sham feedings have been shown to produce mild-to-moderate gallbladder contractions. Gallbladder contractions following sham feeding are blocked by atropine administration and are stimulated by the administration of bethanechol (61–64). In addition to the postprandial contractions, the gallbladder may contract to approximately 25% of its fasting volume during phase III of the interdigesting migratory complex, where motilin is recognized as the hormone responsible for this activity (65). The physiologic role of gallbladder fasting contractions has not been clearly defined. Somatostatin is released from the intestine and pancreas following fatty meal ingestion. Experimentally, somatostatin administration leads to the inhibition of CCKand vagus-mediated gallbladder contractions; therefore, it may be postulated that somatostatin secretion following meal ingestion may play a physiologic role in counterbalancing the effects of CCK (66). The administration of opiates has been shown to inhibit relaxation of the sphincter of Oddi, thus increasing the resistance to gallbladder contractions, which in turn leads to the inhibition of gallbladder emptying (66).

Metabolism of Biliary Solutes In general, the development of gallstones occurs under conditions where the concentrations of biliary solutes exceed their solubility in equilibrium. In this section, the determinants of bile solute saturation are discussed.

Cholesterol Metabolism In general, biliary cholesterol saturation occurs with expansion of the hepatic free cholesterol pool and/or diminished hepatic bile acid secretion. Under conditions where excess cholesterol is available, the excess is primarily eliminated from the body through the liver and biliary system as bile salts and free cholesterol (67,68). Small amounts of cholesterol may be converted to steroid hormones and eliminated by urinary excretion, while a limited amount of cholesterol is eliminated through the turnover of skin and intestinal epithelial cells (67). Within hepatocytes, the free cholesterol pool is derived from de novo synthesis, hydrolysis of cholesteryl ester stores, and uptake as lipoproteins and chylomicron remnants. Following intestinal absorption, dietary cholesterol is first incorporated into chylomicrons and carried through the lymphatic channels to the central venous system. Within the endothelial cells, fatty acids and monoglycerides are separated from the chylomicrons for storage, and the chylomicron remnants are returned to the liver. Rich in cholesterol, the chylomicron remnants are taken up by low-density lipoprotein (LDL) receptors and LDL-receptorrelated proteins on the sinusoidal membranes and internalized and hydrolyzed to form free cholesterol. Similarly, circulating high-density lipoproteins (HDLs) and LDL are taken up by receptors, delivered to the hepatocyte, and metabolized to replenish the free cholesterol pool (67). The metabolic fate of the free cholesterol is highly variable depending upon availability. Under conditions of

Calculous Disease of the Gallbladder and Common Bile Duct

457

Figure 1 Hepatic cholesterol metabolism. Key: 1, Lipoprotein, cholesterol uptake; 2, cholesterol synthesis; 3, structural cholesterol; 4, cholesterol ester pool; 5, bile acid synthesis; 6, biliary vesicles secretion. Source: From Ref. 67.

excess free-cholesterol supply, the free cholesterol may become esterified and stored as cytosolic droplets (69,70). Alternatively, excess cholesterol may be eliminated by reverse cholesterol transport, a process where free cholesterol is extracted from cell membranes by HDL, esterified by lecithin–cholesterol acyl-transferase, and then transferred to very low density lipoprotein (VLDL) and LDL, where the lipid products are removed by the liver and processed into bile acids and cholesterol vesicles for secretion into bile (67). During the process of cholesterol homeostasis, cholesterol esters may be converted to replace a depleted free cholesterol pool during periods of deficits; similarly, free cholesterol may be esterified to form cholestrol esters during periods of cholesterol excess. Acyl–coenzyme-A cholesterol– acyl transferase is the major regulatory enzyme controlling cholesterol ester formation from free cholesterol (69,70), and neutral cholesterol ester hydrolase breaks down cholesterol esters to form free cholesterol and fatty acids (67,71). (Figure 1 contains a simplified cartoon depicting hepatic cholesterol metabolism. (Details of hepatic uptake and metabolism of cholesterol are relevant in gallstone pathogenesis, a number of genetic, physiologic because, and environmental factors may cause the expansion of hepatic free cholesterol pool and excessive biliary cholesterol secretion. (Table 2 contains a list of these conditions.)

Phosphatidylcholine Metabolism Lecithin is the predominant phosphatidylcholine (PC) identified in bile. PC is minimally soluble in aqueous solution, therefore the solubility of PC and cholesterol in bile is dependent on the detergent effects of the bile acids. Once derived, hepatocytes’ PC (lecithin) are delivered to the cytoplasmic leaflet of the canalicular membrane by PC transfer protein and translocated to the outer leaflet by the protein products of the multiple drug–resistant 3 genes (73,74). When bile acids are present in sufficient quantity in the bile canaliculi, lecithin and cholesterol located on the outer leaflet canalicular membrane may become incorporated into vesicles and released into the bile (74).

medwedi.ru

458

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 2 Factors Associated with Cholesterol Gallstone Formation Age Female gender Obesity Weight loss Total parenteral nutrition Pregnancy Drugs Clofibrate Oral contraceptives Estrogen Rx in women Estrogen Rx in men Progestogens Ceftriaxone Octreotide Genetic predisposition Native Americans Scandinavians Terminal ileum diseases Decreased HDL Increased triglycerides

Increased cholesterol secretion into bile and decreased bile acid synthesis Increased cholesterol secretion into bile and increased intestinal transit time Cholesterol hypersecretion into bile and increased cholesterol synthesis via increased HMG-CoA reductase activity Cholesterol hypersecretion into bile, reduced bile acid synthesis, and gallbladder hypomotility Gallbladder hypomotility Increased cholesterol secretion and gallbladder hypomotility Decreased bile acid concentration due to suppression of 7-alpha-hydroxylase activity and decreased ACAT activity, resulting in increased free cholesterol secretion into bile Increased cholesterol secretion Cholesterol hypersecretion into bile and reduced bile acid synthesis Cholesterol hypersecretion into bile Diminished ACAT activities, increased cholesterol secretion, gallbladder hypomotility Precipitation of an insoluble calcium-cetriaxone salt Decreased gallbladder motility Increased cholesterol synthesis and reduced conversion of cholesterol into bile acids Increased cholesterol secretion into bile Hyposecretion of bile acids caused by diminished bile acid pool Increased activity of HMG-CoA reductase Increased activity of HMG-CoA reductase

Abbreviations: ACAT, acyl–coenzyme-A cholesterol–acyl transferase; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A. Source: From Ref. 72.

Bile Acid Metabolism Bile acids make up a major component of bile and function as biologic detergents in facilitating biliary lipids solubility. Because of this important property, defects leading to a reduction in bile acid contents of bile may directly impact biliary lipid solubility (71). In the gasterointestinal tract, approximately 95% of the circulating bile acids are reabsorbed and returned to the liver (enterohepatic circulation), while the fecal losses are replaced by de novo bile acids synthesized by the hepatocytes. Two primary bile acids are synthesized in humans (cholate and chenodeoxycholate), and three secondary bile acids are produced following modification by intestinal bacteria (deoxycholate, lithocholate, and ursodeoxycholate) (55). The compositions of the steroid nucleus and hydroxyl side chains are important determinants of the physiologic and physicochemical properties of bile acids (55). The enterohepatic recycling of bile acids is generally subdivided into the hepatic phase, intestinal phase, and gallbladder storage phases. During the hepatic phase, the specific architecture of the liver sinusoids promotes the efficient passage of protein-bound compounds through endothelial fenestrations into the space of Disse, where transport systems on the sinusoidal membranes extract bile acids bound to albumin. The uptake of bile acids under physiologic conditions occurs preferentially at the periportal hepatocytes as opposed to the perivenous hepatocyte, while under cholestatic conditions, uptake occurs mostly at the perivenous haptocytes. The shift in hepatocyte functionality coupled with the loss of hepatocytes tight junction integrity may lead to excess bile salt loss into the circulation under pathologic conditions (55,72). The sinusoidal uptake of bile acids may occur by Naþ-dependent or Naþ-independent mechanisms. One of the Naþ-dependent mechanisms that has been elucidated is the system involved for the uptake of taurocholate, which is regulated by the activities of the Naþ-taurocholate cotransport polypeptide (NTCP) (19,21,23). The loss of NTCP activity is associated with the development of cholestasis, under several physiologic and pathologic conditions (23).

Presence of excess estrogens, pregnancy, bile duct ligation, and endotoxin administration have been shown to cause cholestasis by downregulating NTCP activities (38,75). A number of Naþ-independent bile acid transport systems have been identified, including several organic acid transporting proteins (OATPs). OATP transporters play a minor physiologic role in the uptake of bile acids; however, their functions are important for the uptake and excretion of various steroid metabolites and drugs (55,72,76). During intracellular transport, bile acids are bound to cytosolic proteins, which protect cells from the detergent effects of bile acids. The binding of bile acids to transfer proteins has been demonstrated to be involved in the regulation of biliary bile acid levels, where the inhibition of bile acid– transport protein formation at the posttranscriptional level may function as a negative feedback mechanism controlling bile acid transport, under conditions associated with extrahepatic homeostasis (24–26,55,72). Canalicular bile acid secretion is primarily mediated by adenosine triphosphate–dependent transporters having substrate specificity for monovalent bile acids, and these bile acid transporters are believed to provide the major driving forces for BSDF (18,21,29–33). Secondarily, bile acid secretion may also occur by a membrane-bound vesicle system associated with the Golgi apparatus (55,72). A mutation in the genes encoding bile acid transport proteins has been linked to the development of a familial form of intrahepatic homeostasis (34–39).

Intestinal Phase The intestines absorb roughly 95% of the bile acids. This passive absorption of bile acids occurs throughout the small intestine and is a process largely determined by intestinal pH and bile acid structure. In general, efficiency of absorption is the greatest for the hydrophobic bile acids, in the most acidic portion of the duodenum, where these bile acids tend to remain in uncharged forms (55). In the brush border membranes along the ileum, the active transport of bile acids occurs by a Naþ-, Kþ-ATPase mediated process (72). The ileal transporters that have been identified share

Chapter 21:

Calculous Disease of the Gallbladder and Common Bile Duct

459

considerable similarity with the sinusoidal bile acid transporter (NTCP) (55). Once taken up, bile acids are transported across the entrocytes and released into the portal circulation. In the portal circulation, bile acids are returned to the liver either as unbound free monomers or bound to albumin or lipoproteins. The reuptake of bile acids by the liver is greatest for unbound and hydrophilic bile acids.

PATHOGENESIS OF GALLSTONES Cholesterol Stones Cholesterol Supersaturation The formation of cholesterol stones is always preceded by biliary cholesterol supersaturation. Circumstances leading to cholesterol supersaturation include physiologic conditions that lead to expansion of the hepatic free cholesterol pool and/or conditions associated with reduced bile acid secretion. Under conditions where bile is unsaturated, the biliary cholesterol exists predominantly as simple and mixed micelles (68). Micelles are bile acids and lipid aggregates with their polar phosphate or hydroxyl groups directed outward toward the aqueous phase and nonpolar hydrocarbon chains directed inward. Mixed micelles are lipid aggregates that form preferentially in the presence of unsaturated bile, bile acids, and lecithin (55,68). As the cholesterol saturation increases in the bile, more of the biliary cholesterol is packaged into vesicles, which are composed of phopholipid bilayers without bile acids and are approximately 10 times larger than micelles. In vesicles, the cholesterol polar groups are directed outward while the hydrophobic hydrocarbon chains are directed inward to promote cholesterol dissolution in the core. As the cholesterol to lecithin ratio in bile increases further, unilamellar vesicles may coalesce into multilamellar vesicles, which are liquid cholesterol crystals that are capable of forming solid cholesterol monohydrate crystals (68,71). The equilibrium solubility of biliary cholesterol may be summarized by a phase diagram with triangular coordinates (Fig. 2), where for given concentrations of lecithin and bile acids, it is possible to determine the phase in which cholesterol will exist (68,78). The phase diagram allows one to determine the cholesterol saturation index (CSI), which is the ratio of the measured concentration of cholesterol to the measured concentration of bile salts plus phospholipid compared with the concentration of each at solubility limit. When the CSI exceeds 1, saturated bile is present. The supersaturation of bile represents a thermodynamically destabilized solution capable of eventual crystallization; however, the rate of crystal growth may or may not lead to stone formation within a biologically relevant time period (71). A number of factors affecting cholesterol crystallization rates have been identified and are discussed below.

Figure 2 Determination of cholesterol saturation index. Incoordinate phase diagram for representing by a single intersecting point (x) relative concentrations of cholesterol, lecithin, and bile salts in bile. In this scheme, relative concentration of each lipid is expressed as a percentage of the sum of the molar concentrations of all three. This manipulation permits representation of the relationships between the three constituents in two dimensions, the water content being invariant at, say, 90% (10% wt/vol solids). In this figure, for example, at point (x), the relative concentration of bile salt from its coordinate is 55% (indicating 55% of the sum of all three lipids), whereas that for lecithin is 30%, and that for cholesterol is 15%. The range of concentrations found consistent with a clear aqueous micellar solution is limited to a small region at the lower left. A solution having the composition represented by point x, on the other hand, would initially be visually turbid and contain precipitated forms of cholesterol crystals in addition to bile salt–mixed micelles. Last, a solution represented by a point falling in the shaded area below the dashed line would be unstable (i.e., metastable-supersaturated), meaning that by prediction it would be initially clear (micellar). Within a short time, however, various precipitated forms of cholesterol crystals would form, and such a solution would, then, be visually turbid, similar to all solutions above the dashed line. Source: From Ref. 77.

the canaliculus, these proteins stabilize biliary vesicles and inhibit the fusion, nucleation, and growth of cholesterol crystal. Several proteins are recognized to promote cholesterol crystal formation, and these include immunoglobulin G, mucous glycoproteins (mucin proteins), aminopeptidase N, and transferrin produced by hepatocytes, bile duct epithelium, and gallbladder mucosa (81–85). When present in pathologically high concentrations, nucleation factors promote cholesterol gallstone formation.

Nucleation

Gallbladder Dysfunction

Nucleation refers to the aggregation of submicroscopic crystals leading to the initiation of cholesterol crystal formation. The process of nucleation is generally slow, and supersaturated cholesterol may remain metastable for days to weeks. However, in the presence of promoters of crystallization (nucleating factors) and/or absence of inhibitors of crystallization (antinucleating factors), bile may become destabilized, leading to rapid crystal formation (71,79). A number of inhibitors of cholesterol crystallization have been identified. Apoprotein Al (80) and immunoglobulin A are produced by hepatocytes. When secreted into

The gallbladder is a pear-shaped organ that stores bile secreted by the liver (Fig. 3). During storage, it concentrates the bile by reabsorbing water and electrolytes from the dilute hepatic bile delivered to it. When a person eats a meal, the gallbladder contracts and delivers its contents into the small intestine to assist in the digestion of intestinal chyme, especially fat components. When fully distended, the gallbladder holds between 30 and 60 ml of bile. Its contractile action is modulated by both neural and hormonal mechanisms, including both parasympathetic (hepatic branch of anterior vagal trunk) and sympathetic (branches

medwedi.ru

460

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

ultrasonographically as low amplitude echoes without postacoustic shadows, which layer out with gravity. Biochemically, sludge is composed of calcium bilirubinate granules and cholesterol monohydrate crystals embedded in a mucus gel. Sludge formation is identified more frequently in patients with conditions associated with gallbladderdysmotility, including pregnancy, octreotide administration, and prolonged administration of total parenteral nutrition. Clinically, sludge may regress to normal bile or progress to cholelithiasis (94–98). The growth of gallstones may occur by deposition of additional insoluble precipitates at the stone–bile interface or by growth of the cholesterol crystals. The mechanisms involved in stone growth have not been elucidated, and it is unknown why some individuals have single stone formation, while others have multiple stones. It has been suggested that different mechanisms may be involved, and it has been shown that the rate of stone recurrence is greater among patients with multiple stones following medical dissolution of gallstones.

Pigment Stones

Figure 3 Anatomy of gallbladder. Source: From Ref. 86.

The formation of pigmented gallstones is predisposed by the deconjugation and precipitation of bilirubin crystals. Pigment gallstones are broadly classified as black or brown pigment stones, which are distinctly different in their pathogenesis.

Black Pigment Stones of the splanchnic nerves) input as well as the hormone CCK. Like other hollow visci, it consists of an inner columnar mucosal layer, a thin lamina propria, a thin layer of smooth muscle fibers and a perimuscular serosa. Both muscular dysmotility and mucosal absorptive dysfunction are thought to play roles in gallstone formation. Incomplete emptying of the gallbladder is one of the factors leading to bile stasis and gallstone formation. A number of physiologic conditions associated with gallbladder dysmotility have been recognized (87–89). During late pregnancy, the fasting volume and postprandial volume of the gallbladder are increased suggesting defects in gallbladder emptying; this response has been linked to the elevation in progestin levels associated with pregnancy. The longterm administration of total parenteral nutrition has also been shown to cause gallbladder stasis and sludge formation within a few weeks of initiation of therapy. A number of gallbladder mucosal dysfunctions have been implicated in gallstone pathogenesis. These include alterations in Naþ and Clþ metabolism, mucin hypersecretion (84), and deficiency in gallbladder bile acidification (90). The secretion of mucin by the gallbladder mucosa is stimulated by prostanoids and inhibited by agents blocking prostaglandin synthesis. In prairie dogs, pretreatment of the animals with aspirin inhibited mucin production and prevented gallstone formation when these animals were fed a high-cholesterol diet (91). In randomized, double-blinded, human trials, aspirin therapy did not lead to the reduction in gallstone occurrence (92,93). Gallbladder mucosal dysfunction leading to deficiency in bile acidification has been shown to correlate with gallstone formation in humans, and this defect is believed to contribute to stone formation by precipitating the formation of calcium salts (71). Precipitates that form in the gallbladder are referred to as biliary sludge or microlithiasis. Sludge can be visualized

Most black pigment stones are composed of calcium salts of bilrubinate, carbonate, and phosphate in a glycoprotein matrix. Clinical conditions affecting bilirubin metabolism, bile acid secretion, and gallbladder functions have been recognized to cause black pigment stone formation (Table 3) (99,100). Bilirubin, a tetrapyrrol-like cholesterol, is insoluble in water in its unconjugated form. Unconjugated bilirubin is taken up and processed by hepatocytes, after which 97% to 98% of the bilirubin is released as conjugated bilirubin. Under normal circumstances, the small amount of unconjugated bilirubin Table 3 Features of Black and Brown Pigment Stones Clinical associations Incidence increases with age Female predominance Hemolysis Cirrhosis/chronic alcoholism Elderly Pancreatitis Total parenteral nutrition Primary hyperparathyroidism Gilbert’s syndrome Duodenal diverticulum Low protein diet Bacterial infections of bile Recurrent stones after removal Location in biliary tree Morphology

X-ray appearance Source: From Ref. 99.

Black pigment stones

Brown pigment stones

Yes

Yes

Yes Yes Yes Yes Yes Yes Yes Yes No No < 5% Uncommon

Yes No No Yes Yes ? ? Yes Yes Yes ~100% Common

Usually limited to gallbladder Black to brown, 50% amorphous, 50% 50% crystalline 67% opaque

Bile ducts and gallbladder Brown, laminated

100% lucent

Chapter 21:

released by hepatocytes is solubilized by mixed micelles. However, in patients with hemolytic tendencies, the increase in unconjugated bilirubin production may exceed the hepatic capacity for bilirubin processing, therefore leading to the release of excess unconjugated bilirubin and formation of calcium bilirubinate stones. Because not all patients with black pigment stones have excess unconjugated bilirubin production, other alternative defects have been identified. Black pigment stone formation in patients with cirrhosis have been shown to occur due to defects in bile acid processing leading to decreased availability of bile acids to the solubilization of unconjugated bilirubin and buffering of ionized calcium. Primary gallbladder dysfunction has also been identified in patients with sickle cell anemia and gallstones. In these patients, it is suspected that gallbladder dysfunction associated with mucin hypersecretion, decreased acidification, and hypomotility may be a factor contributing to stone formation (99,101).

Brown Pigment Stones Brown pigment stones form primarily in the extrahepatic bile ducts. The presumed sequence of events involves bile stasis leading to bacterial infections and the accumulation of mucus and bacterial cytoskeletons in the bile. The presence of enteric bacteria within the bile has been shown to be associated with the presence of several bacterial products in the bile. One of these is the bacteria-derived beta-glucuronidase, which may convert conjugated bilirubin to unconjugated bilirubin. Bacteria-derived phospholipase A may lead to palmitic stearic acid formation from phospholipids, and the bacteria-derived conjugated bile acid hydrolase may lead to the production of unconjugated bile acids. The net results of these reactions are the formation of calcium complexes producing insoluble calcium salts and stones (101–103). When de novo stone formation occurs within the bile ducts (primary choledocholithiasis), it is presumed that biliary stasis is generally a predisposing factor. This presumption has led some surgeons to recommend that the treatment include stone removal as well as biliary drainage to correct the conditions that predispose to stone recurrence (104); however, because recurrent choledocholithiasis may develop over a long period of time, some surgeons believe that prophylactic biliary tract drainage may be unnecessary (105).

CLINICAL MANIFESTATIONS OF GALLSTONE DISEASE Natural History Biliary complications develop in approximately 1% to 2% of patients, per year, with asymptomatic gallstones and in 1% to 3% of patients per year with mild symptoms (106). In a landmark study, Grade and Ransohoff studied 123 University of Michigan faculty members with gallstones, for a period of 15 years. Symptoms developed in 10%, 15%, and 18% of the faculty at 5, 10, and 15 years, respectively (107). The rate of development of symptoms seems to occur at a higher rate in the first five years after diagnosis, and then seems to decline (106–108), although elderly patients tend to have a higher risk of developing biliary complications such as choledocholithiasis, emphysematous or gangrenous cholecystitis, and gallstone ileus secondary to a cholecystoenteric fistula. One potential long-term sequela of benign calculous disease, although rare, is gallbladder cancer, the incidence of which rises after age 40 (109). Gallstones have

Calculous Disease of the Gallbladder and Common Bile Duct

461

been recognized to increase the risk of gallbladder carcinoma by 4- to 5-fold (110) and larger stones, particularly greater than 3 cm, are associated with a higher risk (111).

Asymptomatic Cholelithiasis Given that the risk for development of complications of gallstones is low, expectant management is recommended for most patients with asymptomatic cholelithiasis. Using decision analysis modeling, several authors have demonstrated that expectant management is superior to prophylactic cholecystectomy for the treatment of silent gallstones in the general population (112,113). However, the management of asymptomatic gallstones remains controversial for several high-risk populations. Initial studies suggested that diabetics are at an increased risk for developing complications of cholelithiasis (114), and that cholecystectomy results in higher morbidity and mortality (115). Subsequent studies demonstrated that diabetes was no longer a significant risk factor for complications after adjusting for cardiovascular comorbidities (116). Furthermore, prospective follow-up of non–insulin-dependent diabetic patients revealed that only 4.2% developed complications of initially asymptomatic gallstones at 5 years (117). Using decision analysis modeling, prophylactic surgery for asymptomatic cholelithiasis in diabetics did not increase life expectancy or quality of life (118). Therefore, current recommendations are for expectant management of silent gallstones in diabetic patients. The management of silent gallstones in solid organ– transplant patients (heart/lung, pancreas, and kidney) encompasses the full range of options, including expectant management (119,120), routine screening with prophylactic pretransplant cholecystectomy (121), and prophylactic cholecystectomy in post-transplant patients (122–124). A review of retrospective studies revealed an increased prevalence of gallstones in transplant patients, an increased likelihood of progression to symptoms, and an increased morbidity and mortality from complications of cholelithiasis (125). A decision analysis suggests that prophylactic posttransplant cholecystectomy is preferred in cardiothoracic transplant patients, while expectant management is favored in pancreatic and renal transplant patients with asymptomatic gallstones (126). Given that both morbid obesity and rapid weight loss have been associated with an increased risk of gallstones (127–129), several authors have advocated prophylactic cholecystectomy concomitantly with bariatric procedures. However, this issue remains controversial. Management options range from routine prophylactic cholecystectomy (130) to elective removal only in the presence of gross or sonographic evidence of cholelithiasis (131,132) to expectant management (133).

Symptomatic Cholelithiasis Symptomatic cholelithiasis can manifest as a spectrum of diseases ranging from biliary colic to acute cholecystitis to emphysematous cholecystitis with air in gallbladder wall from severe infection. The clinical presentations, laboratory abnormalities, and radiologic evaluations of the various manifestations of gallstone disease are listed in Table 4. Biliary colic results from transient obstruction by a gallstone or sludge of the cystic duct or infundibulum of the gallbladder. Repeated episodes of inflammation result in chronic cholecystitis. If the stone is impacted in the cystic duct or Hartmann’s pouch, the mucosal edema and neutrophilic infiltration characteristic of acute cholecystitis result. Although acute cholecystitis can progress to sepsis, positive

medwedi.ru

462

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 4 Common Clinical Manifestations of Gallstone Disease Biliary colic

Acute cholecystitis

Pathophysiologic condition

Intermittent obstruction of cystic duct; Impacted stone in cystic duct; acute no inflammation of inflammation of gallbladder gallbladder mucosa mucosa; secondary bacterial infection in 50%

Symptoms

Severe, poorly localized epigastric or 75% preceded by attacks of biliary RUQ visceral pain growing in colic; visceral epigastric pain gives intensity over 15 min and remaining way to moderately severe, localized constant for 1–6 hr, often with pain in RUQ, back, shoulder, or nausea; frequency of attacks varies (rarely) chest; nausea with some from days to months; gas, bloating, emesis frequent; pain lasting >6 hr flatulence, dyspepsia not related suggests cholecystitis (vs. colic) to stones Mild-to-moderate gallbladder Febrile, usually <102 F unless complicated by gangrene or tenderness during attack with mild perforation; right subcostal residual tenderness lasting days; tenderness with inspiratory arrest often completely normal (Murphy’s sign); palpable examination result gallbladder in 33%, especially in first attack; mild jaundice in 20%, higher frequency in elderly Usually normal in patients with Leukocytosis of 12,000–15,000/mm3 with left shift common; serum findings of only uncomplicated bilirubin may be 2–4 mg/dL and biliary colic, elevated bilirubin, aminotransferase and alkaline alkaline phosphatase, or amylase phosphatase levels may be level suggestive of coexisting elevated, even in absence of CBD CBD stones stones or hepatic infection; mild serum amylase elevation even in absence of pancreatitis; if bilirubin >4 mg/dL or amylase >1000 U/L suspect CBD stone

Physical findings

Laboratory findings

Diagnostic tests (see Table 55-4 for details) Natural history

Treatment

Ultrasonography OCG; Meltzer-Lyon test

Ultrasonography; hepatobiliary scintigraphy (DISIDA, HIDA scans); abdominal CT

Choledocholithiasis

Cholangitis

Intermittent obstruction of CBD

Impacted stone in CBD causing bile stasis; bacterial superinfection of stagnant bile; early bacteremia Often asymptomatic; Charcot’s triad (pain, symptoms (when jaundice, fever) present in present) indistinguishable 70%; may be mild, from biliary colic symptoms; transient pain often predisposes to cholangitis accompanied by chills; and acute pancreatitis mental confusion lethargy, and delirium suggestive of bacteremia Often completely normal Fever in 95%, RUQ tender in examination result if 90%; jaundice in 80%; obstruction intermittent; peritoneal signs in 15%; jaundice with pain hypotension with mental suggestive of stones; confusion in 15% painless jaundice and suggestive of gram-negative palpable gallbladder sepsis suggestive of malignancy Elevated serum bilirubin and Leukocytosis in 80%; normal alkaline phosphatase levels WBC count with left shift seen with CBD obstruction; may be only hematologic serum bilirubin level finding in 20%; serum >10 mg/dL suggestive of bilirubin level >2 mg/dL in malignant obstruction or 80%, but when <2 mg/dL coexisting hemolysis; diagnosis may be missed; transient spike in serum serum alkaline aminotransferase or phosphatase level usually amylase levels suggestive elevated; blood culture of stone passage results usually positive, especially during chills or fever spike; grow two organisms in one half of patients ERCP; THC ERCP; THC

After initial attack, no further Spontaneous resolution in 50% in symptoms in 30%; in remainder 7–10 days without surgery; development of symptoms at rate of untreated, 10% complicated by 6%/yr and of severe complications localized perforation, 1% by free at rate of 1%/yr perforation and peritonitis

Natural history not well defined, but complications more frequent and severe than for asymptomatic (gallbladder) stones

Elective laparoscopic cholecystectomy Cholecystectomy with IOC; if stones with IOC ERCP for stone removal if on IOC then CBD exploration or stones on IOC ERCP for stone removal

Stone removal at time of ERCP followed by early laparoscopic cholecystectomy

High mortality rate if unrecognized, with death from septicemia; dramatic improvement of survival rate with emergent decompression of CBD (usually by ERCP) Emergency ERCP with stone removal or at least biliary decompression; antibiotics to cover gram-negative organisms; interval cholecystectomy

Abbreviations: CBD, common bile duct; CT, computed tomography; DISIDA, diisopropyl iminodiacetic acid; ERCP, endoscopic retrograde cholangiopancreatography; HIDA, hydroxy iminodiacetic acid; IOC, intraoperative cholangiography; OCG, oral cholecystography; RUQ, right upper quadrant; THC, transhepatic cholangiography; WBC, white blood cells. Source: From Ref. 134.

bile cultures range from 40% to 70% in patients with this presentation (135–137). Complications of acute cholecystitis include: emphysematous cholecystitis, empyema, perforation, pericholecystic abscess, and cholecystoenteric fistula. The presentation of symptomatic cholelithiasis may mimic that of choledocholithiasis if a stone in the cystic duct results

in compression of the common hepatic duct or actual erosion into it (Mirizzi syndrome). Although Table 4 summarizes the various clinical presentations of gallstone disease, a brief review of a typical patient with acute cholecystitis should prove instructive. Often such a patient will give a history of having eaten a

Chapter 21:

fat-laden meal (e.g., cheeseburger, fried chicken, or french fries). An hour or so later, pain is experienced in the epigastric region, which is often described as ‘‘gnawing’’ or a pressure sensation. Accompanying the pain may be a feeling of nausea, sometimes with associated vomiting, although neither may be present. As gallbladder inflammation intensifies, the pain may penetrate to the back (between the shoulder blades) or localize more to the right upper quadrant. Physical findings commonly develop at this point and are characterized by tenderness in the right upper quadrant, which may be especially pronounced on deep inspiration (Murphy’s sign). A fever may also exist as well as an elevation in the white blood cell count. Because obstruction of the cystic duct by a stone is usually the cause of this scenario, abdominal ultrasound should be obtained to confirm the diagnosis. This imaging study will usually demonstrate the presence of a stone(s) and as well may show a thickened gallbladder wall or pericholecystic fluid, indices of gallbladder inflammation.

Choledocholithiasis Common bile duct (CBD) stones, or choledocholithiasis, are present in 10% to 15% of all patients with cholelithiasis. The majority originate in the gallbladder and secondarily pass into the bile ducts. CBD stones are considered to be primary if they arise de novo in the bile ducts. Postcholecystectomy, CBD stones are considered primary after a 2-year symptom-free interval has passed. Primary duct stones are less common, typically recalcitrant to pharmacologic therapy, and more likely to recur than secondary stones (138). Stasis and bacterial overgrowth are postulated to have a role in the pathogenesis of primary CBD stones, which can be associated with conditions such as biliary strictures, sclerosing cholangitis, sphincter of Oddi dysfunction, and duodenal diverticula. The development of symptoms from common bile duct stones is unpredictable. They may be asymptomatic or may present with right upper quadrant pain. The presentation may be difficult to differentiate from that of biliary colic. Unsuspected CBD stones are present in 5% or less of patients presenting with symptomatic gallstones (139). If the stone is obstructing, the patient may develop jaundice and subsequently cholangitis or gallstone pancreatitis. Choledochoenteric fistulae and common duct strictures are less common complications. Given the difficulty in predicting the natural history of choledocholithiasis, diagnosed stones should be routinely treated unless the patient has multiple comorbidities and is a poor candidate for surgery (139). Multiple studies have attempted to develop a predictive model for preoperatively determining the likelihood of common bile duct stones. A meta-analysis of predictors for the presence of common bile duct stones prior to cholecystectomy demonstrated that no single predictor suffices for the diagnosis, and furthermore, the absence of any single indicator does not preclude the diagnosis. However, patients with cholangitis, preoperative jaundice, or sonographic evidence of CBD stones were more than ten times as likely to have CBD stones than patients lacking any of these indicators (139). Another study determined that the presence of both a serum gamma-glutamyl transferase level greater than seven times normal and a dilated common bile duct accurately predicted the presence of CBD stones in 90% of patients (140). The diagnosis of choledocholithiasis, if suspected, can be made using a variety of imaging modalities. The efficacy, advantages, and disadvantages of the available diagnostic tools are listed in Table 5.

Calculous Disease of the Gallbladder and Common Bile Duct

463

TREATMENT Cholelithiasis Cholecystectomy is the gold standard for treatment of symptomatic cholelithiasis. Over 750,000 laparoscopic cholecystectomies are performed annually in the United States alone (142) and can be performed safely with a mortality rate of less than 0.5%. An alternative operative approach is the mini-cholecystectomy performed through a small, open incision (143). For patients with complicated acute cholecystitis or portal hypertension, some authors advocate a partial or subtotal cholecystectomy, where the posterior wall of the gallbladder is left in place (144). Conversion to an open procedure is still recommended when the laparoscopic or minicholecystectomy cannot be completed safely. Initial treatment of acute cholecystitis includes intravenous fluids, antibiotics, and analgesia. Cholecystectomy, the definitive treatment, should be performed early. Studies have demonstrated that there is no difference between the morbidities associated with early laparoscopic cholecystectomy and interval cholecystectomy after 6 to 8 weeks, and in fact, early surgical intervention is associated with a shorter hospital stay and an earlier return to productivity (145–147). In patients whose concomitant comorbidities preclude safe operative interventions, percutaneous cholecystostomy tube placement is an effective initial treatment option for acute cholecystitis (148). If the patient’s clinical status improves, subsequent cholecystectomy is recommended. Nonoperative alternatives for the treatment of symptomatic cholelithiasis include oral dissolution therapy with ursodeoxycholic acid or chenodeoxycholic acid, topical dissolution therapy with methyl tert-butyl ether (MTBE), and extracorporeal shock-wave lithotripsy. These methods are limited by risk of recurrence after completion of therapy and lack of cost-effectiveness, but may be indicated in selected patients.

Choledocholithiasis Management of secondary CBD stones is cholecystectomy with clearance of the stones by one of the following methods: preoperative endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy, intra-operative common bile duct exploration (CBDE), or post-operative ERCP with sphincterotomy. Intraoperative clearance of stones historically was performed using an open approach, which was associated with increased morbidity and mortality over open cholecystectomy alone. However, multiple studies have demonstrated that a laparoscopic CBDE can be safely and effectively done using either a transcystic approach (149,150) or by performing a choledochotomy (149,151). A biliary drainage procedure such as a choledochoduodenostomy or choledochojejunostomy is recommended in patients with primary CBD stones and a dilated CBD, in patients with multiple recurrences, and in patients with CBD stones and a benign stricture. For patients in whom a stone is impacted at the ampulla of Vater despite attempted endoscopic or operative removal, transduodenal sphincteroplasty is indicated. In patients with short life expectancies or multiple comorbidities, endoscopic treatment alone for choledocholithiasis may suffice. The timing of stone clearance in relation to cholecystectomy for CBD duct stones is controversial. A consensus development conference on CBD stones in 1998 recommended that CBD stones be treated before or during surgery, with postoperative clearance only for retained stones (139). In another study, four strategies for managing

medwedi.ru

464

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 5 Efficacy, Advantages, and Disadvantages of Biliary Imaging Modalities for the Evaluation of Choledocholithiasis Method ERCP MRC Transabdominal US CT

Endoscopic US Intravenous cholangiography

IOC

Laparoscopic US

Laparoscopic choledochoscopy

Diagnostic efficacy for CBDS Sens: 95–100 (mean: 98%); Spec: 95–100 (mean: 98%) Sens: 57–100 (mean: 90%); Spec: 73–100 (mean: 96%) Sens: 20–38%; Spec: 80–100% Unenhanced CT; Sens: 65–90%; Spec: 80–85%; CT/oral contrast; Sens: 90–96%; Spec: 95% Sens: 75–98 (mean: 95%); Spec: 90–100 (mean: 96%) Sens: 88–93%; Spec: 97–99%

Sens: 75–100 (mean: 90%) (reduced sensitivity with static cholangiography); Spec: 75–100 (mean: 95%) Sens: 90–100 (mean: 95%); Spec: 98–100 (mean: 99%) Success rate: 67–100 (mean: 91%)

Advantages Therapeutic capabilities; identifies anatomy and anomalies Noninvasive reproducible; identifies anatomy and anomalies Identifies cholelithiasis in 95% of patients; easy to interpret Widely available; noninvasive

Equipment and expertise required Identifies anatomy and anatomic variants

Identifies anatomy and anatomic variants; special skills and equipment not needed More sensitive than ERC and MRC at identifying CBDS <3 mm; may be repeated during the operation Therapeutic capabilities

Disadvantages Requires sedation, analgesia; patient discomfort; complications No therapeutic capability Limited sensitivity for CBDS Expertise required in the interpretation of nonenhanced CT Requires sedation, analgesia; may miss stones in hepatic ducts Adverse reactions reported in 0–12% of patients with severe reactions reported in 0–9% of patients; not FDA approved in the United States

Requires special equipment and expertise Requires expertise and equipment; may cause pancreatitis, bleeding, and perforation

Abbreviations: Sens, Sensitivity; Spec, specificity; CBDS, common bile duct stones; ERCP, endoscopic retrograde cholangiopancreatography; CT, computed tomography; IOC, intraoperative cholangiography; US, ultrasound. Source: From Ref. 141.

common bile duct stones were evaluated using decision analysis: routine preoperative ERCP, laparoscopic cholecystecomy with intraoperative cholangiogram (IOC) followed by laparoscopic CBDE, laparoscopic cholecystectomy with IOC followed by postoperative ERCP, and expectant management (laparoscopic cholecystectomy without evaluation for CBD stones). The analysis favored laparoscopic common bile duct exploration in terms of cost, although preoperative ERCP resulted in fewer residual CBD stones. If laparoscopic expertise is not available, the analysis favored postoperative versus routine preoperative ERCP unless the probability of CBD stones was high prior to surgery (152). ERCP is also indicated preoperatively in patients with cholangitis and in select patients with severe gallstone pancreatitis. The mainstay of treatment for acute cholangitis is management of the sepsis and biliary decompression. Initial management includes fluid resuscitation, close monitoring of hemodynamic parameters and urine output, and administration of antibiotics. The most commonly isolated organisms associated with cholangitis include: Escherichia coli, Klebsiella, Enterococcus, and Enterobacter species, and antibiotic coverage should be directed against these pathogens. Biliary decompression can be accomplished with ERCP and endoscopic sphincterotomy, placement of a percutaneous biliary drainage tube, or rarely surgical common duct exploration with placement of a T-tube.

Gallstone Ileus Occasionally a large gallstone erodes through the gallbladder wall and the wall of the adjacent intestine, usually the duodenum. This condition creates a cholecystoenteric fistula. The stone now has free access to the small bowel,

and on passage downstream may induce an obstruction, commonly in the region of the ileocecal valve. Abdominal radiographs demonstrate an intestinal obstruction as well as air in the biliary tree; sometimes the gallstone is visualized on an X-ray if it is sufficiently calcified. Patients with this condition are usually elderly, often female, and may present solely with findings suggestive of bowel obstruction, denying any history of gallstone disease. Appropriate therapy is directed at the bowel obstruction with removal of the stone. The fistula usually closes spontaneously and cholecystectomy during a subsequent operation is dictated by the patient’s overall condition.

Gallbladder Cancer Adenocarcinoma of the gallbladder is a rare malignancy with approximately 6000 to 7000 new cases diagnosed annually in the United States. Most patients are women older than 65 years at the time of diagnosis. Cholelithiasis has been implicated as an etiologic factor because as many as 70% to 90% of patients have gallstones, often for many years. Calcification of the gallbladder wall, known as porcelain gallbladder, is commonly seen in patients with gallbladder cancer. Unfortunately, no specific symptoms or signs are diagnostic of gallbladder malignancy. Pain in the right upper quadrant, nausea and vomiting, poor appetite, and weight loss are, nonetheless, frequent findings. Often the disease is first diagnosed at the time of cholecystectomy for what was preoperatively assumed to be chronic cholecystitis. Because of late diagnosis in most patients, the overall 5-year survival rate averages 2% to 3%. Even with resection of all or part of the right lobe of the liver in combination with

Chapter 21:

cholecystectomy as a curative procedure, ultimate outcome is not appreciably improved. Until some means is achieved for diagnosing this tumor earlier, the prognosis for patients with this cancer will continue to be devastating.

Biliary Pancreatitis Occasionally, passage of stones from the gallbladder to the proximal duodenum will result in a stone getting impacted in the distal common duct or transiently blocking the pancreatic duct and, thereby, causing an inflammatory process in the pancreas. This condition is known as biliary pancreatitis. Its management is discussed in the chapter detailing inflammatory disorders of the pancreas.

SUMMARY The discharge of bile into the upper gut by the gallbladder in response to eating a meal plays a major role in the digestion of fat through the formation of micelles. If disproportionate changes in the composition of bile occur through any number of pathophysiologic processes, lithogenic tendencies may supervene with the ultimate formation of gallstones. The gallbladder and common bile duct are the sites for such stone formation with the concomitant development of potentially serious disease. Although a number of strategies have evolved over the years to manage stone disease, cholecystectomy (occasionally in combination with common duct exploration) has been shown to be an effective and durable treatment that not only returns the patient to productive living but also restores the biliary tract to normal function.

REFERENCES 1. Traverso LW. Carl Langenbuch and the first cholecystectomy. Am J Surg 1976; 132:81–82. 2. Danzinger RG, Hofmann AF, Schoenfield LJ, Thistle JL. Dissolution of cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 1972; 286:1–8. 3. Thistle JL, Schoenfield LJ. Lithogenic bile among young Indian women. N Engl J Med 1971; 284:177–181. 4. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002; 122:1500–1511. 5. Kratzer W, Mason RA, Kachele V. Prevalence of gallstones in sonographic surveys worldwide. J Clin Ultrasound 1999; 27:1–7. 6. Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA. Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. N Engl J Med 1970; 283:1358–1364. 7. Everhart JE, Yeh F, Lee ET, et al. Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study. Hepatology 2002; 35:1507–1512. 8. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology 1999; 117:632–639. 9. Gilat T, Feldman C, Halpern Z, Dan M, Bar-Meir S. An increased familial frequency of gallstones. Gastroenterology 1983; 84:242–246. 10. Sarin SK, Negi VS, Dewan R, Sasan S, Saraya A. High familial prevalence of gallstones in the first-degree relatives of gallstone patients. Hepatology 1995; 22:138–141. 11. Antero Kesaniemi Y, Koskenvuo M, Vuoristo M, Miettinen TA. Biliary lipid composition in monozygotic and dizygotic pairs of twins. Gut 1989; 30:1750–1756.

Calculous Disease of the Gallbladder and Common Bile Duct

465

12. Nakeeb A, Comuzzie AG, Martin L, et al. Gallstones: genetics versus environment. Ann Surg 2002; 235:842–849. 13. Wheeler HO. Secretion of bile acids by the liver and their role in the formation of hepatic bile. Arch Intern Med 1972; 130: 533–541. 14. Alpini G, Roberts S, Kuntz SM, et al. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver. Gastroenterology 1996; 110:1636–1643. 15. Alpini G, Ulrich CD II, Phillips JO, Pham LD, Miller LJ, LaRusso NF. Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation. Am J Physiol 1994; 266:G922–G928. 16. Hamada Y, Karjalainen A, Bygrave FL. Hormone-induced bile flow and hepatobiliary calcium fluxes are attenuated in the perfused liver of rats made cholestatic with ethynylestradiol in vivo and with phalloidin in vitro. Hepatology 1995; 21: 1455–1464. 17. Lenzen R, Alpini G, Tavoloni N. Secretin stimulates bile ductular secretory activity through the cAMP system. Am J Physiol 1992; 263:G527–G532. 18. Boyer JL, Bloomer JR. Canalicular bile secretion in man. Studies utilizing the biliary clearance of (14C)mannitol. J Clin Invest 1974; 54:773–781. 19. St-Pierre MV, Kullak-Ublick GA, Hagenbuch B, Meier PJ. Transport of bile acids in hepatic and non-hepatic tissues. J Exp Biol 2001; 204:1673–1686. 20. Hagenbuch B, Meier PJ. Sinusoidal (basolateral) bile salt uptake systems of hepatocytes. Semin Liver Dis 1996; 16: 129–136. 21. Hagenbuch B, Stieger B, Foguet M, Lubbert H, Meier PJ. Functional expression-cloning and characterization of the hepatocyte Naþ/bile acid cotransport system. Proc Natl Acad Sci USA 1991; 88:10629–10633. 22. Latham PS, Kashgarian M. The ultrastructural localization of transport ATPase in the rat liver, at non-bile canalicular plasma membranes. Gastroenterology 1979; 76:988–996. 23. Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ. Hepatic transport of bile salts. Semin Liver Dis 2000; 20:273–292. 24. Erlinger S. Do intracellular organelles have any role in transport of bile acids by hepatocytes? J Hepatol 1996; 24(suppl 1): 88–93. 25. Frimmer M, Ziegler K. The transport of bile acids in liver cells. Biochim Biophys Acta 1988; 947:75–99. 26. Stolz A, Takikawa H, Ookhtens M, Kaplowitz N. The role of cytoplasmic proteins in hepatic bile acid transport. Annu Rev Physiol 1989; 51:161–176. 27. Zucker SD, Goessling W, Gollan JL. Kinetics of bilirubin transfer between serum albumin and membrane vesicles. Insight into the mechanism of organic anion delivery to the hepatocyte plasma membrane. J Biol Chem 1995; 270:1074–1081. 28. Stolz A, Hammond L, Lou H, Takikawa H, Ronk M, Shively JE. cDNA cloning and expression of the human hepatic bile acid-binding protein. A member of the monomeric reductase gene family. J Biol Chem 1993; 268:10448–10457. 29. Meier PJ, St Meier-Abt A, Barrett C, Boyer JL. Mechanisms of taurocholate transport in canalicular and basolateral rat liver plasma membrane vesicles. Evidence for an electrogenie canalicular organic anion carrier. J Biol Chem 1984; 259: 10614–10622. 30. Inoue M, Kinne R, Tran T, Arias IM. Taurocholate transport by rat liver canalicular membrane vesicles. Evidence for the presence of an Naþ-independent transport system. J Clin Invest 1984; 73:659–663. 31. Luther TT, Hammerman P, Rahmaoui CM, et al. Evidence for an ATP-dependent bile acid transport protein other than the canalicular liver ecto-ATPase in rats. Gastroenterology 1997; 113:249–254. 32. Sippel CJ, Suchy FJ, Ananthanarayanan M, Perlmutter DH. The rat liver ecto-ATPase is also a canalicular bile acid transport protein. J Biol Chem 1993; 268:2083–2091. 33. Kast C, Stieger B, Winterhalter KH, Meier PJ. Hepatocellular transport of bile acids. Evidence for distinct subcellular

medwedi.ru

466

34.

35. 36.

37. 38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53. 54.

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen localizations of electrogenic and ATP-dependent taurocholate transport in rat hepatocytes. J Biol Chem 1994; 269: 5179–5186. Strautnieks SS, Kagalwalla AF, Tanner MS, et al. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Am J Hum Genet 1997; 61:630–633. Jansen PL, Muller M. The molecular genetics of familial intrahepatic choleostasis. Gut 2000; 47:1–5. Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic choleostasis. Gastroenterology 1999; 117:1370–1379. Thompson R, Jansen PL. Genetic defects in hepatocanalicular transport. Semin Liver Dis 2000; 20:365–372. Lee J, Boyer JL. Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders. Semin Liver Dis 2000; 20:373–384. Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001; 120: 1448–1458. Ballatori N, Jacob R, Boyer JL. Intrabiliary glutathione hydrolysis. A source of glutamate in bile. J Biol Chem 1986; 261: 7860–7865. Ballatori N, Truong AT. Relation between biliary glutathione excretion and bile acid-independent bile flow. Am J Physiol 1989; 256:G22–G30. Ballatori N, Truong AT, Ma AK, Boyer JL. Determinants of glutathione efflux and biliary GSH/GSSG ratio in perfused rat liver. Am J Physiol 1989; 256:G482–G490. Kartenbeck J, Leuschner U, Mayer R, Keppler D. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 1996; 23:1061–1066. Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 1997; 25:1539–1542. Meier PJ, Knickelbein R, Moseley RH, Dobbins JW, Boyer JL. Evidence for carrier-mediated chloride/bicarbonate exchange in canalicular rat liver plasma membrane vesicles. J Clin Invest 1985; 75:1256–1263. Martinez-Anso E, Castillo JE, Diez J, Medina JF, Prieto J. Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver. Hepatology 1994; 19: 1400–1406. Benedetti A, Strazzabosco M, Corasanti JG, Haddad P, Graf J, Boyer JL. Cl(-)-HCO3-exchanger in isolated rat hepatocytes: role in regulation of intracellular pH. Am J Physiol 1991; 261:G512–G522. Cho WK, Mennone A, Rydberg SA, Boyer JL. Bombesin stimulates bicarbonate secretion from rat cholangiocytes: implications for neural regulation of bile secretion. Gastroenterology 1997; 113:311–321. Kim MS, Lee KY, Chey WY. Plasma secretin concentrations in fasting and postprandial states in dog. Am J Physiol 1979; 236:E539–E544. Tietz PS, Alpini G, Pham LD, Larusso NF. Somatostatin inhibits secretin-induced ductal hypercholeresis and exocytosis by cholangiocytes. Am J Physiol 1995; 269:G110–G118. Magnusson I, Einarsson K, Angelin B, Nyberg B, Bergstrom K, Thulin L. Effects of somatostatin on hepatic bile formation. Gastroenterology 1989; 96:206–212. Alpini G, Lenzi R, Zhai WR, et al. Bile secretory function of intrahepatic biliary epithelium in the rat. Am J Physiol 1989; 257:G124–G133. Boyer JL. Bile duct epithelium: frontiers in transport physiology. Am J Physiol 1996; 270:G1–G5. Elsing C, Hubner C, Fitscher BA, Kassner A, Stremmel W. Muscarinic acetylcholine receptor stimulation of biliary epithelial cells and its effect on bile secretion in the isolated perfused liver [corrected]. Hepatology 1997; 25:804–813.

55. Boyer J. Bile formation. In: Maddrey W, ed. Schiff’s Diseases of the Liver. Philadelphia: Lippincott-Raven, 1999:119–146. 56. Everson GT, Lawson MJ, McKinley C, Showalter R, Kern F Jr. Gallbladder and small intestinal regulation of biliary lipid secretion during intraduodenal infusion of standard stimuli. J Clin Invest 1983; 71:596–603. 57. Fried M, Jansen JB, Harpole T, et al. Pancreatobiliary responses to an intragastric amino acid meal: comparison to albumin, dextrose, and a maximal cholecystokinin stimulus. Gastroenterology 1989; 97:1544–1549. 58. Ladas SD, Isaacs PE, Murphy GM, Sladen GE. Comparison of the effects of medium and long chain triglyceride containing liquid meals on gall bladder and small intestinal function in normal man. Gut 1984; 25:405–411. 59. Murthy SN, Dinoso VP Jr, Clearfield HR. Bile acid and pancreatic trypsin outputs are parallel during intraduodenal infusion of essential amino acids. Dig Dis Sci 1983; 28:27–32. 60. Malagelada JR, DiMagno EP, Summerskill WH, Go VL. Regulation of pancreatic and gallbladder functions by intraluminal fatty acids and bile acids in man. J Clin Invest 1976; 58:493–499. 61. Hopman WP, Jansen JB, Rosenbusch G, Lamers CB. Role of cholecystokinin and the cholinergic system in intestinal stimulation of gallbladder contraction in man. Hepatology 1990; 11:261–265. 62. Hansen WE, Maurer H, Haberland H. The effect of shamfeeding on gallbladder volume and circulation of bile acids. Hepatogastroenterology 1982; 29:108–110. 63. Fisher RS, Rock E, Malmud LS. Cholinergic effects on gallbladder emptying in humans. Gastroenterology 1985; 89: 716–722. 64. Fisher RS, Rock E, Malmud LS. Gallbladder emptying response to sham feeding in humans. Gastroenterology 1986; 90:1854–1857. 65. Sarna SK. Cyclic motor activity; migrating motor complex: 1985. Gastroenterology 1985; 89:894–913. 66. Everson GT. Gallbladder function in gallstone disease. Gastroenterol Clin North Am 1991; 20:85–110. 67. Cooper AD. Metabolic basis of cholesterol gallstone disease. Gastroenterol Clin North Am 1991; 20:21–46. 68. Donovan JM, Carey MC. Physical-chemical basis of gallstone formation. Gastroenterol Clin North Am 1991; 20:47–66. 69. Spector AA, Mathur SN, Kaduce TL. Role of acylcoenzyme A: cholesterol o-acyltransferase in cholesterol metabolism. Prog Lipid Res 1979; 18:31–53. 70. Goodman D, Deykin D, Shiratori T. The formation of cholesterol esters with rat liver enzymes. J Biol Chem 1964; 239: 1335–1345. 71. Heuman D, Wassef W, Vlahcevic R. Gallstones. In: Maddrey W, ed. Schiff’s Diseases of the Liver. Philadelphia: LippincottRaven, 1999:631–647. 72. Dawson P. Bile secretion and the enterohepatic circulation of bile acids. In: Sleisenger M, ed. Sleisenger and Fortran’s Gastrointestinal and Liver Disease. Philadelphia: W.B. Saunders Company, 2002:1051–1064. 73. Nies AT, Gatmaitan Z, Arias IM. ATP-dependent phosphatidylcholine translocation in rat liver canalicular plasma membrane vesicles. J Lipid Res 1996; 37:1125–1136. 74. Oude Elferink RP, Groen AK. Mechanisms of biliary lipid secretion and their role in lipid homeostasis. Semin Liver Dis 2000; 20:293–305. 75. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339:1217–1227. 76. Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, Meier PJ. Expression cloning of a rat liver Na(þ)-independent organic anion transporter. Proc Natl Acad Sci USA 1994; 91:133–137. 77. Holzbach RT. Pathogenesis and medical treatment of gallstones. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 3rd ed. Philadelphia: WB Saunders, 1983. 78. Carey MC, Small DM. The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man. J Clin Invest 1978; 61:998–1026.

Chapter 21: 79. Holan KR, Holzbach RT, Hermann RE, Cooperman AM, Claffey WJ. Nucleation time: a key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 1979; 77:611–617. 80. Kibe A, Holzbach RT, LaRusso NF, Mao SJ. Inhibition of cholesterol crystal formation by apolipoproteins in supersaturated model bile. Science 1984; 225:514–516. 81. Upadhya GA, Harvey PR, Strasberg SM. Effect of human biliary immunoglobulins on the nucleation of cholesterol. J Biol Chem 1993; 268:5193–5200. 82. Yamashita G, Ginanni Corradini S, Secknus R, et al. Biliary haptoglobin, a potent promoter of cholesterol crystallization at physiological concentrations. J Lipid Res 1995; 36:1325–1333. 83. Offner GD, Gong D, Afdhal NH. Identification of a 130-kilodalton human biliary concanavalin A binding protein as aminopeptidase N. Gastroenterology 1994; 106:755–762. 84. Smith BF. Human gallbladder mucin binds biliary lipids and promotes cholesterol crystal nucleation in model bile. J Lipid Res 1987; 28:1088–1097. 85. Abei M, Nuutinen H, Kawczak P, Schwarzendrube J, Pillay SP, Holzbach RT. Identification of human biliary alpha 1-acid glycoprotein as a cholesterol crystallization promoter. Gastroenterology 1994; 106:231–238. 86. Netter FH. CIBA Collection of Medical Illustrations. Vol. 3, Part III. Indianapolis, In: CIBA Pharmaceutical, Division of CIBA-GEIGY, 1964. 87. Roslyn JJ, Pitt HA, Mann LL, Ament ME, DenBesten L. Gallbladder disease in patients on long-term parenteral nutrition. Gastroenterology 1983; 84:148–154. 88. Shaffer EA, Taylor PJ, Logan K, Gadomski S, Corenblum B. The effect of a progestin on gallbladder function in young women. Am J Obstet Gynecol 1984; 148:504–507. 89. Everson GT, McKinley C, Lawson M, Johnson M, Kern F Jr. Gallbladder function in the human female: effect of the ovulatory cycle, pregnancy, and contraceptive steroids. Gastroenterology 1982; 82:711–719. 90. Plevris JN, Bouchier IA. Defective acid base regulation by the gall bladder epithelium and its significance for gall stone formation. Gut 1995; 37:127–131. 91. Lee SP, Carey MC, LaMont JT. Aspirin prevention of cholesterol gallstone formation in prairie dogs. Science 1981; 211:1429–1431. 92. Kurata JH, Marks J, Abbey D. One gram of aspirin per day does not reduce risk of hospitalization for gallstone disease. Dig Dis Sci 1991; 36:1110–1115. 93. Hood KA, Gleeson D, Ruppin DC, Dowling RH. Gall stone recurrence and its prevention: the British/Belgian Gall Stone Study Group’s post-dissolution trial. Gut 1993; 34:1277–1288. 94. Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge. Gastroenterology 1988; 94:170–176. 95. Lee SP, Nicholls JF. Nature and composition of biliary sludge. Gastroenterology 1986; 90:677–686. 96. Messing B, Bories C, Kunstlinger F, Bernier JJ. Does total parenteral nutrition induce gallbladder sludge formation and lithiasis? Gastroenterology 1983; 84:1012–1019. 97. Hussaini SH, Pereira SP, Veysey MJ, et al. Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide induced gall bladder stones. Gut 1996; 38:775–783. 98. Janowitz P, Kratzer W, Zemmler T, Tudyka J, Wechsler JG. Gallbladder sludge: spontaneous course and incidence of complications in patients without stones. Hepatology 1994; 20:291–294. 99. Trotman BW. Pigment gallstone disease. Gastroenterol Clin North Am 1991; 20:111–126. 100. Ostrow JD. The etiology of pigment gallstones. Hepatology 1984; 4:215S–222S. 101. Carey MC. Pathogenesis of gallstones. Am J Surg 1993; 165: 410–419. 102. Soloway RD, Trotman BW, Ostrow JD. Pigment gallstones. Gastroenterology 1977; 72:167–182. 103. Cetta FM. Bile infection documented as initial event in the pathogenesis of brown pigment biliary stones. Hepatology 1986; 6:482–489.

Calculous Disease of the Gallbladder and Common Bile Duct

467

104. Braasch JW, Fender HR, Bonneval MM. Refractory primary common bile duct stone disease. Am J Surg 1980; 139: 526–530. 105. Saharia PC, Zuidema GD, Cameron JL. Primary common duct stones. Ann Surg 1977; 185:598–604. 106. Friedman GD. Natural history of asymptomatic and symptomatic gallstones. Am J Surg 1993; 165:399–404. 107. Grade WA, Ransohoff DF. The natural history of silent gallstones: the innocent gallstone is not a myth. N Engl J Med 1982; 307:798–800. 108. Friedman GD, Raviola CA, Fireman B. Prognosis of gallstones with mild or no symptoms: 25 years of follow-up in a health maintenance organization. J Clin Epidemiol 1989; 42:127–136. 109. Michaud DS. The epidemiology of pancreatic, gallbladder, and other biliary tract cancers. Gastrointest Endosc 2002; 56:S195–S200. 110. Lowenfels AB, Maisonneuve P, Boyle P, Zatonski WA. Epidemiology of gallbladder cancer. Hepatogastroenterology 1999; 46:1529–1532. 111. Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA 1983; 250:2323–2326. 112. Ransohoff DF, Gracie WA, Wolfenson LB, Neuhauser D. Prophylactic cholecystectomy or expectant management for silent gallstones. A decision analysis to assess survival. Ann Intern Med 1983; 99:199–204. 113. Fendrick AM, Gleeson SP, Cabana MD, Schwartz JS. Asymptomatic gallstones-revisited. Is there a role for laparoscopic cholecystectomy? Arch Fam Med 1993; 2:959–968. 114. Gibney EJ. Asymptomatic gallstones. Br J Surg 1990; 77:368–372. 115. Landau O, Deutsch AA, Kott I, Rivlin E, Reiss R. The risk of cholecystectomy for acute cholecystitis in diabetic patients. Hepatogastroenterology 1992; 39:437–438. 116. Sandier RS, Maule WF, Baltus ME. Factors associated with postoperative complications in diabetics after biliary tract surgery. Gastroenterology 1986; 91:157–162. 117. Del Favero G, Caroli A, Meggiato T, et al. Natural history of gallstones in non-insulin-dependent diabetes mellitus. A prospective 5-year follow-up. Dig Dis Sci 1994; 39:1704–1707. 118. Friedman LS, Roberts MS, Brett AS, Marton KI. Management of asymptomatic gallstones in the diabetic patient. A decision analysis. Ann Intern Med 1988; 109:913–919. 119. Hull D, Bartus SA, Perdrizet G, Schweizer RT. Management of cholelithiasis in heart and kidney transplant patients: with review of laparoscopic cholecystectomy. Conn Med 1994; 58:643–647. 120. Steck TB, Costanzo-Nordin MR, Keshavarzian A. Prevalence and management of cholelithiasis in heart transplant patients. J Heart Lung Transplant 1991; 10:1029–1032. 121. Girardet RE, Rosenbloom P, DeWeese BM, et al. Significance of asymptomatic biliary tract disease in heart transplant recipients. J Heart Transplant 1989; 8:391–399. 122. Sekela ME, Hutchins DA, Young JB, Noon GP. Biliary surgery after cardiac transplantation. Arch Surg 1991; 126:571–573. 123. Milas M, Ricketts RR, Amerson JR, Kanter K. Management of biliary tract stones in heart transplant patients. Ann Surg 1996; 223:747–753; discussion 753–756. 124. Menegaux F, Dorent R, Tabbi D, Pavie A, Chigot JP, Gandjbakhch I. Biliary surgery after heart transplantation. Am J Surg 1998; 175:320–321. 125. Kao LS, Ruhr C, Flum DR. Should cholecystectomy be performed for asymptomatic cholelithiasis in transplant patients? JACS 2003; 197(2):302–312. 126. Kao LS, Flowers C, Flum DR. Prophylactic cholecystectomy in transplant patients: a decision analysis. J Gastrointest Surg 2005; 9(7):965–972. 127. Shiffman ML, Sugerman HJ, Kellum JM, Brewer WH, Moore EW. Gallstone formation after rapid weight loss: a prospective study in patients undergoing gastric bypass surgery for treatment of morbid obesity. Am J Gastroenterol 1991; 86: 1000–1005. 128. Shiffman ML, Sugerman HJ, Kellum JH, Brewer WH, Moore EW. Gallstones in patients with morbid obesity. Relationship

medwedi.ru

468

129.

130.

131. 132. 133. 134.

135. 136.

137.

138. 139.

140.

141.

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen to body weight, weight loss and gallbladder bile cholesterol solubility. Int J Obes Relat Metab Disord 1993; 17:153–158. Seinige UL, Sataloff DM, Lieber CP, DellaCroce JM, Sorouri ES. Gallbladder disease in the morbidly obese patient. Obes Surg 1991; 1:51–56. Schmidt JH, Hocking MP, Rout WR, Woodward ER. The case for prophylactic cholecystectomy concomitant with gastric restriction for morbid obesity. Am Surg 1988; 54:269–272. Fakhry SM, Herbst CA, Buckwalter JA. Cholecystectomy in morbidly obese patients. Am Surg 1987; 53:26–28. Jones KB Jr. Simultaneous cholecystectomy: to be or not to be. Obes Surg 1995; 5:52–54. Deitel M, Petrov I. Incidence of symptomatic gallstones after bariatric operations. Surg Gynecol Obstet 1987; 164:549–552. Horton J, Bilhartz L. Gallstone disease and its complications. In: Feldman M, Friedman L, Sleisenger M, eds. Sleisenger and Fortran’s Gastrointestinal and Liver Disease. Philadelphia: W.B. Saunders Company, 2002:1051–1064. Csendes A, Fernandez M, Uribe P. Bacteriology of the gallbladder bile in normal subjects. Am J Surg 1975; 129:629–631. McGahan JP, Lindfors KK. Acute cholecystitis: diagnostic accuracy of percutaneous aspiration of the gallbladder. Radiology 1988; 167:669–671. Thompson JE Jr, Bennion RS, Doty JE, Muller EL, Pitt HA. Predictive factors for bactibilia in acute cholecystitis. Arch Surg 1990; 125:261–264. Thistle JL. Pathophysiology of bile duct stones. World J Surg 1998; 22:1114–1118. Diagnosis and treatment of common bile duct stones (CBDS). Results of a consensus development conference. Scientific Committee of the European Association for Endoscopic Surgery (E.A.E.S.). Surg Endosc 1998; 12:856–864. Prat F, Meduri B, Ducot B, Chiche R, Salimbeni-Bartolini R, Pelletier G. Prediction of common bile duct stones by noninvasive tests. Ann Surg 1999; 229:362–368. Liu TH, Organ CH Jr. Magnetic resonance cholangiography applications in patients with calculous disease of the biliary tract. Asian J Surg 2004; 27:99–107.

142. Graves EJ, Owings MF. 1995 summary: National Hospital Discharge Survey. Adv Data 1997:1–10. 143. McGinn FP, Miles AJ, Uglow M, Ozmen M, Terzi C, Humby M. Randomized trial of laparoscopic cholecystectomy and mini-cholecystectomy. Br J Surg 1995; 82:1374–1377. 144. Ibrarullah MD, Kacker LK, Sikora SS, Saxena R, Kapoor VK, Kaushik SP. Partial cholecystectomy—safe and effective. HPB Surg 1993; 7:61–65. 145. Jarvinen HJ, Hastbacka J. Early cholecystectomy for acute cholecystitis: a prospective randomized study. Ann Surg 1980; 191:501–505. 146. Norrby S, Herlin P, Holmin T, Sjodahl R, Tagesson C. Early or delayed cholecystectomy in acute cholecystitis? A clinical trial. Br J Surg 1983; 70:163–165. 147. Van der Linden W, Edlund G. Early versus delayed cholecystectomy: the effect of a change in management. Br J Surg 1981; 68:753–757. 148. Davis CA, Landercasper J, Gundersen LH, Lambert PJ. Effective use of percutaneous cholecystostomy in high-risk surgical patients: techniques, tube management, and results. Arch Surg 1999; 134:727–731; discussion 731–732. 149. Tokumura H, Umezawa A, Cao H, et al. Laparoscopic management of common bile duct stones: transcystic approach and choledochotomy. J Hepatobiliary Pancreat Surg 2002; 9:206–212. 150. Rojas-Ortega S, Arizpe-Bravo D, Marin Lopez ER, CesinSanchez R, Roman GR, Gomez C. Transcystic common bile duct exploration in the management of patients with choledocholithiasis. J Gastrointest Surg 2003; 7:492–496. 151. Decker G, Borie F, Millat B, et al. One hundred laparoscopic choledochotomies with primary closure of the common bile duct. Surg Endosc 2003; 17:12–18. 152. Urbach DR, Khajanchee YS, Jobe BA, Standage BA, Hansen PD, Swanstrom LL. Cost-effective management of common bile duct stones: a decision analysis of the use of endoscopic retrograde cholangiopancreatography (ERCP), intraoperative cholangiography, and laparoscopic bile duct exploration. Surg Endosc 2001; 15:4–13.

22 Normal Exocrine Function and Inflammatory Diseases of the Pancreas David J. Bentrem and Raymond J. Joehl

INTRODUCTION The pancreas is an extremely important organ that plays a key role in the normal digestion of carbohydrates, protein, and fat as well as the neutralization of acidic chyme through the elaboation of a watery, bicarbonate secretion. Its secretions are under the complex control of a variety of sophisticated neural and humoral mechanisms. Unfortunately, its normal physiologic contributions to the digestive process can become greatly perturbed when challenged by various insults that result in inflammation. This chapter highlights its role in digestion and how acute and/or chronic inflammatory processes can markedly disturb this important function.

EMBRYOLOGY The human pancreas develops during the 4th to 7th weeks of fetal life, arising from dorsal and ventral epithelial evaginations of foregut endoderm into surrounding mesoderm. During the 7th week, the smaller ventral bud fuses with the proximal part of the dorsal pancreas. The ventral component forms the uncinate process and the posteroinferior portion of the pancreatic head. The dorsal bud forms the remainder of the head, body, and tail. The ductal system then develops as the two pancreatic buds grow rapidly. The main pancreatic duct, or duct of Wirsung, is created by the fusion of the duct in the ventral pancreatic bud with the distal portion of the duct in the dorsal pancreatic bud. The proximal portion of the dorsal duct may regress or form an accessory pancreatic duct or the duct of Santorini. Failure of the two pancreatic buds/ducts to fuse leads to development of separate dorsal and ventral ducts known as pancreas divisum. Furthermore, if the ventral pancreatic bud is fixed to the duodenal wall before rotation, a band of pancreatic tissue develops and surrounds the descending duodenum. This is known as an annular pancreas. Both anomalies predispose the patient to bouts of upper abdominal pain and pancreatic inflammation. Annular pancreas can cause duodenal obstruction. The pancreas grows rapidly by the elongation of the primitive ducts. The columnar epithelium of the main duct takes on a cuboidal configuration in the smaller branches. Acini, the secreting units of the exocrine pancreas, are pyramidal cells whose apices are directed toward the lumen of the duct and begin to appear in the 3rd month of development. Centroacinar cells line the ducts from which the acini arise. The ducts then elongate and form intercalated ducts, which connect to form intralobular ducts lined by columnar epithelium. Small zymogen granules also appear

in the cytoplasm of the acinar cells in the 4th month. These zymogen granules increase in number and accumulate in the apical cytoplasm (Fig. 1).

GROSS ANATOMY The end result of pancreatic embryogenesis is a complex adaptive organ consisting of ductal, acinar, islet, and interstitial cells that interact with great precision to carry out normal physiologic function. The pancreas is a solid glandular organ, which lies in the retroperitoneum posterior to the stomach. The pancreas is divided into four portions: the head (to the right of the superior mesenteric vein), the neck (the portion lying over the superior mesenteric vessels), the body, and tail (to the left of the superior mesenteric vessels). The pancreatic head is encircled by the curvature of the duodenum. The connection of both organs is generally loose enough for blunt dissection except for the area of the accessory and main papilla, in which the pancreatic tissue is intimately involved with the duodenal wall (1). The body and tail extend to the left, paralleling the splenic vessels. Two pancreaticoduodenal arcades supply blood to the head region, and are derived from a union of the anterior and posterior branches of the superior and inferior pancreaticoduodenal arteries. Superior pancreaticoduodenal arteries are branches of the gastroduodenal artery, whereas the inferior pancreaticoduodenal arteries originate from the superior

medwedi.ru 469

Figure 1 Diagram of pancreatic acinar cell.

470

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

mesenteric artery. The neck and body of the pancreas derive their blood supply from the dorsal pancreatic artery, which may arise from the splenic artery, the celiac trunk, or the superior mesenteric artery. The functional relationship between pancreatic secretory activity and pancreatic blood flow is poorly understood. Under physiologic conditions, pancreatic blood flow is not a limiting factor for exocrine function. At the microvascular level, the blood supply to the islets and acinar tissue is in the form of a portal system. Approximately 10% to 25% of total pancreatic blood goes to the islets (2); therefore, these cells, which constitute 1% to 2% of the pancreatic mass, are perfused at 10 to 20 times the rate of exocrine tissue.

ACINUS The exocrine cells of the pancreas constitute about 85% of the mass of the gland (3), with the vast majority being acinar cells. Ductal epithelium comprises only about 11% of the gland by volume. Acinar cells are arranged in spheroid clusters of 15 to 20 pyramidal cells oriented with their apical membranes abutting a common lumen (Fig. 2). The lumen, draining the acinus, is an intercalated duct that communicates with intralobular and interlobular ducts and finally with the main pancreatic duct. Each acinar cell synthesizes, processes, stores, and secretes pancreatic enzymes at high rates using an abundant rough endoplasmic reticulum, transitional vesicles, a well-developed Golgi apparatus, and apically located zymogen granules. The synthesis and secretion of enzymes and bicarbonate-rich fluid occurs in acinar and duct cells, respectively.

PANCREATIC EXOCRINE FUNCTION Pancreatic exocrine function consists of protein synthesis, which occurs in the acinar cell, and bicarbonate production, which occurs in the centroacinar and ductular cells. After a meal, pancreatic juice is a mixture of high-volume solutions of sodium bicarbonate and sodium chloride containing high concentrations of digestive enzymes. The principal anions are HCO3 and Cl; the cations are Naþ and lesser amounts of Kþ. The ductular elements and centroacinar cells are the primary site of electrolyte secretion. The initial step in HCO3 secretion is the diffusion of CO2 into the cytosol and its hydration to H2CO3, a reaction that is catalyzed by carbonic anhydrase. After dissociation

Figure 2 Exocrine acinus of the pancreas.

of H2CO3 into Hþ and HCO3, HCO3 accumulates into the cell. A watery, bicarbonate component is important for the neutralization of acidic chyme that enters the duodenum from the stomach creating an appropriate medium for enzymatic activity. The maximal bicarbonate concentration of human pancreatic juice is 130 to 150 mM, and the concentrations of bicarbonate and chloride are flow dependent. The two major anions vary reciprocally: the slower the flow, the greater is the time of interaction between the duct fluid and the interstitial fluid through the duct cells. The bicarbonate diffuses out of the duct system in exchange for chloride. As flow increases, less bicarbonate is lost resulting in higher concentrations delivered in ductal secretions. The rate of secretion has no influence on Naþ concentration at approximately 160 mM (Fig. 3). The digestive enzymes produced are proteases, lipases, amylases, or nucleases. Proteases represent 70% of the total enzyme pool (5). Amylase and lipase are present in small amounts, yet have very high enzymatic acitivities. Acinar cell proteases including trypsin, chymotrypsin, carboxypeptidase, and elastase are synthesized in an inactive zymogen form and packaged into cytoplasmic zymogen granules. These proenzymes are released from the apical membrane into the ductal lumen and transported into the duodenum, where they are activated by enterokinase, a brush-border enzyme. Trypsinogen is activated, and, then, in turn other enzymes can then be activated by trypsin in the small intestine. Protease inhibitors (a1-antitrysin, a2-macroglobulin, and pancreatic secretory trypsin inhibitor) are also found in pancreatic tissue and pancreatic secretions and prevent protease activation (6) in the gland. When the protective mechanisms fail, spontaneous intrapancreatic protease activation occurs to initiate the inflammation of acute pancreatitis. The secretion of the bicarbonate-poor, enzyme-rich fluid of the acinar cell is calcium dependent (7). The rate and pattern of enzyme secretion are stimulated by cholecystokinin (CCK) and acetylcholine. Acinar cells possess membrane receptors for CCK, acetylcholine, bombesin, gastrin, and substance P, which upon activation increase cyclic guanine monophosphate and cytosolic Ca2þ levels (8). This occurs due to the cleavage of polyphosphoinositides and production of inositol triphosphate (IP3) and diacylglycerol. IP3 induces the release of Ca2þ from the endoplasmic reticulum. The polypeptide CCK is a potent stimulatory hormone. CCK is produced by the I cells in the duodenum and proximal jejunum, and has a half-life of two to seven minutes. Primary stimulants of CCK release are intraluminal fats, proteins, and amino acids. The CCK-A receptors located on the basolateral membrane of the acinar cell have a high affinity for CCK and a low affinity for gastrin. The CCK-B/gastrin receptor has an equal affinity for gastrin and CCK, yet is not a biologically active receptor in the pancreatic acinar cell. Vagal stimulation produces an increase in both pancreatic bicarbonate and enzyme secretion (9). Cholinergic agents produce rates of bicarbonate and enzyme secretion similar to those obtained during vagal stimulation. Truncal vagotomy reduces bicarbonate response to exogenous stimulants by 25%, but does not affect maximum enzyme secretion (10). Secretin is a polypeptide of 27 amino acids, which stimulates pancreatic bicarbonate secretion. The stimulatory effect increases the volume and, to a lesser extent, the protein content. It has a half-life of three minutes, and is produced by S cells in the duodenum and proximal jejunum. Mucosal exposure to hydrochloric acid, specifically an intraluminal pH < 4.5, bile salts, and fatty acids stimulates the

Chapter 22:

471

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

Figure 3 The change in sodium (Naþ), potassium (Kþ), chloride (Cl), and bicarbonate (HCO3) as a function of secretory rate in the dog. Source: Adapted from Ref. 4.

release of secretin. Secretin has only one type of receptor and its activation leads to an increase in intracellular second messenger cyclic adenosine monophosphate and activation of protein kinase A, which promotes the cellular response and an increase in pancreatic bicarbonate output. Goblet cells are present in the main and interlobular ducts of the exocrine pancreas. These cells secrete mucin, which form a protective barrier against reflux of bicarbonate and degradation of duct epithelium by digestive enzymes (11).

jejunum. Luminal fatty acids stimulate the release of both secretin and CCK from the duodenum and proximal jejunum, which in turn produce responses in pancreatic bicarbonate and protein output. Luminal peptides and amino acids stimulate pancreatic protein secretion, which is mediated in part by CCK release (15). Neural mechanisms play a contributory role because both truncal vagotomy and atropine reduce the pancreatic response to intraluminal oleate and tryptophan by 50% (16).

CONTROL OF PANCREATIC SECRETION

ACUTE PANCREATITIS

The total pancreatic secretory response to a meal is a complex neural and hormonal interaction, which is divided into three phases: cephalic, gastric, and intestinal. Basal secretion of the pancreas in the period between meals is usually low. Visual and olfactory stimuli increase mainly pancreatic protein secretion. In the dog, the cephalic phase of pancreatic enzyme secretion is approximately 25% of maximum secretory capacity, and bicarbonate secretion is 10% of maximum. The cephalic phase of pancreatic secretion appears to be mediated by the vagus nerves to elicit acinar cell secretion of enzymes (12). A truncal vagotomy completely inhibits this response. Next, pancreatic secretion is influenced by the stomach through gastropancreatic reflexes. Distention of the body or antrum of the stomach results in an increase in both pancreatic enzyme secretion and, to a lesser extent, bicarbonate secretion (10). Studies examining meal-stimulated pancreatic secretory activity following an 80% gastrectomy have found secretion minimally affected, implicating a neural cholinergic reflex and not gastrin release as the cause of the gastric phase. Furthermore, anticholingergic agents and vagotomy abolish the gastropancreatic reflex. As the stomach releases chyme into the intestine, a combination of neural and hormonal stimuli elicits the enteropancreatic response. Regulation of pancreatic exocrine secretion in the intestinal phase is mediated by the release of CCK (Fig. 4). Intraduodenal acid, fat, and amino acids stimulate pancreatic secretion by hormonal mechanisms. Acid entering the duodenum after a meal is a potent stimulus for pancreatic bicarbonate and volume secretion, and is a function of titratable acidity present in the duodenum (14) and of secretin release from the duodenum and proximal

Pancreatitis is an inflammatory process involving the pancreas that can manifest itself in acute and chronic forms. The development of chronic pancreatitis may be insidious or may involve repeated episodes of acute inflammation. The pathophysiology of acute pancreatitis represents a diverse mix of congenital, hereditary, and acquired problems as well as acute and chronic inflammatory disorders. Approximately 250,000 people develop acute pancreatitis in

Stimulatory Inhibitory Cephalic

Gastric Islet

Cholinergic input

Enzyme release

(+)

(_)

(+)

(_)

(+) CCK Nutrients Volume Osmolarity Nutrients

(+) (_) PP

Figure 4 Schematic diagram of stimulatory and inhibitory influences on pancreatic exocrine secretion. Abbreviations: CCK, cholecystokinin; PP, pancreatic polypeptide. Source: From Ref. 13.

medwedi.ru

472

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 1 Causes of Acute Pancreatitis Afferent limb syndrome Alcohol Biliary tract disease Drugs Duodenal obstruction Familial Hypercalcemia Iatrogenic Idiopathic

Infection Ischemia Malnutrition Pancreatic cancer Penetrating duodenal ulcer Trauma Scorpion venom Sphincter of Oddi dysfunction

the United States each year. Multiple causes of acute pancreatitis exist (Table 1). Alcohol-related and gallstone-associated acute pancreatitis account for greater than 90% of all cases. Acetaldehyde, a by-product of ethanol metabolism, induces microtubule disruption and increases acinar cell membrane permeability. The relationship between pancreatic duct obstruction by a gallstone and acute pancreatitis has not been clearly defined. The potential roles of biliary obstruction, pancreatic duct hypertension, bile reflux, pancreatic hyperstimulation, and autoactivation of acinar proteases, all shown to be important in experimental acute pancreatitis, remain unknown. These factors may lead to a similar increased permeability of pancreatic ducts and acinar cells with release and activation of acinar cell contents (enzymes) in the pancreatic interstitium and peripancreatic soft tissues.

Inflammation Acute pancreatitis involves a wide spectrum of illness characterized by acinar cell injury along with regional and systemic inflammatory responses. The majority of patients experience mild to moderate symptoms and show gross pathologic changes of mild parenchymal edema. There is a variable amount of interlobular infiltration by inflammatory cells. The acinar cells appear structurally intact, and blood flow is maintained in the small capillaries and venules (17). Less than 10% of patients develop a life-threatening illness associated with severe hemorrhagic destruction of the gland that can lead to multisystem organ failure or death. The predominant clinical feature of acute pancreatitis is midepigastric abdominal pain that radiates to the back (Fig. 5).

Figure 5 Topographic locations of pancreatic pain. Source: From Ref. 13.

This pain is not infrequently associated with nausea and vomiting. Physical examination commonly reveals fever, tachycardia and tachypnea. Marked epigastric tenderness is the predominant abdominal finding with focal peritoneal irritation. Less commonly, tenderness may exist in all abdominal quadrants. Depending upon the magnitude of the underlying disease, hypotension, hypovolemia and jaundice can also be seen in severe cases. It is not unusual for a patient with pancreatitis to find it difficult to get comfortable. Thus he may thrash about prefering at times to lie on his side, or sit erect, or at other times attempt to lie prone because the supine position often causes pain exacerbation. If the edema and accompanying inflammation surrounding the diseased pancreas is especially pronounced, the pain may extend throughout the retroperitoneum, and acute fluid callections often develops. Fat necrosis is common in acute pancreatitis and appears as raised, whitish-gray areas in the retroperitoneum, omentum, or mesentery. It is thought that calcium binds with free fatty acids in the process of saponification. Although this may contribute to the reduction in serum calcium seen in some patients, there are probably multiple causes for the hypocalcemia. In addition, retroperitoneal hemorrhage may become apparent as blood dissects into the subcutaneous tissues, producing blue discoloration of the flank (Grey Turner’s sign), umbilicus (Cullen’s sign), or inguinal ligament (Fox’s sign). A number of animal models have been developed to study acute pancreatitis on a cellular level (18,19). The fundamental pathologic event is injury to the acinar cell where inappropriate protease activation overcomes endogenous antiprotease defenses. To simulate this either a choline-deficient diet (CDE diet) supplemented by 0.5% ethionine CDE diet or a supramaximal intravenous infusion of the CCK agonist, cerulein, is administered to animals. Results of such experimental work suggest that some pancreatitis-inducing stimuli disrupt the orderly release of inactive proteases at the apical acinar membrane and prevent the extrusion of zymogen granules from individual acinar cells. This situation leads to fusion of the zymogen granules with intracellular lysosomes forming autophagic cytoplasmic vacuoles (20). The enzyme cathepsin B, contained in the lysosome, activates the proenzyme trypsinogen intracellularly (6). This results in the activation of intracellular trypsinogen capable of cellular autodigestion and local extrusion of acinar cell contents. Leakage of large quantities of trypsinogen and activated trypsin from the injured cell into pancreatic interstitium can cause necrosis of the gland. Uptake of these activated enzymes via the lymphatics and portal blood by the systemic circulation predisposes the patient to extrapancreatic injury. The noninfectious destruction of pancreatic parenchyma quickly induces an inflammatory reaction at the site of injury. The initial cellular response involves the infiltration of polymorphonuclear leukocytes into the perivascular regions of the pancreas. Neutrophil-mediated pancreatic capillary endothelial injury from NADPH oxidase–dependent oxygen radicals appears early. Within hours, macrophages and lymphocytes accumulate. Phagocyte-derived oxygen radicals overwhelm antioxidant control mechanisms and participate in a primary injury to pancreatic capillary endothelial cells. The increased microvascular permeability facilitates margination and extravascular migration of additional neutrophils and monocytes, as well as complement products and cytokines, thereby amplifying the inflammatory process. Histamine release, bradykinin generation,

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

and cytokine release play a significant role during the acute inflammation. Following an experimental insult, there is rapid expression of tumor necrosis factor a (TNF-a), interleukin (IL)-6, and IL-1 and chemokines by pancreatic acinar cells and/or transmigrated leukocytes (21). In fact, during experimental acute pancreatitis, knockout mice lacking receptors for IL-1 or TNF-a have significantly improved survival compared with wild-type animals (22). IL-1 and TNF-a are primary inducers of IL-6 and IL-8 production, and are known to initiate and propagate many of the metabolic consequences of sepsis including fever, hypotension, acidosis, and ARDS (23–25). The cellular mechanisms underlying cytokine production are not entirely known. Nuclear factor-kB (NF-kB) is a transcription factor that is important for the activation of many inflammatory mediators and cytokines such as IL-1 and IL-6 (26). The activity of NF-kB is mediated by the activation and translocation of these hetero- and homodimer subunits into the nucleus (27). Initially, NF-kB is sequestered in the cytoplasm bound to its inhibitory element, IkB. With stimulation, IkB is phosphorylated and degraded by proteosomes. This degradation of IkB releases NF-kB, allowing it to translocate into the nucleus, where it binds to its consensus sequence within the promoter region of a number of proinflammatory genes (27). The expression and the activation of NF-kB are known to be involved in other inflammatory conditions such as inflammatory bowel disease (28). Recently, early induction of NF-kB binding activity and decreased IkB expression has been shown in ceruleininduced pancreatitis (29–31). NF-kB activity is dependent on Ca2þ influx and protein kinase C activation (29,30,32). Increased NF-kB activity seems to play an important role in the induction of proinflammatory cytokines, and NF-kB has therefore been considered a therapeutic target. Treatment with NF-kB inhibitors has yielded conflicting results, yet a novel peptide that binds to the NF-kB essential modifier-binding domain attenuates the severity of injury in cerulein pancreatitis (32). Fortunately, reversibility characterizes this inflammatory cascade, but necrosis develops in 5% to 10% of patients. Grossly, the pancreas first appears hemorrhagic and then becomes necrotic. Necrotic areas can be found adjacent to healthy lobules, along with intense inflammatory reaction and cellular infiltration. Ischemia from small vessel thrombosis may play a role in the conversion of edematous pancreatitis into the necrotizing form. Histologic characteristics of advanced disease include extensive acinar cell necrosis, interstitial microabscess formation, peripancreatic fat necrosis, microvascular thrombosis, and local hemorrhage. Adequate fluid resuscitation is crucial to support the circulation as well as renal and cardiovascular function, but it does not prevent the necrotizing injury to the pancreas. The presence of radiographically detected pancreatic necrosis markedly increases the morbidity and mortality associated with acute pancreatitis. In a prospective study, 88 patients with acute pancreatitis underwent contrast-enhanced abdominal computed tomography (CT) (33). Those with pancreatic necrosis had a morbidity of 82% and a mortality of 23%, whereas those without necrosis had a morbidity of 6% and a mortality of 0%. As the percentage of glandular necrosis increased, the morbidity increased.

Fluid Sequestration Significant fluid sequestration is associated with the intense inflammation. More than 6 L of fluid can be lost into the

473

retroperitoneum and abdominal cavity (34). The resultant hypovolemia is responsible for many of the biochemical abnormalities detected, including elevated hematocrit and blood urea nitrogen (BUN). A frequent site of fluid accumulation is the lesser peritoneal sac in addition to the peripancreatic and perinephric spaces. Ascitic fluid can be present and is usually straw colored and becomes more blood tinged in severe cases.

Systemic Response In addition to the localized pancreatic inflammation, a systemic response to the activated neutrophils and complement products exists, and is linked to remote organ dysfunction and multiorgan system failure. This response cannot be attributed solely to the absorption of activated enzymes and inflammatory mediators from the retroperitoneum. A similar microvascular endothelial cell injury takes place in distant target organs (Table 2). A systemic capillary leak may occur secondary to the release of mediators such as histamine and bradykinin. For instance, microvascular lung injury can occur and lead to acute respiratory distress syndrome. Hypoxemia is common in patients with acute pancreatitis, yet most patients do not require mechanical ventilation. Reactive changes such as diaphragmatic elevation, pleural thickening, and pleural effusion are common and usually are found on the left side (35). An increase in pulmonary vascular resistance has been noted (36) and is likely due to the effect of vasoconstrictive substances released from the pancreas. The vital capacity is decreased by 25%, and the ratio of the forced expiratory volume per second to forced vital capacity is reduced by 20% to 35% (37). In response to fluid sequestration in mild acute pancreatitis, cardiac output increases. This is the result of an increase in cardiac rate and contractility. Supplemental fluid administration is usually able to correct intravascular losses. However, in severe pancreatitis, the cardiac output remains unchanged even as the pulse rate increases due to an inadequate contractile response. A progressive depression of left ventricular stroke work and an increased pulmonary capillary wedge pressure (38) can impact tissue perfusion (39). Hypovolemia plays a major role in renal dysfunction as well. In some patients, renal function can be impaired independent of any history of hypovolemia, hypotension, or sepsis. These patients show evidence of a membranous glomerulopathy and acute tubular necrosis. In more severe cases or when fluid replacement is inadequate, acute renal failure can occur and contributes to increased mortality to greater than 60% (40). Elevated blood glucose concentrations are found in the majority of patients with severe acute pancreatitis. Serum glucagon levels are much higher than serum insulin levels as are serum growth hormone and cortisol concentrations (41). During the first 48 to 72 hours after the onset of disease, there is marked fasting hyperglycemia along with hyperglucagonemia and hypoinsulinemia. Table 2 Changes in Cardiopulmonary Function in Acute Pancreatitis Depressed Decreased Decreased Decreased Decreased Decreased Decreased

contractility left ventricular stroke work systemic vascular resistance tissue perfusion vital capacity efficiency of gas exchange oxygen-carrying capacity of hemoglobin

medwedi.ru

474

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Biomarkers Amylase is released from the acinar cell into the pancreatic microcirculation, and the finding of hyperamylasemia is used along with clinical correlation to confirm the diagnosis. Amylase is the most frequently measured pancreatic enzyme in the blood due to the stability of the enzyme and the simplicity and validity of the assay. Amylase may also be derived from the salivary glands, intestine, fallopian tube, breast, and liver. The elevation of lipase is also taken as an evidence of acinar cell injury in acute pancreatitis. The magnitude of the rise in serum pancreatic enzyme level, however, does not correlate with the severity of disease (42), and therefore are not included in common prognostic criteria. Serum amylase and lipase are both cleared through renal excretion, although lipase at a much slower rate. Prompt clearance of amylase may occur prior to clinical evaluation and may account for a relative normal serum amylase level in a patient with acute pancreatitis a few days after disease onset. The combination of clinical assessment and measurement of biochemical abnormalities, such as hematocrit, BUN, creatinine, pO2, and calcium levels, gives an indication of the severity and prognosis of pancreatitis (Table 3). Patients with two or fewer of these prognostic signs require supportive measures, whereas patients with three or more prognostic signs have associated increased morbidity and mortality. Ranson et al. were the first to demonstrate that assessment of certain parameters early in the course of disease predicts the severity and mortality of necrotizing acute pancreatitis (43). The Acute Physiologic and Chronic Health Evaluation (APACHE II) system also accurately predicts the severity of disease, and has the advantage of being applicable at any time during the illness (44). It utilizes 12 physiologic and laboratory parameters, age, and preexisting comorbid conditions. Evaluation of protease inhibitors and inflammatory marker concentrations (45,46) such as C-reactive protein, complement factor, and leukocyte enzymes may be more useful. IL-6 and IL-8, both higher in patients with complicated pancreatitis, were found to be more specific in predicting severity, end-organ failure, mortality, and hospital stay when compared with Ranson’s and APACHE scoring (47–49).

Resolution To date, it is difficult to characterize the response as a healing response. Although morphologic alterations in human acute pancreatitis have not been determined, structural alterations of the pancreas in cases of cerulein-induced acute pancreatitis in rats are known to completely disappear after several days (50,51). Collagen is deposited in the interstitial areas within the pancreas, following induction of pancreatitis with the highest levels seen at seven days. The changes in the Table 3 Ranson’s Prognostic Signs of Acute Pancreatitis At admission Age over 55 years WBC > 16,000 Glucose > 200 mg/dL LDH > 350 IU/dL SGOT > 250 IU/dL

During initial 48 hr Hematocrit fall > 10% BUN elevation > 5 mg/dL Ca2þ fall to < 8 mg/dL Arterial pO2 < 60 mmHg Base deficit > 4 mEq/L Fluid sequestration > 6 L

Abbreviations: BUN, blood urea nitrogen; LDH, lactate dehydrogenase; SGOT, serum glutamic-oxaloacetic transaminase.

pancreas then completely resolve within 18 days after the onset of pancreatitis when compared to control groups (51). The fasting hyperglycemia and hyperglucagonemia resolve with the pancreatitis. Elevated concentrations of glucagon and glucose normalize within 18 to 21 days after resolution of pancreatitis (52).

Scarring/Fibrosis Pancreatic fibrosis is a central histologic response after pancreatitis (53). There is transient collagen deposition with acinar necrosis in acute pancreatitis, while in chronic pancreatitis, there is permanent and disorganized pancreatic fibrosis and parenchymal cell atrophy. Fibrosis serves as a deterrent to future organ regeneration and contributes to endocrine and exocrine dysfunction of the gland. Although this is a well-recognized process, the mechanisms of fibrogenesis are poorly understood. There is evidence that differentiation and proliferation of pancreatic myofibroblast or ‘‘stellate’’ cells may be responsible for an increase in extracellular matrix (ECM) production as in hepatic fibrosis and cirrhosis (54,55). In normal pancreas, quiescent pancreatic stellate cells (PSCs) can be identified by staining for the cytoskeletal protein desmin, a stellate cell selective marker (56). PSCs are found in a periacinar location, with long cytoplasmic processes encircling the base of pancreatic acini (56). In vitro studies with cultured PSCs have revealed that the cells store vitamin A in the form of lipid droplets in the cytoplasm, a feature similar to that described for hepatic stellate cells (56). During pancreatic injury, PSCs are activated and transform into a myofibroblastic phenotype that exhibits positive staining for the cytoskeletal protein, a smooth muscle actin (a-SMA) (51), and secrete increased amounts of collagen as previously described in hepatic stellate cells during liver injury. Proinflammatory cytokines such as TNF-a, IL-1, and IL-6 and reactive oxygen species activate PSCs as evidenced by increased a-SMA expression (57). During regeneration from cerulein-induced pancreatitis, the expression of transforming growth factor-b (TGF-b) is enhanced in acinar and stellate cells of rat pancreas (58,59) and in patients with acute or chronic pancreatitis (60,61). TGF-b protein will increase twofold after 24 to 48 hours and return to normal seven days after insult (62). TGF-b mRNA expression will peak two or three days after an experimental stimulus (59,62). TGF-b is a key regulator of ECM production and myofibroblast proliferation. The expression of procollagen type I mRNA was markedly increased and correlated with the level of TGF-b mRNA (63). Culturing PSC with increasing concentrations of TGF-b raises collagen protein synthesis and inhibits matrix metalloproteinase (MMP)-3 and MMP-9 (64). TGFb–neutralizing antibodies when injected into rats during regeneration from cerulein pancreatitis significantly reduce collagen types I and III protein and mRNA (65). The stellate cells express TGF-b in an autocrine stimulatory loop and enhance fibrosis not only by increased production but also decreased degradation of collagen. Platelets aggregate in injured sites of the pancreas and release growth factors that propoagate fibrosis. Platelets are an early source of TGF-b and platelet-derived growth factor (PDGF), which also can stimulate stellate cell proliferation (66,67) and increased collagen synthesis (56). The signaling pathways involved in PSC stimulation included the extracellular signal-regulated kinases as well as the activation of the activator protein complex (67). PSCs have the capacity to respond to cytokines known to be upregulated in acute pancreatitis. PSCs have the

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

475

potential to be actively involved in both the recovery phase and the progression of the disease. During a self-limited attack of acute pancreatitis, cytokine-activated PSCs may participate in tissue repair by regulating ECM deposition in the gland (57). During repeated attacks of pancreatitis, PSCs may attain a persistently activated state with increased collagen synthesis leading to fibrosis. Tissue repair is a process regulated by a balance between synthesis and degradation of the ECM. ECM degradation is performed by a family of proteolytic enzymes known as MMPs. These MMPs are zinc-bound proteases that degrade at least one component of the ECM, and are bound and inhibited by tissue inhibitors of metalloproteinases. The MMPs are secreted in a latent proenzyme form and are activated by other proteases such as trypsin and a chymotrypsin. MMPs degrade a variety of ECM constituents; MMP-1 degrades collagen types I and III, whereas MMP-2 degrades collagen type IV and fibronectin (68). Imbalance in ECM homeostasis occurs not only from increased production but also decreased degradation through an overall decrease in the action of MMPs (69). Expression of the active form of MMP-9 and the activity of MMP-9 and MMP-2 have been shown to decrease initially in a rat model of pancreatitis induced with cerulein (69). MMP-2 may then play a role in resolution of the fibrotic cascade as well. If monitored one week after the inciting event, MMP-1 and MMP-2 mRNA and protein levels will rise and play a role in preventing uncontrolled deposition of ECM (51,59).

known trophic effects on rodent pancreatic growth (80). The CCK-B receptor binds both gastrin and CCK with equal affinity. It is a G-protein–coupled receptor that activates phospholipase C, phosphatidylinositol hydrolysis, release of intracellular calcium, and the phosphorylation of protein kinase C (81). The trophic effects of gastrin and its receptor remain controversial. The adult rat pancreas has less gastrin receptor present (79). When a transgenic mouse constitutively expressed gastrin receptors in the exocrine pancreas, the expression of the gastrin receptor correlated with a significant increase in pancreas weight (82). The rodent studies of exogenous gastrin as a trophic factor are conflicting: some suggest a trophic effect on pancreatic growth (83,84), whereas others have failed to detect an effect (85,86). IL-10, a potent anti-inflammatory cytokine, limits the severity of acute pancreatitis (87,88). IL-10 can be produced by multiple cell lines and has inhibitory effects on T-cell function and stimulatory effects on B-lymphocytes, augmenting the secretion of immunoglobulins (89). It downregulates TGF-b release by inflammatory cells on stimulation (90). IL-10 has been shown to reduce acinar necrosis, parenchymal infiltration by polymorphonuclear cells and macrophages, and release of inflammatory cytokines (91,92). After repeated induction of acute pancreatitis in mice, endogenous IL-10 limits fibrogensis, collagen deposition, and TGF-b expression. IL-10 knockout mice display a dramatic decrease in acinar cell proliferation and higher levels of activated stellate cells (93).

Regeneration/Growth

TREATMENTS

After the acute injury, a regeneration or repair phase of the pancreas is characterized by the decrease of inflammatory cell infiltrate and of the release of proinflammatory mediators (70). A proliferation of acinar cells occurs as soon as 72 hours, after a cerulein-induced acute pancreatitis in rats, and persists for at least one week (50,70). The extracellular factors and intracellular events that induce pancreatic acinar cell proliferation in the regenerating pancreas are incompletely characterized and are an area of active interest. The mitogen-activated protein kinase (MAPK) activation and expression of cell cycle regulatory proteins play a role in the molecular mechanisms of pancreatic regeneration. The gut hormone, CCK, is a potent trophic factor of the pancreas (71). CCK activations of tyrosine kinases, phosphatidylinositol 3-kinase, and phospholipase D have been reported as early events (72–74), along with stimulation of MAPK cascades (75). Pancreatectomy is known to cause islet cell hypertrophy and also is seen in type II diabetes. Genetic profiling has demonstrated specific gene activation (76). Complexes containing a cyclin and a cyclin-dependent kinase (cdk) orchestrate progression through the cell cycle. Cyclin D family members are found in early G1 phase and cyclin E with Cdk2 in late G1. Sustained activation of p42/p44 MAPKs and Cdk2 along with the overexpression of cyclins D1 and E and reduction of cyclin inhibitors occurs after pancreatectomy, and are factors in signaling during pancreas regeneration (77). The activity of certain genes in the rat pancreas, after subtotal pancreatectomy, has been examined to give further insight into the repression and stimulation of certain genes during regeneration. The oncogenes c-myc and H-ras were overexpressed within 48 hours after resection, as measured by corresponding mRNA concentrations (78). CCK receptors in the gastrointestinal tract have been classified into two subsets, CCK-A and CCK-B (gastrin) receptors (79). The CCK-A receptor and its ligand CCK have

Pain, either persistent or episodic, usually requires treatment. Abstinence from alcohol or other causative agents, administering analgesic medications and performing nerve blocks, are necessary. Nonoperative management is the preferred initial management. Clinical outcomes have improved only to the extent that critical care has evolved in recent years. Derangements in other organ systems indicate severe disease and the need for aggressive intensive care unit management. Aggressive fluid and electrolyte resuscitation should be undertaken to prevent hypovolemia and prerenal azotemia. Serial monitoring of electrolytes and serum glucose is necessary to direct fluid resuscitation. Supplemental oxygen should be administered, and mechanical ventilation instituted in the event of respiratory insufficiency. Invasive monitoring may be necessary in the event of clinical deterioration. Antibiotic prophylaxis has been proposed for all patients with severe acute pancreatitis to prevent subsequent infection. Early studies of prophylactic intravenous antibiotics in the treatment of unselected patients with acute pancreatitis failed to show any effect on morbidity and mortality (94,95). Later studies recognized the importance of pancreatic tissue concentrations of antibiotics after intravenous infusion (96). One study found that early pancreatic infection in severe experimental pancreatitis was reduced with an antibiotic (imipenem) that was concentrated in pancreatic tissue (97), and these results correlated with a multicenter randomized clinical trial (98). The typical organisms found in pancreatic infections are enteric species. Multiple organisms are frequent. Antibiotic prophylaxis is now an accepted practice to reduce incidence of infected necrosis. It can alter the bacteriology of secondary pancreatic infection from predominantly gram-negative coliforms to gram-positive organisms (99). Imipenem and the fluoroquinolones have been the most successful, both because of their

medwedi.ru

476

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

broad spectrum and their penetration into pancreatic tissues. However, in a randomized, prospective trial, patients treated with perfloxacin had an incidence of infected necrosis that was significantly higher than that among patients receiving imipenem (34% vs. 10%) (100). At the present time, intravenous administration of imipenem–cilastatin is recommended. Therapy should begin as soon as the diagnosis of acute necrotizing pancreatitis is made and should continue for at least two to four weeks. The role of surgical intervention is largely limited to (i) cholecystectomy and the clearance of stones from the biliary tree early in gallstone pancreatitis and (ii) debridement of dead tissues and drainage of infection for significant deterioration or sepsis associated with infected pancreatic necrosis. Infection should be suspected when symptoms persist, despite medical treatment. At that time, a constrastenhanced CT scan should be performed. Poor enhancement of the pancreatic tissue indicates pancreatic necrosis. Contrast-enhanced abdominal CT is the gold standard for the noninvasive diagnosis of pancreatic necrosis, with an accuracy of more than 90% when there is more than 30% glandular necrosis (101). The lack of normal contrast enhancement may be better detected several days after initial clinical presentation. Without improvement in the patient’s condition, this area should be aspirated percutaneously, gram stained, and cultured. If infection is present, an operation is indicated. Percutaneous drainage is inadequate. If infection is not present, the CT scan and aspiration are repeated at weekly intervals. Generally, sterile pancreatic necrosis can be safely managed without debridement, whereas infected necrosis should be removed. Deterioration in the patient’s condition, however, may necessitate earlier aspiration or operation, and should not be delayed because infection has not been proven. At operation, the lesser sac is entered, the fluid is drained, and the necrotic pancreas is debrided. Large sump drains are placed for postoperative lavage and drainage. A feeding jejunostomy tube is also placed in most of these critically ill patients. To meet increased metabolic demands and to ‘‘rest’’ the pancreas, total parenteral nutrition (TPN) administered through a central venous catheter is frequently used in patients with severe pancreatitis. This does not limit the course of disease and is associated with increased cost and infectious complications when compared to enteral feeding (102). In two recent randomized, prospective studies, patients with severe acute pancreatitis received either TPN or enteral feeding through a nasoenteric feeding tube placed beyond the ligament of Treitz. Enteral feeding was well tolerated, had no adverse clinical effects, and resulted in significantly fewer total and infectious complications (103,104). Oral intake can be resumed as soon as patients will tolerate it. However, until the associated ileus resolves, the patient should be given nothing by mouth. Somatostatin reduces pancreatic secretion by 70% in healthy patients. In animal models, somatostatin analogs increase DNA synthesis and protein content after induction of pancreatitis, and thus accelerate pancreatic repair and regeneration (105). To date, a sufficiently large trial has not been published to support the use of somatostatin in acute pancreatitis. However, a meta-analysis of controlled trials did suggest a survival advantage (45). The role of exogenous enzymes, CCK antagonists, and somatostatin in chronic pancreatitis remains uncertain, and further study is needed before widespread application is recommended. As it became clear in the early 1990s that pancreatitis was associated with the appearance of inflammatory

cytokines, many postulated that cytokine antagonism would be beneficial. The first study was published by Guice et al. in 1991 using serum from rabbits exposed to murine TNF (anti-TNF antiserum) as a potential TNF antagonist (106). Early results were disappointing. Subsequent work used species-specific anti-TNF antibodies to show the importance of this cytokine to pancreatitis progression. Pretreatment with anti-TNF antibodies attenuated the expected rise of serum TNF, glucose, and amylase (107). The blockade of TNF decreased pancreatic edema, necrosis, and inflammation, while decreasing mortality by more than half (108–110). Similarly, the inhibition of IL-1 activity also prevents the development of severe pancreatitis. Administration of an IL-1 receptor antagonist limited the degree of pancreatic inflammation (111). An IL-1 receptor antagonist inhibits IL-1 from activating surface receptors on target cells (112). Norman et al. have also shown a reduction in mortality from acute pancreatitis with delayed anti IL-1 therapy (113,114). Pretreatment with PAF-antibodies appears to ameliorate the severity of acute pancreatitis (115). Pharmacological inhibition of PSC activation may have the potential to become a new therapeutic approach for the treatment of chronic pancreatitis. Previous development strategies aimed at preventing pancreatic fibrosis have been hampered by incomplete knowledge of the molecular processes that underlie PSC activation. Trapidil, a drug that acts as a competitive antagonist of PDGF and developed as a coronary vasodilator, reduced PDGF-stimulated PSC growth in a dose-dependent manner (67). Nitric oxide (NO) is a potent vasodilator. Its use in acute pancreatitis remains controversial. Some studies have concluded that NO may be harmful (116), while others found that NO administration in established acute pancreatitis benefits both the acute inflammatory process and the associated pulmonary injury (117). These beneficial effects may be due to an inhibitory effect on neutrophil migration and improved pancreatic perfusion. Experimental acute pancreatitis can be modified by the early use of free radical scavengers or antioxidants (118), for superoxide dismutase decreased the arterial vasocontriction and leukocyte adherence associated with experimental acute pancreatitis (119). Use of antiprotease agents such as aprotinin or gabexate mesilate has been disappointing and is not currently supported (96).

Treatment of Chronic Pancreatitis Acute and chronic pancreatitis are distinguished from each other on the basis of structural and functional criteria. The morphologic changes of chronic pancreatitis include varying degrees of edema, and acute inflammation superimposed on a background of chronic changes that include fibrosis, inflammation, and loss of exocrine tissue. Repeated insult and inflammatory cycles result in irreversible parenchymal destruction, which can lead to (53) persistent abdominal pain as well as endocrine and/or exocrine insufficiency. Serum amylase and lipase concentrations may be normal or slightly elevated, particularly if the gland is already compromised by extensive fibrosis. Calcium deposition can be noted primarily in the head of the pancreas and may be seen in up to 30% of plain abdominal radiographs of these patients. A CT scan or ultrasonography may demonstrate the shrunken, constricted, and calcified pancreas characteristic of the disease. The hypersecretion of protein from acinar cells in the absence of increased fluid or bicarbonate secretion from duct cells

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

is characteristic of chronic pancreatitis. Precipitates of proteinaceous material are observed in intercalated and canalicular ducts. Infiltration of the interstitium by inflammatory cells is followed by the deposition of fibrous tissue within and between lobules (53). Endoscopic retrograde cholangio-pancreatography (ERCP) is the gold-standard imaging procedure for the diagnosis of chronic pancreatitis and planning treatment. Fibrosis of the ducts is common and causes intermittent narrowing and dilatation giving the ‘‘chain of lakes’’ appearance on ERCP. Ductal changes on endoscopy can be classified as mild, moderate, or severe. Surgical or endoscopic decompression and ductal drainage may be necessary but does not improve the exocrine or endocrine dysfunction. Endoscopically placed stents or endoprostheses can provide short-term symptom relief, although most of the data reported on their use is from short-term, nonrandomized studies (120,121). Stents can be used for relatively short periods, and the response to drainage can be used to identify patients most likely to benefit from surgical drainage. Chronic pancreatitis produces a depressed insulin and C-peptide response to oral or intravenous glucose, and reduced responsiveness to intravenous arginine, alanine, or glucagon. Insulin-dependent diabetes mellitus occurs in about 40% of patients with chronic pancreatitis. Glucagon responses to arginine, alanine, and insulin-induced hypoglycemia are often suppressed. Abnormal release of pancreatic polypeptide, gastric inhibitory peptide, and motilin has been reported (122). In chronic pancreatitis, exocrine insufficiency may lead to CCK-mediated stimulation of the pancreas. Fat malabsorption and steatorrhea from pancreatic insufficiency occur, when stimulated lipase decreases to less than 10% of normal. Fecal fat can be measured usually over 72 hours during ingestion of a diet containing 70 to 100 g of fat per day. Values greater than 7% of ingested fat in the stool are abnormal. Attempts at mitigating this process include administration of digestive enzymes, CCK receptor antagonists, or somatostatin. Treatment of malabsorption requires delivery of pancreatic enzymes in active form to the duodenum. Gastric acidity serves to inactivate the enzymes when given orally. Large amounts of pancreatic enzymes are given with meals along with histamine-2 receptor antagonists to facilitate delivery.

Medical Treatment Treatment is directed toward the relief of pain and the management of malabsorption and diabetes. Early in the disease, abdominal pain may occur only in association with recurrent episodes of inflammation. With progression, the pain becomes more frequent and each episode lasts longer, so that patients may experience discomfort daily or even continuously. Patients may consume alcohol in an attempt to relieve the discomfort, and many of them also become addicted to narcotics. Every effort should be made to eliminate the use of alcohol. Many of these patients lose weight because eating provokes pain and they voluntarily reduce their food intake. Because carbohydrates are better absorbed than proteins and fats, patients should be given diets with liberal amounts of carbohydrates, as much protein as possible and only as much fat as can be tolerated. Pancreatic enzymes should be provided in an amount that supplies approximately 30,000 lipase units with each meal. In some patients, low gastric pH destroys the lipase before it mixes with chyme. Gastric acid antisecretory drugs should be

477

Table 4 Indications for Surgery in Chronic Pancreatitis Chronic pain that is refractory to nonsurgical treatment Effects of fibrosis on neighboring structures Symptomatic duodenal obstruction Persistent common bile duct obstruction Splenic vein obstruction with portal hypertension and bleeding varices Symptomatic colonic obstruction Effects of ductal disruption Persistent or symptomatic pseudocyst Pancreatic fistula unresponsive to medical therapy Pancreatic ascites unresponsive to medical therapy Suspected pancreatic cancer

prescribed to raise the gastric pH. An alternative is to change the enzyme preparation to one that is enterically coated.

Indications for Surgical Therapy The indications for surgical therapy for chronic pancreatitis are listed in Table 4. In the United States, the vast majority of referrals for surgery are for the management of chronic pain (123). Varying degrees of common duct, duodenal, and vascular obstruction are often present in patients with advanced pancreatic fibrosis, who are referred for surgery because of pain. In the well-documented series of 448 patients operated on at the University of Ulm primarily for the indication of pain, approximately 50% had a common bile duct stenosis, and approximately 25% had some degree of duodenal narrowing (124). Two surgical approaches have been used (i) drainage operations to relieve ductal obstruction or (ii) resection to remove diseased pancreatic tissue, and are listed in Table 5. Patients with a dilated duct (>7 mm) are usually candidates for a drainage procedure; if the duct is narrow, resection is preferred. Ductal anatomy is defined with CT scanning and ERCP.

Drainage Procedure With the longitudinal pancreaticojejunostomy (Puestow procedure), an incision is made through the anterior wall of the main pancreatic duct for its entire length (Fig. 6). A Roux-en-Y limb of jejunum is sutured to the opened pancreas along its length to drain the gland directly into the small intestine. The early results after longitudinal pancreaticojejunostomy are good: 65% to 80% of patients experience initial pain relief. With longer follow-up, however, there is a gradual decline in the percentage of patients who remain pain-free. Consequently, about one-third of patients who undergo this procedure remain pain free, about one-third have early improvement but experience return of pain, and about one-third have an inadequate initial response and continued pain. The Puestow procedure Table 5 Surgical Procedures for the Treatment of Pain in Chronic Pancreatitis Duct drainage procedure Longitudinal pancreaticojejunostomy (Puestow procedure) Pure resection procedures Distal pancreatectomy Pancreaticoduodenectomy (Whipple procedure) Total pancreatectomy with islet cell autotransplantation Combined duct drainage-resection procedures Longitudinal pancreaticojejunostomy with partial pancreatic head resection (Frey procedure) Duodenum-preserving partial resection of the pancreatic head (Beger procedure)

medwedi.ru

478

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Figure 6 (A) Longitudinal incision of the main pancreatic duct in preparation for lateral pancreaticojejunostomy (Peustow procedure): the most frequently used drainage procedure for chronic pancreatitis. (B) A Roux-en-Y limb of jejunum is sutured to the opened pancreatic duct along its length. Source: From Refs. 13, 125.

reduces the elevated interstitial pressure in these patients, and has been associated with a return of pancreatic blood flow (126). Unfortunately, ductal drainage operations have little impact on the degree of malabsorption. Therefore, surgery should not be performed to promote improvement in pancreatic function.

Resection After resection, pain is relieved in about 85% of cases; however, the relief is more durable than after a drainage procedure and more likely to be permanent (Fig. 7). Diabetes requiring insulin for its management is a likely occurrence after major pancreatic resections. Resections of the tail of the pancreas of 40% or less usually do not worsen pancreatic insufficiency. Resections of 50% to 80% of the distal pancreas produce significant steatorrhea in at least 20% of patients. Diabetes mellitus also worsens in up to 30% of patients. In patients undergoing 80% to 95% distal resections, 50% have worsening of both steatorrhea and diabetes. Distal resections

Figure 7 Surgical resection for chronic pancreatitis. (A) Distal resection of the pancreas with pancreaticojejunostomy. (B) Subtotal pancreatectomy. Source: From Ref. 125.

do not alter gastric emptying and the mixing of food with pancreatic juice. Pancreaticoduodenectomy alters both. At least half of all patients have troublesome steatorrhea after this operation. Diabetes worsens in about 10% of patients (Fig. 8). When total pancreatectomy is performed, all patients require insulin and pancreatic enzyme replacement. Furthermore, hypoglycemic episodes are more common in this group, probably due to the absence of pancreatic glucagon. The development of better methods for isolating human pancreatic islets has now made total pancreatectomy, with islet autotransplantation an option in the treatment of chronic pancreatitis. The largest experience has been in Minneapolis (127), where islet autografts were performed in 48 patients, and 75% experienced complete pain relief.

Combined Duct Drainage and Resection Procedures Failures of duct drainage procedures have often been ascribed to inadequate drainage of the head of the pancreas. Frey has pointed out the technical difficulties associated

Figure 8 Pancreaticoduodenectomy (Whipple procedure). (A) Preoperative anatomic relationships. (B) Postoperative reconstruction showing pancreatic, biliary, and gastric anastomoses. A cholecystectomy and bilateral truncal vagotomy are also part of the procedure. In many cases, the distal stomach and pylorus can be preserved, and vagotomy is then unnecessary.

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

with achieving an adequate decompression of the duct of Wirsung in the head of the pancreas, particularly when the head is enlarged (128). Two procedures, the Frey procedure and the Beger procedure, have been designed as combined duct drainage and resection procedures to resect most of the pancreatic head without the high rate of morbidity associated with traditional pancreaticoduodenectomy and with less disruption of upper abdominal anatomy and physiology. In the Frey procedure, the majority of the head of the pancreas is removed piecemeal, resulting in a ‘‘coring-out’’ of the head, leaving a thin remnant of pancreatic head along the duodenal sweep, around the distal common bile duct, and around the portal and superior mesenteric veins. Then routine longitudinal decompression of the pancreatic duct is utilized. Izbicki et al. compared the Frey procedure with the traditional Whipple procedure in a prospective trial (129). The Frey procedure appeared to be as effective as a traditional pancreaticoduodenectomy in terms of pain relief, but was associated with less perioperative morbidity and a better quality of life. The Beger procedure is a subtotal resection of the pancreatic head that leaves a small remnant of pancreas along the common bile duct. It is a technically challenging procedure and has not been widely adopted despite its outstanding results. The Frey procedure and the Beger procedure were compared in a randomized trial (130). At a mean follow-up of 1.5 years, a decrease of 95% and 94% in the pain score after the Beger and Frey procedures and an increase of 67% in the overall quality-of-life index in both groups were observed.

6.

7.

8.

9.

10.

11. 12.

13.

14.

15.

SUMMARY 16.

In acute pancreatitis, a number of inciting factors have been identified, but the final common pathway leading to autodigestion and its systemic manifestations has not yet been identified. Uncomplicated acute pancreatitis is a self-limited disease, and usually resolves without altered digestive function or permanent damage to other organ systems. Recovery is generally complete, and does not recur if the cause is removed. Chronic pancreatitis is associated with permanent damage to the gland. Digestive and endocrine functions are altered according to the degree of glandular damage. This loss of function is usually permanent and in many cases progressive. Patients with chronic pancreatitis may also have recurrent episodes of acute pancreatitis. Surgery has a role in the palliation of refractory pain.

17.

18.

19. 20. 21. 22.

23.

REFERENCES

24. 1. Kimura W, Nagai H. Study of surgical anatomy for duodenum-preserving resection of the head of the pancreas. Ann Surg 1995; 221(4):359–363. 2. Lifson N, Kramlinger KG, Mayrand RR, Lender EJ. Blood flow to the rabbit pancreas with special reference to the islets of Langerhans. Gastroenterology 1980; 79(3):466–473. 3. Bolender RP. Stereological analysis of the guinea pig pancreas. I. Analytical model and quantitative description of nonstimulated pancreatic exocrine cells. J Cell Biol 1974; 61(2): 269–287. 4. Bro-Rasmussen F, Killmann SA, Thaysen JH. The composition of pancreatic juice as compared to sweat, parotid saliva, and tears. Acta Scand 1956; 37:97. 5. Scheele G, Bartelt D, Bieger W. Characterization of human exocrine pancreatic proteins by two-dimensional isoelectric

25. 26. 27. 28.

29.

30.

479

focusing/sodium dodecyl sulfate gel electrophoresis. Gastroenterology 1981; 80(3):461–473. Rinderknecht H. Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Dig Dis Sci 1986; 31(3):314–321. Kanno T, Yamamoto M. Differentiation between the calciumdependent effects of cholecystokinin-pancreaozymin and the bicarbonate-dependent effects of secretin in exocrine secretion of the rat pancreas. J Physiol 1977; 264(3):787–799. Case RM, Clausen T. The relationship between calcium exchange and enzyme secretion in the isolated rat pancreas. J Physiol 1973; 235(1):75–102. Holst JJ, Schaffalitzky de Muckadell OB, Fahrenkrug J. Nervous control of pancreatic exocrine secretion in pigs. Acta Physiol Scand 1979; 105(1):33–51. Lenninger SG, Magee DF, White TT. Effect of gastric, extragastric and truncal vagotomy on the external secretion of the pancreas in the dog. Ann Surg 1965; 162(6):1057–1062. Reber HA, Roberts C, Way LW. The pancreatic duct mucosal barrier. Am J Surg 1979; 137(1):128–134. Katschinski M, Dahmen G, Reinshagen M, et al. Cephalic stimulation of gastrointestinal secretory and motor responses in humans. Gastroenterology 1992; 103(2):383–391. Murayama K, Joehl R. Chronic pancreatitis (Chapter 31). In: Greenfield L, Mulholland M, Oldham K, Zelenock G, Lillimoe K, eds. Surgery: Scientific Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott, Williams and Wilkins, 2002:29–41. Solomon TE, Grossman MI, Meyer JH. Pancreatic response to intestinal perfusion with lactic acid or acidified albumin. Am J Physiol 1978; 235(5):E560–E564. Go VL, Hofmann AF, Summerskill WH. Pancreozymin bioassay in man based on pancreatic enzyme secretion: potency of specific amino acids and other digestive products. J Clin Invest 1970; 49(8):1558–1564. Wang CCGM. Physiological determination of release of secretin and pancreozymin from instestine of dogs with transplanted pancreas. Am J Physiol 1951; 164:527. Toyama MT, Lewis MP, Kusske AM, Reber PU, Ashley SW, Reber HA. Ischaemia-reperfusion mechanisms in acute pancreatitis. Scand J Gastroenterol Suppl 1996; 219:20–23. Yeo C, Cameron JL. Acute pancreatitis. In: Zuidema GD, Turcotte JG, eds. Shackelford’s Surgery of the Alimentary Tract. Philadelphia: WB Saunders, 1991:19–36. Steer ML, Meldolesi J. The cell biology of experimental pancreatitis. N Engl J Med 1987; 316(3):144–150. Steer ML. How and where does acute pancreatitis begin? Arch Surg 1992; 127:1350–1353. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 1998; 175(1):76–83. Denham W, Yang J, Fink G, et al. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis. Gastroenterology 1997; 113(5): 1741–1746. Lowry SF. Cytokine mediators of immunity and inflammation. Arch Surg 1993; 128(11):1235–1241. Dinarello CA. Cytokines as mediators in the pathogenesis of septic shock. Curr Top Microbiol Immunol 1996; 216:133–165. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996; 87(6):2095–2147. Mercurio F, Manning AM. NF-kappaB as a primary regulator of the stress response. Oncogene 1999; 18(45):6163–6171. Thanos D, Maniatis T. NF-kappa B: a lesson in family values. Cell 1995; 80(4):529–532. Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease. Gut 1998; 42(4): 477–484. Han B, Logsdon CD. CCK stimulates mob-1 expression and NF-kappaB activation via protein kinase C and intracellular Ca(2þ). Am J Physiol Cell Physiol 2000; 278(2):C344–C351. Tando Y, Algul H, Wagner M, Weidenbach H, Adler G, Schmid RM. Caerulein-induced NF-kappaB/Rel activation

medwedi.ru

480

31.

32.

33.

34. 35. 36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen requires both Ca2þ and protein kinase C as messengers. Am J Physiol 1999; 277(3 Pt 1):G678–G686. Steinle AU, Weidenbach H, Wagner M, Adler G, Schmid RM. NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology 1999; 116(2):420–430. Ethridge RT, Hashimoto K, Chung DH, Ehlers RA, Rajaraman S, Evers BM. Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute pancreatitis. J Am Coll Surg 2002; 195(4):497–505. Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990; 174(2):331–336. Carey LC. Extra-abdominal manifestations of acute pancreatitis. Surgery 1979; 86(2):337–342. Kaye MD. Pleuropulmonary complications of pancreatitis. Thorax 1968; 23(3):297–306. Halmagyi DF, Karis JH, Stenning FG, Varga D. Pulmonary hypertension in acute hemorrhagic pancreatitis. Surgery 1974; 76(4):637–642. Berry AR, Taylor TV, Davies GC. Pulmonary function and fibrinogen metabolism in acute pancreatitis. Br J Surg 1981; 68(12):870–873. Bradley EL III, Hall JR, Lutz J, Hamner L, Lattouf O. Hemodynamic consequences of severe pancreatitis. Ann Surg 1983; 198(2):130–133. Dubick MA, Conteas CN, Billy HT, Majumdar AP, Geokas MC. Raised serum concentrations of pancreatic enzymes in cigarette smokers. Gut 1987; 28(3):330–335. Toyama MT, Ashley SW, Reber HA. Pathophysiologic basis of management. In: Howard JM, Idezuki Y, Ihse I, Prinz RA, eds. Surgical Diseases of the Pancreas. Baltimore: Williams & Wilkins, 1998:199–205. Drew SI, Joffe B, Vinik A, Seftel H, Singer F. The first 24 hours of acute pancreatitis. Changes in biochemical and endocrine homeostasis in patients with pancreatitis compared with those in control subjects undergoing stress for reasons other than pancreatitis. Am J Med 1978; 64(5):795–803. Pezzilli R, Billi P, Miglioli M, Gullo L. Serum amylase and lipase concentrations and lipase/amylase ratio in assessment of etiology and severity of acute pancreatitis. Dig Dis Sci 1993; 38(7):1265–1269. Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974; 139(1):69–81. Wilson C, Heath DI, Imrie CW. Prediction of outcome in acute pancreatitis: a comparative study of APACHE II, clinical assessment and multiple factor scoring systems. Br J Surg 1990; 77(11):1260–1264. Dominguez-Munoz JE, Carballo F, Garcia MJ, et al. Monitoring of serum proteinase—antiproteinase balance and systemic inflammatory response in prognostic evaluation of acute pancreatitis. Results of a prospective multicenter study. Dig Dis Sci 1993; 38(3):507–513. Heath DI, Cruickshank A, Gudgeon M, Jehanli A, Shenkin A, Imrie CW. Role of interleukin-6 in mediating the acute phase protein response and potential as an early means of severity assessment in acute pancreatitis. Gut 1993; 34(1):41–45. Galloway SW, Kingsnorth AN. Reduction in circulating levels of CD4-positive lymphocytes in acute pancreatitis: relationship to endotoxin, interleukin 6 and disease severity. Br J Surg 1994; 81(2):312. Pezzilli R, Billi P, Miniero R, et al. Serum interleukin-6, interleukin-8, and beta 2-microglobulin in early assessment of severity of acute pancreatitis. Comparison with serum C-reactive protein. Dig Dis Sci 1995; 40(11):2341–2348. Inagaki T, Hoshino M, Hayakawa T, et al. Interleukin-6 is a useful marker for early prediction of the severity of acute pancreatitis. Pancreas 1997; 14(1):1–8. Elsasser HP, Adler G, Kern HF. Fibroblast structure and function during regeneration from hormone-induced acute pancreatitis in the rat. Pancreas 1989; 4(2):169–178.

51. Yokota T, Denham W, Murayama K, Pelham C, Joehl R, Bell RH Jr. Pancreatic stellate cell activation and MMP production in experimental pancreatic fibrosis. J Surg Res 2002; 104(2): 106–111. 52. Solomon SS, Duckworth WC, Jallepalli P, Bobal MA, Iyer R. The glucose intolerance of acute pancreatitis: hormonal response to arginine. Diabetes 1980; 29(1):22–26. 53. Satake K, Yamamoto T, Umeyama K. A serial histologic study of the healing process after relapsing edematous acute pancreatitis in the rat. Surg Gynecol Obstet 1987; 165(2): 148–152. 54. Bachem MG, Schneider E, Gross H, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115(2):421–432. 55. Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998; 43(1):128–133. 56. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 1999; 44(4):534–541. 57. Mews P, Phillips P, Fahmy R, et al. Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis. Gut 2002; 50(4):535–541. 58. Gress T, Muller-Pillasch F, Elsasser HP, et al. Enhancement of transforming growth factor beta 1 expression in the rat pancreas during regeneration from caerulein-induced pancreatitis. Eur J Clin Invest 1994; 24(10):679–685. 59. Kihara Y, Tashiro M, Nakamura H, Yamaguchi T, Yoshikawa H, Otsuki M. Role of TGF-beta1, extracellular matrix, and matrix metalloproteinase in the healing process of the pancreas after induction of acute necrotizing pancreatitis using arginine in rats. Pancreas 2001; 23(3):288–295. 60. di Mola FF, Friess H, Martignoni ME, et al. Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis. Ann Surg 1999; 230(1):63–71. 61. di Mola FF, Friess H, Riesle E, et al. Connective tissue growth factor is involved in pancreatic repair and tissue remodeling in human and rat acute necrotizing pancreatitis. Ann Surg 2002; 235(1):60–67. 62. Muller-Pillasch F, Menke A, Yamaguchi H, et al. TGFbeta and the extracellular matrix in pancreatitis. Hepatogastroenterology 1999; 46(29):2751–2756. 63. Friess H, Lu Z, Riesle E, et al. Enhanced expression of TGFbetas and their receptors in human acute pancreatitis. Ann Surg 1998; 227(1):95–104. 64. Shek FW, Benyon RC, Walker FM, et al. Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol 2002; 160(5):1787–1798. 65. Menke A, Yamaguchi H, Gress TM, Adler G. Extracellular matrix is reduced by inhibition of transforming growth factor beta1 in pancreatitis in the rat. Gastroenterology 1997; 113(1):295–303. 66. Luttenberger T, Schmid-Kotsas A, Menke A, et al. Plateletderived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab Invest 2000; 80(1):47–55. 67. Jaster R, Sparmann G, Emmrich J, Liebe S. Extracellular signal regulated kinases are key mediators of mitogenic signals in rat pancreatic stellate cells. Gut 2002; 51(4):579–584. 68. Baramova E, Foidart JM. Matrix metalloproteinase family. Cell Biol Int 1995; 19(3):239–242. 69. Ng EK, Barent BL, Smith GS, Joehl RJ, Murayama KM. Decreased type IV collagenase activity in experimental pancreatic fibrosis. J Surg Res 2001; 96(1):6–9. 70. Elsasser HP, Adler G, Kern HF. Time course and cellular source of pancreatic regeneration following acute pancreatitis in the rat. Pancreas 1986; 1(5):421–429. 71. Pap A, Boros L, Hajnal F. Essential role of cholecystokinin in pancreatic regeneration after 60% distal resection in rats. Pancreas 1991; 6(4):412–418.

Chapter 22:

Normal Exocrine Function and Inflammatory Diseases of the Pancreas

72. Rivard N, Lebel D, Laine J, Morisset J. Regulation of pancreatic tyrosine kinase and phosphatase activities by cholecystokinin and somatostatin. Am J Physiol 1994; 266(6 Pt 1): G1130–G1138. 73. Rivard N, Rydzewska G, Lods JS, Martinez J, Morisset J. Pancreas growth, tyrosine kinase, PtdIns 3-kinase, and PLD involve high-affinity CCK-receptor occupation. Am J Physiol 1994; 266(1 Pt 1):G62–G70. 74. Rivard N, Rydzewska G, Morisset J. Cholecystokinin-induced pancreatic growth involves the high-affinity CCK receptor and concomitant activation of tyrosine kinase and phospholipase D. Ann NY Acad Sci 1994; 713:422–423. 75. Dabrowski A, Detjen KM, Logsdon CD, Williams JA. Stimulation of both CCK-A and CCK-B receptors activates MAP kinases in AR42J and receptor-transfected CHO cells. Digestion 1997; 58(4):361–367. 76. Lim HW, Lee JE, Shin SJ, et al. Identification of differentially expressed mRNA during pancreas regeneration of rat by mRNA differential display. Biochem Biophys Res Commun 2002; 299(5):806–812. 77. Morisset J, Aliaga JC, Calvo EL, Bourassa J, Rivard N. Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration. Am J Physiol 1999; 277(5 Pt 1):G953–G959. 78. Calvo EL, Dusetti NJ, Cadenas MB, Dagorn JC, Iovanna JL. Changes in gene expression during pancreatic regeneration: activation of c-myc and H-ras oncogenes in the rat pancreas. Pancreas 1991; 6(2):150–156. 79. Zhou W, Povoski SP, Bell RH Jr. Characterization of cholecystokinin receptors and messenger RNA expression in rat pancreas: evidence for expression of cholecystokinin-A receptors but not cholecystokinin-B (gastrin) receptors. J Surg Res 1995; 58(3):281–289. 80. Povoski SP, Zhou W, Longnecker DS, Jensen RT, Mantey SA, Bell RH Jr. Stimulation of in vivo pancreatic growth in the rat is mediated specifically by way of cholecystokinin-A receptors. Gastroenterology 1994; 107(4):1135–1146. 81. Tsunoda Y, Takeda H, Otaki T, Asaka M, Nakagaki I, Sasaki S. Intracellular Ca2þ shift and signal transduction from the tubulovesicular portion of gastric parietal cells during gastrin stimulation or Ca2þ ionophore treatment: comparison between luminescent and fluorescent probes, and electron probe X-ray microanalyzer. Biochem Cell Biol 1988; 66(4): 279–287. 82. Yen TW, Sandgren EP, Liggitt HD, et al. The gastrin receptor promotes pancreatic growth in transgenic mice. Pancreas 2002; 24(2):121–129. 83. Dembinski AB, Johnson LR. Stimulation of pancreatic growth by secretin, caerulein, and pentagastrin. Endocrinology 1980; 106(1):323–328. 84. Balas D, Senegas-Balas F, Pradayrol L, Vayssette J, Bertrand C, Ribet A. Long-term comparative effect of cholecystokinin and gastrin on mouse stomach, antrum, intestine, and exocrine pancreas. Am J Anat 1985; 174(1):27–43. 85. Chen D, Nylander AG, Norlen P, Hakanson R. Gastrin does not stimulate growth of the rat pancreas. Scand J Gastroenterol 1996; 31(4):404–410. 86. Ryberg B, Axelson J, Hakanson R, Sundler F, Mattsson H. Trophic effects of continuous infusion of [Leu15]-gastrin-17 in the rat. Gastroenterology 1990; 98(1):33–38. 87. Kusske AM, Rongione AJ, Ashley SW, McFadden DW, Reber HA. Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice. Surgery 1996; 120(2):284–288; discussion 289. 88. Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology 1997; 112(3):960–967. 89. Selzman CH, Shames BD, Miller SA, et al. Therapeutic implications of interleukin-10 in surgical disease. Shock 1998; 10(5):309–318. 90. Rongione AJ, Kusske AM, Ashley SW, Reber HA, McFadden DW. Interleukin-10 prevents early cytokine release in severe

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102. 103.

104.

105.

106.

107.

108.

109.

110.

481

intraabdominal infection and sepsis. J Surg Res 1997; 70(2):107–112. van Laethem JL, Deviere J, Resibois A, et al. Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology 1995; 108(6):1873–1881. van Laethem JL, Marchant A, Delvaux A, et al. Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. Gastroenterology 1995; 108(6):1917–1922. Demols A, Van Laethem JL, Quertinmont E, et al. Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2002; 282(6):G1105–G1112. Finch WT, Sawyers JL, Schenker S. A prospective study to determine the efficacy of antibiotics in acute pancreatitis. Ann Surg 1976; 183(6):667–671. Howes R, Zuidema GD, Cameron JL. Evaluation of prophylactic antibiotics in acute pancreatitis. J Surg Res 1975; 18(2):197–200. Buchler M, Malfertheiner P, Friess H, et al. Human pancreatic tissue concentration of bactericidal antibiotics. Gastroenterology 1992; 103(6):1902–1908. Foitzik T, Fernandez-del Castillo C, Ferraro MJ, Mithofer K, Rattner DW, Warshaw AL. Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis. Ann Surg 1995; 222(2):179–185. Pederzoli P, Bassi C, Vesentini S, Campedelli A. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993; 176(5):480–483. Howard TJ, Temple MB. Prophylactic antibiotics alter the bacteriology of infected necrosis in severe acute pancreatitis. J Am Coll Surg 2002; 195(6):759–767. Bassi C, Falconi M, Talamini G, et al. Controlled clinical trial of pefloxacin versus imipenem in severe acute pancreatitis. Gastroenterology 1998; 115(6):1513–1517. Balthazar EJ, Freeny PC, vanSonnenberg E. Imaging and intervention in acute pancreatitis. Radiology 1994; 193(2): 297–306. Baron TH, Morgan DE. Acute necrotizing pancreatitis. N Engl J Med 1999; 340(18):1412–1417. Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998; 42(3):431–435. Kalfarentzos F, Kehagias J, Mead N, Kokkinis K, Gogos CA. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomized prospective trial. Br J Surg 1997; 84(12):1665–1669. Gong Z, Yuan Y, Lou K, Tu S, Zhai Z, Xu J. Mechanisms of Chinese herb emodin and somatostatin analogs on pancreatic regeneration in acute pancreatitis in rats. Pancreas 2002; 25(2):154–160. Guice KS, Oldham KT, Remick DG, Kunkel SL, Ward PA. Anti-tumor necrosis factor antibody augments edema formation in caerulein-induced acute pancreatitis. J Surg Res 1991; 51(6):495–499. Grewal HP, Mohey el Din A, Gaber L, Kotb M, Gaber AO. Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg 1994; 167(1):214–218; discussion 218–219. Hughes CB, el-Din AB, Kotb M, Gaber LW, Gaber AO. Calcium channel blockade inhibits release of TNF alpha and improves survival in a rat model of acute pancreatitis. Pancreas 1996; 13(1):22–28. Hughes CB, Gaber LW, Mohey el-Din AB, et al. Inhibition of TNF alpha improves survival in an experimental model of acute pancreatitis. Am Surg 1996; 62(1):8–13. Hughes CB, Grewal HP, Gaber LW, et al. Anti-TNFalpha therapy improves survival and ameliorates the pathophysiologic sequelae in acute pancreatitis in the rat. Am J Surg 1996; 171(2):274–280.

medwedi.ru

482

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

111. Norman J, Franz M, Fabri PJ, Gower WR. Decreased severity of experimental acute pancreatitis by pre or post treatment with interleukin-1 receptor antagonist. Gastroenterology 1994; 106:A311. 112. Tanaka N, Murata A, Uda K, et al. Interleukin-1 receptor antagonist modifies the changes in vital organs induced by acute necrotizing pancreatitis in a rat experimental model. Crit Care Med 1995; 23(5):901–908. 113. Norman J, Franz M, Messina J, et al. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery 1995; 117(6):648–655. 114. Norman JG, Franz MG, Fink GS, et al. Decreased mortality of severe acute pancreatitis after proximal cytokine blockade. Ann Surg 1995; 221(6):625–631; discussion 631–624. 115. Konturek SJ, Dembinski A, Konturek PJ, et al. Role of platelet activating factor in pathogenesis of acute pancreatitis in rats. Gut 1992; 33(9):1268–1274. 116. Dabrowski A, Gabryelewicz A. Nitric oxide contributes to multiorgan oxidative stress in acute experimental pancreatitis. Scand J Gastroenterol 1994; 29(10):943–948. 117. Closa D, Hotter G, Prats N, et al. Prostanoid generation in early stages of acute pancreatitis: a role for nitric oxide. Inflammation 1994; 18(5):469–480. 118. Sanfey H, Bulkley GB, Cameron JL. The role of oxygenderived free radicals in the pathogenesis of acute pancreatitis. Ann Surg 1984; 200(4):405–413. 119. Kusterer K, Poschmann T, Friedemann A, Enghofer M, Zendler S, Usadel KH. Arterial constriction, ischemiareperfusion, and leukocyte adherence in acute pancreatitis. Am J Physiol 1993; 265(1 Pt 1):G165–G171. 120. Geenen JE, Rolny P. Endoscopic therapy of acute and chronic pancreatitis. Gastrointest Endosc 1991; 37(3):377–382.

121. Cremer M, Deviere J, Delhaye M, Baize M, Vandermeeren A. Stenting in severe chronic pancreatitis: results of mediumterm follow-up in seventy-six patients. Endoscopy 1991; 23(3):171–176. 122. Nealon WH, Townsend CM Jr, Thompson JC. The time course of beta cell dysfunction in chronic ethanol-induced pancreatitis: a prospective analysis. Surgery 1988; 104(6):1074–1079. 123. Bell RH Jr. Surgical options in the patient with chronic pancreatitis. Curr Gastroenterol Rep 2000; 2(2):146–151. 124. Beger HG, Schlosser W, Siech M, Poch B. The surgical management of chronic pancreatitis: duodenum-preserving pancreatectomy. Adv Surg 1999; 32:87–104. 125. Way L. Current Surgical Diagnosis and Treatment. Los Altos: Lange Medical Books, 1985. 126. Wedgwood KR, Farmer RC, Reber HA. A model of hemorrhagic pancreatitis in cats—role of 16,16-dimethyl prostaglandin E2. Gastroenterology 1986; 90(1):32–39. 127. Wahoff DC, Papalois BE, Najarian JS, et al. Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann Surg 1995; 222(4):562–575; discussion 575–579. 128. Frey CF. The surgical management of chronic pancreatitis: the Frey procedure. Adv Surg 1999; 32:41–85. 129. Izbicki JR, Bloechle C, Broering DC, Knoefel WT, Kuechler T, Broelsch CE. Extended drainage versus resection in surgery for chronic pancreatitis: a prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg 1998; 228(6):771–779. 130. Izbicki JR, Bloechle C, Knoefel WT, Kuechler T, Binmoeller KF, Broelsch CE. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995; 221(4):350–358.

23 The Jaundiced Patient Attila Nakeeb and Henry A. Pitt

INTRODUCTION The evaluation and management of the jaundiced patient is a common problem facing the general surgeon. Jaundice, or icterus, refers to a yellow staining of the skin, mucous membranes, and body fluids by bilirubin. Serum bilirubin concentration is normally between 0.5 and 1.3 mg/dL, and jaundice usually becomes clinically apparent when the serum bilirubin concentration exceeds 2.0 mg/dL. During the past century, significant advances have been made in our understanding of the pathophysiology, diagnosis, and management of the jaundiced patient. Biochemists have elucidated normal bilirubin metabolism and have described specific defects that result in different clinical syndromes. The development of diagnostic imaging techniques such as ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), percutaneous and endoscopic cholangiography, endoscopic US (EUS), and staging laparoscopy have dramatically changed the current diagnostic approach to the jaundiced patient. Many of these techniques have led to newer therapeutic options to relieve biliary obstruction. Similarly, advances have been made in perioperative and operative managements that have resulted in improved operative survival of the jaundiced patient. Before discussing the various diagnostic and therapeutic modalities available for the management of the jaundiced patient, normal and abnormal bilirubin metabolism will be reviewed, a classification system of jaundice will be presented, and the multiple pathophysiologic effects of jaundice will be explained.

into bile. Unconjugated bilirubin is transported across the sinusoidal membrane of the hepatocyte into the cytoplasm. Once inside the hepatocyte, unconjugated bilirubin is again bound by a cytoplasmic protein, in this case a glutathione S-transferase. The microsomal enzyme uridine diphosphate glucuronyl transferase then conjugates the insoluble unconjugated bilirubin with glucuronic acid to form the water-soluble conjugated forms, bilirubin monoglucuronide (15%) and bilirubin diglucuronide (85%). Conjugated bilirubin is then excreted from the hepatocyte into the bile canaliculus by an active transport mechanism. Excretion into bile is the rate-limiting step in bilirubin metabolism. After excretion, bile flows through the biliary ductal–collecting system, may or may not be stored in the gallbladder, and enters the duodenum. In the terminal ileum and colon, bilirubin is converted by bacterial enzymes into urobilinogen. About 10% to 20% of the urobilinogen is then reabsorbed from the intestine into the portal circulation, creating an enterohepatic circulation. This recycled urobilinogen may be reexcreted either into the bile by the liver or into urine by the kidney. The remaining urobilinogen in the intestine is converted to fecobilinogen, which gives stool its characteristic brown color. Normal bilirubin metabolism can be summarized as a series of steps including (i) production, (ii) uptake by the hepatocyte, (iii) conjugation, (iv) excretion into bile ducts, and (v) delivery to the intestine. Jaundice can result from defects in any of these steps of bilirubin metabolism.

CLASSIFICATION OF JAUNDICE BILIRUBIN METABOLISM In adults, between 250 and 350 mg of bilirubin is produced each day. Approximately 80% to 85% of this bilirubin is derived from the destruction of senescent red blood cells by the reticuloendothelial system. The remaining 15% to 20% comes from the breakdown of nonhemoglobin proteins such as myoglobin and the cytochromes. The metabolism of bilirubin is reviewed in Figure 1. In reticuloendothelial cells, the microsomal enzyme heme oxygenase cleaves heme into biliverdin. Biliverdin is then reduced to bilirubin by the cytosolic enzyme biliverdin reductase before being released into the circulation. In this unconjugated form, bilirubin is water insoluble and is transported to the liver, tightly bound to albumin. The liver removes unconjugated bilirubin and other organic anions bound to albumin from plasma. After the bilirubin–albumin complex enters the sinusoidal circulation of the liver, three distinct metabolic phases are recognized: (i) hepatocyte uptake, (ii) conjugation, and (iii) excretion

Numerous systems for the classification of jaundice have been proposed based on factors such as pathogenic mechanisms, disease processes, and treatment regimens. However, the most widely accepted classification system is one that relates jaundice to an alteration in normal bilirubin metabolism. In this system, jaundice may result from (i) increased production of bilirubin, (ii) impaired uptake of bilirubin, (iii) impaired conjugation of bilirubin, (iv) impaired transport or excretion of bilirubin into the bile canaliculus, or (v) obstruction of the intrahepatic or extrahepatic biliary tree (Table 1). Overproduction, impaired uptake, and impaired conjugation of bilirubin all lead to a predominately unconjugated hyperbilirubinemia. Impaired transport and excretion or biliary ductal obstruction results in hyperbilirubinemia that is primarily conjugated. Some patients have multiple defects in normal metabolism. For example, a patient with biliary obstruction from tumor may develop secondary hepatocellular dysfunction. Therefore, these classification systems may be simplifications of more complex disease processes.

medwedi.ru 483

484

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

is a congenital defect that results in unconjugated hyperbilirubinemia because of reduced bilirubin glucuronyl transferase levels within hepatocytes. The bilirubin level fluctuates depending on the clinical state but rarely exceeds 3.0 mg/dL. In the Crigler–Najjar syndromes, there is either a complete absence of glucuronyl transferase activity (type I) or a marked decrease in glucuronyl transferase activity (type II). Type I disease is usually fatal within the first year of life.

Impaired Transport or Excretion Impairment of bilirubin transport or excretion into the bile canaliculus results in intrahepatic cholestasis or ‘‘medical’’ jaundice. Hepatitis—viral, alcoholic, or drug induced—is the most common cause of intrahepatic cholestasis. Drugs such as the ‘‘statins,’’ oral contraceptives, and anabolic steroids also may cause a defect in the excretion of bilirubin. Genetic defects in the hepatic excretion of bilirubin and other organic anions across the hepatocyte membrane exist in both the Dubin–Johnson and Rotor syndromes. In the Dubin–Johnson syndrome, pigments accumulate within hepatocytes, causing the liver to turn black. The Rotor syndrome has a similar defect in hepatic storage of bilirubin, except that no pigment accumulates within the liver parenchyma. Figure 1 Schematic representation of normal bilirubin metabolism. Abbreviations: GT, glucuronyl transferase; BMG, bilirubin monoglucuronide; BDG, bilirubin diglucuronide; EHC, enterohepatic circulation.

Increased Production Overproduction of bilirubin can result from either congenital or acquired hemolysis. Hereditary causes include spherocytosis, thalassemia, and sickle cell disease. Acquired causes of hemolysis include sepsis, burns, infections, drugs, transfusion reactions, and acquired autoimmune diseases. When the capacity of the liver to remove bilirubin from the circulation is exceeded, unconjugated hyperbilirubinemia occurs. The total bilirubin level in hemolysis rarely exceeds 4 to 5 mg/dL. However, if underlying hepatocellular dysfunction is also present, much higher bilirubin levels may occur.

Biliary Obstruction Jaundice due to biliary obstruction is often referred to as ‘‘surgical’’ jaundice. With biliary obstruction, hyperbilirubinemia is primarily conjugated, but unconjugated bilirubin is often also moderately elevated. Common causes of surgical jaundice are depicted in Table 1, and will be the primary focus of the remainder of this chapter.

PATHOPHYSIOLOGY OF JAUNDICE Biliary obstruction produces local effects on the bile ducts that lead to derangements of hepatic function and, ultimately, to widespread systemic effects. Patients who are jaundiced have an increased risk of developing hepatic dysfunction, renal failure, cardiovascular impairments, nutritional deficiencies, bleeding problems, infections, and wound complications, and of dying after surgery.

Impaired Uptake and Conjugation

Hepatobiliary

Impaired uptake of unconjugated bilirubin by hepatocytes can be caused by drugs, prolonged fasting, and sepsis and following viral hepatitis. Neonatal jaundice results from an immaturity of the hepatic conjugating and transport system. This problem occurs between the second and fifth days of life, and usually disappears by two weeks, as the enzyme systems mature. Gilbert’s syndrome is the most common cause of unconjugated nonhemolytic hyperbilirubinemia and affects between 2.5% and 7% of the population. Gilbert’s syndrome

The biliary system normally has a low pressure (5–10 cm H2O). In the setting of complete or partial biliary obstruction, biliary pressure can approach 30 cmH2O (1). As biliary pressure increases, the tight junctions between hepatocytes and bile duct cells are disrupted, resulting in an increase in bile duct and canalicular permeability. Bile contents can freely reflux into liver sinusoids, causing a marked inflammatory response in the portal triads. In patients with long-standing obstruction, intrahepatic bile ductule proliferation occurs and can lead to the development of biliary cirrhosis.

Table 1 Classification of Jaundice Defect in bilirubin metabolism Increased production Impaired hepatocyte uptake Reduced conjugation Impaired transport and excretion Biliary obstruction

Predominant hyperbilirubinemia Unconjugated Unconjugated Unconjugated Conjugated Conjugated

Examples Congenital hemoglobinopathies, hemolysis, multiple transfusions, sepsis, burns Gilbert’s disease, drug induced Neonatal jaundice, Crigler–Najjar syndrome Hepatitis, cirrhosis, Dubin–Johnson syndrome, Rotor syndrome Choledocholithiasis, benign strictures, chronic pancreatitis, sclerosing cholangitis, periampullary cancer, cholangiocarcinoma

Chapter 23: The Jaundiced Patient

Extrahepatic biliary obstruction and jaundice also can alter important secretory, metabolic, and synthetic functions of the liver. When biliary pressure rises above 20 cmH2O, hepatic bile secretion is diminished and hepatocytes cannot excrete efficiently against the high ductal pressure. As a result, excretory products of the hepatocytes reflux directly into the vascular system leading to systemic toxicity. Jaundiced patients have a decreased capacity to excrete drugs, such as antibiotics, that are normally secreted into bile (2). The increased concentration of bile acids associated with obstructive jaundice results in inhibition of the hepatic cytochrome P450 enzymes and, therefore, in a decrease in the rate of oxidative metabolism in the liver. In addition, bile acids in abnormally high concentrations can induce apoptosis (programmed cell death) in hepatocytes (3). The synthetic function of the hepatocyte is also decreased with obstructive jaundice, as evidenced by decreased plasma levels of albumin, clotting factors, and secretory immunoglobulins. The Kupffer cell is a tissue macrophage that is the predominant cell type of the hepatic reticuloendothelial system. Normally, infectious agents, damaged blood cells, cellular debris, fibrin degradation products, and endotoxin that are absorbed or formed in the portal circulation are effectively filtered by Kupffer cells and removed from the systemic circulation. Kupffer cells also play an interactive role with hepatocytes, modulating synthesis of hepatic proteins. Obstructive jaundice has been shown to have profound effects on Kupffer cells, including decreased endocytosis, phagocytosis, clearance of bacteria and endotoxin, and expression of the major histocompatibility complex class II antigen and a subsequent diminished ability to process antigen (4–6). In addition, biliary obstruction has been shown to increase levels of proinflammatory cytokines, including tumor necrosis factor a and interleukin-6. Several authors have reported impairment of both macro- and microvascular perfusion of the liver in obstructive jaundice. Intravital fluorescence microscopy has shown a significant increase in the number of nonperfused sinusoids after three days of extrahepatic cholestasis. In perfused sinusoids, a 35% decrease in the mean diameter and a 25% decrease in flow velocity were noted (7).

Cardiovascular In addition to hepatic dysfunction, obstructive jaundice is known to cause severe hemodynamic and cardiac disturbances. Experimental animals with obstructive jaundice tend to be hypotensive and exhibit an exaggerated hypotensive response to hemorrhage. Studies in experimental animals have demonstrated that bile duct–ligated animals have (i) decreased cardiac contractility, (ii) reduced left ventricular pressures, (iii) impaired response to b-agonist drugs such as isoproterenol and norepinephrine, and (iv) decreased peripheral vascular resistance (8–10). In a study of nine patients with obstructive or cholestatic jaundice, Lumlertgul et al. (11) have shown a significantly blunted response in left ventricular ejection fraction compared to normal volunteers, following the infusion of the positive inotrope dobutamine. Recently, Padillo et al. (12) have shown a negative correlation between serum bilirubin and left ventricular systolic work in 13 patients with biliary obstruction and no previous history of heart, lung, or kidney disease. Moreover, successful internal biliary drainage in their patients was associated with a significant increase in cardiac output, compliance, and contractility. The combination of depressed cardiac function and decreased total peripheral resistance most likely makes the jaundiced

485

patient more susceptible to the development of postoperative shock than nonjaundiced patients.

Renal The association between jaundice and postoperative renal failure has been known for many years. The reported incidence of postoperative acute renal failure approaches 10%. Moreover, the mortality rate in jaundiced patients developing renal failure has been reported to be as high as 70% (13). Important factors that may play a role in the development of renal failure in obstructive jaundice include (i) depressed cardiac function, (ii) hypovolemia, and (iii) endotoxemia. The decreased cardiac function associated with obstructive jaundice leads to a decrease in renal perfusion. Moreover, it has been postulated that this decreased cardiac output results in stretching of the atrium and an increase in production of the hormone atrial natriuretic peptide (ANP). ANP is known to cause natriuresis, to counter the action of water- and sodium-retaining hormones, to inhibit the thirst mechanism and produce peripheral vasodilatation. Plasma levels of ANP have been shown to be increased in both experimental animals and patients with extrahepatic biliary obstruction (12,14). In addition to the direct effects of jaundice on the heart and peripheral vasculature discussed above, the increased serum levels of bile acids associated with obstructive jaundice have a direct diuretic and natriuretic effect on the kidney, resulting in significant extracellular volume depletion and hypovolemia. In dogs, the infusion of bile into the renal artery results in increased urine flow, natriuresis, and kaliuresis. This diuretic effect may be mediated by increased prostaglandin E2–production by the kidney (15). The third factor in the development of renal failure is endotoxemia. Approximately 50% of patients with obstructive jaundice (16,17) have endotoxin in their peripheral blood. This phenomenon may be the result of a lack of bile salts in the gut lumen that normally prevent absorption of endotoxins and inhibit anaerobic bacterial growth as well as the decreased hepatic clearance of endotoxin by Kupffer cells. Endotoxin also causes renal vasoconstriction and redistribution of renal blood flow away from the cortex and disturbances in coagulation including the activation of complement, macrophages, leukocytes, and platelets (16). As a result, glomerular and peritubular fibrin is deposited. This factor, in combination with reduced renal cortical blood flow, results in the tubular and cortical necrosis observed in jaundiced patients with renal failure. Mechanisms of the pathophysiology of renal failure in obstructive jaundice are summarized in Figure 2.

Coagulation Disturbances of blood coagulation are also commonly present in jaundiced patients. The most frequently observed clotting defect in patients with biliary obstruction is prolongation of the prothrombin time (PT). This problem results from impaired vitamin K absorption from the gut, secondary to a lack of intestinal bile. This coagulopathy is usually reversible by the parenteral administration of vitamin K. Decreased bile levels in the small intestine may also result in diminished absorption of other fat-soluble vitamins and fats, which results in weight loss and loss of calcium. This latter factor, as well as the above-mentioned increase in circulating endotoxin, may further contribute to clotting abnormalities. In experimental animals, endotoxin affects factors XI and XII and causes platelet and direct endothelial damage

medwedi.ru

486

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Obstructive Jaundice

Systemic Bile Salts Gut Bile Salts

Kupffer Cell Clearance

Clearance of Cardiotoxins?

Endotoxemia

Cardiovascular System

LV Function

ANP and Hypodypsia

ANP and Cytokines

Plasma Volume

Peripheral Resistance

Blood Pressure

Systemic Bilirubin

Renal System

Coagulation System

Prostaglandins and Cytokines

Peritubular Fibrin Deposition

Altered Intrarenal Hemodynamics

Direct Parenchyma Toxicity

Renal Vascular Resistance Renal Permeability

Figure 2 Mechanism of renal dysfunction in jaundice. Abbreviations: LV, left ventricular; ANP, atrial natriuretic peptide.

Renal Impairment or Acute Renal Failure

(16). Moreover, endotoxin release in jaundiced patients results in a low-grade disseminated intravascular coagulation (DIC) with increased fibrin degradation products. Hunt (18) has shown that jaundiced patients with circulating endotoxin or increased fibrin degradation product levels before surgery are at increased risk for hemorrhagic complications. In addition to problems with endotoxemia, cirrhotic patients may have even more complicated clotting abnormalities, such as problems with thrombocytopenia from hypersplenism and fibrinolysis.

Immune System Surgery in the jaundiced patient is associated with a significant rate of postoperative septic complications. Jaundiced patients have a number of defects in cellular immunity that make them more prone to infection. Cainzos et al. (19) have demonstrated an association between jaundice and altered delayed type hypersensitivity. Only 16% of 118 jaundiced patients were immunocompetent compared to 76% of 59 healthy controls when tested with a battery of seven skin antigens. Several authors have shown impaired T-cell proliferation (20), decreased neutrophil chemotaxis (21), and defective bacterial phagocytosis (22) following bile duct ligation in rats. As mentioned earlier, the ability of the reticuloendothelial system, specifically liver Kupffer cells, to clear bacteria and endotoxin from the circulation is also reduced in obstructive jaundice. The absence of bile from the intestinal tract also plays a role in the infectious complications seen in patients with obstructive jaundice. Bacterial translocation from the gut has been shown to be increased in the setting of bile duct obstruction (23). Obstruction causes a disruption of the enterohepatic circulation and results in the loss of the emulsifying antiendotoxin effect of bile acids. Therefore, a larger pool of endotoxin is available within the intestine for absorption into the portal circulation. The combination of a lack of bile in the intestine and the impairment of cellular

immunity and reticuloendothelial cell function most likely results in the observed increase in septic and infectious complications in the jaundiced patient.

Wound Healing Delayed wound healing and a high incidence of wound dehiscence and incisional hernias have been observed in patients undergoing surgery for the relief of obstructive jaundice. Patients with obstructive jaundice have decreased activity of the enzyme propylhydroxylase in their skin. Propylhydroxylase is necessary for the incorporation of proline amino acid residues into collagen, and its activity has been used as a measure of collagen synthesis. Grande et al. (24) measured skin propylhydroxylase activity in 95 patients with extrahepatic bile duct obstruction and 123 nonjaundiced control patients undergoing cholecystectomy. The jaundiced patients had only 11% of the skin propylhydroxylase activity of the controls. In the subgroup of patients that had jaundice secondary to malignancy, the propylhydroxylase activity was less than 7% of that in controls. With relief of obstruction, the activity increased to 22% of that in controls. Interestingly, in patients with jaundice secondary to benign obstruction, the activity increased to 100% of that in controls.

Other Factors Other problems that face jaundiced patients are anorexia, weight loss, and resultant malnutrition. Appetite is adversely influenced by the lack of bile salts in the intestinal tract. In addition, patients with pancreatic or periampullary malignant lesions may have partial duodenal obstruction or abnormal gastric emptying, perhaps secondary to tumor infiltration of the celiac nerve plexus. Patients with pancreatic or ampullary tumors may also have pancreatic endocrine and exocrine insufficiency. This latter problem may further compound other nutritional defects that, in turn, may multiply the immune deficits of the jaundiced patient.

Chapter 23: The Jaundiced Patient

487

a benign biliary stricture or retained common duct stones. A history of biliary colic points toward choledocholithiasis. Pancreatic cancer, on the other hand, is more likely to present with progressive, painless jaundice and weight loss. The presence of fever, chills, and upper abdominal pain in addition to jaundice (Charcot’s triad) is suggestive of cholangitis, which occurs more often in patients with choledocholithiasis than in those with malignant obstruction. On physical examination, the abdomen should be carefully palpated. A small liver may be discovered in severe cirrhosis or hepatitis. A tender liver edge may be found in hepatitis, congestive heart failure, or alcoholic hepatitis. A palpable, nontender gallbladder may be noted in pancreatic or ampullary carcinoma (Courvoisier’s sign). A tender gallbladder, on the other hand, may be palpated in choledocholithiasis with associated cholecystitis. The signs of cirrhosis (i.e., ascites, spider angioma, or periumbilical venous enlargement) should also be noted.

In recent years, it has become clear that the many physiologic derangements that occur with obstructive jaundice take a long time to reverse. For example, Koyama et al. (25) have shown that hepatic mitochondrial function does not return to normal even seven weeks after relief of obstruction. This same prolonged effect of obstructive jaundice has been noted with lymphocyte, polymorphonuclear, and Kupffer cell function. Therefore, even patients who have had temporary relief of biliary obstruction via percutaneous or endoscopic stents are likely to remain at risk for the development of significant complications following surgery.

DIAGNOSTIC APPROACH When confronted with a patient with jaundice, the objective of the physician is to identify any potentially treatable causes. The most important distinction to be made is whether the jaundice is caused by intrahepatic cholestasis or extrahepatic obstruction. Fortunately, the distinction between ‘‘medical’’ and ‘‘surgical’’ jaundice can be made relatively easily with a careful history, physical examination, review of serum chemistries, and radiological evaluation. An algorithm for the evaluation of the jaundiced patient is shown in Figure 3. The following discussion will present an approach to the jaundiced patient that will allow for an accurate diagnosis to be made without subjecting the patient to needless risk, discomfort, or expense.

Biochemical Evaluation Along with the history and physical examination, biochemical evaluation is an integral part of the initial workup of the jaundiced patient. Hyperbilirubinemia is the sine qua non of jaundice, and the level of bilirubin can indicate the severity of the disease process. Moreover, bilirubin levels can be used to follow disease progression. The routine laboratory tests that should be performed on all jaundiced patients include direct (conjugated) and indirect (unconjugated) bilirubin, alkaline phosphatase, serum transaminases, and amylase determinations (Table 2). Patients with hemolysis have an increase in the indirect (unconjugated) fraction of bilirubin, whereas the direct (conjugated) bilirubin level is normal. As stated previously, the total bilirubin concentration in hemolysis rarely exceeds 4 to 5 mg/dL. Bilirubin is absent in the urine of patients with hemolysis, because indirect bilirubin is not excreted by the kidney.

Clinical Evaluation The first and most important step in the workup of the jaundiced patient is to obtain a careful history. Important historical points to consider include occupational exposures, travel history, prior blood transfusions, and alcohol consumption and a complete review of all medications. Previous surgery, especially biliary, raises the suspicion of

Jaundice

Indirect hyperbilirubinemia

Hemolysis workup

History, physical exam, laboratory tests

Direct hyperbilirubinemia

Suspect extrahepatic disorder

Suspect intrahepatic disease Medical workup

Surgical workup

Suspect stone disease

CT scan

Ultrasound CBD stones

Suspect malignancy

Hepatitis screen, observation, liver biopsy

Dilated ducts

No CBD stones

Suspect proximal obstruction

Suspect distal obstruction

EUS MRCP

EUS

ERCP+ES

LC

LC + LCBDE

ERCP

PTC

ERCP

medwedi.ru

Figure 3 Algorithm for the evaluation of jaundice. Abbreviations: CBD, common bile duct; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; EUS, endoscopic ultrasound; MRCP, magnetic resonance cholangiopancreatography; PTC, percutaneous transhepatic cholangiography; LC, laparoscopic cholecystectomy; LCBDE, laparoscopic common bile duct exploration.

488

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 2 Laboratory Tests in the Diagnosis of Jaundice Serum bilirubin Cause of jaundice Hemolysis Hepatocellular dysfunction Intrahepatic cholestasis Extrahepatic obstruction

Conjugated

Unconjugated

Serum alkaline phosphatase

$ "" """ """

""" "" "" ""

$ " "" """

Urine Serum transaminases

Bilirubin

Urobilinogen

$ """ "" "

0 "" """ """

"" " 0 or # 0 or #

0 ¼ none; # ¼ decreased; $ ¼ no change; " ¼ mild elevation; "" ¼ moderate elevation; """ ¼ marked elevation.

The amino acid transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are serum markers for hepatocyte damage. AST is found in liver, heart, kidney, skeletal muscle, and brain tissue. ALT is found predominantly within hepatocytes, making ALT more specific for identifying liver injury. In cases of hepatic parenchymal disease, broad derangements of liver function tests are seen. The concentrations of both conjugated and unconjugated fractions of bilirubin are increased. With the increased level of conjugated bilirubin in the serum, bilirubinuria develops. In patients with acute hepatitis, serum ALT and AST are markedly elevated. In contrast, alkaline phosphatase and bilirubin levels in these patients may be only slightly elevated. As in hepatitis, the serum transaminases are elevated in alcoholic liver disease, with serum AST levels usually being greater than twice serum ALT levels. In the cirrhotic patient, serum bilirubin levels increase in proportion to the degree of parenchymal damage. Albumin and the coagulation factors V, VII, IX, and X, prothrombin, and fibrinogen are all synthesized in the liver. Therefore, the measurement of serum albumin levels and PT may be helpful in assessing the degree of parenchymal liver injury. In extrahepatic obstruction, the fraction of direct bilirubin is increased along with a moderate increase in indirect bilirubin. The highest elevations of bilirubin are usually found in patients with malignant extrahepatic obstruction where bilirubin levels may exceed 20 mg/dL. With malignant obstruction, the alkaline phosphatase is also elevated to the same degree. Other liver function tests are usually normal or only slightly elevated, and the amylase concentration is usually normal. Common bile duct stones, on the other hand, rarely cause an increased bilirubin level greater than 10 to 12 mg/dL. With choledocholithiasis, alkaline phosphatase is also usually elevated to a moderate degree. As a gallstone passes through and momentarily obstructs the ampulla of Vater, serum transaminase levels may transiently rise. In this setting, hyperamylasemia may also develop. If longstanding extrahepatic obstruction is present, liver damage and fibrosis can occur, thus resulting in a combined intra- and extrahepatic biochemical profile. Serum alkaline phosphatase is often a more sensitive indicator of obstruction and may be elevated when the bilirubin level is normal. This circumstance occurs most commonly with incomplete or partial obstruction. However, increased levels of alkaline phosphatase activity may also result from bone disease. If this possibility is suspected, serum 50 -nucleotidase or serum g-glutamyl transpeptidase levels should be measured, because both of these parallel changes in alkaline phosphatase from a hepatobiliary source and are not found in bone. By obtaining a careful history, performing a physical examination, and interpreting laboratory tests, an experienced clinician can usually accurately differentiate intrahepatic diseases from extrahepatic obstruction. O’Connor et al.

(26) reported that the accuracies in diagnosing extrahepatic obstruction by clinical evaluation, CT, US, and biliary scintigraphy were 84%, 81%, 78%, and 68%, respectively. This analysis suggests that clinical evaluation is comparable to noninvasive radiological tests in the detection of extrahepatic biliary obstruction. However, although the sensitivity of clinical examination in this study was 95%, the specificity was only 76%. Thus, nearly one-fourth of patients diagnosed as having extrahepatic obstructive disease will actually have hepatocellular disease. Therefore, although the history and physical examination are vital in evaluating the patient with jaundice, further tests are usually essential to diagnose the specific cause of jaundice.

Radiologic Evaluation The goals of the radiologic evaluation of the jaundiced patient include: (i) the confirmation of clinically suspected extrahepatic biliary obstruction by the demonstration of a dilated biliary tree, (ii) the identification of the cause and site of extrahepatic biliary obstruction, and (iii) the selection of patients in whom surgical or interventional radiologic or endoscopic treatment is indicated.

Abdominal Plain Films The likelihood of a plain abdominal X-ray film providing diagnostic information in the jaundiced patient is low. Abdominal X-ray may reveal gallstones, a calcified gallbladder wall, or the outline of a distended gallbladder. Approximately 15% to 20% of gallstones are radiopaque and can be visualized by radiography. However, cholangiography will still be necessary to determine whether common duct stones are present and to rule out other causes of jaundice such as hepatic parenchymal disease or an obstructing tumor.

Ultrasonography Transabdominal US is commonly performed as the initial screening procedure in the jaundiced patient. US is noninvasive, inexpensive, and widely available. Dilated intrahepatic bile ducts are a reliable sign of extrahepatic biliary obstruction, and most series report that US can detect dilatation of the intrahepatic or proximal extrahepatic bile ducts with at least an 80% accuracy rate (27,28). The normal extrahepatic bile duct diameter is less than 10 mm, and normal intrahepatic duct diameter is less than 4 mm. Dilated ducts are easily detectable by ultrasonography and often can be identified before the onset of clinical jaundice. Failure of ultrasonography to detect dilated ducts usually indicates an intrahepatic source of jaundice. However, the absence of ductal dilatation does not entirely rule out extrahepatic obstruction. In intermittent or partial obstruction, the intrahepatic biliary tree may not be dilated. Likewise, in long-standing obstruction, especially if secondary biliary fibrosis or cirrhosis is present, dilated ducts may not be seen.

Chapter 23: The Jaundiced Patient

489

Table 3 Comparison Between US and CT in the Diagnosis of the Jaundiced Patient Criterion Identification of ductal dilatation Identification of cause of obstruction Patient selection Other factors

US

CT

80–85% 35–40% Thin patients, pregnancy, suspected choledocholithiasis Less expensive, no radiation

> 90% 40–80% Obese patients, bowel gas, suspected malignancy More expensive, radiation

Abbreviations: CT, computed tomography; US, ultrasound.

In these cases, where extrahepatic obstruction is suspected despite a negative US, cholangiography may be necessary. US can differentiate between extrahepatic obstruction and hepatocellular causes of jaundice in up to 96% of cases (29). Unfortunately, US is limited in its ability to identify the cause and exact location of an obstructing lesion. The anatomic level of the obstruction can be estimated in up to half of the patients. The cause of the obstruction is evident in a far lower proportion. This low yield in determining the cause of obstruction is caused by a failure to visualize the entire common bile duct, especially the distal third, and an inconsistency in the ability of US to detect common duct stones. The distal end of the bile duct is frequently obscured by duodenal or colonic gas. Studies indicate that US successfully identifies the presence of common bile duct stones in at most 70% of patients. Therefore, although US is a valuable initial step in the evaluation of the jaundiced patient, further diagnostic studies such as CT or cholangiography are usually necessary to identify the cause and exact location of the obstruction.

Computed Tomography CT can also be used to differentiate intrahepatic disease with nondilated ducts from extrahepatic obstruction. CT is more than 90% accurate in detecting the presence of ductal dilation (Table 3). This slightly higher success rate compared to US is because CT provides better definition of

anatomic structures and can use contrast media to enhance delineations (Fig. 4A). The accuracy of CT in determining the site and cause of obstruction is controversial, with rates ranging between 30% and 96% (27,30). This wide range of reported accuracy of CT in diagnosing the cause and anatomic location of an obstructing lesion results primarily from differences in the reported ability of CT to detect obstructing common bile duct stones. CT shows the common bile duct in cross-section instead of longitudinally, and small stones in the common bile duct may not be identified. In addition, CT scanning, especially with newer spiral techniques and three-dimensional reconstructions (Fig. 4B), can also provide highly accurate information regarding retroperitoneal extension, vascular invasion, and spread to the liver in malignant causes of biliary obstruction. In summary, CT and US have similar value in the diagnosis of biliary ductal dilation. CT may be the preferred initial screening procedure in obese patients, or in patients with suspected malignancy. Most authorities agree that CT is slightly more accurate than US in detecting the nature and anatomic level of obstruction. CT also has the advantage of routinely being able to visualize the pancreas and, therefore, is probably the screening procedure of choice if a periampullary tumor is suspected. On the other hand, US is less expensive, is more widely available, and does not

Figure 4 (A) CT of a patient demonstrating dilation primarily on the left, but also of the right hepatic duct. (B) Three-dimensional CT vascular reconstruction. Abbreviations: LGA, left gastric artery; CHA, common hepatic artery; GDA, gastroduodenal artery; PHA, proper hepatic artery; LHA, left hepatic artery; RHA, right hepatic artery; CT, computed tomography.

medwedi.ru

490

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

expose the patient to radiation. Therefore, US should be performed initially if stone disease is suspected.

Magnetic Resonance Imaging Over the past decade, MRI has become a powerful noninvasive technique for the evaluation of obstructive jaundice. Magnetic resonance cholangiopancreatography (MRCP) is performed with T2-weighted sequences that depict the biliary tract and pancreatic ducts as a high-signal intensity or bright structure without the use of contrast material, instrumentation, or ionizing radiation (Fig. 5). MRCP is frequently used for the noninvasive diagnosis of common bile duct stones. Recent studies with state-of-the-art techniques yield sensitivities of 90% to 100%, specificities of 92% to 100%, positive predictive values of 93% to 100%, and negative predictive values of 96% to 100% in the setting of suspected choledocholithiasis (31). Patients found to have stones can then go on to have stone extraction through endoscopic retrograde cholangiopancreatography (ERCP) or surgery. MRCP can also be helpful in the diagnosis of biliary strictures. Lopera et al. (32) studied 29 patients with malignant hilar biliary strictures with MRCP and percutaneous transhepatic cholangiography (PTC), and showed that MRCP was able to accurately predict biliary tract morphology in 96% of patients. Early strictures that have not yet caused biliary dilatation may be missed by MRCP, because the ducts are not distended with contrast. Advantages of MRI and MRCP in the evaluation of the jaundiced patient include the ability to visualize the proximal and distal extension of tumor within the bile ducts and to evaluate the liver, pancreas, and associated blood vessels for local tumor invasion or metastasis.

Endoscopic Ultrasound EUS is a relatively new modality that is beginning to play a significant role in the evaluation of the jaundiced patient. EUS can diagnose the most common causes of extrahepatic

Figure 5 A magnetic resonance cholangiogram showing a nondilated biliary tree and a moderately dilated proximal pancreatic duct.

biliary obstruction such as choledocholithiasis and pancreaticobiliary malignancies (Fig. 6) with the same or with better accuracy than direct cholangiography or ERCP. EUS is a semi-invasive test that can be performed with a very low rate of complications (less than 0.1%) (33). Several authors have shown that EUS can be used for the diagnosis of common bile duct stones, with a sensitivity between 92% and 100% and a specificity between 95% and 100%. The negative predictive value for EUS is more than 97% (34). Therefore, when EUS is negative for common duct stones, ERCP or intraoperative cholangiography can be avoided. EUS is the most sensitive modality for the diagnosis of pancreatic carcinoma. The strengths of EUS techniques for pancreatic cancer are clarification of small lesions (< 2 cm) when CT findings are questionable or negative, detection of malignant lymphadenopathy, and the ability to perform EUS-guided fine needle aspiration (FNA) for definitive diagnosis and staging. The accuracy of EUS without FNA averages 85% for T stage and 70% for N stage disease. The combination of EUS and FNA has a sensitivity of 93% and a specificity of 100% for T stage and an accuracy of 88% for N stage (35).

Biliary Scintigraphy Technetium-99m labeled iminodiacetic acid derivatives (HIDA, DISIDA, and P1PIDA) are injected intravenously, rapidly extracted from the blood, and excreted into the bile. These radionuclide scans provide functional information about the liver’s ability to excrete radiolabelled substances into a nonobstructed biliary tree. Biliary scintigraphy is useful in the workup of neonatal jaundice, the detection of bile leaks, and the diagnosis of acute cholecystitis. Cholescintigraphy also provides a method to noninvasively evaluate the patency and function of biliary–enteric anastomoses and for studying the kinetics of bile flow in patients suspected of having disorders of biliary motility. Biliary scintigraphy plays only a limited role in the evaluation of a patient with jaundice. The technique has been shown to be useful in the diagnosis of complete common bile duct obstruction. Any appearance of the

Figure 6 Endoscopic ultrasound showing a mass in the head of the pancreas adjacent to the portal vein. Abbreviations: GB, gallbladder; PD, pancreatic duct; PV, portal vein; PANC, pancreas.

Chapter 23: The Jaundiced Patient

nucleotide in the gastrointestinal (GI) tract indicates patency of bile flow into the duodenum. However, other available noninvasive tests such as US, CT, and MRI have generally been shown to be more accurate and, therefore, are preferred.

Percutaneous Transhepatic Cholangiography Direct cholangiography is indicated if dilated bile ducts are visualized on US or CT, or if the clinical suspicion of extrahepatic biliary obstruction remains high despite a negative noninvasive imaging. Direct cholangiography may be performed percutaneously or endoscopically. PTC involves the cannulation of intrahepatic bile ducts with a thin, flexible Chiba needle under radiographic control, followed by the injection of contrast material to outline the bile ducts. PTC is successful in differentiating intrahepatic from extrahepatic obstruction in up to 96% of cases (36). Percutaneous cholangiography is highly accurate in defining the site and cause of extrahepatic obstruction (Fig. 7). PTC can define the site of an obstructing lesion in approximately 95% of patients, and the cause of the obstruction in nearly 90% of cases (37). Diagnostic cholangiography can also be combined with a series of therapeutic maneuvers such as the insertion of biliary stents or endoprostheses, percutaneous stone extraction, biliary dilation, and cholangioscopy. In addition, cholangiography provides an

Figure 7 A transhepatic cholangiogram showing a benign postoperative stricture (note multiple surgical clips near the bifurcation of the common hepatic duct).

491

anatomical road map of the biliary tree that is useful during surgical procedures. The success rate of entering a bile duct during PTC increases with the experience of the radiologist. In patients with dilated intrahepatic ducts, PTC is nearly 100% successful. In patients with nondilated bile ducts, the success rate is approximately 70%. Although PTC is an invasive procedure, it has an acceptably low complication rate (38). The major complication rate of transhepatic cholangiography at most centers is less than 5%. The most commonly reported complications include hemorrhage (2.5%), sepsis (2.5%), bile peritonitis (1.8%), and pneumothorax or empyema (1.8%). The procedure-related mortality rate is approximately 0.5%. Even with more frequent passes of the needle (i.e., as many as 15 attempts), no increase in the complication rate has been reported. Thus, in the management of the jaundiced patient, the advantages of PTC are the ability to (i) establish a diagnosis, (ii) determine the site and cause of obstruction, and (iii) provide specific anatomic detail.

Endoscopic Retrograde Cholangiography Endoscopic retrograde cholangiography (ERC) is the other option for direct visualization of the biliary system (Fig. 8). The technique of ERC requires a skilled endoscopist

Figure 8 Endoscopic retrograde cholangiopancreatography showing a dilated extrahepatic biliary tree from a common duct stone and a normal pancreatic duct.

medwedi.ru

492

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 4 Comparison of Percutaneous Transhepatic Cholangiography and Endoscopic Retrograde Cholangiography Criterion Success rate Identification of cause of obstruction Complications Mortality Expense Skill required Patient selection

Transhepatic cholangiography > 90% with dilated ducts, 70% with nondilated ducts 90–100% 5% (range 3–10%) 0.2–0.9% Less Less Proximal lesions, altered gastroduodenal anatomy, failed endoscopic cholangiography

who is capable of cannulating the sphincter of Oddi with a side-viewing duodenoscope and then filling the biliary tree with contrast material in a retrograde fashion. The success rate of ERC is approximately 85% to 90% and improves with the experience of the endoscopist. ERC is able to define the site and cause of extrahepatic obstructive jaundice in 75% to 90% of patients (27,39). As in PTC, the complication and mortality rates of ERC are acceptably low. A complication rate of less than 3% and a mortality rate of less than 0.1% can be expected (40,41). The two major complications of the procedure are sepsis and acute pancreatitis. Prophylactic antibiotics should be administered before the procedure if biliary obstruction is suspected. In the jaundiced patient identified as having dilated ducts on US or CT, direct cholangiography by either PTC or ERC is the next procedure to be used (Table 4). PTC is less expensive, is more widely available, requires less expertise than ERC, and has a higher success rate if dilated ducts are present. In patients with total biliary obstruction, PTC provides the surgeon with information about the proximal biliary tree, whereas ERC frequently can only delineate the anatomy of the distal bile duct. PTC is the preferred procedure if therapeutic manipulations such as biliary drainage, balloon dilation, or endoprosthesis placement are necessary for hilar bile duct lesions. ERC may be difficult or impossible to perform in patients with ampullary stenosis or in those who have altered GI anatomy secondary to previous surgery. However, in several instances ERC is preferable to PTC. Percutaneous cholangiography is contraindicated in patients with an uncorrectable coagulopathy or with significant ascites. ERC allows for endoscopic visualization of the upper GI tract and ampullary region. Therefore, lesions can be biopsied and varices identified during the course of an ERC. Moreover, cannulation and injection with contrast of the pancreatic duct is often helpful in patients suspected of having pancreatic cancer. In patients with postcholecystectomy symptoms or sphincter of Oddi dyskinesia, ERC enables visualization and cannulation of the ampulla and manometric pressure recordings. As with PTC, therapeutic manipulations such as endoscopic sphincterotomy (ES) and stenting may be carried out in conjunction with ERC. In summary, the method of direct cholangiography that is chosen, either PTC or ERC, is individualized in each case. In certain situations such as totally obstructing proximal lesions, PTC may be the procedure of choice. On the other hand, when noninvasive studies suggest periampullary or pancreatic pathology, ERC provides additional useful information. The choice between these two procedures may ultimately be decided by the expertise of the radiologists and endoscopists at an individual institution.

Endoscopic cholangiography 80–90% with either dilated or nondilated ducts 75–90% 5% (range 2–7%) 0.1–0.2% More More Distal lesions, pancreatic pathology, coagulopathy, ascites, failed transhepatic cholangiography

Liver Biopsy The development of US and CT has made percutaneous liver biopsy unnecessary in most cases of jaundice caused by extrahepatic obstruction. However, numerous indications for liver biopsy remain. If clinical and laboratory data indicate intrahepatic cholestasis and if dilated bile ducts are not present on US or CT scans, a liver biopsy is usually the next test. Liver biopsy may be useful if diagnostic studies are negative or equivocal, or if parenchymal disease is suspected along with extrahepatic obstruction. A liver biopsy can aid in the diagnosis of intrahepatic cholestasis, storage diseases, unexplained hepatomegaly, and liver infections. Among the cholestatic causes of jaundice in which a liver biopsy may be helpful are hepatitis, cirrhosis, drug-induced cholestasis, primary biliary cirrhosis, and sclerosing cholangitis. Other indications for percutaneous liver biopsy are diseases such as amyloidosis, glycogen storage disease, and liver infections such as tuberculosis, histoplasmosis, and coccidiomycosis. Liver biopsy is a relatively safe procedure. In reviews of very large series of liver biopsies, mortality rates of 0.01% to 0.02% and a serious complication rate of 0.2% to 0.4% have been reported. The most frequent complications of liver biopsy are hemorrhage and bacteremia. This latter problem occurs most frequently in patients with chronic bile duct infections. Percutaneous liver biopsy is contraindicated if the patient is uncooperative or if an uncorrectable coagulation defect is present. If the patient has a prolonged PT or partial thromboplastin time (PTT) or a diminished platelet count, attempts should be made to correct these abnormalities with vitamin K, fresh frozen plasma, or specific component therapy. If the coagulopathy persists and liver biopsy is essential, laparoscopic or open liver biopsy must be considered.

PATIENT MANAGEMENT Once it has been determined that extrahepatic biliary obstruction is the cause of jaundice, a surgeon should become intimately involved in the management of the jaundiced patient. Extrahepatic biliary obstruction, or ‘‘surgical’’ jaundice, may be the result of either benign or malignant disease processes. Jaundice from benign lesions can be caused by congenital defects, by complications of gallstone disease, and from inflammatory or traumatic strictures of the bile duct. Malignant causes of extrahepatic biliary obstruction include cholangiocarcinomas, gallbladder cancers, and cancers of the head of the pancreas, ampulla, or duodenum. Prior to a discussion of the management of common causes of ‘‘surgical’’ jaundice, important issues in the general management of the jaundiced patient will be described.

Chapter 23: The Jaundiced Patient

Assessment of Risk In the past, the only option for the relief of obstructive jaundice had been operative. However, with the development of therapeutic techniques such as percutaneous and endoscopic stenting, balloon dilatation, and ES, many nonoperative options for the relief of obstructive jaundice are now available. The surgeon must determine the safest and most efficacious form of therapy for each individual patient, as well as adequately prepare them for surgery or nonoperative therapeutic interventions. In an effort to determine which patients undergoing biliary surgery were at greatest risk, Pitt et al. (42) analyzed 15 clinical and laboratory parameters in 155 consecutive patients. These authors found that eight factors (advanced age, malignant obstruction, anemia, leukocytosis, hyperbilirubinemia, increased alkaline phosphatase, increased creatinine, and hypoalbuminemia) were associated with an increased risk of death following surgery. Subsequent analyses by Hunt (18), Blarney et al. (43), and Dixon et al. (44) have also confirmed these findings. In these analyses the most consistent predictors of outcome were shown to be the presence of malignancy, elevated serum bilirubin, hypoalbuminemia, and increased serum creatinine. In a 1987 report, Little (45) defined a mortality index that employs albumin, creatinine, and a cholangitis score (Table 5) to predict which patients with jaundice are at increased risk. In a prospective study of 40 patients, Little’s mortality index was 100% accurate in predicting outcome. Thus, the assessment of nutritional status, renal function, and sepsis may be the most important factors to consider when attempting to determine who should or should not be an operative candidate.

Management Issues Patients with obstructive jaundice and those with hepatocellular disease severe enough to cause jaundice are prone to develop many secondary problems. Jaundiced patients are at increased risk for the development of renal failure, GI bleeding, infections, and wound complications (see section ‘‘Pathophysiology of Jaundice’’). Cardiac, pulmonary, and renal function must be considered in every patient undergoing major abdominal surgery. In addition, special attention must be focused on the jaundiced patient’s nutritional status, coagulability, immune function, and presence or absence of biliary sepsis. Patients with chronic liver disease and cirrhosis may also develop ascites and encephalopathy, which may require specific treatment.

Cardiopulmonary In assessing cardiopulmonary status, the patient’s age, history of recent myocardial infarction, presence of congestive heart failure, significant valvular aortic stenosis, or a disturbance of normal cardiac rhythm have all been Table 5 Little’s Mortality Index Mortality index ¼ 0.0016 serum creatinine (mM/L) 0.0227 albumin (g/L) þ 0.0641 cholangitis score þ 0.6935 Cholangitis score: 0 if afebrile 1 if temperature <37.5 C 2 if > 37.5 C without rigors 3 if > 37.5 C with rigors, RUQ pain 4 if fever with shock and/or mental changes (obtundation) An index of 0.4 or greater is associated with a high risk of death. Abbreviation: RUQ, right upper quadrant.

493

correlated with increased operative risk (46). In addition, patients with severe pulmonary disease may not be candidates for extensive abdominal surgery.

Renal Jaundiced patients, especially those with cirrhosis and cholangitis, are at increased risk of developing renal insufficiency. The maintenance of adequate blood volume and the correction of dehydration are extremely important if renal complications are to be avoided. However, fluid management can be quite complex in jaundiced patients. These patients may benefit from invasive hemodynamic monitoring with central venous catheters and, in some cases, pulmonary artery catheters to assist in assessing intravascular volume. Certain oral bile salts have been shown to be efficacious in preventing the development of postoperative renal dysfunction. In a study by Evans et al. (47), two of nine jaundiced patients not receiving oral sodium taurocholate before surgery developed acute renal failure. Creatinine clearance in these patients decreased from a mean value of 85 to 55 mL/min. In contrast, none of the nine jaundiced patients treated before surgery with oral bile salts developed renal failure, with the mean creatinine clearance increasing from 79 to 99 mL/min. In a study by Cahill (17), 54% of 24 jaundiced patients not given oral bile salts before surgery were found to have systemic endotoxemia, which was associated with renal impairment in two-thirds of the cases. In comparison, none of eight jaundiced patients given 500 mg of sodium deoxycholate every eight hours for 48 hours before surgery had portal or systemic endotoxemia. Moreover, none of these eight patients had evidence of renal impairment.

Nutrition Malnutrition is a significant risk factor for surgery in the setting of obstructive jaundice. Halliday et al. (48) noted that patients who died in the postoperative period following surgery for obstructive jaundice had a significant reduction in body weight, mid-arm circumference, total body potassium, and reactivity to skin test antigens. In a study from Italy (49), enteral hyperalimentation was found to significantly decrease operative morbidity and mortality in a group of patients treated with 20 days of preoperative percutaneous biliary drainage. Although most patients with benign biliary problems are adequately nourished, various degrees of malnutrition are frequently present in patients with malignant obstruction. Therefore, patients with malignant obstructive jaundice should be evaluated for evidence of malnutrition and nutritional support instituted if necessary.

Coagulation Patients with obstructive jaundice, cholangitis, or cirrhosis are all prone to excessive intraoperative bleeding. The most common clotting defect in patients with obstructive jaundice is prolongation of the PT, which is usually reversible by the administration of parenteral vitamin K. Patients with severe jaundice and/or cholangitis may also develop DIC, which may require infusion of platelets and fresh frozen plasma. Reversal of DIC also requires control of the underlying sepsis, which usually includes biliary drainage and systemic antibiotics. In cirrhotic patients, clotting abnormalities may be more complicated and include (i) thrombocytopenia secondary to hypersplenism, (ii) prolongation of PTand PTT, and (iii) fibrinolysis. Vitamin K should be administered if the PT is prolonged. If no effect is seen and/or the PTT is also prolonged, fresh

medwedi.ru

494

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

frozen plasma should be given. Thrombocytopenia can usually be managed by intraoperative platelet infusions. If the patient has a shortened clot lysis time and hypofibrinogenemia, epsilonaminocaproic acid may be indicated.

Pruritus Pruritus is often a distressing problem in the jaundiced patient. The exact cause of pruritus remains obscure, but increased bile salts, histamines, and central nervous system opiate receptors have been implicated (50). In some patients, relief from itching can be obtained by bile salt–binding agents such as cholestyramine. Various sedatives and antihistamines can also provide relief of itching in jaundiced patients. However, relief of biliary obstruction remains the most effective method for managing this problem.

Cholangitis Biliary sepsis has also been identified as a major risk factor in the jaundiced patient. Cholangitis occurs when there is partial or complete obstruction of the bile duct, resulting in increased intraluminal pressure, and infected bile behind the obstruction. Patients with cholangitis present with right upper quadrant (RUQ) abdominal pain, fever, and jaundice (Charcot’s triad). Patients with ‘‘toxic’’ cholangitis, Charcot’s triad plus shock and mental confusion (Reynold’s pentad), have significant mortality with appropriate antibiotic therapy alone and, therefore, require emergent biliary decompression. Gigot et al. (51) identified seven prognostic factors that are indications for urgent biliary decompression. These factors included: (i) acute renal failure, (ii) liver abscesses, (iii) cirrhosis, (iv) high malignant stricture, (v) PTC, (vi) female gender, and (vii) advanced age. However, emergent surgical treatment is associated with significant morbidity and mortality. Therefore, both percutaneous and endoscopic biliary drainage have been proposed as effective therapy for the 5% to 10% of patients with cholangitis who are unresponsive to conservative therapy. Lai et al. (52) have shown in a series of 82 patients with severe acute cholangitis that endoscopic drainage is associated with a lower morbidity, 34% versus 66%, and mortality, 10% versus 32%, than operative drainage.

Antibiotic Coverage Because of the depressed immune system that accompanies jaundice, adequate antibiotic coverage needs to be provided for the treatment of cholangitis and prior to any manipulation of the biliary tree. Under normal conditions, bile, the biliary tree, and the liver are sterile. However, biliary stasis, obstruction, biliary–enteric anastomoses, and foreign bodies predispose the biliary system to infection. The organisms most commonly isolated from the biliary tree include Escherichia coli, Klebsiella pneumonia, Enterococcus, and, with increasing frequency, the anaerobe Bacteroides fragilis. Approximately two-thirds of patients with bactobilia will have gram-negative aerobes, and 25% to 30% will have enterococcus in their bile. Anaerobes are found in the bile of older patients, those with cholangitis, and those with complex biliary problems and indwelling tubes (53). Four factors must be considered when choosing antibiotics for the jaundiced patient. These properties include: (i) the antibacterial spectrum of the antibiotic, (ii) serum and liver concentrations, (iii) biliary excretion, and (iv) toxicity. In acute cholangitis, gram-negative aerobes play a major role and are well covered by the second or third generation

cephalosporins, aminoglycosides, ureidopenicillins, carbapenems, and the fluoroquinolones. Ureidopenicillins, such as piperacillin, offer the advantage of gram-positive coverage, including enterococci, and of anaerobic coverage. When combined with a beta-lactamase inhibitor such as tazobactam, piperacillin offers extended and improved coverage against organisms with acquired resistance. Most fluoroquinolones like ciprofloxacin do not cover the anaerobes, and should be used in combination with an agent with anaerobic coverage (i.e., metronidazole). Pseudomonas has been recovered with increased frequency in patients with cholangitis, particularly those with chronic indwelling stents, and should be covered in severely ill patients. Both mezlocillin and piperacillin have performed as well as combination therapy including an aminoglycoside in prospective randomized trials in patients with cholangitis. In patients with biliary obstruction and cholangitis, serum levels of antibiotics are more important than biliary excretion levels. The biliary excretion of antibiotics is significantly reduced in the setting of biliary obstruction, making it difficult to achieve high bile levels of antibiotics in the situations where they are most needed. Therefore, antibacterial specificity and toxicity should be the most important factors to consider in the selection of antibiotic therapy. Prophylactic antibiotics should be administered in all patients undergoing operative or nonoperative manipulations of the biliary tree including cholangiography and sphincterotomy. Meijer et al. (54) published a meta-analysis of 42 controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. They demonstrated that patients undergoing prophylactic antibiotic therapy had a 9% lower incidence of infection. The authors also concluded that second and third generation cephalosporins were no more effective in preventing infection than first generation cephalosporins. Therefore, in uncomplicated cases, a broad spectrum first generation cephalosporin usually provides adequate coverage for prophylaxis.

Preoperative Drainage The preoperative relief of jaundice and the reversal of its systemic effects by either endoscopic or transhepatic biliary decompression has been proposed as a method to decrease the risk of surgery in jaundiced patients. However, several prospective randomized studies have shown that the routine use of preoperative biliary drainage does not reduce operative morbidity or mortality in patients with obstructive jaundice. In addition, a recent meta-analysis also concluded that preoperative biliary drainage increased rather than decreased overall complications (from surgery and the drainage procedure), and provided no benefit in terms of reduced mortality or decreased hospital stay (55). In fact, several studies have documented a higher incidence of infectious complications (wound infection and pancreatic fistula) and even mortality in patients undergoing pancreatic or biliary tract resection after preoperative biliary decompression (55,56). Lai et al. (57) have also documented similar results when endoscopic drainage has been used to decompress the biliary tree preoperatively. Several other studies (58–60) have confirmed these findings (Table 6). Moreover, preoperative biliary tract drainage has been shown to significantly lengthen the hospital stay for these patients. Thus, although retrospective analyses suggested that preoperative drainage might be beneficial, prospective, randomized studies have not supported this finding. A criticism of these prospective studies is that the duration of preoperative drainage (10–18 days) may not have

Chapter 23: The Jaundiced Patient

495

Table 6 Results of Randomized Trials Comparing Preoperative Biliary Drainage Postoperative mortality (%) Authors Hatfield et al. (58) McPherson et al. (59) Pitt et al. (60) Lai et al. (57)

No. of patients

Type of drainage

No drainage

Preoperative drainage

55 65 75 85

Transhepatic Transhepatic Transhepatic Endoscopic

15 19 5 14

14 32 8 15

been long enough to reverse the multiple metabolic and immunologic abnormalities associated with severe obstructive jaundice. Both animal and human studies demonstrate that the recovery of various metabolic and immune functions require at least six weeks after the relief of biliary obstruction (61–64). Similarly, animal studies strongly suggest that return of bile to the intestinal tract has significant advantages over external biliary drainage (65). Although the data suggest that preoperative biliary drainage may not be of any benefit in the routine patient, this maneuver may have some value in selected patients with advanced malnutrition, biliary sepsis, and hilar malignancies requiring liver resection. Preoperatively placed catheters are also of value in the operating room during difficult biliary dissections as well as in aiding in the placement of long-term transhepatic stents.

BENIGN DISEASE Choledocholithiasis The most common benign cause of obstructive jaundice is choledocholithiasis. The incidence of stones in the bile ducts of patients undergoing laparoscopic cholecystectomy is approximately 5% to 10%, and the incidence of retained bile duct stones following cholecystectomy and common bile duct exploration (CBDE) has been 5% to 10%. The most common symptoms of choledocholithiasis are pain, jaundice, and fever. Biliary colic results from intermittent obstruction of the cystic or common duct. With choledocholithiasis, serum bilirubin levels usually range from 2 to 8 mg/dL, with a mean of approximately 5 mg/dL. Fever and chills result from the cholangitis that often accompanies choledocholithiasis. Positive bile cultures are found in almost 90% of patients with primary bile duct stones. Patients with common duct stones require treatment to prevent the complications of choledocholithiasis. These complications include cholangitis, liver abscesses, secondary biliary cirrhosis, and pancreatitis. Prior to the development of endoscopic and laparoscopic techniques, open cholecystectomy with CBDE was the treatment of choice for choledocholithiasis. However, in the era of laparoscopic cholecystectomy and ES, the management of choledocholithiasis has become more controversial. The options for treatment now include: (i) preoperative ERCP and sphincterotomy followed by laparoscopic cholecystectomy, (ii) open cholecystectomy and open CBDE, (iii) laparoscopic cholecystectomy with laparoscopic CBDE, or (iv) laparoscopic cholecystectomy and postoperative ERCP and sphincterotomy. ES is accepted as a valuable technique in the management of choledocholithiasis in patients who previously have undergone cholecystectomy. ES is a relatively safe and effective procedure for the removal of common duct stones and can achieve a clearance rate of almost 90% (66). In recent series, procedure-related mortality occurs in less than 1%

of patients, with major postprocedure morbidity averaging 8% (Table 7). The long-term complication rate is 13% and includes sphincter stenosis and recurrent stones (67). Until recently, the option for the management of choledocholithiasis discovered intraoperatively was either postoperative ERCP or open bile duct exploration. With the development of new equipment and techniques for laparoscopic common duct exploration, open surgery and sphincterotomy may be avoidable. Laparoscopic duct exploration can be accomplished by intubating the cystic duct or by creating a choledochotomy. In the transcystic duct approach, the cystic duct is dilated, and common duct stones can be retrieved with a basket under fluoroscopic guidance or direct vision using a flexible choledochoscope. Laparoscopic choledochotomy is technically more challenging, but has the advantage of being able to extract larger impacted stones and to retrieve stones from the common hepatic duct. The success rate for laparoscopic CBDE is approximately 85%. In addition, prospective randomized trial has shown that laparoscopic CBDE at the time of laparoscopic cholecystectomy is as effective as ERC at achieving stone clearance (68). The procedure-related complication rates are similar with both approaches, but the laparoscopic bile duct exploration is associated with a significantly shorter length of stay (Table 8). As surgeons gain more experience with laparoscopic techniques and appropriate equipment becomes available, more patients may be able to undergo laparoscopic bile duct exploration for the management of choledocholithiasis.

Bile Duct Strictures Benign bile duct strictures can be caused by pancreatitis, primary sclerosing cholangitis, acute cholangitis, autoimmune disorders, or following either blunt or penetrating abdominal trauma. However, the vast majority of benign strictures follow iatrogenic bile duct injury, most commonly during laparoscopic cholecystectomy. The majority Table 7 Mortality, Morbidity, and Late Complications of Endoscopic Sphincterotomy Complications Mortality Major morbidity Hemorrhage Pancreatitis Cholangitis/impaction Duodenal perforation Emergency surgery Unsuccessful procedure Late complications Gallbladder problems Recurrent stones Sphincter stenosis

medwedi.ru

Mean (%)

Range (%)

1.1 8.2 2.8 2.7 1.8 1 1.5 9.8

0.4–1.7 4.4–8.7 1.8–5 0.6–3.3 0.8–2.3 0.2–1.5 0.4–2.4 3.4–14

14.9 5.9 3

14.7–15.2 2.8–20.5 0.8–3.7

496

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 8 Laparoscopic Bile Duct Exploration vs. Postoperative ERC for Bile Duct Stones

Lap CBDE Post op ERC þ ES

N

Primary duct clearance (%)

Secondary duct clearance (%)

Morbidity (%)

Mean hospital length of stay (days)

40 40

75 75

100 93

18 15

1.0 3.5

Abbreviations: CBDE, common bile duct exploration; ERC þ ES, endoscopic retrograde cholangiography plus endoscopic sphincterotomy. Source: From Ref. 68.

of injuries are recognized intraoperatively or during the early postoperative period, and with appropriate management, the long-term results are acceptable. However, with unrecognized or inappropriately managed biliary strictures, recurrent cholangitis, secondary biliary cirrhosis, and portal hypertension may eventually develop. The exact incidence of bile duct injury during open cholecystectomy has been estimated at 0.1% to 0.2%. With the advent of laparoscopic cholecystectomy, this rate has increased to approximately 0.3% to 0.5%. Factors such as acute inflammation, anatomical variants, excessive bleeding, obesity, lack of adequate assistance, and the surgeon’s experience have been associated with bile duct injuries during laparoscopic cholecystectomy. Bile duct strictures can also occur at sites of previous biliary–enteric anastomoses. Ischemia of the anastomosis from excessive dissection of the duct prior to anastomosis is a likely cause of these strictures. The clinical presentation of postoperative strictures is variable, with nearly 80% being identified within one year of the initial operation. Patients developing strictures early after cholecystectomy usually present either with progressive elevations in serum bilirubin and alkaline phosphatase or with bile leaks, whereas patients presenting months or years after surgery often present with cholangitis. Excessive pain in the early postoperative period may also be an indication that bile is leaking. The diagnostic evaluation in the jaundiced patient with a suspected bile duct injury begins with an abdominal CT scan or US. This evaluation will demonstrate the presence of intrahepatic and extrahepatic ductal dilation. These studies also can provide some anatomic information about the level of the injury, whether the ductal system to one segment or lobe is affected or whether the entire intrahepatic ductal system is involved. In patients with intrahepatic ductal dilation from a biliary stricture, PTC and placement of a transhepatic stent will decompress the biliary tree, relieve the jaundice, and define the proximal extent of the injury, which is critical in determining the appropriate treatment. Prior to the definitive management of benign bile duct strictures, adequate control of biliary sepsis by either endoscopic or transhepatic biliary drainage and optimal nutritional status are important. Once these goals have been accomplished, three options for the management of the stricture include: (i) surgical excision with reconstruction, (ii) percutaneous balloon dilatation, and (iii) endoscopic dilatation and stenting. The goal of surgical therapy is to re-establish the flow of bile from the liver to the proximal intestine and to prevent the formation of a recurrent stricture. These goals are best achieved by the creation of a Roux-en-Y biliary–enteric anastomosis (Fig. 9). Principles to be observed in the surgical repair of bile duct strictures include complete resection of the stricture, trimming back of the proximal bile duct to expose healthy biliary mucosa, and the creation of a

tension free mucosa-to-mucosa anastomosis to a 40 to 60 cm Roux-en-Y jejunal limb (69). Acceptable results are achieved in the majority of patients undergoing operative repair of bile duct stricture or injury. The operative mortality associated with repair of a bile duct injury has been less than 1% in several large series, and common complications have included cholangitis, subhepatic or subphrenic abscess, bile leak, and hemobilia. Long-term follow-up is necessary to fully evaluate the results of either operative or nonoperative bile duct injury management. Restenosis of a biliary–enteric anastomosis can manifest itself many years following operative repair. Two-thirds of recurrences, however, will become symptomatic within two years after repair. In one large series, 91% of patients were free of jaundice and cholangitis after undergoing operative repair of a laparoscopic bile duct injury (70). Several factors may influence the eventual success of biliary reconstruction for bile duct injuries. More proximal strictures (at or proximal to the hepatic duct bifurcation) have a lower success rate, when compared with distal strictures (distal to the hepatic duct bifurcation). Percutaneous balloon dilation and stenting also has a significantly lower success rate (64%) than operative repair.

Figure 9 Postoperative cholangiogram showing bilateral Roux-en-Y hepaticojejunostomies in a patient with a bile duct injury secondary to laparoscopic cholecystectomy.

Chapter 23: The Jaundiced Patient

Nonoperative options for the management of a benign bile duct strictures are percutaneous and endoscopic balloon dilatation and stenting. Both techniques involve intubating the biliary system, from above in the case of percutaneous dilatation and from below with endoscopic dilatation, crossing the stricture with a guidewire under fluoroscopic guidance, inflating an angioplasty-type balloon to dilate the stricture, and then stenting the lesion. With both techniques, patients often require multiple stricture dilatations. Results for both procedures are similar with success rates ranging between 55% to 87% for percutaneous dilatations, and 53% to 96% for endoscopic dilatation (71). The complication rate for transhepatic dilatation ranges between 20% and 30% and includes cholangitis, bleeding, and bile leaks. The mortality rate is 1%. The complications associated with endoscopic balloon dilatation are similar to that reported for ES, with cholangitis, pancreatitis, bleeding, and perforation of the duodenum occurring in 8% to 10% of patients. When analyzing data on the efficacy of nonoperative stricture management, the length of follow-up is very important. Surgical experience has demonstrated that recurrence of strictures may occur many years after treatment. In a report from the Johns Hopkins Hospital, Pitt et al. (72) compared the results of operative stricture repair with Roux-en-Y hepaticojejunostomy and long-term stenting in 25 patients, with percutaneous balloon dilatation in 20 patients. Eighty-eight percent of patients managed surgically had a successful outcome at 57 months, whereas only 55% of patients managed with dilatation had a good outcome at 59 months. Therefore, the authors recommended that surgical therapy should be offered to young, healthy patients, and that nonoperative therapy be reserved for patients who have a prohibitive operative risk or have a short life expectancy.

MALIGNANT DISEASE Periampullary Carcinoma Periampullary cancers are a group of malignant neoplasms that cause jaundice by obstructing the distal common bile duct. Adenocarcinoma of the head of the pancreas accounts for 50% to 60% of all periampullary cancers, whereas carcinoma of the ampulla of Vater (20–30%), distal bile duct (10–15%), and duodenum (10%) account for the rest. Patients usually present with jaundice, acholic stools, dark urine, pruritus, and weight loss. The presence of a palpable nontender gallbladder in a jaundiced patient suggests neoplastic obstruction of the distal common bile duct. Serum bilirubin levels are usually higher than those seen with benign biliary obstruction and may exceed 20 mg/dL. The best available tumor markers are carcinoembryonic antigen and carbohydrate antigen (CA) 19–9. A CA-19–9 value greater than 200 in the absence of jaundice is 95% accurate in predicting malignancy. CA-19–9 levels should be obtained preoperatively and followed postoperatively as an indication of recurrent tumor. Postresection increase in these tumor markers often precede the radiographic demonstration of recurrent malignancy. Patients who are suspected of having a periampullary neoplasm should undergo thin section dynamic contrast–enhanced CT scanning. The CT scan can document dilated intrahepatic and extrahepatic bile ducts and localize a periampullary mass. The presence of a dilated distal pancreatic duct in addition to a dilated distal bile duct suggests pancreatic cancer. The CT scan can also demon-

497

strate local tumor extension, involvement of contiguous structures, distant metastasis, or invasion of the mesenteric and portal vessels. MRI offers no advantage over CT in the diagnoses of periampullary cancers. However, EUS can play a role in the preoperative staging of periampullary neoplasms. The main uses for EUS are for the detection of small pancreatic lesions (< 2 cm) and for detecting lymph node and vascular involvement. EUS is not effective in assessing metastatic disease to the liver. In patients that require a tissue diagnosis (poor operative candidates or patients undergoing neoadjuvant therapy), EUS-guided FNA can be used to acquire tissue samples for cytologic analysis. Traditionally, the next step in the evaluation of the jaundiced patient has been ERCP. The endoscopic approach allows for the visualization of the duodenum and ampulla, and biopsies can be performed if necessary. In addition, ERCP allows for direct imaging of the pancreatic duct. The sensitivity of ERCP for the diagnosis of pancreatic cancer approaches 90%. The finding of a long irregular stricture in an otherwise normal pancreatic duct is highly suggestive of a pancreatic cancer. Although ERCP is reliable in confirming the clinical suspicion of pancreatic cancer, it should not be used routinely. Diagnostic ERCP should be reserved for patients with presumed periampullary cancer and obstructive jaundice in whom no mass is demonstrated on CT scanning, the symptomatic but nonjaundiced patient without an obvious pancreatic mass, or the patient with chronic pancreatitis in whom the development of a pancreatic mass is suspected based on clinical determination or the development of jaundice. Routine preoperative biliary drainage should be avoided, and its use limited to patients with biliary sepsis secondary to cholangitis and in patients with major nutritional deficiency states and high-grade biliary obstructions. As mentioned earlier, several randomized prospective trials have shown that routine preoperative biliary decompression does not reduce operative mortality and may prolong hospital stay. Surgical resection offers the only chance for long-term survival from periampullary malignancies. The operative management of periampullary cancer consists of two phases: first, assessing tumor resectability and then, if the tumor is resectable, completing a pancreaticoduodenectomy. After opening the abdomen, a careful search for tumor outside the limits of a pancreaticoduodenal resection should be carried out. The liver, omentum, and peritoneal surfaces are inspected and palpated, and suspicious lesions biopsied and submitted for frozen section analysis. Regional lymph nodes are next evaluated for the presence of tumor involvement. Tumor present in the periaortic lymph nodes of the celiac axis indicates that the tumor is beyond the limits of normal resection. However, the presence of tumor-bearing lymph nodes that normally would be incorporated within the resection specimen do not constitute a contraindication to resection. Once distant metastases have been excluded, an assessment is made as to whether the primary tumor is resectable. Local factors that preclude pancreaticoduodenal resection include retroperitoneal extension of the tumor to involve the inferior vena cava or aorta, or direct involvement or encasement of the superior mesenteric artery, superior mesenteric vein, or portal vein. If no contraindication to resection is present, either a pylorus-preserving pancreaticoduodenectomy or a classic Whipple procedure can be performed. Palliative surgery for periampullary cancer is appropriate in patients with unresectable disease discovered at

medwedi.ru

498

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Nonoperative methods of palliation should be considered in patients in whom preoperative staging suggests distant metastatic disease or a locally unresectable tumor, patients who are not candidates for operative intervention, or in patients not expected to survive for more than three months. Long-term survival for periampullary cancers is dependent on the type of cancer, stage, and resection status. Data from The Johns Hopkins Hospital in 242 patients undergoing pancreaticoduodenectomy for periampullary carcinoma shows a five-year actual survival of 15% for pancreatic primaries, 27% for distal bile duct primaries, 39% for ampulla primaries, and 59% for duodenal primaries (81). Patients with unresected tumors have an expected survival between six and nine months.

exploration or in good-risk patients in whom tumor-related symptoms are poorly alleviated through nonoperative means. Palliative surgery is designed to (i) relieve biliary obstruction, (ii) prevent gastric outlet obstruction, and (iii) palliate tumor-associated pain. Recent studies (73,74) have shown that surgical palliation of jaundice with either a choledocho- or hepaticojejunostomy can be accomplished safely, with a mortality rate less than 3%, an overall morbidity rate of 30% to 40%, and a recurrent jaundice rate of 3%. In patients without symptoms of gastric outlet obstruction, a debate has existed as to whether or not to perform a prophylactic gastric bypass at the time of biliary bypass. Surgeons that do not perform prophylactic bypass feel that it needlessly increases postoperative length of stay and can be associated with delayed gastric emptying and increased morbidity and mortality. However, data from a recent prospective randomized trial of prophylactic gastrojejunostomy in patients with unresectable cancer does not support this view (75). In this study, 44 patients were randomized to a gastrojejunostomy, and 43 did not undergo gastric bypass. No mortality occurred in either group. In addition, no differences existed in either the complication rate or the postoperative length of stay. However, 19% of the nonbypassed patients developed late duodenal obstruction (P < 0.05). Therefore, prophylactic gastrojejunostomy should be performed in patients undergoing surgical palliation for unresectable periampullary carcinoma. The management of pain in patients dying of carcinoma of the pancreas is one of the most important aspects of their care. In a prospective randomized trial, Lillemoe et al. (76) have demonstrated that the intraoperative injection of 50% alcohol into the celiac plexus at the time of surgery can significantly reduce and prevent the development of pain in patients with unresectable cancer. In patients with malignant obstruction of the biliary tract, the placement of endoscopic or percutaneous biliary stents have been proposed as alternatives to surgical palliation. Four prospective randomized trials comparing nonoperative biliary stenting with surgical biliary bypass for malignant obstructive jaundice have been published (77–80). As Table 9 demonstrates, both operative and nonoperative techniques are equally effective in relieving jaundice. Nonoperative therapy, however, was associated with a lower complication rate and shorter initial hospital stays. Advocates of surgical palliation criticize these studies on two counts. First, the 30-day hospital mortality rate for the surgical arms of these studies was high, ranging from 14% to 24%, compared to more recent series, with mortality rates of 2% to 8%. The second reason that surgical palliation is favored by some authors is that nonoperative palliation is frequently associated with the late complications of recurrent jaundice and gastric-outlet obstruction.

Cholangiocarcinoma Cholangiocarcinoma can occur in any portion of the biliary tree. A clinically useful classification system of cholangiocarcinoma divides them into intrahepatic, perihilar, distal, and diffuse types (82). The intrahepatic tumors are managed similarly to primary liver tumors, and the distal cholangiocarcinomas are managed with pancreaticoduodenectomy. The perihilar, or Klatskin, tumors comprise 60% to 80% of all cholangiocarcinomas and are the most difficult to manage. Over 90% of cholangiocarcinomas present with jaundice. Serum bilirubin in cases of malignant jaundice can be markedly elevated, attaining levels between 20 and 30 mg/dL. The radiological evaluation of patients with cholangiocarcinoma should delineate the overall extent of the tumor including involvement of the bile ducts, liver, portal vessels, and distant metastases. The initial radiographic studies consist of either abdominal US or CT scanning. Intrahepatic cholangiocarcinomas are easily visualized on CT scans; however, perihilar and distal tumors are often difficult to visualize on US and standard CT scan. A hilar cholangiocarcinoma will give a picture of a dilated intrahepatic biliary tree and a normal or collapsed gallbladder and extrahepatic biliary tree. Distal tumors will lead to dilation of the gallbladder and both the intra- and extrahepatic biliary tree. After documentation of bile duct dilation, biliary anatomy has been traditionally defined cholangiographically through either the percutaneous transhepatic or the endoscopic retrograde routes. The most proximal extent of the tumor is the most important feature in determining resectability in patients with perihilar tumors, and the percutaneous route is favored in these patients because it defines the proximal extent of tumor involvement most reliably. Recently, magnetic resonance cholangiography (MRC) has documented diagnostic accuracy comparable to percutaneous and endoscopic cholangiography. Curative treatment of patients with cholangiocarcinoma is only possible with complete resection. The

Table 9 Results of Operative vs. Nonoperative Palliation of Malignant Obstructive Jaundice Jaundice relief (%) Author Bornman et al. (77) Shepard et al. (78) Andersen et al. (79) Smith et al. (80)

Mortality (%)

Complications (%)

Recurrent jaundice (%)

Late duodenal obstruction (%)

N

Stent

Surg

Stent

Surg

Stent

Surg

Stent

Surg

Stent

Surg

Stent

50 48 50 201

Transhepatic Endoscopic Endoscopic Endoscopic

76 92 88 91

84 82 96 92

20 20 24 14

8 9 20 3

32 56 20 29

28 30 36 11

16 0 – 2

38 30 – 36

0 4 0 7

14 9 0 17

P<0.05 vs. surgical palliation.

Chapter 23: The Jaundiced Patient

100 90

Margin (–) resection Margin (+) resection

80 70 % Survival

operative approach depends on the site and extent of the tumor. Patients with perihilar tumors involving the bifurcation or proximal common hepatic duct (bismuth type I or II) that have no vascular invasion are candidates for local tumor excision. Biliary enteric continuity is restored with bilateral hepaticojejunostomies (82,83). If preoperative evaluation suggests involvement of the right or left hepatic duct (bismuth type IIIa or IIIb), right or left hepatic lobectomy, respectively, should be planned. To achieve negative margins, resection of the adjacent caudate lobe may be required (83). A greater percentage of margin-negative resections has been achieved with an increased use of combined bile duct and hepatic resection. However, these more extensive procedures have been associated with an increase in operative morbidity and mortality. For patients with resectable distal cholangiocarcinoma, pancreaticoduodenectomy is the optimal procedure. Surgical exploration should be undertaken in ‘‘goodrisk’’ patients without evidence of metastatic or locally unresectable disease; however, intraoperatively, more than half of these patients are found to have either peritoneal or hepatic metastases or, more likely, locally unresectable disease (82–84). Selective use of laparoscopy in patients with locally advanced but potentially resectable perihilar cholangiocarcinoma may avoid laparotomy in some patients with metastatic disease (85). In patients with extensive metastatic disease, preoperative biliary stents may be left in place. However, a cholecystectomy should be performed to avoid the risk of acute cholecystitis, which occurs in patients with long-term indwelling biliary stents. In patients with locally advanced unresectable perihilar tumors, several operative approaches are available for palliation including a Roux-en-Y choledochojejunostomy with intraoperative placement of silastic biliary catheters or a segment III or V cholangiojejunostomy. Most distal bile duct tumors are resectable; but if resection is not possible due to vascular encasement, cholecystectomy, Roux-en-Y hepaticojejunostomy proximal to the tumor, and a gastrojejunostomy to prevent gastric outlet obstruction should be performed. Patients with unequivocal evidence of unresectable cholangiocarcinoma at initial evaluation are palliated nonoperatively. Nonoperative palliation can be achieved both endoscopically and percutaneously. Percutaneous biliary drainage has several advantages over endoscopic management in patients with perihilar cholangiocarcinoma, whereas endoscopic palliation is the preferred approach in patients with distal cholangiocarcinoma. More recently, metallic stents have been used to palliate patients with malignant biliary obstruction. These stents remain patent longer than plastic stents and require fewer subsequent manipulations. A study comparing percutaneous and operative palliation for unresectable hilar cholangiocarcinoma demonstrated that the hospital mortality was lower (7% vs. 14%) and the mean survival significantly longer (eight months vs. five months) for the surgically treated group (86). Long-term survival in patients with cholangiocarcinoma is highly dependent on the stage of disease at presentation and on whether the patient is treated by a palliative procedure or complete tumor resection. Overall five-year survival for patients with resectable perihilar tumors has been only 10% to 20%, but may be as high as 24% to 46% in patients with negative microscopic margins (Fig. 10) (83,84,87). Patients with resectable distal bile duct cancer have the highest rate of resection. Even with multimodality adjuvant therapy, median survival for patients with unresectable perihilar tumors varies between five and eight months.

499

60 50 40 30 20 10 0 0

4

8 Years

12

16

Figure 10 Actuarial survival for patients undergoing margin-negative vs. margin-positive resection for perihilar cholangiocarcinoma. Source: From Ref. 83.

SUMMARY Over the past few decades, tremendous strides have been made in our ability to care for the jaundiced patient. Clinicians now have a better understanding of normal bilirubin metabolism and can classify the diseases that cause jaundice as defects in normal metabolism. Similarly, scientists are beginning to elucidate the multiple pathophysiological effects of jaundice and, thus, explain why jaundiced patients are at risk for increased morbidity and mortality during surgery. Our ability to accurately diagnose the cause of jaundice has increased with the development of noninvasive and invasive imaging techniques such as ultrasonography, CT scanning, EUS, MRC, transhepatic cholangiography, and ERC. These advances in diagnostic imaging have led to new and effective nonoperative therapeutic options for the relief of jaundice. ES, balloon dilatation, and the placement of endoprostheses for obstructive jaundice can all be performed in the jaundiced patient as primary therapy or as an adjunct to surgical therapy. However, the surgeon must decide which options will be the most efficacious, safe, and cost-effective in the diagnosis and treatment of each patient with jaundice.

REFERENCES 1. Mallet-Guy P. Value of preoperative manometric and roentgraphic examination in the diagnosis of pathological changes and functional disturbances of the biliary tract. Surg Gynecol Obstet 1952; 94:385–393. 2. Blenkharn JI, Habib N, Mok D, et al. Decreased biliary excretion of Piperacillin after percutaneous relief of extrahepatic obstructive jaundice. Antimicrob Agents Chemother 1985; 28: 778–780. 3. Patel T, Bronk SF, Gores GJ. Increase in intracellular magnesium promotes glycodeoxycholate-induced apoptosis in rat hepatocytes. J Clin Invest 1994; 94:2183–2192. 4. Holman JM, Rikkers LF. Biliary obstruction and host defense failure. J Surg Res 1982; 32:208–213. 5. Puntis MCA, Jiang WG. Plasma cytokine levels and monocyte activation in patients with obstructive jaundice. J Gastroenterol Hepatol 1996; 11:7–13. 6. Nehez L, Anderson R. Compromise of immune function in obstructive jaundice. Eur J Surg 2002; 168:315–328.

medwedi.ru

500

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

7. Koeppel TA, Trauner M, Baas JC, et al. Extrahepatic biliary obstruction impairs microvascular perfusion and increases leukocyte adhesion in rat liver. Hepatology 1997; 26:1085–1091. 8. Jacob G, Nassar N, Hayam G, et al. Cardiac function and responsiveness to a-adrenoceptor agonists in rats with obstructive jaundice. Am J Physiol 1993; 265:G314–G320. 9. Melzer E, Krepel Z, Bar-Meir S. Recovery of pressor response to norepinephrine following relief of the obstructed common bile duct in the rat. Res Exp Med 1993; 193:163–167. 10. Ma Z, Zhang Y, Huet PM, Lee SS. Differential effects of jaundice and cirrhosis on ct-adrenoceptor signaling in three rat models of cirrhotic cardiomyopathy. J Hepatol 1999; 30:485–491. 11. Lumlertgul D, Boonyaprapa S, Bunnachak D, et al. The jaundiced heart: evidence of a blunted response to positive inotropic stimulation. Ren Fail 1991; 13:15–22. 12. Padillo J, Puente J, Gomez M, et al. Improved cardiac function in patients with obstructive jaundice after internal biliary drainage: hemodynamic and hormonal assessment. Ann Surg 2001; 234:652–656. 13. Fogarty BJ, Parks RW, Rowlands BJ, Diamond T. Renal dysfunction in obstructive jaundice. Br J Surg 1995; 82:877–884. 14. Pereira JA, Torregrosa MA, Martinez-Rodenas, et al. Increased cardiac endocrine activity after common bile duct ligation in the rabbit:atrial endocrine cells in obstructive jaundice. Ann Surg 1994; 219:73–78. 15. Green J, Better OS. Circulatory disturbance and renal dysfunction in liver disease and in obstructive jaundice. Isr J Med Sci 1994; 30:48–65. 16. Hunt DR, Allison ME, Prentice CR, Blumgart, LH. Endotoxemia, disturbance of coagulation, and obstructive jaundice. Am J Surg 1982; 144:325–329. 17. Cahill CJ. Prevention of postoperative renal failure in patients with obstructive jaundice: the role of bile salts. Br J Surg 1983; 70:590–595. 18. Hunt DR. The identification of risk factors and their application to the management of obstructive jaundice. Aust NZ J Surg 1980; 50:476–480. 19. Cainzos M, Alcalde JA, Potel J, Puente JL. Hyperbilirubinemia, jaundice and anergy. Hepatogastroenterology 1992; 39:330–332. 20. Thompson JE Jr, Pitt HA, Doty JE, Coleman J, Irving C. Broad spectrum penicillin as adequate therapy for acute cholangitis. Surg Gyn Obstet 1990; 171:275–282. 21. Andy OJ Jr, Grogan JB, Griswold JA, Scott-Conner CE. Peritoneal neutrophil chemotaxis is impaired in biliary obstruction. Am Surg 1992; 58:28–31. 22. Scott-Conner CE, Grogan JB, Scher KS, Bernstein JM, BaileyBerk C. Impaired bacterial killing in early obstructive jaundice. Am J Surg 1993; 166:308–310. 23. Deitch EA, Sittig K, Li M, Berg R, Specian RD. Obstructive jaundice promotes bacterial translocation from the gut. Am J Surg 1990; 159:79–84. 24. Grande L, Garcia-Valdecasas JC, Fuster J, Visa J, Pera C. Obstructive jaundice and wound healing. Br J Surg 1990; 77:440–442. 25. Koyama K, Takagi Y, Ito K, Sato T. Experimental and clinical studies on the effect of biliary drainage in obstructive jaundice. Am J Surg 1981; 142:293–299. 26. O’Connor KW, Snodgrass PJ, Swonder JE, et al. A blinded prospective study comparing four current noninvasive approaches in the differential diagnosis of medical vs. surgical jaundice. Gastroenterology 1983; 84:1498–1504. 27. Thomas MJ, Pellegrini CA, Way LW. Usefulness of diagnostic tests for biliary obstruction. Am J Surg 1982; 144:102–108. 28. Baron RL, Stanley RJ, Lee JK, et al. A prospective comparison of the evaluation of biliary obstruction using computed tomography and ultrasonography. Radiology 1982; 145:91–98. 29. Taylor KJW, Rosenfield AT, Spiro HM. Diagnostic accuracy of gray-scale ultrasonography for the jaundiced patient: a report of 275 cases. Arch Intern Med 1979; 139:60–63. 30. Pedrosa CS, Casanova R, Rodriquez R. Computed tomography in obstructive jaundice: the level of obstruction. Radiology 1981; 139:627–634.

31. Fulcher AS. MRCP and ERCP in the diagnosis of common bile duct stones. Gastrointest Endosc 2002; 56:s178-s182. 32. Lopera JE, Soto JA, Munera F. Malignant hilar and perihilar biliary obstruction: use of MR cholangiography to define the extent of ductal involvement and plan percutaneous interventions. Radiology 2001; 220:90–96. 33. Rosch T, Dittler HJ, Fockens P, et al. Major complications of endoscopic ultrasonography: results of a survey of 42105 cases. Gastrointest Endosc 1993; 39:341. 34. Vilgrain V, Palazzo L. Choledocholithiasis: role of US and endoscopic ultrasound. Abdom Imaging 2001; 26:7–14. 35. Dye CE, Waxman I. Endoscopic ultrasound. Gastroenterol Clin N Am 2002; 31:863–879. 36. Gold RP, Casarella WJ, Stern G, Seaman WB. Transhepatic cholangiography: the radiological method of choice in suspected obstructive jaundice. Radiology 1979; 133:39–44. 37. Gibbons CP, Griffiths GJ, Cormack A. The role of percutaneous transhepatic cholangiography and grey-scale ultrasound in the investigation and treatment of bile duct obstruction. Br J Surg 1983; 70:494–496. 38. D’Agostino HB, et al. Imaging and radiologic intervention of the biliary tree. In: Braasch JW, Tompkins RK, eds. Surgical Diseases of the Biliary Tract and Pancreas. St. Louis: MosbyYear Book, 1994:68–114. 39. Pasanen PA, Partanen K, Pikkarainen P, Alhava E, Pirinen A, Janatuinen E. Diagnostic accuracy of ultrasound, computed tomography, and endoscopic retrograde cholangiopancreatography in the detection of obstructive jaundice. Scand J Gastroenterol 1991; 28:185–189. 40. Bilbao MK, Dotter CT, Lee TG, Katon RM. Complications of endoscopic retrograde cholangiopancreatography (ERCP): a study of 10,000 cases. Gastroenterology 1976; 70:314–320. 41. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996; 335: 909–918. 42. Pitt HA, Cameron JL, Postier RG, Gadacz TR. Factors affecting mortality in biliary tract surgery. Am J Surg 1981; 141:66–72. 43. Blamey SL, Fearon KCH, Gilmour VH, Osborne DH, Carter DCI. Prediction of risk in biliary surgery. Br J Surg 1983; 70: 535–538. 44. Dixon JM, Armstong CP, Duffy SW, Davies GC. Factors affecting morbidity and mortality after surgery for obstructive jaundice: a review of 373 patients. Gut 1983; 24:845–852. 45. Little JM. A prospective evaluation of computerized estimates of risk in the management of obstructive jaundice. Surgery 1987; 102:473–476. 46. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977; 297:845–850. 47. Evans HJR, Torrealba V, Hudd C, Knight M. The effect of preoperative bile salt administration on postoperative renal function in patients with obstructive jaundice. Br J Surg 1982; 69:706–708. 48. Halliday AW, Benjamin IS, Blumgart LH. Nutritional risk factors in major hepatobiliary surgery. J Parent Ent Nutr 1988; 12:43–48. 49. Foschi D, Cavagna G, Callioni F, Morandi E, Rovati V. Hyperalimentation of jaundiced patients on percutaneous transhepatic biliary drainage. Br J Surg 1986; 73:716–719. 50. Gillespie DA, Vickers CR. Pruritus and cholestasis: therapeutic options. J Gastroenterol Hepatol 1993; 8:168–173. 51. Gigot JF, Leese T, Dereme T, Coutinho J, Castaing D, Bismuth H. Acute cholangitis: multivariate analysis of risk factors. Ann Surg 1989; 209:435–438. 52. Lai ECS, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med 1992; 326:1582–1586. 53. Lippset PA, Pitt HA. Biliary infection: prophylaxis and treatment. In: Toouli J, ed. Surgery of the Biliary Tract. Edinburgh: Churchville Livingstone, 1993:59–70. 54. Meijer WS, Schmitz PIM, Jeekel J. Meta-analysis of randomized, controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Surgery 1990; 70:283–290. 55. Sewnath ME, Karsten TM, Prins MH, Rauws EJA, Obertop H, Gouma DJ. Meta-analysis on the efficacy of preoperative

Chapter 23: The Jaundiced Patient

56.

57.

58. 59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69. 70.

71.

biliary drainage for tumors causing obstructive jaundice. Ann Surg 2002; 236:17–27. Sohn TA, Yeo CJ, Cameron JL, Pitt HA, Lillemoe KD. Do preoperative biliary stents increase postpancreaticoduodenectomy complications? J Gastrointest Surg 2000; 4:258–268. Lai ECS, Mok FPT, Fan ST, et al. Preoperative endoscopic drainage for malignant obstructive jaundice. Br J Surg 1994; 81:1195–1198. Hatfield AR, Tobias R, Terblanche J, et al. Preoperative external biliary drainage in obstructive jaundice. Lancet 1982; 2:896–899. McPherson GAD, Benjamin IS, Hodgson HJF, Bowley NB, Allison DJ, Blumgart LH. Preoperative percutaneous transhepatic biliary drainage: the results of a controlled trial. Br J Surg 1984; 71:371–375. Pitt HA, Gomes AS, Lois JF, Mann LL, Deutsch LS, Longmire WP Jr. Does preoperative percutaneous biliary drainage reduce operative risk or increase hospital cost? Ann Surg 1985; 201:545–552. Clements WD, Halliday MI, McCaigue MD, Barclay RG, Rowlands BJ. Effects of extrahepatic obstructive jaundice on Kuppfer cell clearance capacity. Arch Surg 1993; 128:200–204. Greve JW, Gouma DJ, Soeters PB, Buurman WA. Suppression of cellular immunity of obstructive jaundice is caused by endotoxins: a study with germ-free rats. Gastroenterology 1990; 98:478–485. Kennedy JA, Kirk SJ, McCrory DC, Halliday MI, Barclay GR, Rowlands BJ. Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat. Br J Surg 1994; 81:1199–1201. Thompson RL, Hoper M, Diamond T, Rowlands BJ. Development and reversibility of T lymphocyte dysfunction in experimental obstructive jaundice. Br J Surg 1990; 77:1229–1232. Roughneen PT, Gouma DJ, Kulkarni AD, Fanslow WF, Rowlands BJ. Impaired specific cell-mediated immunity in experimental biliary obstruction and its reversibility by internal biliary drainage. J Surg Res 1986; 41:113–125. Cotton PB, Vallon AG. British experience with duodenoscopic sphincterotomy for removal of bile duct stones. Br J Surg 1981; 68:373–375. Hawes R, Cotton PB, Vallon AG. Follow-up 6 to 11 years after duodenoscopic sphincterotomy for stones in patients with prior cholecystectomy. Gastroenterology 1990; 98:1008–1012. Rhodes M, Sussman L, Cohen L, Lewis MP. Randomized trial of laparoscopic exploration of common bile duct versus postoperative endoscopic retrograde cholangiography for common bile duct stones. Lancet 1998; 351:159–161. Lillemoe KD, Pitt HA, Cameron JL. Current management of benign bile duct strictures. Adv Surg 1992; 25:119–174. Lillemoe KD, Melton GB, Cameron JL, et al. Postoperative bile duct strictures: management and outcome in the 1990s. Ann Surg 2000; 232:430–441. Moote DJ, Malone DE. Non-operative management of benign bile duct strictures. In: Toouli J, ed. Surgery of the Biliary Tract. Edinburgh: Churchville Livingstone, 1993:327–348.

501

72. Pitt HA, Kaufman SL, Coleman J, White RI, Cameron JL. Benign postoperative biliary strictures: Operate or dilate? Ann Surg 1989; 210:417–427. 73. Lillemoe KD, Sauter PK, Pitt HA, Yeo CJ, Cameron JL. Current status of surgical palliation of periampullary carcinoma. Surg Gynecol Obstet 1993; 176:1–10. 74. van Wagensveld BA, Coene PP, van Gulik TM, Rauws EA, Obertop H, Gouma DJ. Outcome of palliative biliary and gastric bypass surgery for pancreatic head carcinoma in 126 patients. Br J Surg 1997; 84:1402–1406. 75. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg 1999; 230:322–330. 76. Lillemoe KD, Cameron JL, Kaufman HS, Yeo CJ, Pitt HA, Sauter PK. Chemical splanchnicectomy in patients with unresectable pancreatic cancer: a prospective randomized trial. Ann Surg 1993; 217:447–457. 77. Bornman PC, Harries-Jones EP, Tobias R, Van Stiegmann G, Terblanche J. Prospective controlled trial of transhepatic biliary endoprosthesis versus bypass surgery for incurable carcinoma of head of pancreas. Lancet 1986; 1:69–71. 78. Shepard HA, Royle G, Ross AP, Diba A, Arthur M, Colin-Jones D. Endoscopic biliary prosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg 1988; 75:1166–1168. 79. Andersen JR, Sorensen SM, Kruse A, Rokkjaer M, Matzen P. Randomized trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut 1989; 30: 1132–1135. 80. Smith AC, et al. Randomized trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet 1994; 344:1655–1660. 81. Yeo CJ, Sohn TA, Cameron JL, Hruban RH, Lillemoe KD, Pitt HA. Periampullary adenocarcinoma: analysis of 5-year survivors. Ann Surg 1998; 227:821–831. 82. Nakeeb A, Pitt HA, Coleman J, et al. Cholangiocarcinoma: a spectrum of interhepatic, perihilar, and distal tumors. Ann Surg 1996; 224:463– 475. 83. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg 2000; 232:166–174. 84. Nakeeb A, Tran KQ, Black MJ, et al. Improved survival in resected biliary malignancies. Surgery 2002; 132:555–564. 85. Weber SM, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR. Staging laparoscopy in patients with extrahepatic biliary carcinoma: analysis of 100 patients. Ann Surg 2002; 235:392–399. 86. Nordback IH, Pitt HA, Coleman J, et al. Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 1994; 115:597–603. 87. Klempnauer J, Ridder GJ, von Wasielewski R, Werner M, Weimann A, Pichlmayr R. Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 1997; 15:947–954.

medwedi.ru

24 The Spleen Haytham M. A. Kaafarani and Kamal M. F. Itani

INTRODUCTION Declared by Galen as the organ of mystery (organum mysterium), thought of by many as the organ that clears ‘‘melancholic residues,’’ and discussed by giant physicians and philosophers like Hippocrates, Aristotle, Vesalius, Malpighi, and Billroth, the spleen remains today an organ of great interest to anatomists, physicians, and surgeons. It was not until well into the 20th century that our knowledge of the spleen began to take its current shape. A report in 1929 of a case of postsplenectomy sepsis and the recognition by King and Schumacker of this entity in 1952 questioned the previous assumption of the expendability of the spleen. The description by Christo in 1962 of the segmental anatomy of the spleen helped surgeons perform a partial splenectomy, thus decreasing the risk of postsplenectomy sepsis. The application of modern diagnostic tools like computed tomography (CT) scans and modern techniques like laparoscopy has revolutionized splenic surgery, and few will disagree now that one should attempt to save the spleen when possible and that caution is of ultimate importance when the decision of splenectomy is made. This chapter describes the current knowledge of the surgical physiology and pathophysiology of the spleen and places particular emphasis on splenectomy, its indications and complications, and suggested alternative procedures.

The principal arterial supply of the spleen is the splenic artery, which arises from the celiac trunk and takes a tortuous and peculiar course along the superior margin of the pancreas before entering the splenic hilum. In rare cases, it can be partially or totally embedded within pancreatic parenchyma (2). At the hilum, the splenic artery divides into four to eight segmental branches that are true end arteries; it is this arrangement that allows segmental splenectomy. The spleen, moreover, receives collateral blood from the inferior or transverse pancreatic artery, short gastric arteries, and left gastroepiploic artery. Venous drainage of the spleen is via the splenic vein, which receives tributaries from the pancreas while coursing behind its head and joins the inferior and superior mesenteric veins to form the portal vein. Short gastric veins also contribute to the splenic venous drainage.

EMBRYOLOGY At approximately the fifth week of gestation, the spleen arises from mesenchymal cells located between the layers of the dorsal mesogastrium. It is embryologically unique in that it is neither a midline structure nor the remnant of what arose as a bilaterally symmetric structure. Blood vessels appear in the splenic tissue by the eighth week of development, and as they proliferate, reticular cells and fibers form sheaths around them. Leukocytes appear later (around the

GROSS ANATOMY The spleen is a solid, purplish-red organ located in the posterior left uppermost quadrant of the abdomen at the level of the 8th to 11th ribs (Fig. 1). Its adult weight is around 150 g ranging between 50 and 300 g and usually decreasing by weight and size with age (1). According to Michels, the spleen has three potential shapes: wedge (44%), tetrahedral (42%), or triangular (14%) (2). These shapes are determined, in part, by the organs that it abuts, principally the diaphragm, stomach, and left kidney (Fig. 1). The eight splenic ligaments are surgically important because they must be divided during splenectomy. The four major ligaments include the splenorenal, splenocolic, splenophrenic, and gastrosplenic ligaments (Fig. 1). With the exception of the latter, these suspensory ligaments are largely avascular unless the patient has advanced portal hypertension. The gastrosplenic ligament, however, is usually vascular and contains the short gastric vessels (Fig. 1). The other four ligaments with splenic attachments are the presplenic fold, the pancreaticosplenic, phrenicocolic, and pancreaticocolic ligaments. Although surgically less important, these minor ligaments can lead to injury of the spleen or its neighboring organs with careless traction or incision (2).

Figure 1 Anatomic relationships and ligaments of the spleen.

medwedi.ru 503

504

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 1 Possible Locations of Accessory Spleens by Decreasing Frequency Splenic hilum Tail of pancreas Gastrosplenic ligament Splenocolic ligament Splenorenal ligament Greater omentum Left mesocolon Connective tissue below left hemidiaphragm Small bowel mesentery Left adnexal/left peritesticular region

fourth month of gestation) and consist of a mixture of lymphocytes, predominantly of the B type. This predominance of B-lymphocytes persists throughout fetal life. The presence of hematopoietic cells in the fetal spleen in late fetal life has been suggested to be due to the filtration of these precursor cells from the blood rather than being of splenic origin (1). Accessory spleens have been reported to be present in as much as 10% of the population and are usually found in the vicinity of the spleen itself, but can be present in distant sites such as the pelvis (Table 1). Accessory spleens are morphologically and physiologically identical to the primary spleen, and may even enlarge after splenectomy and result in a relapse of the original disease (1). A search for accessory spleens when splenectomy is performed for hematological disorders is necessary.

HISTOLOGY The spleen is covered by a 1 to 2 mm thick connective tissue capsule, which contains major afferent and efferent blood vessels, nerves, and lymphatic vessels. From the capsule, which is covered with a thin layer of peritoneal mesothelium, several trabeculae arise and divide the splenic parenchyma into many small, but communicating, compartments. The splenic parenchyma is histologically and functionally formed by two different types of tissue called red pulp and white

pulp (Fig. 2). The area separating the two ‘‘pulps’’ is called the marginal zone, and is believed to be the initial site of antigen trapping and processing.

Red Pulp Approximately 75% of splenic tissue is composed of the sponge-like red pulp. This red pulp, formed embryologically from the early proliferation of blood vessels and reticular tissue, consists of the splenic sinusoids and the splenic cords (cords of Billroth) (Fig. 2). The thin-walled sinusoids are lined by elongated endothelial cells that are transversely encircled by highly fenestrated strands of basement membrane. However, there are no true endothelial spaces. This specific architecture assists in the degradation of old or abnormal erythrocytes. Moreover, the endothelial cells express the CD8 antigen, usually found on cytotoxic T-cells, which may indicate their importance in the recognition of infected cells and foreign antigens (1). The sinusoids are supported by the cords of Billroth, which are composed of collagen fibers, reticulin fibers, fibroblasts, lymphocytes, and macrophages.

White Pulp If the spleen is transected, the white pulp can be grossly visualized as 1 to 2 mm white nodules (Malpighian corpuscles), which consist of lymphoid tissue. The white pulp is formed by the T-cell–rich periarteriolar lymphoid sheaths (PALS) and the B-cell–rich follicles (Fig. 2). Like the spleen itself, the morphology of the white pulp varies to a great extent, depending on the age and degree of antigenic exposure of the individual.

Splenic Microcirculation The splenic artery divides into trabecular arteries that leave the trabeculae and enter the white pulp as large central arteries. These central arteries are covered by sheaths formed of dense accumulations of lymphocytes (predominantly T-cells), plasmacytes, and macrophages, which form a cylindrical cuff around the artery. This cuff is called the PALS. Lymphoid follicles (which contain B-lymphocytes) occur periodically as outgrowths of PALS, usually at arterial branch points. The central arteries end in the marginal zone,

Figure 2 Microanatomy and microcirculation of the spleen.

Chapter 24: The Spleen

and blood percolates in the cords and sinusoids throughout the red pulp, reaches the pulp veins, the trabecular veins, and then exits the spleen by way of the splenic vein. However, based on washout and scanning electron microscopy studies, the microcirculation of the spleen appears to be more complex with three different pathways described: fast, intermediate, and slow (1,3). The fast pathway, which accounts for 90% of splenic blood flow, but only 10% of erythrocytes, is responsible for the quick blood flow through the blood vessels. The intermediate pathway, in comparison, accounts for 70% of erythrocytes, and is thought to be associated with their remodeling and phagocytosis in the red pulp. Finally, cells traveling through the slow pathway are mainly reticulocytes that adhere to filtration beds in order to mature (1,4). The fast and intermediate components of splenic blood flow correspond anatomically to the closed and the open pathway theories of the spleen microcirculation (Fig. 2), a topic that is the subject of controversy among histologists. The closed theory describes a closed vascular system where blood flows directly from the capillaries into the sinuses and back to veins, like in most organs of the body. In contrast, the open theory suggests that the 5 mm fenestrations in the sinusoids permit entry of erythrocytes into and out of the cords of Billroth. The environment within these cords is acidotic and hypoxic and contains limited quantities of available energy substrate, thus promoting the degradation of senescent red blood cells (RBCs).

PHYSIOLOGY AND FUNCTION OF THE SPLEEN The physiology of the spleen is closely related to its circulatory and immunologic role in the human body (Table 2). Due to its tight and hypoxic circulation, the spleen serves as a ‘‘fine-tooth comb’’ of the peripheral blood, clearing aged or abnormal RBCs and removing intracellular debris and particulate material. Moreover, as one of the body’s essential lymphoid organs, the spleen plays a crucial role in the protection of the human body against foreign particles and pathogens, especially encapsulated bacteria. The role of the spleen in hematopoiesis is not well defined.

Circulatory Function Erythrocyte Destruction

and physiologic barriers that the spleen presents to the erythrocyte with the older cells being unable to adapt to this ‘‘harsh’’ splenic environment. Although the exact mechanism of RBC destruction is not well understood, it is clear that the red cell membrane loses some of its plasticity with aging, making the erythrocyte less able to cross the fenestrated basement membranes of the sinusoids (5,6). Some investigators suggest that the aging erythrocyte is preferentially recognized by the phagocytes of the spleen, possibly due to the presence or absence of specific carbohydrate antigens on its surface (7–9). Another popular, but controversial, mechanism emphasizes the crucial role that the harsh splenic milieu plays. It proposes that the blood in the spleen, as it becomes more concentrated, leads to stagnation and delay of transit of the RBCs; hypoxia and acidosis decrease the availability of oxygen and glucose to the glycolysis-dependent RBC. This results in the decreased availability of adenosine triphosphate (ATP), dysfunction of the ATP-dependent sodium–potassium pump, and subsequent swelling and destruction of the red cell. In addition to clearing senescent erythrocytes, the spleen also recognizes and removes abnormal RBCs, regardless of whether the abnormality is intrinsic (e.g., membrane defect) or extrinsic (e.g., antibody mediated).

Intraerythrocytic Inclusions Removal As part of the reticuloendothelial system, the spleen is responsible for the maintenance of the RBCs by removing nuclear remnants and abnormal cytoplasmic material, also known as intraerythrocytic inclusions. The inclusioncontaining part of the RBC is less deformable and fails to cross the slits between endothelial cells; it is then ‘‘pitted’’ by macrophages, and the viable inclusion-free cell returns to the circulation. The recovery of cells with these remnants in the peripheral blood is diagnostic of splenectomy or asplenia. These cells include reticulocytes, target cells (immature cells), spur cells in addition to those cells with nuclear remnant (Howell–Jolly bodies), denatured hemoglobin (Heinz bodies), iron granules (Pappenheimer bodies), or malarial parasites.

Erythrocyte Maturation

The splenic red pulp clears about 20 mL of aged RBCs daily. This is most likely due to a combination of anatomic Table 2 Functions of the Spleen Circulatory function Erythrocyte destruction Intraerythrocytic inclusions removal Erythrocyte maturation Cellular reservoir Hematopoietic functiona Immunologic function Defense against encapsulated bacteria Primary and secondary immune response Antibody secretion Opsonization Phagocytosis Alternative complement pathway activation a

505

The spleen plays a role in the transformation of the reticulocyte to a mature erythrocyte, possibly by eliminating a specific high-molecular-weight membrane–protein complex. The spleen, in addition, removes excess membrane and nuclear material from the RBC, thus helping its transformation from the spherical shape into the biconcave, mature shape.

Cellular Reservoir

Hematopoietic function of the spleen is documented only during early fetal life. Whether the spleen produces blood elements in a pathologic condition such as idiopathic myelofibrosis is more controversial.

Compared to the spleen of animals, the human spleen is a very poor RBC reservoir, containing at most 40 mL of RBCs. This is due to the fact that the capsule of the human spleen contains little smooth muscle and is therefore incapable of contraction. In contrast, more than 30% of platelets are stored in the human spleen (1) and can be mobilized by adrenergic stimulation, leading to a significant increase in platelet counts (10,11). Large numbers of mature granulocytes are also stored within the normal spleen (10). In the case of splenomegaly, splenic blood flow and splenic entrapment of blood cells will increase significantly; up to 20% of RBCs and up to 90% of platelets may pool in the enlarged spleen (12).

medwedi.ru

506

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Hematopoietic Function The spleen plays a crucial role in the production of red and white blood cells in the early life of a fetus. This role is thought to end by the fifth month of gestation when the fetal bone marrow becomes active. The presence of bone marrow precursors in the spleen in late fetal life and in some pathologic adult conditions like myeloid metaplasia and myelofibrosis is believed to be due to filtration of these precursors, rather than production by the spleen proper.

Immunologic Function The spleen is one of the largest secondary lymphoid organs of the body. It contains about 30% of the T-cell exchangeable pool and about 15% of the B-cell exchangeable pool (12). The spleen’s role in the immune surveillance and host defenses cannot be overemphasized. It ranges from complement activation, opsonization, and phagocytosis of foreign particles to antigen detection and antibody secretion. The importance of the spleen in the defense against encapsulated bacteria became evident when asplenic individuals were found to be at a higher risk for fulminant infections with organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meninigitidis. This entity is called overwhelming postsplenectomy sepsis, and will be discussed in a latter section of this chapter. Antigen-presenting phagocytic cells in the spleen are able to activate T-helper cells, which in turn stimulate the differentiation of B-cells. The primary B-cell follicle within the white pulp develops into a germinal center within three to four days following exposure to the new antigen. This germinal center reaction lasts three to four weeks, and if there is successful elimination of the antigen, ends with the disappearance of the center. Within 16 hours of a second exposure to the same antigen, the memory B-cells, thought to have emigrated from the site of the initial germinal center to the peripheral zone of the follicle, are able to initiate an immunologic response. This leads to the formation of the secondary follicle and rapid secretion of antibodies directed against the specific antigen (1,12). The spleen has been found to be a major source of properdin, a glycoprotein opsonin secreted by endothelial and peripheral blood cells (13) and capable of stabilizing the C3bBb complex involved in the alternative pathway activation (14,15). The clinical significance of this function has been challenged, however, by the failure of several studies to find decreased levels of the complement in splenectomized patients (16–18). Tuftsin, another opsonin, is a tetrapeptide cleaved in the spleen from the Fc fragment of immunoglobulin G (IgG). Tuftsin enhances the phagocytic ability of polymorphonuclear cells in a poorly understood way and helps in the clearance of opsonized bacteria (19). Bacteria (or foreign particles) that are fully opsonized by Igs, properdin, or tuftsin may be phagocytosed in the liver. The spleen’s role seems to be more important with the incompletely opsonized bacteria that the liver fails to clear. The spleen is able to clear these organisms, because it has a more complex circulation than the liver, forcing these partially coated bacteria or particles to have a longer exposure to its phagocytic cells. The phagocytic function of the spleen, in turn, amounts to more than 25% of the total body phagocytic capacity (12). Many immunologic changes have been recorded after splenectomy, thus exposing these patients to a greater risk of infection. Children and adults with hematologic disorders are the most susceptible to serious postsplenectomy infections when compared to patients who underwent splenectomy

after trauma (20). Studies have shown decreased primary and secondary immunologic responses to the introduction of an antigen in asplenic or splenectomized patients. This decrease in the immunologic reaction holds true when the antigen is introduced only intravenously, while both responses seem to be rather normal if the antigen’s initial route of entry was intradermal, intramuscular, intraperitoneal, or subcutaneous (21). Decreased levels of IgM antibodies, and sometimes IgG, were also found in patients who underwent splenectomy irrespective of the cause. Additionally, a decrease in the general activity and function of the phagocytes in the reticuloendothelial system was also found, thus making the patient need larger amounts of antibodies to overcome the foreign particles (22). As mentioned previously, decreased levels of properdin and tuftsin were noted, though the complement levels seem to be unchanged.

Dysfunction of the Spleen Hypersplenism The terms ‘‘splenomegaly and hypersplenism,’’ although used interchangeably by some authors, are different phenomena. Splenomegaly is the enlargement of the spleen and is usually sufficient to make the spleen palpable on physical examination. Hypersplenism, on the other hand, is a hyperfunction of the spleen with sequestration of blood elements leading to anemia, neutropenia, and thrombocytopenia alone or in any combination. Splenomegaly and bone marrow hyperplasia are often present with hypersplenism. Hypersplenism is classified as primary when the spleen is histologically normal and when an underlying disorder cannot be identified. Secondary hypersplenism results in the sequestration of abnormal blood cells in an otherwise normal spleen or the sequestration of normal cells in a pathologically abnormal spleen. The most common cause of secondary hypersplenism is portal hypertension resulting from extrahepatic portal obstruction or splenic vein obstruction. The cause and mechanisms of cytopenias observed with liver disease, like cirrhosis, are not completely understood, but can be partially explained by the trapping and sequestration of blood in the enlarged spleen (23). Splenectomy is usually curative for primary hypersplenism, while its role in hypersplenism secondary to portal hypertension is less evident. Portal decompression usually improves the cytopenias seen with cirrhotic portal hypertension. On the other hand, hypersplenism associated with isolated splenic vein thrombosis that results in left-sided portal hypertension should be managed by splenectomy (24,25)(26,27). The latter entity has been called segmental or sinistral portal hypertension and typically results from pancreatic pathology leading to splenic vein thrombosis with hypersplenism and/or gastric varices. Concomitant splenectomy should be considered in those patients undergoing surgical treatment for persistent pancreatitis, pancreatic pseudocysts or pancreatic carcinoma, if evidence of hypersplenism or segmental portal hypertension is present (26,27).

Hyposplenism Hyposplenism is defined as a decrease in splenic activity. This can be due to the anatomical absence (e.g., after splenectomy) or functional failure of the spleen. Congenital asplenia is another possible, but rare cause of hyposplenism. Functional hyposplenism has been defined, by Eppinger, as the failure of the spleen to take up technetium sulfur colloid on a radionuclide scan (28). Hyposplenism is

Chapter 24: The Spleen

practically recognized by the presence of Howell–Jolly bodies and other intracellular inclusions in the peripheral circulation. More sophisticated methods have been developed to recognize functional asplenia, such as the quantification of RBC surface abnormalities by interference phase microscopy or the measurement of splenic sequestration of labeled RBCs (28,29); however, these tests remain technically complex and have not replaced the more accessible and cost-effective light microscopy. Hyposplenism has been reported with a large number of disorders, the most common of which are celiac disease, inflammatory bowel disease, hemoglobinopathies, systemic lupus erythematosus, rheumatoid arthritis, and Graves’ disease. The clinical significance of functional hyposplenism is similar to postsurgical or congenital asplenia. Complications like rapidly fatal sepsis with encapsulated organisms were reported with most of these clinical entities, necessitating the identification of functional hyposplenism and taking the necessary prophylactic steps to avoid overwhelming infections.

HEMATOLOGIC DISORDERS AND SPLENECTOMY Splenectomy is indicated in many hematologic disorders where it can be considered as the definitive, adjunctive, or palliative mode of treatment (Table 3). These hematologic entities include platelet disorders, erythrocyte disorders and, rarely, white blood cell disorders.

Platelet Disorders Idiopathic Thrombocytopenic Purpura Idiopathic thrombocytopenic purpura (ITP) is an acquired disease in which IgG antibodies against platelets are produced by the spleen. The platelet–antibody complexes are then sequestered and destroyed in the reticuloendothelial system including splenic tissue, resulting in thrombocytopenia. ITP in children occurs acutely, most often after an upper respiratory infection, and is usually self-limited, while chronic ITP is classically observed in women in their mid30s. Nonetheless, the incidence of chronic ITP is increasing and involving more males in the elderly population. The typical presentation of ITP consists of easy bruising, petechiae, purpura, menorrhagia, or mucosal bleeding; the most common diagnosis of ITP occurs after the incidental finding of thrombocytopenia on routine blood tests. Intracranial and subarachnoid hemorrhages are relatively uncommon complications, but remain among the most feared ones, especially in children. Significant bleeding does not usually occur with ITP unless the platelet count is less than 10,000/mL. This is due to the fact that the platelets in ITP are young and hyperfunctional, resulting in a bleeding time less than predicted for the amount of thrombocytopenia (30). Diagnostic criteria for ITP include the concomitant findings of unexplained peripheral thrombocytopenia and normal to increased bone marrow megakaryocytes as well as the absence of splenomegaly. Conditions known to produce thrombocytopenia have to be ruled out before the diagnosis of ITP is made (Table 4). Findings of increased megakaryocytes on bone marrow examination are commensurate with increased platelet production, although some recent studies are suggesting that ITP may be associated with decreased, rather than increased platelet production along with their increased destruction (31). Despite the fact that a number of antibodies involved in ITP have already

507

Table 3 Potential Indications for Splenectomy Splenectomy as part of a complex operation Hematologic indications Platelet disorders Idiopathic thrombocytopenic purpura Thrombotic thrombocytopenic purpura HIV-related thrombocytopenia Congenital hemolytic anemia Disorders of RBC membrane Hereditary spherocytosis Hereditary elliptocytosis Hereditary stomatocytosis Rh null disease Disorders of RBC metabolism G6PD deficiency Pyruvate kinase deficiency Other metabolic enzyme deficiencies Disorders of hemoglobin Sickle cell disease Thalassemia Acquired autoimmune hemolytic anemia Splenic neutropenia Oncologic indications Lymphoproliferative disorders Hodgkin’s lymphoma (staging) Non-Hodgkin’s lymphoma Chronic lymphocytic leukemia Hairy cell leukemia Myeloproliferative disorders Idiopathic myelofibrosis Chronic myeloid leukemia Solid tumors Hemangiosarcoma Kaposi’s sarcoma Metastatic melanoma Miscellaneous indications Splenic abscess Splenic cyst Splenic pseudocyst Splenic benign tumors Felty’s syndrome Gaucher’s disease Sarcoidosis Amyloidosis Splenic trauma Abbreviation: RBC, red blood cell.

been identified (32), the American Society of Hematology does not recommend antiplatelet antibody testing or demonstration of splenic sequestration of platelets by nuclide studies to diagnose ITP (33). The peripheral smear in ITP should show normal or only slightly enlarged platelets along with normal erythrocytes and leukocytes morphology (33). In Evans syndrome, ITP occurs with an autoimmune hemolytic anemia demonstrated by a positive direct Coombs’ test, and responds to splenectomy, though the course of this entity tends to be more chronic and relapsing and the prognosis worse than that of isolated ITP. The goal of therapy in ITP is to maintain a ‘‘relatively safe’’ platelet count that would prevent serious bleeding. No treatment is required for counts above 30,000/mL, even preoperatively. Some authors advocate 20,000/mL as an equally safe threshold for asymptomatic patients or those with minor purpura (32,33). Therapy for the acute form of the disease is conservative, with these patients often recovering spontaneously.

medwedi.ru

508

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Table 4 Conditions Associated with Thrombocytopenia Condition

Suggestive characteristics

TTP-HUS

Neurologic symptoms, hemolytic anemia, shistocytes, renal failure (HUS) History heparin administration, sulfonamides, methyldopa or quinine intake, positive Coombs’ test Jaundice, icterus, ascites, elevated liver enzymes Positive serological testing for HIV Positive Monospot test Positive ANA, positive anti-dsDNA Positive anti-IgG antibodies (rheumatoid factor) History of recent transfusion Abnormal thyroid function tests

Drug intake

Liver disease HIV EBV SLE Rheumatoid arthritis Transfusion reaction Thyroid disease (hypo- or hyperthyroidism) Hematologic malignancies Familial thrombocytopenia Gestational thrombocytopenia/ preeclampsia/HELLP syndrome DIC

Abnormal RBCs on blood smear, splenomegaly, weight loss Family history Female gender, usually in the third trimester of pregnancy, proteinuria, elevated liver enzymes Critically ill patient, increased fibrin degradation products, decreased coagulation factors and fibrinogen, shistocytes

Abbreviations: TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; EBV, Epstein–Barr virus; SLE, systemic lupus erythematosus; DIC, disseminated intravascular coagulopathy; ANA, antinuclear antibody; IgG, immunoglobulin G; HIV, human immunodeficiency virus.

Patients with the chronic form of ITP are treated with prednisone (1 mg/kg/day), with numerous studies showing a transient increase in platelet count occurring within three to seven days. However, complete remission is rare, and thrombocytopenia often recurs with tapering of the steroid dose. Splenectomy remains the second choice for therapy with two-thirds of patients responding within few days of the operation (31,32). At the time of surgery, a careful search for accessory spleens should be performed because 20% of patients with refractory ITP will have an accessory spleen (34). The subsequent discovery of an accessory spleen in unresponsive or relapsing ITP patients after an initial splenectomy is sufficient to justify a return to the operating room for accessory splenectomy. Response to this procedure is encouraging, and several reports of remission of ‘‘resistant’’ ITP are documented after resection of accessory spleens. Splenectomies performed for ITP refractory to corticosteroids increases the platelet count to ‘‘safe’’ levels in more than 70% of patients (34–36). Because the spleen is of normal size in ITP, laparoscopic splenectomy (LS) offers similar long-term results to open splenectomy in addition to decreased hospital stay and faster recovery (37,38). Other therapies that are used in the nonoperative management of ITP include intravenous immunoglobulins (IVIG), high-dose methylprednisolone, immunosuppressive therapy (cyclophosphamide, azathioprine, and vinca alkaloids), dapsone, danazol, rituximab (anti-CD20), plasmapheresis, and spleen radiotherapy. The use of anti-D immune globulin as initial therapy in Rhesus-positive individuals has been recently reported to be highly successful, but is still under investigation (35). These modalities of

treatment are mentioned repeatedly in literature, and though many are promising, the long-term remission with the nonoperative management of chronic ITP is being achieved in less than 20% of patients (12). Moreover, many of the drugs used are notorious for causing serious side effects, and are therefore used only after failure of the combination of corticosteroids and splenectomy. The preoperative use of Igs transiently increases the platelet count and should be used as an adjunct to steroids when platelet levels are less than 30,000/mL (33). Preoperative administration of platelets is not necessary if the platelet count is above 20,000/mL in children or 10,000/mL in adults (33). Some surgeons prefer to administer platelets after clamping the splenic pedicle to prevent sequestration of the platelets by the spleen.

Thrombotic Thrombocytopenic Purpura Thrombotic thrombocytopenic purpura (TTP) is a disease of the microvasculature with widespread deposition of hyaline material composed of platelet microthrombi and fibrin in subendothelial and intraluminal sites leading to arteriolar and capillary occlusion. The etiology of the disease is unknown, although the fact that it can be initiated by various factors such as infections, pregnancy, and drugs is well documented. Some authors have proposed that endothelial cells pathologic apoptosis could be the initial insult, but this is still under investigation (39). TTP presents as a pentad of purpuric thrombocytopenia, microangiopathic hemolytic anemia, progressive renal failure, fluctuating neurologic manifestations (seizures, aphasia, and confusion), and fever. The platelet count is reduced consequent to thrombosis and platelet deposition, while the microangiopathic anemia results from the destruction of erythrocytes while passing through damaged arterioles. In contrast to ITP, hepatosplenomegaly occurs in about one-third of patients with TTP. Plasma exchange (plasmapheresis with fresh frozen plasma replacement) has been shown in two trials to be more effective than the previously used plasma infusion alone and resulted in 78% remission and survival rates (40,41). Adjunctive therapies include antiplatelet drugs like aspirin and dipyridamole as well as immunosuppressive therapy with corticosteroids, azathioprine, cyclosporine, and cyclophosphamide. In cases of failure of plasma exchange, splenectomy may be performed and improves the response to either plasma exchange or corticosteroids (42,43). Even though no direct link to the spleen has been established in the pathophysiology of the disease, splenectomy, as a treatment option, is defended by the fact that most TTP patients with long-term survival had their spleen removed, and that TTP, if not treated, is rapidly fatal.

HIV-Related Thrombocytopenia It is estimated that 5% to 15% of HIV-infected individuals will suffer from thrombocytopenia. This entity, possibly related to both reduced platelet survival and ineffective platelet production, is independent of the clinical and immunologic status of the patient. Zidovudine, a protease inhibitor used in the treatment of HIV patients, is also used as the main therapy in HIV-associated thrombocytopenia, along with corticosteroids and immunoglobulins (44). HIV patients with refractory thrombocytopenia generally benefit from splenectomy. In a series of 21 patients who underwent splenectomy for HIV-related thrombocytopenia, Aboolian et al. described a 100% response rate to splenectomy in HIV patients and an 83% response rate in those who had

Chapter 24: The Spleen

acquired immunodeficiency syndrome (AIDS) (45). These patients tolerated the operation well with minimal morbidity and succeeded in maintaining a good platelet response after splenectomy in most of the cases. Early concerns that splenectomy is a factor in converting or accelerating the conversion of asymptomatic HIV to AIDS were defeated by later data supporting the safety of the procedure (45,46).

Congenital Hemolytic Anemias General Considerations Congenital RBC disorders frequently result in hemolytic anemia with the spleen playing a prominent role in the sequestration and accelerated destruction of the involved RBCs. Patients with hemolytic anemia present with variable degrees of pallor, jaundice, and splenomegaly. Bilirubin gallstones with resulting biliary symptoms commonly form due to chronic hemolysis. Serum chemistry will reveal unconjugated hyperbilirubinemia due to extravascular RBC destruction. A decrease in the levels of haptoglobin, which immediately binds the released hemoglobin in intravascular hemolysis, will occasionally occur. Bone marrow examination will reflect cellular hyperplasia. The peripheral blood smear often offers a strong clue as to the specific type of hemolytic anemia by showing characteristic morphologies or abnormalities of the RBC. Erythrocytes’ osmotic fragility, which is measured by placing the RBCs in hypotonic saline solutions of decreasing concentrations and noting the concentration at which various degrees of cell hemolysis occur, is often increased in patients with hemolytic anemias. The surgeon’s role in these cases is linked to the decision of whether a specific patient with an already diagnosed RBC disorder will benefit from splenectomy or not. In many of the congenital hemolytic disorders, splenectomy is of great benefit and is sometimes the ‘‘definitive therapy.’’ If laparoscopic splenectomy is to be performed, preoperative ultrasonography of the gallbladder is essential to decide whether cholecystectomy should be performed along with the splenectomy when gallstones are discovered. This is not always needed in the open surgical technique because the gallbladder can be palpated intraoperatively for stones, and the decision for concomitant cholecystectomy can be made in the operating room. Several congenital erythrocyte defects exist, including disorders of the RBC membrane, disorders of the RBC metabolism, and disorders of hemoglobin synthesis.

Disorders of the RBC Membrane Hereditary spherocytosis (HS) is the most common disorder of the RBC membrane, with an incidence of about 200 per million. Autosomal dominant and autosomal recessive forms exist, and the latter is associated with a worse clinical picture, worse response to splenectomy, and a worse overall prognosis. The extent of spectrin deficiency, one of the largest structural proteins of the erythrocyte membrane, has been found in most cases of spherocytosis to correlate well with the severity of the disease. Spectrin deficiency makes the RBC smaller, more spherical (elevated mean cell hemoglobin concentration), and thus susceptible to earlier hemolysis upon measurement of the osmotic fragility. This increase in osmotic fragility results from a decreased cellular surface to volume ratio rather than a disturbance of the channels controlling ionic traffic at the level of the membrane. The spleen accelerates the destruction of these less deformable cells that fail to withstand its highly hypoxic, acidic, and aggressively

509

phagocytic environment resulting in various degrees of hemolysis. Severe aplastic crisis can also occur and is seen most commonly after infection with the human parvovirus B19. Although folic acid supplements and blood transfusions during aplastic crises are the mainstay of therapy, splenectomy remains the definitive management. In the majority of patients following splenectomy, hematocrit levels return to normal, even though the RBC’s survival rate remains less than normal. Delaying splenectomy until adolescence in order to avoid postsplenectomy infections is advised, unless hemolytic and aplastic crises are frequent. Hereditary elliptocytosis (HE), also known as ovalocytosis, can result from other abnormalities of structural membrane proteins, some of them again involving spectrin, but in different genetic mutations than spherocytosis. The heterozygous form of HE presents with mild anemia and normal osmotic fragility. The homozygous form is more severe, with reticulocytosis as high as 20%, severe anemia and abnormal osmotic fragility, and occasionally results in death during infancy. Splenomegaly is commonly present when the anemia is severe, making splenectomy an effective mode of therapy for both the anemia and the splenic enlargement. Hereditary stomatocytosis (also known as hydrocytosis) and Rh null disease are two rare entities that present in a similar way as HS, specifically with respect to increased osmotic fragility and decreased RBC survival. Hereditary stomatocytosis is characterized by the presence of abnormal RBC permeability, while Rh null disease is characterized by RBCs, which lack the Rh-Hr antigens (47). Splenectomy is successful in improving the anemia in both these entities. Nonetheless, several reports have shown an increased incidence of thromboembolic phenomena in patients undergoing splenectomy for stomatocytosis (48–50), raising caution about the safety of splenectomy in this disorder.

Disorders of the RBC Metabolism The mature circulating erythrocyte is incapable of oxidative phosphorylation consequent to the loss of mitochondria during maturation and is therefore totally dependent on anaerobic glycolysis to meet its energy requirements. Enzyme deficiencies in the glycolytic pathway necessary for glucose metabolism and the hexose monophosphate shunt involved in NADPH production and nucleotide synthesis decrease the availability of intracellular energy substrates necessary for the erythrocytes to withstand the stressful splenic conditions. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an x-linked disease, is the most common disorder in this group, affecting between 10% and 15% of African-Americans (51). Because G6PD is essential for the restoration of glutathione levels, G6PD-deficient RBCs are more susceptible to oxidative damage. This translates clinically into a chronic baseline hemolysis, or, more commonly, episodic hemolytic crises, which are often triggered by oxidative drugs (e.g., sulfa drugs, primaquine, and dapsone), infections (e.g., salmonella, streptococcus, and hepatitis), or intake of Fava beans. The Fava bean, a popular food of the Mediterranean area where G6PD deficiency is common, is capable of causing hemolytic anemia in patients with this enzyme deficiency. This is due to the fact that one of the substances contained in Fava beans is hydrolyzed after ingestion into a fairly oxidative toxin that is poorly cleared in the absence of G6PD. Avoidance of these precipitating agents is essential in individuals with G6PD deficiency. Antioxidant agents like vitamin E have been tried with no proven benefit (52). Splenectomy can be performed in cases of symptomatic anemia. The

medwedi.ru

510

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

postsplenectomy response has not been consistent in terms of long-term benefit, but modest increases in hemoglobin concentration are noted after the procedure in patients who present with chronic rather than episodic hemolysis (12). Pyruvate kinase (PK) deficiency is the second most common enzyme deficiency causing RBC hemolysis. It is transmitted as an x-linked disorder, one-third of affected patients present with neonatal jaundice. In the remainder of cases, the anemia is mild and may not present until late childhood. One proposed mechanism suggests that the deficiency of PK leads to a deficiency in ATP substrates consequently resulting in electrolyte imbalance with cellular swelling and destruction. This mechanism may be too simplistic, because some studies have failed to find decreased levels of ATP in affected patients. Infections have been described to exacerbate the hemolysis and anemia. Splenectomy is effective but not curative in PK deficiency, and the benefit from splenectomy is usually directly proportional to the severity of the anemia (12). Other glycolytic enzyme abnormalities such as glucose phosphate isomerase, hexokinase, and phosphofructokinase deficiencies or hexose monophosphate pathway disorders like adenosine deaminase hyperactivity and pyrimidine-50 nucleotidase deficiency result in similar hemolytic anemias, and many of them respond at least partially to splenectomy.

Disorders of Hemoglobin Hemoglobinopathies lead to hemolysis through the formation of Heinz bodies and their removal along with part of the RBC in the spleen. These cells, now smaller and with a decreased cell surface area, are less deformable, and thus more prone to destruction by the spleen. Splenectomy has been advocated in patients with moderate disease and is effective in reducing the morbidity of the specific hemoglobinopathy, mainly by decreasing the need for transfusions. In patients with severe disease, splenectomy has been less successful, probably because other reticuloendothelial organs such as the liver or lymph nodes can assume the spleen’s function in destroying these cells. When advocated, splenectomy is better deferred until late childhood, in order to decrease the risk of postsplenectomy infection. Sickle cell anemia is the most common hemoglobinopathy seen in clinical practice. In this hereditary disorder, the abnormal hemoglobin S results from the substitution of valine for glutamic acid in the sixth position of the b chain of hemoglobin A. Sickling occurs when the cell is subjected to low oxygen tension, with crystallization of the abnormal hemoglobin and formation of long fibers that distort the RBC shape into a crescent or sickle shape. These less deformable cells lead to both hemolytic anemia and vasoocclusive episodes when they fail to cross the splenic and systemic vasculature, respectively. In addition to the hemolysis, symptoms of sickle cell anemia include growth retardation, strokes, cardiac failure, and chronic renal disease. Bone marrow aplastic crises also occur and commonly follow viral infections. Due to massive hemolytic activity, the spleen in sickle cell disease begins to enlarge in the first few years of life. It progressively decreases in size later in life due to multiple infarcts caused by vasoocclusion of the vessels by abnormal RBCs, a process called ‘‘autosplenectomy.’’ Earlier elective splenectomy is beneficial when significant splenic sequestration, hypersplenism, or massive splenomegaly is present. According to the Medical Research Council Laboratories, splenectomy is advised after one major splenic sequestration

attack resulting in systemic symptoms like fever, cough, and diarrhea. Splenectomy is also advocated after minor acute splenic sequestration (anemia and splenomegaly), if evidence of hypersplenism is present (53). Splenic abscesses, which are not uncommon in sickle cell disease, may be an additional indication for splenectomy (54). It is of importance to note that recent studies found the incidence of postsplenectomy infections or sepsis in patients with sickle cell disease to be comparable to that in sickle patients who did not undergo a splenectomy (55), probably due to the autosplenectomy phenomenon in this latter group. The more common heterozygous (sickle cell trait) state is rarely associated with morbidity, and is even thought to confer effective immunity to the malarial parasites. This is possibly why the population with the sickle cell gene matches the geographic distribution of malarial infections in central Africa and the Mediterranean basin. With about 20% to 40% of the hemoglobin being hemoglobin S, these patients can have sickling episodes under stressful situations like infections. Nonetheless, splenic sequestration in sickle cell trait is rare and splenectomy is not indicated. Additional similar hemoglobinopathies have been reported; for example, the combination of hemoglobin C with hemoglobin S results in a hemoglobinopathy as severe as that of patients with homozygous sickle cell disease. Hypersplenism and symptomatic splenomegaly are common in these mixed hemoglobinopathies, making splenectomy a beneficial mode of treatment. Thalassemia (Mediterranean anemia) is a constellation of syndromes reflecting specific genetic mutations resulting in the formation of an abnormal hemoglobin tetramer or resulting in the decrease of synthesis of globulin chains. The disease may be divided into a and b subtypes according to the chain involved and into major or minor depending on whether the patient is homozygous or heterozygous for the mutation. a-Thalassemia can occur from the deletion of one or more of the four normally present a-globulin genes. There is no indication for splenectomy in any of the a-thalassemia variants, because the disease either results in a clinically mild anemia or in a severe form that rarely responds to splenectomy. b-Thalassemia minor occurs with the inheritance of one defective b gene, and is usually asymptomatic. b-Thalassemia intermedia occurs with the inheritance of two defective b genes, but is genetically and clinically a different entity than thalassemia major, where both b genes are also abnormal. In fact, thalassemia intermedia results in a relatively moderate anemia, requiring occasional transfusions, while thalassemia major (or Cooley’s anemia) manifests clinically in the first year of life due to the production of completely abnormal b-globulin. The erythrocytes of patients with thalassemia major have a decreased survival. In addition, hypersplenism and splenic sequestration are severe, rapidly rendering these patients transfusion dependent. Splenectomy has been shown by many investigators to result in a significant decrease in the transfusion requirements in patients with b-thalassemia major and in some patients with thalassemia intermedia, specifically those who present with significant hypersplenism (56,57). Partial splenectomy is generally accepted as a temporary measure in children less than five years old, in order to decrease the risk of postoperative infections and sepsis.

Acquired Autoimmune Hemolytic Anemia Acquired autoimmune hemolytic anemias are common syndromes caused by IgG or IgM antibodies that coat the surface of the erythrocyte, decreasing its life span. The

Chapter 24: The Spleen

decreased survival is due to both intravascular hemolysis and extravascular hemolysis within the spleen and the liver. A direct Coombs’ test is positive, and two different types of antibodies have been described depending on the ideal temperature at which they better react with the RBC. Warm antibodies, which are of the IgG class, coat the surface of the RBC preferably at 37 C, and make it more available for phagocytosis by the spleen macrophages. These antibodies are often directed against a drug antigen (hapten) attached to the erythrocyte surface rather than against the RBC itself. The hemolysis induced by warm antibodies is independent of the complement system, and is, in general, responsive to splenectomy (12,58). Nonetheless, splenectomy is reserved for those cases that fail to respond to steroids, which are the first choice of therapy in warm antibody hemolysis. Splenectomy is reported to be as effective as steroids in this entity, with patients showing improvement of their anemia, or at least requiring reduced amounts of steroids to maintain remission (59). Adjunctive treatment modalities include immunosuppressive therapy, IVIG and anti-CD20 (rituximab). Conversely, cold antibodies are usually of the IgM type, have increased affinity to RBCs at 2 C to 4 C, and bind to them mostly in the peripheral circulation like the nose, fingertips, or ears. This cold antibody–mediated hemolytic anemia is complement dependent and only rarely responds to splenectomy (12,58). In fact, the cold antibody type of hemolytic anemia rarely responds to any type of therapy including steroids, with avoidance of cold exposure being the mainstay of management. Surgical and medical therapies that are successful in the warm antibody type may be tried in severe cases of cold antibody hemolytic anemia, but with a lesser chance of success (58).

Splenic Neutropenia Splenic neutropenia is a rare condition characterized by severe neutropenia of unclear etiology and mechanism, but is thought to be related to antibodies produced by the spleen against the neutrophil. The neutrophil counts are lower than 1000/mm3 in more than 40% of the patients with this entity. Patients with splenic neutropenia suffer from recurrent and persistent infections. Although they respond to steroids transiently, the majority of patients will require a splenectomy, which is curative in 95% of cases.

MALIGNANCIES AND SPLENECTOMY Lymphoproliferative Disorders The spleen is a lymphoid organ and is thus often involved in lymphomas and leukemias. The hypersplenism and splenomegaly frequently observed in patients with these entities have been advocated as strong indications for splenectomy. On the other hand, splenectomy as a diagnostic and staging tool in lymphoproliferative disorders has become more controversial and is currently indicated only in specific clinical situations and will be discussed in the next section of this chapter.

Hodgkin’s Lymphoma Hodgkin’s disease (HD) is a malignant lymphoma characterized by the clonal presence on microscopic examination of a typical multinucleated Reed–Sternberg cell along with a reactive inflammatory background. Patients usually present with asymptomatic lymphadenopathy, mostly in the cervical region. Constitutional symptoms, called the B symptoms,

511

also occur and include fever, night sweats, and weight loss. Histologic classification, which depends on the relative amounts of lymphocytes and Reed–Sternberg cells present, is a good indicator of the prognosis of HD. Based on this concept, subtypes of this disease have been developed and are, from the most to the least favorable in prognosis, lymphocyte-predominant, nodular sclerosis, mixed cellularity, and lymphocyte-depleted. HD usually spreads in a predictable way through lymphatic channels, nodes, and organs. This allowed a reliable clinical classification of the disease, known as the Ann Arbor classification, which is helpful in directing the choice of treatment (Table 5). HD is treated with radiotherapy, chemotherapy, or both, and responds well in more than 75% of cases (60). Accurate staging is the most important step for the decision on the treatment modality; historically, a staging laparotomy was essential and used to be performed for almost every case of Hodgkin’s lymphoma. Currently, staging laparotomy is more controversial due to the advances in radiologic techniques, especially in the area of helical CT and positron emission tomography and due to the more liberal use of less-toxic chemotherapeutic agents. It is generally agreed upon that operative staging is important only for those patients that are candidates for radiotherapy as a sole treatment; this includes patients in stages I and II in whom the extent of disease spread below the diaphragm is unclear on radiographic staging. Patients with B symptoms or with more advanced stages usually benefit from chemotherapy and thus do not need a staging laparotomy. However, stage IIIA is an area of controversy. Many studies found that laparotomy upstages or downstages the extent of the disease by 10% to 40%, and thus may be essential for the hematologist’s choice between chemotherapy and radiotherapy for patients with suspected stage IIIA. On the other hand, the high recurrence rate observed in patients with stage IIIA HD, when radiotherapy alone is used, has encouraged many physicians to use a combination of radiotherapy and chemotherapy. This allows less dependency on laparotomy in case of suspicion of stage IIIA. Finally, and in addition to its role in staging, splenectomy is helpful in the treatment of HD when evidence of hypersplenism is present (61). When indicated, staging laparotomy consists of a thorough abdominal exploration, a splenectomy, a wedge biopsy of the liver, and selective biopsies of nodes in the mesenteric, splenic, caval, iliac, portal, and celiac areas, depending on radiologic and intraoperative findings. Bone marrow biopsies are also performed. In addition, the ovaries are usually moved to a position behind the uterus in order to put them Table 5 Ann Arbor Classification of Hodgkin’s Lymphoma Stage I

Involvement of a single lymph node region or a single lymphoid organ Stage II Involvement of two lymph node regions on same side of diaphragm Stage III Involvement of lymph nodes or organs on both sides of the diaphragm, with the possible inclusion of the spleen (IIIS) Stage IV Diffuse involvement of extranodal organs or tissues Additional designations Subscript E Involvement of a single extranodal site contiguous to a known nodal site Subscript B Presence of systemic symptoms (unexplained fever, night sweats, and more than 10% weight loss over the last 6 mo) Subscript A Absence of the above symptoms

medwedi.ru

512

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

outside the radiation field and thereby decrease the incidence of gonadal radiation injury. All the components of the staging procedure can be performed by laparoscopy, and reports of decreased morbidity and quicker recovery in laparoscopic staging are encouraging (62,63). The price of splenectomy here, as elsewhere, is an increased susceptibility to infection, with this risk being the highest in patients who receive both total nodal radiotherapy and combined chemotherapy.

Non-Hodgkin’s Lymphoma Non-Hodgkin’s lymphoma (NHL) is the most common tumor to involve the spleen, with 30% to 80% of the patients with NHL reported to have splenic involvement. It is much less critical in NHL to have an accurate staging, because the modality of treatment is not strictly dependent on the stage of the disease. Splenomegaly and hypersplenism are two of the most common features in NHL, and splenectomy is commonly performed to relieve the symptoms of an enlarged spleen. Splenectomy performed for hypersplenism has been reported in different studies to be successful in correcting 50% to 82% of cytopenias in patients with NHL (61,64).

Lymphocytic Leukemias Chronic lymphocytic leukemia (CLL) is a slowly progressive B-cell leukemia that occurs mainly in men after the age of 50. The typical presentation is that of palpable lymphadenopathy, peripheral lymphocytosis, and splenomegaly. Treatment with different chemotherapeutic drugs, steroids, and radiotherapy, alone or in combination, have allowed patients to lead an almost normal life. Splenectomy is indicated as a palliative treatment for massive splenomegaly or for cytopenias associated with hypersplenism. The correction rate of cytopenias after splenectomy in CLL patients is around 60% to 70% along with some evidence of increased survival (65). The increase in survival rates is more significant for patients with advanced stages of CLL, where the two-year survival rate increased from 28% to 51%, according to a case-control study conducted in 1997 (65). Hairy cell leukemia (HCL) is a relatively uncommon B-cell leukemia characterized by pancytopenia, splenomegaly, and infiltration of the bone marrow by leukemic cells. In contrast to CLL, no lymphadenopathy is usually present. The leukemic cells look ‘‘hairy’’ on light microscopy because they have filamentous cytoplasmic projections. Around 15% of patients have only a few ‘‘hairy’’ cells and a normal spleen size. These patients have an indolent course of the disease and usually require no treatment or splenectomy. The remainder may suffer from hypersplenism with or without splenomegaly; in these cases, a splenectomy is helpful in removing the enlarged spleen and in correcting the peripheral counts in about 40% to 70% of patients (66,67). The use of splenectomy in HCL has decreased with the recent consistent reports of short and long-term success with purine analogs, namely pentostatin and cladribine, as well as with interferon alpha and monoclonal antibodies. The previously claimed risk of secondary malignancies several years after treatment of HCL is not substantiated by recent investigations (68).

mainstay of treatment in WM. Because WM is usually accompanied by hypersplenism and splenomegaly, and because the spleen is an important site for IgM production, splenectomy has been tried for WM with several reports of durable remission of the entity (69,70). The International Workshop on WM currently recommends splenectomy in case WM is accompanied by hypersplenism or painful splenomegaly (71).

Myeloproliferative Disorders Idiopathic Myelofibrosis Idiopathic myelofibrosis, also known as agnogenic myeloid metaplasia, is a clonal stem-cell disorder characterized by ineffective erythropoiesis and a reactive bone marrow infiltration with connective tissue and fibrous material. Clinical presentation commonly includes cachexia, marked hepatosplenomegaly, anemia, and hyperuricemia. The peripheral blood smear shows myelophthisis, a condition that includes immature granulocytes, abnormal nucleated erythrocytes, and ‘‘teardrop’’ misshapen RBCs. Bone marrow aspiration may reveal a dry tap depending on the degree of myelofibrosis. One of the common complications of myeloid metaplasia is portal hypertension that results from intrahepatic thrombosis of small portal veins or from increased portal flow associated with the marked splenomegaly that invariably accompanies this entity (72). Splenic infarct is another complication characterized by acute or subacute onset of severe left upper quadrant abdominal pain radiating to the shoulder. Splenic infarct can be diagnosed by CT and usually resolves on its own within a few days, but can present as a large necrotic splenic mass in rare instances (Fig. 3). Treatment of idiopathic myelofibrosis is palliative and includes regular transfusions and administration of corticosteroids and androgen analogs (e.g., danazol) that help in decreasing the anemia. Hydroxyurea and alpha interferon are partially effective in dealing with the hepatosplenomegaly, thrombocytosis, and leukocytosis that accompany the disease. Some of the largest spleens have been associated with myeloid metaplasia and these often lead to mass effect symptoms

Waldenstrom’s Macroglobulinemia Waldenstrom’s macroglobulinemia (WM) is a lymphoplasmacytic disorder characterized by increased monoclonal IgM production, hyperviscosity, and anemia. Alkylating agents, nucleoside analogues and rituximab, constitute the

Figure 3 Splenic pseudocyst resulting from liquefaction of an old infarct in a patient with idiopathic myelofibrosis.

Chapter 24: The Spleen

such as compression of the stomach with resultant early satiety, diaphragmatic irritation, and interference with the normal inspiration leading to significant dyspnea. Splenectomy is of clear benefit in these cases. In the absence of these symptoms, splenectomy is still indicated as a palliative treatment in myelofibrosis but may be reserved for those cases with portal hypertension, hydroxyurea-resistant splenomegaly, and unresponsive anemia. In a study of 223 patients, the one-year benefit after splenectomy was highest in these patients with constitutional symptoms or portal hypertension, and lowest in patients with thrombocytopenia (73,74). Massive liver enlargement, marked thrombocytosis, and acute leukemic transformation are not uncommonly reported in patients undergoing splenectomy for idiopathic myelofibrosis (75,76), and constitute a major concern postoperatively. It is always advisable to check coagulation parameters and fibrin degradation products before operating on these patients; a high level of D-dimers preoperatively may indicate a subclinical coagulopathy and is associated with serious perioperative bleeding in idiopathic myelofibrosis. Surgery should be delayed in these patients (74).

Chronic Myeloid Leukemia Chronic myeloid leukemia (CML), which accounts for about 20% of leukemias in adults, is characterized by neoplastic proliferation of myeloid elements that are present in all stages of maturation. The distinguishing mark of CML is its association with a chromosome marker, the Philadelphia chromosome, which is formed by the fusion of fragments of chromosomes 9 and 22. CML, which can present almost at any age, is a triphasic disease: the chronic phase is usually asymptomatic, the accelerated phase is associated with constitutional symptoms, and the often-fatal blast phase is dominated by blasts’ proliferation, splenomegaly, and serious cytopenias. Chemotherapy (hydroxyurea and busulfan), interferon alpha, and tyrosine kinase inhibitors are recognized modes of therapy in different stages of CML. Bone marrow transplantation may be curative in selected chronic cases. Splenectomy is reserved as a last-resort option for patients that fail to respond to medical therapy. It does not offer any survival or long-term benefit nor does it alter the natural history of the disease (75).

Primary and Metastatic Tumors of the Spleen Primary malignant tumors of the spleen are extremely rare, and the most common among them is hemangiosarcoma. Hemangiosarcoma is a highly aggressive and rapidly fatal tumor. Splenic rupture is frequently described with this entity. Its prognosis is dismal, especially because the diagnosis is often made too late after the patient becomes symptomatic. Nonetheless, splenectomy can and should be performed in specific situations including the ‘‘fortunate’’ cases where the tumor is detected in the asymptomatic phase and before widespread metastasis has occurred (77). Kaposi’s sarcoma of the spleen has been reported in some cases of AIDS, but remains rare and difficult to diagnose (78). Metastasis to the spleen is also uncommon and usually indicates that the primary tumor has already metastasized to other tissues and organs. A vast majority of cancers are known to metastasize to the spleen, especially melanomas, breast, lung, colonic, and ovarian cancer. More than 50% of these metastatic cases are due to melanoma, where the long-term survival is limited to a few months. Splenectomy can provide good palliation in case the splenic metastasis is symptomatic and causing abdominal pain or discomfort. In

513

a study published in July of 2003, long-term disease-free survival has been found to increase with splenectomy, if the spleen is the sole organ of metastasis in cases of melanoma (79).

MISCELLANEOUS CONDITIONS Splenic Abscess Splenic abscess is a relatively uncommon, but life-threatening condition. The rarity of this entity is evidenced by less than 700 cases reported in the literature in the last century (80). Nevertheless, the incidence of splenic abscesses has been on the rise in the last few years with the increase in the number of immunocompromised patients, particularly due to the use of aggressive chemotherapeutic and transplant immunosuppressive drugs (80). The organisms most commonly involved in the etiology of splenic abscesses are staphylococcus, streptococcus, salmonella, and Escherichia coli. Salmonella is especially common in the areas where sickle cell disease, which is associated with splenic abscesses, is prevalent. Reports of mycobacteria (81,82) and fungal abscesses (83) are also increasing, especially in immunocompromised patients. It is thought that preexisting splenic pathology, such as splenic tumors or splenic infarction secondary to splenic vessels thrombosis or embolization, facilitates the hematologic or contiguous spread of an infection to the affected area of the spleen. The clinical triad of splenic abscess is fever, leukocytosis, and abdominal pain. The pain, which is present in only 50% of the patients, can be diffuse or localized to the left upper quadrant of the abdomen. Diagnosis of the abscess can be made by ultrasonography or technetium 99m sulfur-colloid scan, but CT scan remains the diagnostic tool of choice with a reported sensitivity over 95% (80,84). Antibiotics have significantly decreased the mortality associated with these abscesses and should be administered as soon as the diagnosis is established. Splenectomy remains the gold standard for treatment of splenic abscesses, but reports of success of ultrasonographic or CT-guided percutaneaous drainage procedure in specific cases are increasing (85–87). Currently, these procedures are recommended for solitary, well-delineated, and unilocular abscesses (85,86). Fungal abscesses can be managed successfully with antifungal therapy without a splenectomy, as long as the diagnosis is clear and certain (83,88). Suspicion of failure of percutaneaous procedures or of antifungal therapy should immediately lead to splenectomy.

Splenic Cysts The splenic cyst is an unusual and asymptomatic entity, often discovered incidentally on ultrasound or CT examination. Occasionally, these cysts can reach large sizes, at which point symptoms may emerge from compression of adjacent organs or from diaphragmatic irritation. These symptoms include early satiety, shoulder pain, dyspnea, pleuritic chest pain, and abdominal heaviness, pain, or tenderness. Splenic cysts are divided into two classifications: true cysts, which can be either parasitic or nonparasitic in origin, and pseudocysts. True parasitic cysts are the most common splenic cysts worldwide, and are almost exclusively due to hydatid disease (Echinococcus species). Some studies suggest that the spleen is the third most common location of involvement of hydatid disease after the liver and the lung (89). Typical ultrasonographic findings include cystic membranes and septa. CT shows cyst wall calcification with internal wall scolices (daughter cysts), and is specific in more than 90% of the cases (90). Serologic testing for Echinococcus may

medwedi.ru

514

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

prove helpful. Although the incidence of echinococcal splenic cysts in the United States is very low, the surgeon should always rule it out before operating on a patient with a splenic cyst. This is necessary because if the cyst ruptures intraoperatively, spillage of echinococcal material can result in severe anaphylactic shock and peritoneal seeding. Splenectomy is still the treatment of choice in case of echinococcal cysts, because medical therapy with Albendazole or Mebendazole is ineffective alone (90). Some radiologists strongly suggest that the sonographically guided percutaneaous puncture, aspiration, injection, and reaspiration (PAIR) technique with the use of sclerosing agents like alcohol, hypertonic saline, or silver nitrate solutions is an effective and reliable choice of treatment (91). However, because only a few cases reporting the use of the PAIR technique exist, further outcome studies are needed to establish it as a first-line therapy in place of splenectomy. True nonparasitic cysts are rare and include entities such as epidermoid and dermoid cysts as well as benign cystic tumors such as cystic hemangioma and cystic lymphangioma. The majority of these cysts are easily diagnosed on CT scans. Surgery is indicated only if the cysts become large and symptomatic, and consists of total splenectomy. Partial splenectomy is advised by some surgeons in order to preserve splenic function and avoid postsplenectomy infections, especially in children. Percutaneous drainage attempts were generally unsuccessful. Pseudocysts are much more common than true nonparasitic cysts and even more common than echinococcal cysts in nonendemic areas like the United States. These cysts, often unilocular and with a thick wall, lack an epithelial lining and often result from liquefaction of old hematomas and areas of old infection, inflammation, or infarction (due to sickle cell disease or idiopathic myelofibrosis for example) (Fig. 3). A careful history often succeeds in eliciting the memory of a previous trauma to the abdomen. It is generally agreed upon that pseudocysts should be observed, because many will involute over time. If the pseudocyst becomes symptomatic, however, surgical treatment is highly successful. Splenectomy, partial or complete, is the preferred procedure. Percutaneaous drainage techniques or cyst decapsulation have also been reported as successful adjunctive modes of management if the diagnosis is certain (92). Pancreatic pseudocysts, a common complication of pancreatitis, are capable on rare occasions of eroding into the spleen and involving its parenchyma. Diagnosed by CT scan, these pseudocysts have a high risk for profuse bleeding resulting in significant morbidity and mortality. Immediate surgical intervention is needed, even if the patient is clinically stable, and a splenectomy along with a distal pancreatectomy should be performed and is usually curative (93,94). Moreover, pancreatitis can result in direct splenic involvement in about 1% to 5% of patients and is usually due to pancreatic enzymes leakage and erosion through splenic structures. Splenic abscesses, hemorrhages, hematomas, ruptures, and infarctions have all been reported after pancreatitis (Fig. 4) (95).

Benign Tumors of the Spleen Benign tumors of the spleen are uncommon and are often identified incidentally on a CT scan, intraoperatively or at autopsy. The most common among these tumors are hemangiomas and lymphangiomas. Lipomas, hamartomas, and inflammatory pseudotumors are additional rare entities that may involve the spleen. The latter can mimic lymphomas clinically, and immunohistochemical testing is often

Figure 4 Splenic hematoma resulting from pancreatitis.

necessary to differentiate between the two (12). No malignant potential has been reported with inflammatory pseudotumors of the spleen. Treatment for these entities is not needed unless they become symptomatic by causing splenomegaly, irritation of the diaphragm, or, in the case of hemangioma, result in coagulation disorders. Splenectomy for inflammatory pseudotumors can be difficult because of the extensive inflammation and adhesions often associated with this entity.

Felty’s Syndrome Felty’s syndrome is an uncommon but severe disease consisting of a triad of rheumatoid arthritis, granulocytopenia, and splenomegaly. Often splenomegaly and neutropenia do not show up until late in the course of the disease. The etiology is similar to rheumatoid arthritis with antibodies against granulocytes and granulocyte growth factor often found in the patient’s serum (96). The arthritis is severe, resulting in joint and bone deformities while the granulocytopenia predisposes the patient to serious and recurrent infections. Leg ulcers are another common complication of Felty’s syndrome. Although the size of the spleen does not correlate well with the severity of the arthritis or with the severity of the neutropenia, splenectomy, along with hematopoietic growth factors, remains an essential component in the treatment of Felty’s syndrome. Improvement of arthritis (97) and leg ulcers (98) has been previously reported after splenectomy. In addition, splenectomy is successful in elevating the granulocyte count in most patients; however, neutropenia recurs in almost 25% of patients. The effectiveness of splenectomy in preventing infections and prolonging survival is more controversial. Currently, splenectomy is performed after drug therapy fails, mainly on those patients with severe recurrent infections or with significant neutropenia (< 1000/mm3). Other classic drugs in the treatment of rheumatoid arthritis like gold salts and methotrexate have been tried with evidence of limited success in improving both the rheumatologic and the hematologic manifestations of Felty’s syndrome.

Gaucher’s Disease Gaucher’s disease is an autosomal recessive lysosomal storage disease caused by the deficiency of glucocerebrosidase with resultant accumulation of glucocerebrosides in the

Chapter 24: The Spleen

lysosomes of the cells, particularly those of the reticuloendothelial system. Three types have been described, each with a different degree of enzyme deficiency. More than 99% of patients suffer from type I disease, the form seen in adults; types II and III are more severe and start in infancy. Splenomegaly is usually the earliest and most common sign of Gaucher’s disease; it has often been described as the most impressive splenomegaly a surgeon will encounter in clinical practice. Hepatomegaly is often present, and cirrhosis may be seen in severe cases. Skeletal involvement includes osteopenia and failure of bone remodeling that result in growth retardation and spontaneous fractures. Anemia and thrombocytopenia are additional manifestations of the disease and are related to hypersplenism rather than to the involvement of the bone marrow. Patients with severe anemia and thrombocytopenia or with morbid splenomegaly partially benefit from splenectomy. The introduction of intravenous enzyme replacement therapy (ERT) in the early 1990s limited the use of splenectomy significantly. ERT currently includes two similar enzymes: alglucerase, produced from human placenta, and imiglucerase, prepared by DNA recombinant technology. The molecular engineering of alglucerase and imiglucerase is a real ‘‘chef-d’oeuvre.’’ They are modified enzymes that have been attached to mannose residues, which will help them to be recognized specifically by the abnormal and enzyme-deficient lysosomes. ERT in Gaucher’s disease may reverse most of the manifestations of this disease. Hepatosplenomegaly and hematologic abnormalities are significantly decreased during the time span of less than one year (99,100). Skeletal disease is slower to respond. However, type II disease, for which no current treatment exists, does not respond to ERT. The costs of ERT, which can amount to more than $500,000 annually, raise important financial and ethical dilemmas in relation to treatment and patient care issues and require special attention. Substrate reduction therapy, with the use of agents like miglustat that decrease the biosynthesis of glucocerebrosides, is a new approach for the treatment of Gaucher’s disease. This treatment modality is based on the premise that decreasing the amount of substrate of glucocerebrosidase can balance the deficiency of this enzyme in Gaucher’s disease (101). Limited, but encouraging results are available. Currently, splenectomy is reserved only for uncommon cases that fail to respond to enzymatic therapy. Previous claims of the association of splenectomy with risk of cancer development in this disease have not been substantiated by recent studies.

Sarcoidosis Sarcoidosis is a systemic disease that can involve almost any organ of the body with noncaseating granulomas. Pulmonary and dermatologic involvements are usually present with cough, dyspnea, hilar lymphadenopathy, and skin lesions as the most frequent presentations. Hypercalcemia is almost universal. The spleen is involved in 6% to 31% of the cases, with evidence of splenomegaly and hypersplenism (12). Spontaneous splenic rupture can occasionally occur. Although no large series on the effect of splenectomy in sarcoidosis is available, the response to splenectomy seems to be acceptable with improvement in the cytopenias associated with hypersplenism (102). Decrease in hypercalcemia has also been reported after splenectomy (103).

Splenic Artery Aneurysm Splenic artery aneurysms are rare and occur most frequently in women, usually as a manifestation of medial dysplasia of

515

the arterial wall. In men, atherosclerosis is the most common cause for these aneurysms followed by pancreatitis, trauma, and septic emboli. When asymptomatic, the aneurysms are discovered incidentally on conventional abdominal X rays and appear as ‘‘eggshell’’ calcifications in the left upper quadrant. Symptomatic presentation is uncommon, and, when present, is nonspecific. The risk of rupture, estimated to be around 7%, is life threatening, and increases significantly in liver transplant recipients and in pregnant women. Therefore, resection or ligation is recommended whenever the aneurysm is symptomatic, larger than 2.5 cm or occurs in a woman anticipating pregnancy (12). Concomitant splenectomy may be needed depending on the location of the aneurysm and its proximity to the splenic hilum. Percutaneous embolization and coiling are currently used and are gaining popularity in the treatment of small and multiple splenic artery aneurysms.

SPLENIC TRAUMA The management of splenic trauma underwent considerable changes in the last few decades. Much controversy exists with respect to the operative versus nonoperative approach in the trauma patient with a splenic injury. The next section will elucidate some of the these controversies, suggest guidelines of management, and emphasize evidence-based material in view of the flood of conflicting studies and reports regarding splenic injury in the last few years.

Injury to the Spleen The spleen is the most commonly injured organ in both blunt and penetrating abdominal trauma. Motor vehicle accidents are the leading cause of injury to the spleen with pedestrian or bicycle accidents, falls, and blunt trauma induced by physical assaults or sports (e.g., boxing) as additional common causes. The anatomy of the spleen plays an important role in its pattern of injury. Attached in place by its suspensory ligaments and partially protected by the lower costal margin, the spleen is susceptible to decelerating injury in motor vehicle accidents (104), directly transferred kinetic energy, or occasionally a puncture or laceration injury when the lower ribs are fractured. In motor vehicle accidents, lateral impact seems to be an additional risk factor for splenic involvement, with the person seated closer to the side of collision placed at greater risk (105). Seat belts do not protect against splenic injury and can even contribute to splenic contusion occurring during the accident (105). The ability of the spleen to withstand the impact of a disruptive force, measured as the ‘‘breaking stress,’’ decreases significantly once its capsule is disrupted (104). Children are particularly susceptible to splenic injury following blunt abdominal trauma, because they have more compact torsos, smaller anteroposterior diameter, and less of a protective fat layer than adults.

Diagnosis Undetected splenic injuries result in a significant increase in mortality and morbidity for the patient. This injury can present as intra-abdominal bleeding with hemodynamic instability, pain in the left upper quadrant of the abdomen in a hemodynamically stable patient, or as an incidental finding on CT scan. Occasional patients present with a ‘‘delayed’’ rupture after a seemingly minor abdominal trauma. Abdominal trauma is often associated with head trauma, spinal trauma, or intake of intoxicating substances,

medwedi.ru

516

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

making the history and physical exam unreliable. Conventional radiographs are rarely necessary, but can identify left lower rib fractures or pelvic fractures that often accompany splenic injury. The three most important modalities of diagnosis and evaluation of abdominal trauma in general, and splenic injury specifically, are diagnostic peritoneal lavage (DPL), ultrasonography [focused assessment with sonography for trauma (FAST)], and CT scan.

Diagnostic Peritoneal Lavage Several previous reports on the sensitivity of DPL appeared in the early use of this procedure, most of them finding values approximating 100%; thus DPL was considered as the ideal test for the detection of intra-abdominal injury. However, surgeons later discovered that DPL’s high sensitivity might not be as ‘‘ideal’’ or desirable as previously thought. Many laparotomies, performed on the results of the lavage, revealed only minimal intra-abdominal injuries and in retrospect were classified as ‘‘nonindicated’’ or ‘‘nontherapeutic.’’ An additional shortcoming of DPL is its lower specificity in splenic injury when compared to CT scanning. DPL specificity, described in earlier reports as above 98% (106), was found in two separate prospective studies to be between 84% and 87% (107,108). Another prospective study conducted in 1999 suggested that the use of DPL may not be essential for the evaluation of blunt abdominal trauma, and that algorithms based on clinical stability, CT scanning, and ultrasonography are less invasive and have comparable results (109).

Ultrasonography Ultrasonographic examination is gaining a wider acceptance as part of the initial screening of patients with abdominal trauma. FAST has its enthusiastic supporters as a fiveminute, noninvasive, and inexpensive survey that can be performed bedside by trained surgeons to evaluate patients with abdominal trauma. Today, in an effort to decrease the number of nontherapeutic laparotomies, FAST is proposed and generally accepted as an alternative to peritoneal lavage in the evaluation of the trauma patient for the presence or absence of intraperitoneal hemorrhage. Several prospective studies evaluated the sensitivity and specificity of ultrasound or FAST in cases of blunt abdominal trauma, especially with respect to the presence of peritoneal cavity fluids. These were found to be between 86% and 92% for the sensitivity and between 92% and 98% for the specificity (107,110,111). A positive ultrasound is thus a reasonable indication to laparotomy, while a negative result will not rule out the need for surgery, making evaluation by CT scan a necessity. This was again emphasized by another study by Miller et al. in 2003, which suggested that FAST cannot be the sole screening technique in hemodynamically stable patients because it leads to the underdiagnosis of intra-abdominal injuries (112).

and is reported in most recent studies to be above 95% (107,113,114). CT scan is also able to provide details on the extent of injury of the spleen not matched by the previously discussed diagnostic tools. In addition, the application of helical and spiral techniques has significantly enhanced the diagnostic ability of CT, with an increase in the resolution of the imaging and in the ability to manipulate separate images to obtain the best three-dimensional understanding of the injury (115). Although not proven by clinical trials, oral and intravenous contrast agents increase the utility of CT scanning in splenic trauma by providing a better definition of the extent of injury of the spleen, a better detection of hematomas (Fig. 5) and a better visualization of bowels and their differentiation from adjacent tissue. An additional benefit of CT scanning is its ability to quantify, and not just detect hemoperitoneum. However, the major role of CT remains its potential ability to delineate a certain guideline to select patients for nonoperative management. In the late 1980s, The American Association for the Surgery of Trauma (AAST) devised and published injury severity scores for individual organs, including the spleen (Table 6) (116). This scale, which was revised in 1994, is mainly helpful in clinical research and in communication among surgeons, radiologists, and researchers. Moreover, it has been useful in establishing a tentative framework that helps trauma surgeons in deciding the plan of management depending on the severity of the splenic injury. In a multicenter experience, the failure rate of nonoperative treatment correlated well with the AAST classification and was reported as 0% for grade I, 8% for grade II, 19% for grade III, and 100% for grade IV injuries (117). Other attempts at classification and scoring the extent of injury are useful in specific situations, but are clinically less reliable. Currently, and according to the extensive evidence-based search and evaluation of literature done by the Eastern Association for the Surgery of Trauma (EAST) in 2003 (113), the severity of splenic injury, as assessed by CT grading, is not a contraindication to nonoperative management. This is based, according to the same association, on ‘‘reasonably justifiable scientific evidence’’ and is ‘‘strongly supported by expert opinion.’’

Computed Tomography Abdominal CT scan is the most reliable method to diagnose and evaluate the extent of splenic injury in abdominal trauma (113). In fact, the concept of nonoperative management of abdominal injuries was proposed after the frequent incidental discovery of splenic injury in asymptomatic hemodynamically stable patients. The sensitivity of CT scanning in blunt abdominal trauma and in the detection of splenic injury is between 90% and 98%. Its specificity is higher than peritoneal lavage,

Figure 5 Splenic subcapsular hematoma secondary to blunt trauma to the abdomen. Source: Courtesy of A. Hirshberg MD, Ben Taub General Hospital, Houston, Texas, U.S.A.

Chapter 24: The Spleen

Table 6 AAST Classification of Splenic Injury Grade I. Hematoma Laceration II. Hematoma Laceration III. Hematoma

Laceration IV. Laceration

V. Laceration Vascular

Injury Subcapsular, < 10% surface area Capsular tear, < 1 cm parenchymal depth Subcapsular, 10–50% surface area; intraparenchymal, < 5 cm in diameter 1–3 cm parenchymal depth, which does not involve a trabecular vessel Subcapsular, > 50% surface area or expanding; ruptured subcapsular, or parenchymal hematoma Intraparenchymal hematoma > 5 cm or expanding > 3 cm parenchymal depth or involving trabecular vessels Laceration involving segmental or hilar vessels producing major devascularization ( > 25% of spleen) Completely shattered spleen Hilar vascular injury, which devascularizes spleen

Source: From Ref. 116.

Angiography Although angiography is not routinely used in the management of splenic injury, it remains both a diagnostic and an interventional adjunct tool available to the trauma surgeon. It may be performed when a major vessel injury is suspected on CT scan or ultrasound or in order to localize an ongoing bleed. In a 1995-study, Sclafani et al. suggested that arteriography could help in a more ‘‘clever’’ choice of plan of management. Their study found a good correlation between the absence of contrast material extravasation (‘‘contrast blush’’) on angiography of the spleen and the success of nonsurgical treatment (113,118). Extravasation, whether discovered by CT scan or angiography, is thus an indication for surgical approach or for selective embolization in stable patients. This latter procedure, which can be done with coils or gelfoam pledgets, has been successful in the treatment of more than 75% of patients with contrast blush in the spleen, thus increasing the number of patients managed nonoperatively (113,118,119). The percentage of success of nonoperative management can be even higher if splenic artery pseudoaneurysms are identified and embolized during the same procedure (119).

517

the extent of organ disruption, and (iii) the excessive appearance in medical literature of the term ‘‘nontherapeutic laparotomy’’ where laparotomies performed on the basis of clinical presentation and peritoneal lavage revealed only minimal splenic injury that could not justify its removal. Nonoperative management of splenic injury is now the standard of care in the pediatric population and is reported to be successful in about 97% of patients (120). The success of nonoperative therapy with children was extended to the adult population with more than 65% of adult trauma cases successfully managed without laparotomy (120,121). This approach was of great importance in decreasing the morbidity and mortality associated with nontherapeutic laparotomies and the potential devastating effects of splenectomy on the immune system. Support for the nonoperative choice has increased significantly in the last 10 to 15 years, and the choice of adult trauma patients that will be managed nonsurgically became more liberal. In fact, the question today in the practice of surgical trauma of the spleen is not whether nonoperative choice is successful but whether the right patient is being selected. An impressive number of articles regarding indications and contraindications for nonoperative management exists and presents conflicting data; thus, the surgeon must be critical in selecting guidelines for the management of splenic trauma. According to the practice guidelines of the EAST, ‘‘there are class II and mostly class III data to suggest that nonoperative management of blunt hepatic and/or splenic injuries in a hemodynamically stable patient is reasonable’’ (113). With current literature, hemodynamic instability, tentatively defined as systolic blood pressure below 85 mmHg or pulse rate above 125 beats per minute, is the most reliable predictor of the failure of nonsurgical approach. Extravasation of contrast material on CT scanning (contrast blush) suggests active hemorrhage and is a strong indication for operative choice (Fig. 6) (113,122). Those patients who were treated conservatively despite this finding were consistently at a greater risk for failure of their nonsurgical management (115,123). Although higher grades of splenic injuries (like grade IV or V injury on the AAST Organ Injury Scale)(Fig. 7) or the

Management Nonoperative Approach Management of splenic injury has evolved to a great extent over the last three decades. During the early 1970s, a positive DPL was a clear indication for an exploratory laparotomy because one might miss an ongoing hemorrhage or other intra-abdominal injuries. The traditional teaching in academic hospitals was that once the spleen is injured, a splenectomy is guaranteed because this ‘‘nonvital’’ organ can rebleed and endanger the life of the patient. Later in the 20th century, surgeons, especially pediatric surgeons, started to be more selective in their choice of patients to undergo laparotomy or splenectomy. Factors which led to the concept of nonoperative management of splenic injuries include (i) the repetitive reporting and description of serious and fatal infections in patients who underwent splenectomy, especially children, (ii) the rapid advance of radiologic techniques, especially ultrasonography and CT, and their help in discovering and delineating

Figure 6 CT scan of a patient with splenic trauma showing contrast material extravasation (contrast blush). Abbreviation: CT, computed tomography. Source: From Ref. 122.

medwedi.ru

518

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

Splenic Salvage Techniques

Figure 7 Grade V splenic injury in a patient with blunt abdominal trauma. Source: Courtesy of A. Hirshberg MD, Ben Taub General Hospital, Houston, Texas, U.S.A.

presence of hemoperitoneum may be associated with a higher risk of failure (121), these alone are not considered contraindications to nonoperative approach (113), and a significant number of retrospective studies succeeded in demonstrating acceptable rates of success with nonsurgical treatment (124). Nonetheless, in a recent prospective study published by Velmahos et al. (125), 206 patients with abdominal trauma were followed and higher rates of failure of nonoperative treatment were recorded. The failure rate for nonsurgical management of splenic injury was higher (34%) than that of hepatic injury (17%). The same study also suggests that positive ultrasonographic findings in a hemodynamically stable patient, significant hemoperitoneum (>300 mL), and the need for transfusions are independent predictors of the failure of nonoperative choice. The presence of splenic injury along with these three factors predicted nonsurgical treatment failure in 96% of the patients (125). The need for further prospective investigations to delineate indications for nonoperative approach in stable patients with severe splenic injury and/or hemoperitoneum cannot be overemphasized. According to recent investigations, previously existent splenic pathology, neurologic impairment (altered mental status), and older age (>55 years) are not contraindications to nonoperative management as previously thought, and the success rates in these specific groups compares well to the rest of the nonoperatively managed trauma population (121,126,127). Nonoperative approach is associated with some complications, especially when applied to extensive high-grade splenic injuries. Delayed splenic rupture is a potentially lethal complication and includes a missed primary splenic rupture or a true secondary rupture not present upon review of the initial CT scan. This true rupture could be due to an increase in osmotic pressure accompanying the lysis of the clot or due to the expansion of a subcapsular hematoma (127). Other potential complications include formation of arteriovenous fistulae, arterial pseudoaneurysms, splenic abscesses, and splenic pseudocysts.

Attempts at repairing the spleen began as a result of the recognition of its immunologic role and the potential morbidities and mortalities associated with splenectomy, most important of which being the serious overwhelming postsplenectomy sepsis. Moreover, it was noted that the empty abdominal space created after the performance of a splenectomy rapidly fills with blood clots, creating a suitable niche for bacterial infection and subsequent abscess formation. A nine-year experience at an urban trauma center revealed that splenorrhaphy, or splenic repair, was possible in slightly less than one half of patients (128). Splenic salvage is now performed less often because of the recognition of the success of nonoperative management. In general, splenic repair should be attempted, instead of a total splenectomy, whenever feasible. Hemodynamic instability, serious multiple organ injury, or major lacerations that involve the hilum prelude splenic salvage and should lead to splenectomy. If the patient requires more than two units of blood intraoperatively, or the salvage procedure requires a long operative time (>40 minutes), the risk of transfusion or procedure-related complications may outweigh the risk of postsplenectomy sepsis, and total splenectomy becomes a better choice. The risk of bleeding with splenic repair, if done properly, is minimal and does not exceed 1% (128,129). A full mobilization of the spleen from its anatomic bed to the abdominal incision wound is necessary by division of the splenic ligaments and the peritoneal attachments (Fig. 8). This is one of the most important steps of the procedure, and should be done carefully in order to avoid putting traction on the spleen and risking rupture of the splenic capsule. The tail of the pancreas should be visualized at all times in order to avoid its injury. Once the spleen is free and completely under vision, the surgeon should inspect it and decide what mode of repair would be most suitable. Compression of the splenic artery, as it courses in the tail of the pancreas or at the hilum, helps in adequate control of bleeding in order to evaluate the situation. Removal of blood clots, ligation of bleeding vessels, and debridement of fragmented, loose, or nonviable tissue are essential. Superficial injuries or injuries of low grades on the AAST scale can be successfully treated with cauterization, argon beam laser, or by application of one of the several hemostatic agents available. These include gelfoam, microcrystalline collagen, topical thrombin sponges, fibrin glue, and oxidized cellulose. Among these, fibrin glue has been reported to result in excellent hemostatic results with minimal recurrent or persistent bleeding (130). Deeper injuries of the spleen will need suturing (splenorrhaphy), partial splenectomy, or mesh wrapping. The use of 3–0 Prolene interrupted suturing should be done along the capsule and tied without putting too much traction or shearing forces on the spleen. With the capsule of an elderly patient being usually weaker, Teflon or collagen pledgets should be used as a platform over which the sutures are placed. This gives the surgeon a wider margin of error and prevents excessive injury to the splenic capsule. If nonviable parenchymal tissue has been debrided, the omentum can be used as a bridge between the two sides of the splenic parenchyma and the sutures taken on either side of that bridge (Fig. 8A). Tamponade of the spleen with mesh wrapping is an effective option that can be applied for higher grades of splenic injury, especially when there are multiple splenic lacerations or tears. This mesh is usually composed of

Chapter 24: The Spleen

biodegradable polyglycolic acid or polyglactin and should be wrapped around the full body of the spleen (Fig. 8B). In case of failure of suturing, or if a defined segment(s) of the spleen is injured, partial splenectomy can be attempted. This is possibly due to the segmental anatomy of the spleen and the division of the splenic artery into different branches before entering the hilum. Arteries that supply this designed segment or even adjacent segments can be ligated before resection of the segment as an attempt to minimize fluid loss (Fig. 8C). Surgeons are encouraged to save a part of the resected spleen in case autotransplantation is considered. This latter procedure, which can be done following splenorrhaphy or partial or total splenectomy, involves cutting 1- to 2-mm slices of splenic parenchyma and implanting them in different areas of the abdomen. Larger sizes are less viable and often rapidly undergo necrosis. The omental pouch has been found in animal studies to be the best site to perform this autotransplantation. This technique is based on the assumption that ‘‘splenosis’’ or functional remnant splenic tissue might help prevent postsplenectomy infections. In fact, some splenic phagocytic function is preserved with autotransplantation and the levels of IgM commonly return to normal. Decreases in the amount of Howell–Jolly bodies and pitted RBCs are also reported (131). Whether this implanted splenic tissue actually helps in decreasing the risk of postsplenectomy sepsis or not is more controversial. The current data is not solid or convincing enough to suggest less susceptibility to overwhelming postsplenectomy infection (OPSI). Moreover, some studies suggest that more than 40% of the initial splenic mass is needed in order to significantly preserve splenic function (132), and that implantation of up to 80% of the splenic tissue is necessary to provide optimum survival in case of bacteremic sepsis (133). This could make partial splenectomy with good arterial preservation a more practical option than splenic autotransplantation. Splenectomy is reserved for those patients who fail salvage trials and for those who initially present with severe

519

hemodynamic instability or serious injuries like a shuttered or avulsed spleen. The trauma surgeon should not hesitate to shift to the option of splenectomy whenever nonsurgical or salvage attempts seem to be failing.

Follow-Up Evaluations Several studies were published to establish the need for radiologic follow-up of abdominal trauma patients, especially those treated nonoperatively. However, an agreement on follow-up treatment has not been reached and the need for randomized clinical trials to help elucidate the benefit of follow-up CT scans or ultrasounds is increasing. This is mainly due to the benefits of nonsurgical treatment being challenged by the delayed complications not previously known when splenectomy was the standard of care. Some of these complications, as discussed previously, can be managed nonsurgically with interventional radiology, which encouraged many physicians to practice regular follow-up imaging (127). As an example, Davis et al. strongly recommend follow-up CT scans and suggest that 74% of contrast blush incidences and a large number of pseudoaneurysms are detected on these follow-up images and thus can be managed accordingly (119). According to the EAST Work Group, there is no evidence-based data that suggest a benefit from serial CT scanning without clinical indications (113). Moreover, there is no scientific evidence to suggest that bed rest or restricted activity is beneficial for the patients managed nonsurgically, but evidence of healing must be present before the patient is advised to resume regular activities, including contact sports (113). The time needed for the spleen to recover was evaluated in a study published in 2001 and demonstrated that the healing time is largely dependent on the AAST grade of injury. For example, 88% of grade II injuries healed within 64 days, while 77% of grade IV injuries needed 81 days to heal (134). Therefore, a period of three months is a reasonable time for patients to resume regular or sports-related activity.

Figure 8 Injured spleen mobilized into the abdominal incision. Splenic salvage techniques include: (A) omental bridging of debrided splenic parenchyma with the placement of interrupted sutures; (B) polyglactin mesh tamponade for multiple splenic lacerations; (C) partial splenectomy after segmental artery ligation.

medwedi.ru

520

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

SPLENECTOMY Preoperative Preparation The surgeon must be aware of the specific condition of the patient and all the complications of the entity that caused the splenic disease. The need for transfusion of platelets should be assessed and addressed preoperatively. If the platelet count is above 25,000/mL and the platelet function is normal, there is rarely a need for such a transfusion. Patients with ITP and severe thrombocytopenia may require the use of agents such as IVIG, which help in elevating the platelets counts to relatively safe levels. Prophylactic antibiotics may be administered for those patients who suffer from immunosppression secondary to their primary disease or to the mode of therapy they already received. Preoperative vaccination is an important step of the preparation of patients for an elective splenectomy. However, an urgent splenectomy, as in the case of trauma, rarely offers such an opportunity. The most important of the vaccines, preferably given several weeks before the operation, is the pnemococcal vaccine. Additional vaccines are the H. influenzae B and the meningococcal vaccines, which should be given when possible, especially for high-risk groups. The importance of these vaccines and the best timing of their administration pre- and postoperatively (which will be discussed in a latter section of this chapter) are derived from the potential seriousness of postsplenectomy infections, especially with encapsulated bacteria.

Open Splenectomy Several incisions are possible in order to access the spleen including upper midline, left subcostal, and even thoracoabdominal incisions. A search for accessory spleens is performed first. The spleen is then mobilized by dividing the splenorenal, splenophrenic, and splenocolic ligaments. Intact ligaments may hinder control of any unexpected bleeding if ligation of splenic vessels is attempted before division of the ligaments. The spleen is moved anteriorly and out of the abdomen. The gastrosplenic ligament may then be divided with particular attention to the short gastric vessels that must be identified and ligated without running the risk of injuring the gastric wall. The splenic artery and vein are then separately ligated, while the tail of the pancreas is constantly under vision. The best place to ligate these vessels may be next to their entry into the splenic parenchyma in order to avoid pancreatic injury. The spleen is then removed medially, the short gastric vessels and the vessels around the tail of the pancreas checked for hemostasis, and the abdomen closed. Alternatively, in cases of massive splenomegaly, the splenic vessels can be accessed and ligated through the lesser sac, resulting in the shrinking of the spleen to a certain extent and decreasing the risk of bleeding. A drain is usually not advised because it increases the risk of intraperitoneal infection. If a drain is placed, it should be of the closed suction type and should be removed as soon as the surgeon feels confident that no persistent bleeding is present.

Laparoscopic Splenectomy LS is today’s procedure of choice for elective splenectomies. Several recent reports confirmed that LS has comparable postoperative results to open splenectomy along with the advantages of a minimally invasive technique. These include less mean blood loss, earlier tolerance of regular diet, less postoperative pain with significantly less need for intravenous narcotics, shorter hospital stay, and better cosmetic results. The laparoscopic approach is successful

in both children and adults and is particularly effective for the removal of normal-sized spleens like those found in patients with ITP. Application of LS in cases of massive splenomegaly is also feasible and has been described. The use of hand-assisted laparoscopic surgery for very large spleens is probably helpful because it offers the advantages of a minimally invasive procedure in the presence of a giant spleen (135). Splenic embolization with fragments of sterile sponge gelatin that ablate a large proportion of the arterial supply of the spleen is occasionally needed before LS to decrease blood loss (Fig. 9); however, ablation of more than 70% of the splenic vasculature has been proposed for optimal results (12). A study performed in 1998 suggested that this technique is mostly useful in spleens with a length between 20 and 30 cm only, while those patients with shorter and longer spleens do not benefit from preoperative splenic embolization (136). The patient is placed in the right lateral position, and four trocars are placed along the left costal margin while the port for the camera is placed more inferiorly. The sequence of intraoperative steps to be followed laparoscopically is similar to that already described in the open technique. By the end of the procedure, the spleen is placed in a special extraction bag, fragmented, and carefully retrieved in pieces from a trocar site. Disadvantages of LS include a longer operative time than open splenectomy and the possibility of conversion to the open technique. Nevertheless, this operative time difference has been found to be related to the learning curve of the surgeon, and both the operative time and the rate of conversion were found to decrease significantly after the surgeon performs the first 10 to 20 operations (137). Application of robotics technology has been tried in gastrointestinal procedures and in LS specifically, and has shown significant promise. The advantages of the robot-assisted technique include filtering of the surgeon’s hand tremor and transforming the large-scale hand motion into small movements of the robotic arm (138,139).

Accessory Splenectomy Some cases of relapsing hematologic disorders, especially in patients with ITP, have been suggested to be due to an undetected accessory spleen at the time of initial surgery. Due to difficulty in locating accessory spleens at reoperation, detection of splenic tissue preoperatively is advised. This can be done with the use of technetium-99 sulfur colloid or, in the case of ITP, with indium 111 platelet-labeled radionuclide studies. If splenic tissue is detected, accessory splenectomy is necessary (34). These accessory spleens, found in 15% to 30% of the population with recurrent ITP, are most commonly located in the area of the previous spleen; however, a search for them in more distant sites is recommended as well (Table 1). Preoperative injection of radiolabeled platelets in patients with ITP along with the intraoperative use of a sterile hand-held gamma probe is very helpful in the localization of accessory splenic tissue and in the confirmation of its complete excision. Several reports of successful remission of relapsing or persistent ITP are present in literature, some of which suggesting a remission rate as high as 66% after accessory splenectomy (34).

Complications of Splenectomy In addition to the complications potentially seen after any gastrointestinal operation such as intraoperative blood loss, pulmonary lower lobe atelactasis, postoperative ileus, and

Chapter 24: The Spleen

Figure 9 Angiographic embolization. (A) Pre-embolization splenic vessels (B) postembolization with gelfoam pledgets distally and coils proximally. Source: Courtesy of C. Whigham MD, Ben Taub General Hospital, Houston, Texas, U.S.A.

wound infection, splenectomy has been associated with some serious sequelae such as postoperative sepsis and thrombocytosis. Moreover, intraoperative iatrogenic injury to the pancreas may result in pancreatitis, pancreatic pseudocyst, or pancreatic fistula. In addition, injuring the stomach may lead to abscess or gastric fistula formation.

Thrombocytosis Platelet levels increase in the first one to three weeks after splenectomy. These levels can reach as high as 2,000,000/mL, especially in patients with myeloproliferative disorders. Although the relationship between this thrombocytosis and thrombotic events has not been demonstrated (140), the seriousness of any potential thromboembolic phenomenon like deep venous thrombosis or pulmonary embolism is sufficient to warrant an antiplatelet agent such as aspirin, when the platelet counts reach levels higher than 1,000,000/mL. In a study by Pimpl in 1989, a review of 37,012 autopsies of patients, who underwent splenectomies, was performed. The risk of pulmonary embolism as a cause of death was found to be higher than in control autopsies (141). The causal relationship between this increased incidence of embolism and the presence of thrombocytosis has not been demonstrated.

Overwhelming Postsplenectomy Infection As repeatedly mentioned in earlier sections, patients who undergo splenectomy are at an increased risk for fulminant sepsis due to encapsulated bacteria, mostly S. pneumoniae. This entity, called OPSI, changed the view of the spleen as a dispensable organ in the mid-20th century. Although OPSI can occur in any asplenic patient, its incidence is highest among the pediatric population and in those patients who undergo splenectomy for hematologic and oncologic disorders, and lowest for the adults who undergo splenectomy for trauma. It is especially prevalent in patients with thalassemia major and Hodgkin’s lymphoma (12,143,144). The risk of postsplenectomy sepsis is particularly high during the first two postoperative years (144), but this risk persists indefinitely with a lifetime prevalence estimated to be between 1% and 5% (12,143). Mortality from OPSI exceeds 50%, and mortalities as high as 80% have been described in pnemococcal infections. Survivors often struggle for a long period of time in the intensive care unit. Pathogens. The pathogens responsible for this entity are mainly S. pneumoniae, H. influenzae, and N. meningitidis.

521

E. coli, Pseudomonas and group B streptococcus are less commonly involved. Capnocytophaga canimorsus has also been reported as a rare cause of OPSI, classically occurring after dog scratches or dog bites (145). The asplenic patient is also at an increased risk for parasitic infections like malaria and babesiosis. In fact, one-third of clinical human babesiosis, a protozoan disease similar to malaria, occurs in asplenic patients (146). This parasitic infection, which presents as a flu-like illness in normal people, progresses to a fulminant parasitemia and to lethal respiratory distress and hemolytic anemia in an asplenic patient (900, 902). Still, more emphasis is placed on S. pneumoniae, as it is responsible for more than 70% of fulminant sepsis described in literature (143). Clinical presentation. Patients with OPSI present with signs and symptoms of an upper respiratory tract infection, but rapidly thereafter manifest high-grade fever, chills, vomiting, petechiae, purpura, and hypotension. Some patients are reported to present with an acute abdomen picture (145). The patient’s neurologic status deteriorates quickly from an altered sensorium to coma, and, not uncommonly, death. Investigation. Laboratory studies in OPSI show a picture similar to that of disseminated intravascular coagulation, with depleted complement levels, fibrinogen, and platelets. Leukocytosis may be present, but most patients will have granulocytopenia instead. Acute renal failure and acute adrenal failure (Waterhouse–Friderichsen syndrome) can occur and are due to intraorgan hemorrhage and necrosis. Peripheral smear often shows bacteria; blood cultures are positive in the absence of prophylactic antibiotic intake. Management. As soon as the diagnosis of postsplenectomy sepsis is suspected, empiric broad-spectrum antibiotics should be administrated intravenously, and the patient should be monitored closely in the hospital. Fluid therapy should be combined with inotropes for a better response in case of hemodynamic instability. Ventilatory support is generally needed because of the frequent association of this entity with hypoxemia, respiratory distress and neurologic impairment. High-dose penicillin is the standard antibiotic for OPSI. In areas with increased incidence of pneumococcal resistance, however, the preferred empiric antibiotics are high-dose vancomycin and ceftriaxone given simultaneously. IVIG are under investigations but showed significant success in animal studies (147). Prevention. The best way to prevent postsplenectomy infection and sepsis is by avoiding splenectomy when possible, or by performing one of the splenic salvage techniques described previously in this chapter. Weighing the risk– benefit ratio associated with total splenectomy is necessary, but the fear of OPSI should not be a deterrent to performing the procedure when needed. Immunization with polyvalent pneumococcal, meningococcal polysaccharide, and conjugate H. influenzae vaccines is essential and has been proven to decrease the risk of OPSI. In the case of an elective splenectomy, the vaccines should be administered 14 days preoperatively for the best results. This is not always possible, as in the case of trauma, at which time postoperative vaccination becomes crucial. The timing of postoperative vaccination is a matter of controversy. Two studies published in 1998 and 2002 compared serum antibody titers of patients vaccinated on the 1st, 7th, 14th, and 28th day postoperatively. These studies found similar antibody levels irrespective of the day of vaccination, but the functional activity of these antibodies was significantly more elevated in those patients vaccinated 14 days postoperatively (148,149). Therefore, delaying immunization until two weeks postoperatively is currently recommended

medwedi.ru

522

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

to enhance the response to the vaccine. In the presence of hypovolemic shock, prior to splenectomy, immediate vaccination within 24 hours may be more beneficial (150). Revaccination within two to six years is well tolerated and seems reasonable to keep an adequate antibody level and provide protection against encapsulated bacteria (151). A poor antibody level response after pneumococcal polysaccharide vaccine in patients with hematological disorders, such as HL, suggests an increased risk of pneumococcal infection despite repetitive re-vaccinations (152). Chemoprophylaxis of splenectomized pediatric patients with daily penicillin is widely practiced and is reported to result in a marked decrease in the incidence of postsplenectomy infections. Antibiotic prophylaxis in adults is more controversial and is recommended currently for high-risk groups like those with immunocompromised states or hematologic malignancies. Because the risk of OPSI is present indefinitely, and because the pneumococcal resistance to penicillin is increasing rapidly, the duration of chemoprophylaxis is questionable and should be addressed in future studies. Finally, patients should be instructed of the risk of lethal sepsis with splenectomy, and should be able to recognize early signs of an infection. They should be keep antibiotics (amoxicillin) with them and start an adequate regimen in case of fever or other infectious signs, even before examination by a physician. A medical-alert bracelet indicating the patient’s asplenic status can be lifesaving in case of an emergency.

REFERENCES 1. Chadburn A. The spleen: anatomy and anatomical function. Semin Hematol 2000; 37(1 suppl 1):13–21. 2. Skandalakis PN, Colborn GL, Skandalakis LJ, Richardson DD, Mitchell WE Jr, Skandalakis JE. The surgical anatomy of the spleen. Surg Clin North Am 1993; 73(4):747–768. 3. Fujita T, Kashimura M, Adachi K. Scanning electron microscopy (SEM) studies of the spleen-normal and pathological. Scan Electron Microsc; 1982 (pt 1):435–444. 4. Kashimura M, Fujita T. A scanning electron microscopy study of human spleen: relationship between the microcirculation and functions. Scanning Microsc 1987; 1(2):841–851. 5. Bosh FH, Were JM, Schipper L, et al. Determinants of red blood cell deformability in relation to cell age. Eur J Haematol 1994; 52(1):35–41. 6. Baumann M. Cell ageing for 1 day alters both membrane elasticity and viscosity. Pflugers Arch 2003; 445(5):551–555. 7. Benett GD, Kay MM. Homeostatic removal of senescent murine erythrocytes by splenic macrophages. Exp Hematol 1981; 9(3):297–307. 8. Bratosin D, Mazurier J, Tissier JP, et al. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie 1998; 80(2):173–195. 9. Malaise MG, Hoyoux C, Franchimont P, Mahieu PR. Evidence for a role of accessible galactosyl or mannosyl residues of Fc domain in the in vivo clearance of IgG antibody-coated autologous erythrocytes in the rat. Clin Immunol Immunopathol 1990; 54(3):469–483. 10. Schaffner A, Augustiny N, Otto RC, Fehr J. The hypersplenic spleen. A contractile reservoir of granulocytes and platelets. Arch Intern Med 1985; 145(4):651–654. 11. Freden K, Lundborg P, Vilen L, Kutti J. The peripheral platelet count in response to adrenergic alpha- and beta-1-receptor stimulation. Scand J Haematol 1978; 21(5):427–432. 12. Coon WW. Surgical aspects of splenic disease and lymphoma. Curr Probl Surg 1998; 35(7):543–646. 13. Bongrazio M, Pries AR, Zakrzewicz A. The endothelium as physiological source of properdin: role of wall shear stress. Mol Immunol 2003; 39(11):669–675.

14. Maves KK, Weiler JM. Properdin: approaching four decades of research. Immunol Res 1993; 12(3):233–243. 15. Jelezarova E, Lutz HU. Assembly and regulation of the complement amplification loop in the blood: the role of the C3b-C3b-IgG complexes. Mol Immunol 1999; 36(13–14):837–842. 16. Nielson JL, Buskjaer L, Lamm LU, Solling J, Ellegaard J. Complement studies in splenectomized patients. Scand J Haematol 1983; 30(3):194–200. 17. Wang WC, Herrod HG, Valenski WR, Wyatt RJ. Lymphocyte and complement abnormalities in splenectomized patients with hematologic disorders. Am J Hematol 1988; 28(4):239–245. 18. Downey EC, Shackford SR, Fridlund PH, Ninnemann JL. Long-term depressed immune function in patients splenectomized for trauma. J Trauma 1987; 27(6):661–663. 19. Siemion IZ, Kluczyk A. Tuftsin: on the 30-year anniversary of Victor Najjar’s discovery. Peptides 1999; 20(5):645–674. 20. Konigswieser H. Incidence of serious infections after splenectomy in childhood. Prog Pediatr Surg 1985; 18:173–181. 21. Barron PT, Richter M. immunodeficiency following splenectomy in the early postimmunization period. Br J Surg 1990; 77(3):316–319. 22. Hosea SW, Brown EJ, Hambuburger MI, Frank MM. Opsonic requirements for intravascular clearance after splenectomy. N Engl J Med 1981; 304(5):245–250. 23. Peck-Radosavljevic M. Hypersplenism. Eur J Gastroenterol Hepatol 2001; 13(4):317–323. 24. Luketic VA, Sanyal AJ. Esophageal varices. II. TIPS (transjugular intrahepatic portosystemic shunt) and surgical therapy. Gastroenterol Clin North Am 2000; 29(2):387–421. 25. Collins JC, Sarfeh IJ. Surgical management of portal hypertension. West J Med 1995; 162(6):527–535. 26. Sakorafas GH, Sarr MG, Farley Dr, Farnell MB. The significance of sinistral portal hypertension complicating chronic pancreatitis. Am J Surg 2000; 179(2):129–133. 27. Loftus JP, Nagorney DM, Ilstrup D, Kunselman AR. Sinistral hypertension. Splenectomy or expectant management. Ann Surg 1993; 217(1):35–40. 28. Doll DC, List AF, Yarbro JW. Functional hyposplenism. South Med J 1987; 80(8):999–1006. 29. Casper JT, Koethe S, Rodey GE, Thatcher LG. A new method for studying splenic reticuloendothelial dysfunction in sickle cell disease patients and its clinical application: a brief report. Blood 1976; 47(2):183–188. 30. Rand ML, Dean JA. Platelet function in autoimmune (idiopathic) thrombocytopenic purpura. Acta Paediatr Suppl 1998; 424:57–60. 31. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest 1987; 80(1):33–40. 32. Cines DB, Blanchette VS, Chir B. Immune thrombocytopenic purpura. N Engl J Med 2002; 346(13):995–1008. 33. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88(1):3–40. 34. Akwari OE, Itani KM, Coleman RE, Rosse WF. Splenectomy for primary and recurrent immune thrombocytopenic purpura (ITP). Current criteria for patient selection and results. Ann Surg 1987; 206(4):529–541. 35. Mcmillan R. Classical management of refractory adult immune (idiopathic) thrombocytopenic purpura. Blood Rev 2002; 16(1):51–55. 36. Pamuk GE, Pamuk ON, Baslar Z, et al. Overview of 321 patients with idiopathic thrombocytopenic purpura. Retrospective analysis of the clinical features and response to therapy. Ann Hematol 2002; 81(8):436–440. 37. Park AE, Birgisson G, Mastrangelo MJ, Marcaccio MJ, Witzke DB. Laparoscopic splenectomy: outcomes and lessons learned from over 200 cases. Surgery 2000; 128(4):660–667. 38. Pace DE, Chiasson PM, Schlachta CM, Mamazza J, Poulin EC. Laparoscopic splenectomy for idiopathic thrombocytopenic

Chapter 24: The Spleen

39.

40.

41.

42.

43.

44. 45.

46.

47. 48.

49.

50.

51. 52.

53.

54.

55.

56. 57.

58. 59. 60.

61.

purpura (ITP). Long-term follow-up data. Surg Endosc 2003; 17(1):95–98. Dang CT, Magid MS, Weksler B, Chadburn A, Laurence J. Enhanced endothelial cell apoptosis in splenic tissues of patients with thrombotic thrombocytopenic purpura. Blood 1999; 93(4):1264–1270. Clark WF, Rock GA, Buskard N, et al. Therapeutic plasma exchange: an update from the Canadian Apheresis Group. Ann Intern Med 1999; 131(6):453–462. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991; 325(6):398–403. Mant MJ, Turner AR, Bruce D, Ritchie C, Larratt LM. Splenectomy during partial remission in thrombotic thrombocytopenic purpura with prolonged plasma exchange dependency. Am J Hematol 1999; 62(1):56–57. Thompson CE, Damon LE, Ries CA, Linker CA. Thrombotic microangiopathies in the 1980s: clinical features, response to treatment, and the impact of the human immunodeficiency virus epidemic. Blood 1992; 80(8):1890–1895. Scaradavou A. HIV-related thrombocytopenia. Blood Rev 2002; 16(1):73–76. Aboolian A, Ricci M, Shapiro K, Connors A, LaRaja RD. Surgical treatment of HIV-related immune thrombocytopenia. Int Surg 1999; 84(1):81–85. Kemeny MM, Cooke V, Melester TS, et al. Splenectomy in patients with AIDS and AIDS-related complex. AIDS 1993; 7(8):1063–1067. Seidl S, Spielmann W, Martin H. Two siblings with Rh null disease. Vox Sang 1972; 23(3):182–189. Stewart GW, Amess JA, Eber SW, et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol 1996; 93(2):303–310. Perel Y, Dhermy D, Carrere A, et al. Portal vein thrombosis after splenectomy for hereditary stomatocytosis in childhood. Eur J Pediatr 1999; 158(8):628–630. Bolton-Maggs PH. The diagnosis and management of hereditary spherocytosis. Baillieres Best Pract Res Clin Haematol 2000; 13(3):327–342. Calvert AF, Trimble GE. Glucose-6-phosphate dehydrogenase in an Afro-American population. Hum Hered 1980; 30(5):271–277. Johnson GJ, Vatassery GT, Finkel B, Allen DW. High-dose vitamin E does not decrease the rate of chronic hemolysis in glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1983; 308(17):1014–1017. Topley JM, Rogers DW, Stevens MC, Serjeant GR. Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 1981; 56(10):765–769. Al-Salem AH, Qaisaruddin S, Al Jam’a A, Al-Kalaf J, ElBashier AM. Splenic abscess and sickle cell disease. Am J Hematol 1998; 58(2):100–104. Sorrells DL, Morrissey TB, Brown MF. Septic complications after splenectomy for sickle cell sequestration crisis. Pediatr Surg Int 1998; 13(2–3):100–103. Al-Salem AH, Nasserulla Z. Splenectomy for children with thalassemia. Int Surg 2002; 87(4):269–273. Cohen A, Gayer R, Mizanin J. Long-term effect of splenectomy on transfusion requirements in thalassemia major. Am J Hematol 1989; 30(4):254–356. Petz LD. Treatment of autoimmune hemolytic anemias. Curr Opin Hematol 2001; 8(6):411–416. Pirofsky B. Immune haemolytic disease: the autoimmune haemolytic anaemias. Clin Haematol 1975; 4(1):167–180. Fung HC, Nademanee AP. Approach to Hodgkin’s lymphoma in the new millennium. Hematol Oncol 2002; 20(1): 1–15. Morel P, Dupriez B, Gosselin B, et al. Role of early splenectomy in malignant lymphomas with prominent splenic involvement (primary lymphomas of the spleen). A study of 59 cases. Cancer 1993; 71(1):207–215.

523

62. Walsh RM, Heniford BT. Role of laparoscopy for Hodgkin’s and non-Hodgkin’s lymphoma. Semin Surg Oncol 1999; 16(4): 284–292. 63. Lefor AT. Laparoscopic interventions in lymphoma management. Semin Laparosc Surg 2000; 7(2):129–139. 64. Lehne G, Hannisdal E, Langholm R, Nome O. A 10-year experience with splenectomy in patients with malignant non-Hodgkin’s lymphoma at the Norwegian Radium Hospital. Cancer 1994; 74(3):933–939. 65. Cusack JC Jr, Seymour JF, Lerner S, Keating MJ, Pollock RE. Role of splenectomy in chronic lymphocytic leukemia. J Am Coll Surg 1997; 185(3):237–243. 66. Golomb HM, Vardiman JW. Response to splenectomy in 65 patients with hairy cell leukemia: an evaluation of spleen weight and bone marrow involvement. Blood 1983; 61(2): 349–352. 67. Jansen J, Hermans J. Splenectomy in hairy cell leukemia: a retrospective multicenter analysis. Cancer 1981; 47(8):2066–2076. 68. Federico M, Zinzani PL, Frassoldati A, et al. Italian Cooperative Group for the Study of Hairy Cell Leukemia. Risk of second cancer in patients with hairy cell leukemia: long-term follow-up. J Clin Oncol 2002; 20(3):638–646. 69. Takemori N, Hirai K, Onodera R, Kimura S, Katagiri M. Durable remission after splenectomy for Waldenstrom’s macroglobulinemia with massive splenomegaly in leukemic phase. Leuk Lymphoma 1997; 26(3–4):387–393. 70. Humphrey JS, Conley CL. Durable complete remission of macroglobulinemia after splenectomy: a report of two cases and review of the literature. Am J Hematol 1995; 48(4):262–266. 71. Gertz MA, Anagnostopoulos A, Anderson K, et al. Treatment recommendations in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol 2003; 30(2):121–126. 72. Wanless IR, Peterson P, Das A, Boitnott JK, Moore GW, Bernier V. Hepatic vascular disease and portal hypertension in polycythemia vera and agnogenic myeloid metaplasia: a clinicopathological study of 145 patients examined at autopsy. Hepatology 1990; 12(5):1166–1174. 73. Tefferi A, Mesa RA, Nagorney DM, Schroeder G, Silverstein MN. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000; 95(7):2226–2233. 74. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med 2000; 342(17):1255–1265. 75. Mesa RA, Elliott MA, Tefferi A. Splenectomy in chronic myeloid leukemia and myelofibrosis with myeloid metaplasia. Blood Rev 2000; 14(3):121–129. 76. Akpek G, McAneny D, Weintraub L. Risks and benefits of splenectomy in myelofibrosis with myeloid metaplasia: a retrospective analysis of 26 cases. J Surg Oncol 2001; 77(1):42–48. 77. Karakas HM, Demir M, Ozyilmaz F, Cakir B. Primary angiosarcoma of the spleen: in vivo and in vitro MRI findings. Clin Imaging 2001; 25(3):192–196. 78. Sarode VR, Datta BN, Savitri K, Singh K, Bhasin D. Kaposi’s sarcoma of spleen with unusual clinical and histologic features. Arch Pathol Lab Med 1991; 115(10):1042–1044. 79. De Wilt JH, McCarthy WH, Thompson JF. Surgical treatment of splenic metastases in patients with melanoma. J Am Coll Surg 2003; 197(1):38–43. 80. Ooi LL, Leong SS. Splenic abscesses from 1987 to 1995. Am J Surg 1997; 174(1):87–93. 81. Wilson SE, Robinson G, Williams RA, et al. Acquired immune deficiency syndrome (AIDS). Indications for abdominal surgery, pathology, and outcome. Ann Surg 1989; 210(4):428–433. 82. Wolff MJ, Bitran J, Northland RG, Levy IL. Splenic abscesses due to Mycobacterium tuberculosis in patients with AIDS. Rev Infect Dis 1991; 13(3):373–375. 83. Helton WS, Carrico CJ, Zaveruha PA, Schaller R. Diagnosis and treatment of splenic fungal abscesses in the immunesuppressed patient. Arch Surg 1986; 121(5):580–586.

medwedi.ru

524

Part Two: The Alimentary Tract—Liver, Biliary Tract, Pancreas, Spleen

84. Green BT. Splenic abscess: report of six cases and review of the literature. Am Surg 2001; 67(1):80–85. 85. Levison MA. Percutaneous versus open operative drainage of intra-abdominal abscesses. Infect Dis Clin North Am 1992; 6(3):525–544. 86. Gleich S, Wolin DA, Herbsman H. A review of percutaneous drainage in splenic abscess. Surg Gynecol Obstet 1988; 167(3):211–216. 87. Thanos L, Dailiana T, Papaioannou G, Nikita A, Koutrouvelis H, Kelekis DA. Percutaneous CT-guided drainage of splenic abscess. AJR Am J Roentgenol 2002; 179(3):629–632. 88. Nelken N, Ignatius J, Skinner M, Christensen N. Changing clinical spectrum of splenic abscess. A multicenter study and review of the literature. Am J Surg 1987; 154(1):27–34. 89. Pedrosa I, Saiz A, Arrazola J, Ferreiros J, Pedrosa CS. Hydatid disease: radiologic and pathologic features and complications. Radiographics 2000; 20(3):795–817. 90. Munzer D. New perspectives in the diagnosis of Echinococcus disease. J Clin Gastroenterol 1991; 13(4):415–423. 91. Odev K, Paksoy Y, Arslan A, et al. Sonographically guided percutaneous treatment of hepatic hydatid cysts: long-term results. J Clin Ultrasound 2000; 28(9):469–478. 92. Ravera M, Cocozza E. Post traumatic pseudocyst of the spleen: case report on a conservative management through percutaneous drainage. G Chir 1999; 20(11–12):471–473. 93. Heider R, Behrns KE. Pancreatic pseudocysts complicated by splenic parenchymal involvement: results of operative and percutaneous management. Pancreas 2001; 23(1):20–25. 94. McMahon NG, Norwood SH, Silva JS. Pancreatic pseudocyst with splenic involvement: an uncommon complication of pancreatitis. South Med J 1988; 81(7):910–912. 95. Fishman EK, Soyer P, Bliss DF, Bluemke DA, Devine N. Splenic involvement in pancreatitis: spectrum of CT findings. Am J Roentgenol 1995; 164(3):631–635. 96. Hellmich B, Csernok E, Schatz H, Gross WL, Schnabel A. Autoantibodies against granulocyte colony-stimulating factor in Felty’s syndrome and neutropenic systemic lupus erythematosus. Arthritis Rheum 2002; 46(9):2384–2391. 97. Khan MA, Kushner I. Improvement of rheumatoid arthritis following splenectomy for Felty syndrome. JAMA 1977; 237(11):1116–1118. 98. Laszlo J, Jones R, Silberman HR, Banks PM. Splenectomy for Felty’s syndrome. Clinicopathological study of 27 patients. Arch Intern Med 1978; 138(4):597–602. 99. Barton NW, Furbish FS, Murray GJ, Garfield M, Brady RO. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA 1990; 87(5):1913–1916. 100. Gaucher disease. Current issues in diagnosis and treatment. NIH Technology Assessment Panel on Gaucher Disease. JAMA 1996; 275(7):548–553. 101. Pastores GM, Barnett NL. Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1. Expert Opin Investig Drugs 2003; 12(2):273–281. 102. Webb AK, Mitchell DN, Bradstreet CM, Salsbury AJ. Splenomegaly and splenectomy in sarcoidosis. J Clin Pathol 1979; 32(10):1050–1053. 103. Kruithoff KL, Gyetko MR, Scheiman JM. Giant splenomegaly and refractory hypercalcemia due to extrapulmonary sarcoidosis. Successful treatment by splenectomy. Arch Intern Med 1993; 153(24):2793–2796. 104. Seki S, Iwamoto H. Disruptive forces for swine heart, liver, and spleen: their breaking stresses. J Trauma 1998; 45(6): 1079–1083. 105. Arajarvi E, Santavirta S, Tolonen J. Abdominal injuries sustained in severe traffic accidents by seatbelt wearers. J Trauma 1987; 27(4):393–397. 106. Meyer DM, Thal ER, Weigelt JA, Redman HC. Evaluation of computed tomography and diagnostic peritoneal lavage in blunt abdominal trauma. J Trauma 1989; 29(8):1168–1170. 107. Liu M, Lee CH, P’eng FK. Prospective comparison of diagnostic peritoneal lavage, computed tomographic scanning, and

108.

109.

110.

111.

112. 113.

114.

115.

116.

117.

118.

119.

120. 121.

122.

123.

124.

125.

126.

127. 128.

ultrasonography for the diagnosis of blunt abdominal trauma. J Trauma 1993; 35(2):267–270. Sriussadaporn S, Pak-art R, Pattaratiwanon M, Phadungwidthayakorn A, Wongwiwatseree Y, Labchitkusol T. Clinical uses of diagnostic peritoneal lavage in stab wounds of the anterior abdomen: a prospective study. Eur J Surg 2002; 168(8–9):490–493. Shih HC, Wen YS, Ko TJ, Wu JK, Su CH, Lee CH. Noninvasive evaluation of blunt abdominal trauma: prospective study using diagnostic algorithms to minimize nontherapeutic laparotomy. World J Surg 1999; 23(3):265–269. Foo E, Su JW, Menon D, Tan D, Chan ST. A prospective evaluation of surgeon performed sonography as a screening test in blunt abdominal trauma. Ann Acad Med Singapore 2001; 30(1):11–14. Healey MA, Simons RK, Winchell RJ, et al. A prospective evaluation of abdominal ultrasound in blunt trauma: is it useful? J Trauma 1996; 40(6):875–883. Miller MT, Pasquale MD, Bromberg WJ, Wasser TE, Cox J. Not so FAST. J Trauma 2003; 54(1):52–59. EAST Practice Management Guidelines Work Group. Practice management guidelines for the nonoperative management of blunt injury to the liver and spleen. Eastern Association for the Surgery of Trauma (EAST), 2003. Minarik L, Slim M, Rachlin S, Brudnicki A. Diagnostic imaging in the follow-up of nonoperative management of splenic trauma in children. Pediatr Surg Int 2002; 18(5–6):429–431. Delgado Millan MA, Deballon PO. Computed tomography, angiography, and endoscopic retrograde cholangiopancreatography in the nonoperative management of hepatic and splenic trauma. World J Surg 2001; 25(11):1397–1402. Moore EE, Cogbill TH, Jurkovich GJ, Shackford SR, Malangoni MA, Champion HR. Organ injury scaling: spleen and liver (1994 revision). J Trauma 1995; 38(3):323–324. Cogbill TH, Moore EE, Jurkovich GJ, et al. Nonoperative management of blunt splenic trauma: a multicenter experience. J Trauma 1989; 29(10):1312–1317. Sclafani SJ, Shaftan GW, Scalea TM, et al. Nonoperative salvage of computed tomography-diagnosed splenic injuries: utilization of angiography for triage and embolization for hemostasis. J Trauma 1995; 39(5):818–825. Davis KA, Fabian TC, Croce MA, et al. Improved success in nonoperative management of blunt splenic injuries: embolization of splenic artery pseudoaneurysms. J Trauma 1998; 44(6): 1008–1013. Knudson MM, Maull KI. Nonoperative management of solid organ injuries. Surg Clin North Am 1999; 79(6):1357–1371. Ochsner MG. Factors of failure for nonoperative management of blunt liver and splenic injuries. World J Surg 2001; 25(11):1393–1396. Omert LA, Salyer D, Dunham CM, Porter J, Silva A, Protetch J. Implications of the ‘‘contrast blush’’ finding on computed tomographic scan of the spleen in trauma. J Trauma 2001; 51(2):272–277. Schurr MJ, Fabian TC, Gavant M, et al. Management of blunt splenic trauma: computed tomographic contrast blush predicts failure of nonoperative management. J Trauma 1995; 39(3):507–512. Bee TK, Croce MA, Miller PR, Pritchard FE, Fabian TC. Failures of splenic nonoperative management: is the glass half empty or half full? J Trauma 2001; 50(2):230–236. Velmahos GC, Toutouzas KG, Radin R, Chan L, Demetriades D. Nonoperative treatment of blunt injury to solid abdominal organs: a prospective study. Arch Surg 2003; 138(8):844–851. Nix JA, Costanza M, Daley BJ, Powell MA, Enderson BL. Outcome of the current management of splenic injuries. J Trauma 2001; 50(5):835–842. Schwab CW. Selection of nonoperative management candidates. World J Surg 2001; 25(11):1389–1392. Goffette PP, Laterre PF. Traumatic injuries: imaging and intervention in post-traumatic complications (delayed intervention). Eur Radiol 2002; 12(5):994–1021.

Chapter 24: The Spleen 129. Feliciano DV, Spjut-Patrinely V, Burch JM, et al. Splenorrhaphy. The alternative. Ann Surg 1990; 211(5):569–580. 130. Feliciano DV, Bitondo CG, Mattox KL, Rumisek JD, Burch JM, Jordan GL Jr. A four-year experience with splenectomy versus splenorrhaphy. Ann Surg 1985; 201(5):568–575. 131. Kuzu A, Aydintug S, Karayalcin K, Koksoy C, Yerdel MA, Eraslan S. Use of autologous fibrin glue in the treatment of splenic trauma: an experimental study. J R Coll Surg Edinb 1992; 37(3):162–164. 132. Zhang H, Chen J, Kaiser GM, et al. The value of partial splenic autotransplantation in patients with portal hypertension: a prospective randomized study. Arch Surg 2002; 137(1): 89–93. 133. Shokouh-Amiri MH, Rahimi-Saber S, Hansen CP, Olsen PS, Jensen SL. Does survival depend on the amount of autotransplanted splenic tissue? Arch Surg 1990; 125(11):1472–1474. 134. Steely WM, Satava RM, Brigham RA, Setser ER, Davies RS. Splenic autotransplantation: determination of the optimum amount required for maximum survival. J Surg Res 1988; 45(3):327–332. 135. Rovin JD, Alford BA, McIlhenny TJ, Burns RC, Rodgers BM, McGahren ED. Follow-up abdominal computed tomography after splenic trauma in children may not be necessary. Am Surg 2001; 67(2):127–130. 136. Borrazzo EC, Daly JM, Morrisey KP, et al. Hand-assisted laparoscopic splenectomy for giant spleens. Surg Endosc 2003; 17(6):918–920. 137. Poulin EC, Mamazza J, Schlachta CM. Splenic artery embolization before laparoscopic splenectomy. An update. Surg Endosc 1998; 12(6):870–875. 138. Cusick RA, Waldhausen JH. The learning curve associated with pediatric laparoscopic splenectomy. Am J Surg 2001; 181(5):393–397. 139. Talamini M, Campbell K, Stanfield C. Robotic gastrointestinal surgery: early experience and system description. J Laparoendosc Adv Surg Tech A 2002; 12(4):225–232. 140. Lorincz A, Langenburg S, Klein MD. Robotics and the pediatric surgeon. Curr Opin Pediatr 2003; 15(3):262–266. 141. Boxer MA, Braun J, Ellman L. Thromboembolic risk of postsplenectomy thrombocytosis. Arch Surg 1978; 113(7):808–809.

525

142. Pimpl W, Dapunt O, Kaindl H, Thalhamer J. Incidence of septic and thromboembolic-related deaths after splenectomy in adults. Br J Surg 1989; 76(5):517–521. 143. Davidson RN, Wall RA. Prevention and management of infections in patients without a spleen. Clin Microbiol Infect 2001; 7(12):657–660. 144. Williams DN, Kaur B. Postsplenectomy care. Strategies to decrease the risk of infection. Postgrad Med 1996; 100(1): 195–198,201,205. 145. Sawmiller CJ, Dudrick SJ, Hamzi M. Postsplenectomy Capnocytophaga canimorsus sepsis presenting as an acute abdomen. Arch Surg 1998; 133(12):1362–1365. 146. Rosner F, Zarrabi MH, Benach JL, Habicht GS. Babesiosis in splenectomized adults. Review of 22 reported cases. Am J Med 1984; 76(4):696–701. 147. Camel JE, Kim KS, Tchejeyan GH, Mahour GH. Efficacy of passive immunotherapy in experimental postsplenectomy sepsis due to Haemophilus influenzae type B. J Pediatr Surg 1993; 28(11):1441–1444. 148. Shatz DV, Schinsky MF, Pais LB, Romero-Steiner S, Kirton OC, Carlone GM. Immune responses of splenectomized trauma patients to the 23-valent pneumococcal polysaccharide vaccine at 1 versus 7 versus 14 days after splenectomy. J Trauma 1998; 44(5):760–765. 149. Shatz DV, Romero-Steiner S, Elie CM, Holder PF, Carlone GM. Antibody responses in postsplenectomy trauma patients receiving the 23-valent pneumococcal polysaccharide vaccine at 14 versus 28 days postoperatively. J Trauma 2002; 53(6): 1037–1042. 150. Werner AM, Katner HP, Vogel R, et al. Delayed vaccination does not improve antibody responses in splenectomized rats experiencing hypovolemic shock. Am Surg 2001; 67(9): 834–838. 151. Rutherford EJ, Livengood J, Higginbotham M, et al. Efficacy and safety of pneumococcal revaccination after splenectomy for trauma. J Trauma 1995; 39(3):448–452. 152. Cherif H, Landgren O, Konradsen HB, et al. Poor antibody response to pneumococcal vaccination suggests increased susceptibility to pneumococcal infection in splenectomized patients with hematological diseases. Vaccine 2006; 24(1):75–81.

medwedi.ru

OTHER CONDITIONS

25 Gastrointestinal Hemorrhage Kevin Bruen and Leigh Neumayer

INTRODUCTION Gastrointestinal (GI) hemorrhage is a centuries-old problem that continues to be significant today. The incidence of GI hemorrhage remains constant at 100 per 100,000 hospitalizations per year from upper sources and 20.5 per 100,000 from lower sources (1,2). A more elderly population with multiple comorbidities is thought to be a major contributing factor. With the advent of evidence-based medicine, there has been increased awareness and demand for proven approaches in medicine. GI bleeding is no exception, and there has been a relative increase in the number of studies analyzing treatment approaches. A recent review of the literature reveals efforts to standardize the care of these patients to obtain better outcomes and to more efficiently utilize resources. There have been several developments in recent years with regard to diagnosing and managing GI hemorrhage. Endoscopy is a proven modality for the evaluation of upper GI bleeding. A recent study of cost and length of hospital stay in patients with GI hemorrhage found that early endoscopy and protocol-driven decision-making in patient care decreases length of stay and cost (3). Advances in diagnostic and therapeutic interventional radiology techniques have also increased the effectiveness of evaluating and treating GI hemorrhage with fewer complications. Establishing evaluative measures to determine early on which patients require aggressive care and which can be managed as outpatients has also been studied. Capsule endoscopy in which the entire length of the intestine is imaged by swallowing a microcamera that transmits images has become a reality. Knowledge of this development and others is an important step toward obtaining better patient outcomes.

INITIAL EVALUATION AND MANAGEMENT The physiology of GI hemorrhage can be categorized into two distinct entities: the physiology of hypovolemia and the physiology of the underlying etiology of the bleed. The initial assessment of the patient focuses on evaluating and establishing hemodynamic stability prior to embarking on a search for the bleeding source. The patient with a GI hemorrhage presents somewhere along a spectrum. At one end of the spectrum and most concerning is the patient with gross hematemesis, melena, and hemodynamic instability. This presentation should place into motion a cascade of actions not unfamiliar to the surgeon. The ABCs of airway, breathing, and circulation should be evaluated and established. The patient with gross hematemesis may require a controlled intubation to avoid aspiration and to secure the airway prior to anticipated endoscopy. Two large bore IVs should be placed and aggressive fluid resuscitation with crystalloid initiated while blood is typed and crossed.

Baseline labs including hematocrit and coagulation factors should be sent with the assumption that the hematocrit may be considerably lower than the initially obtained value. If necessary, blood products should be infused as the resuscitative effort continues. Midway along the spectrum is the patient who is not in extremis, but may still have signs of hemodynamic compromise. A history of intermittent hematemesis suggests an upper GI source, while hematochezia, or bright red blood per rectum, suggests a lower intestinal source. It should be noted, however, that up to 18% of patients presenting with suspected lower GI hemorrhage will in fact have an upper GI source (2). Duodenal ulcer is the most common cause in this case, followed by a gastric ulcer (4). Conversely, melena,a although classically regarded as an upper GI source, may in fact be from the lower intestine. Symptoms of weakness, dizziness, or presyncope may be reported. Orthostatic blood pressures can be taken knowing that a drop in blood pressure of 20 mmHg or an increase in pulse by 20 indicates significant blood loss. At the other end of the spectrum is the patient with chronic or occult blood loss. The history may lack obvious visualization of blood loss; however, the patient may also complain of weakness and symptoms of orthostasis. Often, the patient is referred for evaluation of GI bleeding after being found to have anemia or positive fecal occult blood cards. These individuals will most likely be seen in the outpatient setting. A systemic approach to the evaluation of these patients should also be employed with upper and lower endoscopy followed by consideration of examining the small bowel. Once the patient has been hemodynamically stabilized, the next goal is to determine the source of bleeding (Fig. 1). Upper and lower intestinal bleeding is classically delineated by that which occurs above and below the ligament of Treitz, respectively. Placement of a nasogastric tube is a reasonable first step. Suctioning of gross blood immediately confirms an upper GI source. Clear, nonbilious fluid makes a gastric source less likely; however, it does not rule out a lesion beyond the pylorus in the duodenum. Bilious aspirate without evidence of blood most frequently suggests a lower GI source. Analyzing nasogastric aspirate may be of questionable utility however. The incidence of an upper GI bleed in the setting of clear aspirate is still 20% (5). The vast majority of patients with suspected upper GI hemorrhage based on history or an observed account will undergo upper endoscopy for confirmation. Gastric lavage ice-cold solutions are no longer utilized; however, warm solutions maybe of benefit to clear the GI tract prior to endoscopy.

a

A black, tarry stool that results from blood having been digested as it passes through the GI tract.

medwedi.ru 527

528

Part Two: The Alimentary Tract—Other Conditions

Gastrointestinal Hemorrhage

Table 1 Addenbrooke’s Pre-Endoscopic Stratification for Risk of Mortality and Need for Urgent Treatment in Patients with Acute Upper GI Hemorrhage Risk group

Nasogastric tube

High Nonbilious,

Bloody fluid

Nonbloody fluid

Possible UGI Source

UGI source

Bilious, nonbloody fluid

Probably LGI source

UGI endoscopy

Diagnostic

Nondiagnostic

Massive hemorrhage Appropriate Treatment

Selective visceral angiography

No source identified

Intermediate

RBC scan repeat UGI endosopy

Figure 1 Diagnostic steps in the evaluation of acute gastrointestinal hemorrhage.

Risk stratification has been an area of investigation in several recent studies. Risk factors for increased mortality include increased age and medical comorbidities (6). Patient history, vital signs, and physical examination all have a role in predicting the potential severity of a GI hemorrhage. One study looking at patients with lower-intestinal bleed identified several factors as predictors of having a severe bleed (transfusion of more than two units of blood in 24 hours, a drop in hematocrit of 20%, continued bleeding after 24 hours of hemodynamic stability, or readmission within one week). Specifically, a patient with a HR >100, systolic blood pressure lower than 115, and a history of syncope has a relative risk of nearly three times or greater of meeting the criteria for a severe bleed (7). Risk stratification can also be used to predict rebleeding and mortality. Rebleeding is of particular interest due to the fact that 25% of patients with a peptic ulcer source, who rebleed do not survive (8). A study from the United Kingdom classified patients with upper GI sources into high, medium, or low risk upon admission (9). The highest single factor present determined risk stratification (Table 1). Following a total of 1349 consecutive patients over a three-year period, the two-week mortality was 12%, 3%, and 0% in high-, medium-, and low-risk groups, respectively. Incidence of rebleeding in each of the groups was 44%, 2.3%, and 0%. Multiple logistical regression was then utilized to determine risk factors predictive of mortality. Perhaps as anticipated, systolic blood pressure less than 100, persistent tachycardia, age greater than 60, coagulopathy, abnormal liver function tests, and the presence of another comorbidity all increased the odds of mortality. The study criteria draw attention to the key portions of the work-up and can be used as a guide to direct resource priority and utilization. Patients with absence of any of the listed risk factors (low-risk classification—76 patients in this study) can be managed as outpatients. In an era of staffing and bed shortages, the study supports the utilization of intensive care unit (ICU) beds for highest risk patients. The initial evaluation of hematemesis is by upper endoscopy. Endoscopy has been shown to decrease mortality

Low

Variable Recurrent bleeding (any of: resting tachycardia and supine hypotension with no obvious cause; further fresh blood hematemesis; ruddy melena; falling hemoglobin concentration more than could be explained by hemodilution) Persistent tachycardia (pulse >100 beats/min despite resuscitation) History of esophageal varices Systolic blood pressure <100 mmHg (supine) Coagulopathy (prothrombin time >17 sec) Thrombocytopenia (platelet count <100,000) Postural hypotension >20 mmHg on negative chronotropes (e.g., beta blockers) Age >60 Hemoglobin <11 g/dL (on admission) Comorbidity (any clinically significant coexisting disease) Passage of melena or presence on digital rectal examination Excessive alcohol ( >28 units/wk or >10 units in the previous 24 hr) NSAIDs (current or recent NSAID or aspirin) Previous gastrointestinal bleed or peptic ulceration Abnormal liver biochemistry (transaminases, alkaline phosphatase, or bilirubin) Postural hypotension >10 mmHg (sitting or standing compared with supine) Systolic blood pressure >20 mmHg below patient’s normal (if known) None of the aforementioned factors

Note: Patients stratified into highest risk group for which at least one risk factor was present. Abbreviations: GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs. Source: From Ref. 9.

from acute bleeding as well as length of stay (3,10). A community-based study looking at early endoscopy within 24 hours of admission decreased the odds of surgery or rebleeding in all patients (OR ¼ 0.70) and most significantly in patients considered at highest risk (OR ¼ 0.20). Length of stay was also decreased by 30% (11). Another study employing endoscopy within 12 hours of presentation randomized low risk patients to hospital admission or discharge with outpatient follow-up. The incidence of rebleeding in the two groups was 2%. The cost of outpatient management strategy was $340 compared to $3940 with in-hospital admission (12).

UPPER INTESTINAL BLEEDING Etiology Esophageal Varices Esophageal varices are a common and significant complication of liver disease and cirrhosis. Approximately 40% of patients with cirrhosis develop varices with an estimated mortality rate of 30% to 50% (13,14). Ascites, telangiectasias, gynecomastia, splenomegaly, and hepatic synthetic dysfunction are all suggestive of cirrhosis. Overall, esophageal hemorrhage accounts for 14% of cases of upper GI hemorrhage (Table 2). The esophagus and its blood supply may be divided into three regions—cervical, thoracic, and abdominal. The cervical esophagus is supplied by branches of the inferior

Chapter 25: Gastrointestinal Hemorrhage

529

Table 2 Causes of Acute Upper GI Bleeding Common Duodenal ulcers Gastric ulcers Gastritis Duodenitis Esophagitis Mallory–Weiss tear Cirrhosis-associated lesions Esophageal varices Gastric varices Portal gastropathy Anastomotic (marginal ulcer) Angiodysplasia Dieulafoy lesion

Uncommon Duodenal Crohn’s disease Leiomyoma Hemobilia Gastric polyps Aortoenteric fistula Polypectomy bleeding Malignancy Esophageal squamous cell cancer Esophageal adenocarcinoma Gastric adenocarcinoma Gastric lymphoma Gastric Kaposi’s sarcoma Gastric antral vascular ectasia

Abbreviation: GI, gastrointestinal. Source: From Ref. 15.

thyroid artery. The venous return follows in similar fashion via the inferior thyroid vein. The thoracic esophagus receives branches from the descending aorta, bronchial arteries, and intercostals. A venous plexus lines the esophagus, with drainage to the azygous, hemiazygous, and accessory azygous veins. The abdominal portion of the esophagus receives its blood from the left gastric and inferior phrenic arteries. The venous return empties into the left gastric vein. The left gastric vein is the only vein draining the esophagus, which communicates with the portal vein instead of the systemic circulation. This anatomical fact leads to the development of esophageal varices in the presence of portal hypertension. The typical presentation of an esophageal bleed is hematemesis. Aggressive resuscitation including securing an airway is critical. Urgent endoscopy is necessary following resuscitation. Varices typically have an appearance of serpiginous, longitudinally oriented gray projections (15). Active bleeding, clots, red discoloration, or blisters are all suggestive of recent bleeding (15). It should be noted, however, that approximately 50% of bleeding episodes in the patient with cirrhosis are not related to varices. Management of variceal bleeding has improved in recent years. Early endoscopy and medical management with agents such as octreotide have reduced mortality to 15% (in hospital and up to 6 weeks postbleed) (16). Although vasopressin has traditionally been used in the past to reduce portal pressure, other pharmaceutical agents have been found to be as effective without the cardiovascular side effects. For example, terlipressin, an analogue of vasopressin, is the only agent to have demonstrated a mortality benefit and similar effectiveness as endoscopy (17). Both 0.2 and 1 mg every four hours have been studied with 80% and 90% success rates, respectively, at controlling bleeding by day 2 of hemorrhage. The higher dosing regimen was also found to decrease the need for blood products without an increased incidence of side effects (18). Balloon tamponade using a triple lumen tube with gastric esophageal balloons has been used as a temporizing measure in acute hemorrhage. Following X-ray confirmation of balloon placement, the gastric balloon is inflated with 150 to 200 cc of normal saline. If bleeding continues, the esophageal balloon may also be inflated with 40 to 60 mmHg pressure. The balloon should be deflated every two hours to allow adequate esophageal perfusion. Balloon tamponade has been shown to be effective in approximately

Figure 2 Esophageal banding is an effective technique in primary prevention, as well as in actively bleeding varices.

90% of patients. It is however a temporizing measure with rebleeding in two-thirds of patients upon deflation. Unfortunately, balloon tamponade has also been associated with aspiration pneumonia, esophageal necrosis, and rupture. Acute endoscopic therapeutic options include banding, sclerotherapy, injection with epinephrine or a combination of techniques. Sclerotherapy has been shown to be effective, stopping 96% of initial bleeding episodes (19,20). Interestingly, a recent meta-analysis comparing sclerotherapy to vasopressin, somatostatin, octreotide, or terlipressin found no advantage for sclerotherapy over medical management with any of the aforementioned agents. This study took into account 12 trials and looked at a number of measures including failure to control bleeding, rebleeding, transfusion, and mortality (21). Banding causes thrombosis and has been shown to be more effective than sclerotherapy for long-term results (22). Band ligation is also frequently used as a second-line treatment being performed every one to two weeks until varices are obliterated (Fig. 2). Combination therapy with medical and endoscopic techniques is most frequently used in current practice. Meta-analysis reviewing a number of techniques and pharmaceutical agents has found that an overall small benefit is gained in obtaining initial hemostasis (relative risk 1.1) and five-day hemostasis (relative risk l.28) using combination therapy (23). Propranolol has been used for many years as primary prophylaxis and still persists today as the initial standard treatment for esophageal varices (24). Band ligation has been advocated as an alternative to propranolol for primary prophylaxis and has been demonstrated to be as effective and without side effects (25). Long-term treatment options also include transjugular intrahepatic portosystemic shunting (TIPS) and portocaval shunts. In retrospective studies, TIPS has been shown to reduce long-term mortality when compared to sclerotherapy and band ligation alone (26). Unfortunately, the complication rate of TIPS is high with two-year mortality and shunt failure rates approaching 50% (27).

Mallory–Weiss Tear A tear in the mucosa near the gastroesophageal junction may be a direct result of vomiting or retching. The process

medwedi.ru

530

Part Two: The Alimentary Tract—Other Conditions

Figure 3 The Mallory–Weiss tear is located at the gastroesophageal (GE) junction located on the gastric side of GE junction made visible here with retroflexing of the endoscope.

of vomiting originates in several centrally located sites including the medulla and chemotrigger zone located on the floor of the fourth ventricle. Sensory input from a number of sources may trigger the vomiting reflex. Anatomically, the process of vomiting begins in the duodenum. A reverse wave of peristalsis occurs with subsequent contraction of the abdominal musculature raising the pressures at the distal esophagus. The pressure may reach a difference of up to 200 mmHg between the distal esophagus pressure and the negative pressure of the thorax. The subsequent force directed against the distal esophagus creates a Mallory–Weiss tear. Such lesions make up 6% of all upper GI bleeding sources (28). The classic presentation is a patient with a history of alcohol abuse, who forcefully vomits and subsequently develops hematemesis. Endoscopy typically reveals a linear mucosal tear oriented longitudinally, most commonly located on the gastric side of the gastroesophageal (GE) junction (Fig. 3) (15). Frequently, bleeding from these lesions has already ceased upon presentation for medical care. Studies comparing medical and endoscopic treatment with either banding ligation/hemiclip application or epinephrine injection suggest that unless there is active bleeding, medical therapy is as effective as endoscopic intervention (29).

over a 50-month period, gastric ulcers made up 32% of episodes and duodenal ulcers contributed 28% (28). It is estimated that approximately 20% of patients with peptic ulcer disease experience bleeding at some point during the course of the disease. Presentation is typically with either hematemesis or melena. However, as previously discussed, hematochezia may also be seen initially. The gastroduodenal artery is located posterior to the duodenum and is frequently the source of bleeding (Fig. 4). A major risk factor for ulcer formation is nonsteroidal anti-inflammatory drugs (NSAIDs). Each year, over 70 million prescription drugs and 30 billion over-the-counter preparations are sold (31). NSAIDs have long been known to be a risk factor for GI hemorrhage. A recent meta-analysis using a combination of data from randomized controlled, case controlled, and cohort studies found a 2.5 to 5.5 times increased relative risk of GI bleeding with concurrent NSAID use. The association of Helicobacter pylori, a bacteria implicated in the etiology of peptic ulcer disease, with GI hemorrhage has recently been called into question. A case–control study confirmed previous studies demonstrating that the incidence of H. pylori infection was actually lower in patients with hemorrhage and most likely not a risk factor for bleeding (32). Eradication of H. pylori however has been shown to decrease the rate of rebleeding (33). The use of lansoprazole following H. pylori eradication in patients who continue to require aspirin therapy has been found to reduce the risk of recurrent complication from 15% to 1.5% (34). The interaction of H. pylori disease and NSAIDs has also been evaluated. While untreated H. pylori infection contributes to the risk of upper GI hemorrhage in those individuals starting NSAID therapy, in those who have a history of long-term NSAID usage, the greatest risk is attributed to the NSAID use (35). GI injury arises from the imbalance of acid production and an altered gastric mucosal barrier. Studies have found an equal incidence of disease due to enteric-coated formulations suggesting that the systemic effects of decreased prostaglandin synthesis are primarily responsible. Selective cyclo-oxygenase-2 inhibitors (Cox-2 inhibitors) have been developed to work as anti-inflammatory agents while maintaining prostaglandin synthesis. A large population cohort study including over 40,000 patients compared the incidence of disease due to traditional NSAIDs to that due to diclofenac plus misoprostol, rofecoxib, and celecoxib. Misoprostol is a prostaglandin analogue preparation, while rofecoxib and celecoxib are Cox-2 inhibitors. The study

Dieulafoy Lesion The Dieulafoy lesion is a relatively rare cause of upper GI hemorrhage representing a dilated superficial vessel located just below the mucosa. Most lesions are located on the lesser curvature of the stomach near the GE junction as a prominent pigmented vessel without evidence of ulceration (30). The etiology is unknown. These lesions typically present with significant hematochezia without hematemesis. Combination therapy with epinephrine injection and bipolar coagulation as well as marking the lesion with India ink in the event that rebleeding requires repeat endoscopy or surgery has been advocated (4).

Peptic Ulcer Disease Peptic ulcer disease makes up nearly 60% of upper GI bleeds. In one inner city series analyzing patients presenting

Figure 4 Duodenal ulcer with large overlying clot.

531

Chapter 25: Gastrointestinal Hemorrhage

found no increased risk of upper GI hemorrhage compared to an unopposed cohort with the use of celecoxib. There was an increased relative risk of 4.4 for traditional NSAIDs, 3.2 for diclofenac plus misoprostol, and 1.9 for rofecoxib compared to celecoxib (36). Initial medical treatment for suspected peptic ulcer hemorrhage includes starting a proton pump inhibitor (PPI), such as omeprazole. Misoprostol has been found to be beneficial in healing peptic ulcers, however less effective and less well tolerated than omeprazole (37). H2-receptor antagonists and, more recently, PPI have been shown to promote healing of peptic ulcers. The ASTRONAUT Trial— Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID Associated Ulcer Treatment—found 80% healing of peptic ulcers with 20 or 40 mg of omeprazole orally daily compared to 63% with 150 mg of ranitidine twice daily (38). PPIs have also been show to have a benefit over H2 blockers in preventing rebleeding after successful coagulation. In a randomized, placebo, double-blinded study, omeprazole was found to decrease the incidence of rebleeding and the need for surgery in patients with a nonbleeding, visible vessel or an adherent clot. PPIs were not however found to be beneficial in patients with vessels that had arterial spurting or oozing (39). A cost analysis looking at IV omeprazole found hospital costs to be less by avoiding one episode of rebleeding after endoscopic treatment (40). Morgan found that continuous IV pantoprazole was more effective than bolus therapy alone in preventing rebleeding, suggesting greatest effect with a bolus of 80 mg followed by 8 mg/hr infusion over three days (41). However, there has not been a demonstrated effect on mortality (42). Another study looking at oral omeprazole following endoscopic therapy found omeprazole to reduce the number of rebleeding episodes by 50% (43). A bleeding ulcer may appear in several forms upon endoscopic visualization. The ulcer may be obvious and acutely bleeding, or on the contrary difficult to identify. Different variations on the theme exist and are classified by Forrest classifications. These include actively spurting vessel (la); actively bleeding, nonspurting vessel (Ib); visible nonbleeding vessel (IIa) (Fig. 5); nonbleeding ulcer with overlying clot (IIb); ulcer with black base (IIc); and ulcer

with clean base (III). Studies have also demonstrated that the greatest risk factor for rebleeding is based on Forrest classification (44). Actively bleeding vessels have a 88% chance of rebleeding and visible vessels have a 40% to 50% chance of rebleeding, while those with adherent clot a 30% chance (Table 3) (4,45). Other risk factors included ulcer size and site, hematemesis upon presentation, cirrhosis, hypotension, and recent surgery (44). Endoscopy with therapeutic intervention has been shown to decrease mortality and the need for surgery (46). Obtaining adequate visualization may be difficult at times; however, erythromycin, which enhances gastric emptying, has been found to provide a clearer view during endoscopy when given 20 minutes prior to the procedure. The need for second-look endoscopy is also found to be reduced from 33% down to 12% (47). There are two primary modes of thermal therapy used today—electrocoagulation and heater probes. In multipolar or bipolar electrocoagulation, electrical current runs between three adjacent bipolar microelectrodes creating heat with subsequent coagulation of tissue proteins and vessel constriction (4). Heater probes work similarly, consisting of a hollow aluminum cylinder and coil. Small, randomized studies have found heater probes favorable to hemoclips in achieving hemostasis (48). Laser and argon plasma coagulation are also frequently used as thermal modalities. For the actively bleeding vessel, combining bipolar or heater probe techniques with epinephrine is recommended, while in the nonbleeding visible vessel, bipolar or heater probe therapy is sufficient (4,49). Removal of clot from a nonbleeding ulcer with precedent treatment involving injection with epinephrine followed by heater probe or bipolar electrocoagulation has been shown to reduce the risk of rebleeding to zero compared to 35% with medical therapy alone (50). Oozing ulcers typically have a rebleeding rate of 10% to 27% and can be reduced to 5% with epinephrine or thermal probe. Finally, clean-based ulcers have a 5% risk of bleeding and patients with this disorder have been managed successfully as outpatients (4,45,51). Once initial bleeding is controlled, debate exists whether second-look endoscopy is a cost and clinically effective strategy. Using probability estimates from current literature, a decision analysis calculated second-look endoscopy in high-risk patients only as most effective and least expensive (52). Massive bleeding from duodenal ulcer disease, perhaps more so than any other source of bleeding and especially with failure of endoscopy, is often times best managed with surgical intervention. In a study of 738 patients admitted for Table 3 Prevalence and Rebleeding Rate of Various Stigmata of Ulcer Hemorrhage in the CURE Study of 200 Consecutive Patients Admitted to an ICU Stigmata Active arterial bleeding Nonbleeding visible vessel Nonbleeding clot Oozing bleeding without stigmata Nonbleeding flat spots Clean ulcer base a

Figure 5 Gastric ulcers with a visible nonbleeding vessel (Forrest classification IIa) have a 50% chance of rebleeding without endoscopic intervention.

Prevalence (%) Rebleeding ratea (%) 12 22 10 14 10 32

88 50 33 10 7 3

Rebleeding refers to clinically significant rebleeding with the transfusion of additional units of packed red blood cells beyond those for the initial resuscitation in patients receiving medical therapy without endoscopic hemostasis. Abbreviation: ICU, intensive care unit. Source: From Ref. 4.

medwedi.ru

532

Part Two: The Alimentary Tract—Other Conditions

acute bleeding peptic ulcers, 32 patients required surgery. Twenty-five patients failed epinephrine or polidocanol injection (3.4%), six had gastric or duodenal perforation from endoscopy (0.8%), and one developed gastric necrosis. The overall mortality rate of gastric ulcer bleeding is 10% (8). Classical indications have included a six-unit blood loss in 24-hour period and persistent blood loss with hemodynamic instability. Early surgical intervention has been advocated following initial endoscopic hemostasis and in one small series reduced mortality to 0% (53). Considering the present era of medical management of peptic ulcer disease and reservation of surgery for unstable patients, it has been argued that surgery should be focused and expedient. Bleeding gastric ulcers can be excised with a limited resection. Hemorrhage from a duodenal ulcer is controlled by placing sutures in the ulcer base, ligating the gastroduodenal artery source. The risk/benefit of spending additional time performing a vagotomy procedure in a critically ill patient is controversial.

Stress Gastritis Stress gastritis is not uncommon in the ICU setting, and is typically characterized by multiple, acute, shallow gastric ulcers. Stress ulcers are formed from a complex pathophysiology that involves tissue ischemia and reperfusion injury (54). The two most significant risk factors include mechanical ventilation and coagulopathy (55). Prophylaxis with either PPI or H2 blockers has been shown to prevent the incidence of GI bleeding in both patient populations (56). There is however debate as to whether PPIs are superior to H2 blockers. Studies have suggested that while maintaining a pH > 4 preserves gastric mucosa, a pH > 6, which can only be achieved through the use of PPIs, may further decrease the risk of bleeding (54).

Other Sources of Upper GI Bleeding Angiodysplasia accounts for 4% of upper GI bleeds and is associated with renal failure and aortic stenosis (57,58). These lesions are superficial dilated vessels most frequently located on the stomach and duodenum. On endoscopy, angiodysplasia appears as a network of vascular structures consisting of 2 to 8 mm diameter individual lesions with a starburst pattern (15). Coagulation with thermal techniques is highly effective. Hemobilia is defined as bleeding into the biliary tract. A number of oncologic, traumatic, infectious, and vascular etiologies exist. A recent literature review of 222 cases identified two-thirds of causes to be iatrogenic (59). The majority of cases are diagnosed by angiography with medical therapy and embolization utilized as initial treatment. Overall mortality is 5%. Splenic artery aneurysms are typically incidental findings on angiography. Splenic artery pseudoaneurysm has been reported to occur in up to 10% of patients with pancreatitis (60). There have been case reports of rupture into the stomach presenting as severe upper GI hemorrhage (61). Aortoenteric fistula may present as a result of abdominal aortic aneurysm, or following aneurysm repair with grafting (62). The incidence of both circumstances is considerably low. Patients classically present with a history of a sentinel bleeding, abdominal pain, fever, and a pulsatile mass on physical examination. Endoscopy and computed tomography (CT) scanning have been used successfully in evaluation. Fatal exsanguination occurs if not recognized. Clinical suspicion with prompt surgical intervention has been advocated as the key to patient survival (63).

The advent of laparoscopic gastric bypass surgery has introduced another post-surgical cause of bleeding. In a series of 155 patients, on whom Roux-en-y reconstruction was performed, five developed postoperative bleeding. Two of these patients required surgical intervention and in both cases, bleeding was identified at the staple line (64). Late hemorrhage following gastric bypass has also been studied. Braley reports four cases occurring at an average of 15.5 years after surgery, who presented with massive hemorrhage. Initial work-up included endoscopy, nuclear scan, and arteriography. Intraoperative endoscopy of the gastric remnant was performed followed by subtotal gastrectomy with three out of the four bleeding sources in the resected gastric remnant and duodenum (65).

LOWER INTESTINAL BLEEDING Lower intestinal bleeding makes up 25% of all GI hemorrhages and typically presents with hematochezia. Darker stools, although usually associated with an upper GI source of bleeding, can certainly occur with lower GI bleeding as well. A large based population study found the incidence of lower intestinal bleeding to be 24/100,000 for males and 17/100,000 for females. The rate increases over 200fold in the third to ninth decades of life (2). The most common etiologies were diverticulosis 41.6%, colorectal malignancy 9%, and ischemic colitis 8.7% (Table 4). Other causes of bleeding having an incidence of approximately 5% each include rectal ulcers, post-polypectomy bleed, colonic angiomas, or radiation telangiectasis (4). Overall mortality in this study of 219 patients with lower GI bleeding was 5% (2). The same guidelines for initial evaluation, as previously discussed, which include obtaining adequate IV access and initiating fluid resuscitation, are recommended. The patient’s presentation may give insight into the cause of bleeding. Diverticulosis frequently presents with brisk bleeding, whereas ulcerative colitis or infectious colitis are associated with constitutional symptoms and bloody diarrhea. NSAIDs may cause ulcerations, and warfarin may precipitate bleeding from already present pathology. Individuals who recently underwent colonoscopy and polypectomy may also present with bleeding.

Table 4 Causes of Lower Intestinal Hemorrhage Diverticulosis Colon cancer Polyps/postpolypectomy Ischemic colitis Arteriovenous malformations Inflammatory bowel disease Ulcerative colitis Chron’s disease Infectious colitis E. coli Salmonella Shigella Yersinia Vibrio Campylobacter Chlamydia Clostridium difficile Abbreviations: CMV, inflammatory drug.

cytomegalovirus;

HIV associated CMV Kaposi’s sarcoma Radiation colitis NSAID-induced ulcer Coagulopathy Anorectal Hemorrhoids Fistula Fissure Rectal ulcers Rectal cancer

NSAID,

nonsteroidal

anti-

Chapter 25: Gastrointestinal Hemorrhage

Evaluation Colonoscopy The decision to utilize, as well as the timing of, colonoscopy has been a subject of debate. The presence of severe bleeding in which visualization would be difficult is a frequently cited reason for not pursuing urgent colonoscopy. A retrospective review of 90 patients (urgent colonoscopy was performed in 39) found a definitive source in only three patients, a probable source in 26 patients, and no source in the remaining 10 patients (66). Other researchers have found urgent colonoscopy as the initial evaluative method of choice, allowing for immediate intervention and decreasing the need for surgery (67). Oral preparation to purge blood and clots is safe and increases the rate of successful localization. In one prospective study, urgent colonoscopy was performed after upper endoscopy and oral purge in a series of patients with ongoing severe hematochezia. A colonic source was found 74% of the time, and an upper GI source was found 11% of the time. The remaining 15% were classified as having either a presumed small intestine or an undiagnosed source (68). Another recent retrospective review of 345 patients identified a bleeding site in nearly 90% of cases (69). Early utilization of colonoscopy has also been found to decrease the length of hospital stay by identifying and discharging patients without evidence of active bleeding (Fig. 6) (70).

Arteriography In patients with hemorrhage that is severe, not amenable to or following unsuccessful colonoscopy, arteriography should be considered. Arteriography is able to detect bleeding at a minimum of 0.5 mL/min with optimal visualization at a rate of 1 mL/min (71). It has frequently been used preoperatively to mark the source of hemorrhage via injection of methylene blue. Interventional techniques allow placement of embolic coil or local infusion of vasopressin. Vasopressin is given at a rate of 0.2 units/min once the catheter is positioned in a distal vessel near the source and may be increased up to 0.4 units/min to control bleeding. If successful, the infusion is continued for 12 to 24 hours followed by a 24-hour taper. Unfortunately, this technique is associated with a rebleeding

Lower Gastrointestinal Hemorrhage

Nasogastric tube Rule out UGI source Proctoscopy Rule out rectal source Continued massive

Low rate or

hemorrhage

intermittent hemorrhage

Angiography Diagnostic

Nondiagnostic

Colonscopy Nondiagnostic

Diagnostic

Figure 6 Diagnostic steps in the evaluation of lower gastrointestinal hemorrhage.

533

rate of approximately 50%. Vasopressin is also not without side effects, the most significant being coronary vasoconstriction. Concurrent intravenous nitroglycerin therefore may be required. Updated studies using super-selective embolization with coils have recently been published. One series obtained initial hemostasis in all 27 patients. Subsequently, six patients developed rebleeding and two patients developed colonic ischemia (72). Another series controlled initial bleeding sources in all 10 patients, two of whom subsequently rebled (73).

Nucleotide Scan Nucleotide scan uses 99mTc sulfur colloid or 99mTc-tagged red blood cells to find occult sources of bleeding. The modality is frequently performed when colonoscopy is negative, and is more sensitive than arteriography, detecting bleeding at a rate of 0.l cc/min (74). A positive scan is identified by extravasation, pooling, or configuration to the bowel lumen. The accuracy in localizing colonic bleeding using nucleotide scans has been reported as 75% (75). Other studies, however, report less-impressive figures of 24.4% using Tc sulfur colloid and 27.5% using Tc RBC (76). Peristalsis in part also accounts for the difficulty in localizing the site of bleeding (71). Increasing the duration of scan has been shown to increase the detection rate and may account for study discrepancies.

Helical CT Helical CT scanning has recently been evaluated in a small series. Nineteen of 26 patients evaluated by colonoscopy, enteroscopy, or surgery had an accurate diagnosis with helical CT. Additionally, four of five small bowel hemorrhages and 10 of 14 colonic sources were identified. Overall, the primary diagnosis was made by CT in 10 of 19 patients (74).

Etiology Diverticulosis Diverticulosis is an out-pouching of the mucosa and submucosa as the vasa recta penetrate the circular muscular layer. Recent theories suggest a component of taenia coli elastosis with sigmoid shortening and diverticulum formation (77). The descending colon is the most common site of diverticulosis with right-sided lesions seen more frequently in younger patients. Diverticular disease is estimated to affect 30% to 60% of the general population; however, only 5% of patients will have GI hemorrhage (78). In 75% of patients, bleeding will stop spontaneously (79). Findings with colonoscopy of recent bleeding may include a visible or actively bleeding diverticulum or adherent clot (Fig. 7). Local injection with epinephrine, bipolar electrocoagulation, or both have been found to stop active bleeding with a very low incidence of rebleeding (67). AVM Arteriovenous malformations (AVMs) are a result of the failure of the precapillary sphincters entering the intestinal capillary bed. An increase in blood flow subsequently occurs with potential for rupture into the adjacent mucosal tissue. Bleeding is typically intermittent, causing a chronic anemic state. Endoscopic therapy consists of coagulation via colonoscopy and may require several treatments to treat multiple sites (4). Segmental resection of multiple lesions unamendable to endoscopic therapy is also a treatment option.

medwedi.ru

534

Part Two: The Alimentary Tract—Other Conditions

Tumors Adenocarcinoma causes bleeding through ulcerative erosion during colonic invasion and is responsible for 9% of lower bleeding causes (2). Presentation is typically of occult blood loss or anemia and rarely of acute bleed. Colonoscopy is diagnostic and is utilized in biopsy of polyps and ulcers. The incidence of severe bleeding requiring hospitalization following polpectomy is 0.2% (83). Other Causes Other causes of lower GI bleeding include anorectal sources, coagulopathy, HIV, and NSAIDs. Evaluation of the anus and rectum is the first step in the patient with hematochezia. Hemorrhoids, rectal ulcers, fissure, and fistulas are all common causes of rectal bleeding. In younger patients in whom definitive rectal pathology is not identified, sigmoidoscopy is utilized. A study looking at the yield of colonoscopy in 1766 subjects found that there was no evidence of cancer beyond the length of a sigmoidoscope in subjects less than 40 years old. The study also found that 7% of patients in this age category had a proximal lesion that accounted for their bleeding (84). It is however recommended that all patients older than 40 years undergo full colonoscopy. Bleeding or anemia in the setting of anticoagulation therapy raises the question of a proximal lesion and not simply drug induced. GI bleeding in HIV patients is most frequently associated with CMV infection, followed by idiopathic colonic ulcers and intestinal Kaposi’s sarcoma (85). Finally, ASA and NSAIDs, although classically associated with peptic ulcer disease, are also known to cause similar ulcerative lesions in the colon (31).

Treatment

Figure 7 (A–C) Bleeding diverticulum located in the sigmoid colon. Endoscopic treatment with bipolar electrocoagulation is performed with resulting hemostasis.

Colitis Several etiologies of colitis exist, including ischemia, infection, radiation, and inflammatory bowel disease. Ischemic colitis represents 9% of causes of lower GI bleeding (2). The entity is seen in the elderly and affects the watershed areas of the colon. Infectious causes of colitis include E. coli, Salmonella, Shigella, Yersinia, Vibrio, Campylobacter, Chlamydia, and Clostridium difficile (80). Cytomegalovirus (CMV) is known to cause an infectious colitis in patients with HIV infection (81). Colonoscopy’s role is that of biopsy rather than specific therapeutic intervention. Radiation therapy causes the formation of colonic telangiectasias that are susceptible to bleeding. Ulcerative colitis and Crohn’s disease rarely present with major acute hemorrhage accounting for 0.1% and 1.2% of admissions for these disease entities, respectively (82). Recurrent bleeding is an indication for surgical resection.

Surgery in lower intestinal bleeding is not infrequently used as a procedure of last resort. Historically, colectomy procedures have been associated with poor outcomes. Mortality rates have ranged from 30% to 75% with blind segmental colectomy having the highest rebleeding and mortality (86). Ideally, a localization study should be performed to direct colonic resection. Emergent surgery is an option when other diagnostic modalities fail or in those patients who would not survive the delay for catheter-based intervention. Once the decision is made to proceed with surgery, total abdominal colectomy is the recommended procedure. Baker in his series found a mortality of 6%, compared to 15% with limited resection (87). Differences in outcome compared to previous studies with higher mortality rates are most likely due to patient selection, bleeding severity, and other comorbidities.

Small Intestine Bleeding When both upper endoscopy and colonoscopy fail to reveal a source of bleeding, the possibility of a small intestine source should be considered. Vascular lesions are the most common cause including AVM, vascular ectasia, hemangiomas, and hemangiodysplasias. Other causes include small bowel tumors such as leiomyomas, lymphomas, Crohn’s disease, Meckel’s diverticulum, and jejunal diverticulum.

Evaluation Push Enteroscopy Evaluation of the small intestine is a diagnostic challenge, and several options exist. Previously, radiographic upper GI barium study with small bowel follow-through was frequently used, primarily aimed at identifying a bleeding

Chapter 25: Gastrointestinal Hemorrhage

mass lesion. The sensitivity of this technique, however, has been reported at only 10% and thus, it no longer serves a role in modern-day management. Push enteroscopy is the continuation of the upper endoscopy beyond the ligament of Treitz. It can be used to assess the small bowel into the distal jejunum. The main advantage is the ability to see a larger portion of the intestine; however, the ileum is typically out of reach during evaluation. In addition to small intestine length, the presence of rugal folds contributes to the difficulty in identifying a hemorrhagic source; however, if found, the option does exist for therapeutic intervention. Intraoperative Enteroscopy Intraoperative enteroscopy is another technique to evaluate the small intestine. The technique utilizes a pediatric enteroscope advanced orally or via an enterotomy. The scope is passed rostrally and caudally to evaluate for the source of bleeding. One series identified 16 of 20 small intestine bleeding sources, which were subsequently managed with small bowel resection. The rebleeding rate, however, was 30%, and two of the patients with negative examination subsequently died of massive hemorrhage (88). This incidence of rebleeding is similar to that in other studies with the majority of rebleeding lesions being AVMs (89). Capsule Endoscopy The advent of capsule endoscopy is a sign of the everevolving medical technology. The capsule is a small camera that can be swallowed by the patient and that serially takes images along its voyage through the GI tract. This technique allows the entire tract—including the distal jejunum and the ileum—to be visualized. The first prospective trial of its use followed 32 patients with chronic bleeding evaluated using conventional modalities including small bowel followthrough, scintigraphy, arteriography, push endoscopy, and capsule endoscopy. Conventional methods were diagnostic in 16% of cases, push endoscopy in 28%, and capsule endoscopy in 66% (90).

OCCULT BLEEDING Occult bleeding refers to blood loss in a patient with anemia or guiac positive stools. Obscure bleeding is a term used in reference to an unknown bleeding source in a patient with known GI hemorrhage. A number of techniques including arteriography and tagged red blood cell scans are available as previously discussed. The work-up for occult bleeding is common to all patients presenting with GI hemorrhage and includes history, physical examination, and ultimately endoscopy (Table 5). The differential diagnosis of occult bleeding is extensive. These may be divided into two classifications—those associated with positive fecal occult testing and those with iron-deficiency anemia (Table 5). History and physical examination may reveal clues as to the possible source. Several associations are implicit, such as a history of NSAIDs or weight loss associated with cancer in an older patient. Blue rubber nevus syndrome may present in a younger patient with cutaneous hemangiomas, while oral mucosal and extremity hemangiomas may be found in a patient with hereditary hemorrhagic telangiectasia (91). Family history may reveal a history of polyposis syndromes, also associated with occult bleeding. Endoscopy should be the next step in evaluation. The initial choice of colonoscopy or endoscopy is frequently

535

Table 5 Causes of Occult GI Bleeding Positive FOBT Upper GI lesions Esophagitis Peptic ulcer disease Gastritis/erosions Duodenitis/ erosions Angiodysplasia Esophageal or gastric varices Gastric cancer

Gastric or duodenal polyps

Colonic lesions Colon polyps Colon cancer Angiodysplasia Colonic ulcers

Iron deficiency anemia Upper GI lesions Esophagitis Peptic ulcer disease Gastritis/erosions Duodenitis Angiodysplasia Portalhypertensive gastropathy Gastric or esophageal cancer Gastric or duodenal polyps Celiac sprue Crohn’s disease Gastric/duodenal lymphoma Partial gastrectomy GAVE

Colonic lesions Colon polyps Colon cancer Angiodysplasia Colonic ulcers Colitis/IBD Parasitic infestation Hemorrhoids

Diverticular disease

Abbreviations: IBD, inflammatory bowel disease; GAVE, gastric antral vascular ectasia; GI, gastrointestinal. Source: From Ref. 91.

based on symptoms. In an elderly patient, searching for a source of cancer is of priority. The positive predictive value of fecal occult testing for colon cancer is only 7%, leaving a number of other possibilities (92). However, colon polyps and cancer are associated with bleeding 70% of the time (92). Examination of the upper GI tract will also frequently reveal a source. Studies have found the majority of lesions via esophagogastroduodenoscopy (EGD). One of the many studies categorizing sources of occult bleeding examined 248 patients with positive fecal occult blood test (FOBT) and found a lower bleeding source in 54 patients and an upper source in 71 patients (93). Negative upper and lower endoscopy presents a dilemma to the clinician. Repeat upper endoscopy in particular identifies initially missed lesions in 30% to 75% of cases. Most frequently, Cameron’s ulcer located in hiatial hernias, peptic ulcer disease, and vascular ectasia are subsequently found (91). The decision to proceed with further evaluation should be based on the severity and the recurrence of anemia. When colonoscopy and upper endoscopy are negative in patients with anemia, 83% will respond to iron therapy alone (94). In those patients with significant persistent losses, the small bowel is considered next for evaluation. Push enteroscopy is most frequently utilized in the setting of occult bleeding. As previously discussed, the technique uses an endoscope advanced past the ligament of Treitz. Success in identifying a lesion occurs 50% of the time, with AVMs being the most common lesion (89). Push enteroscopy has also been advocated as the initial test rather than EGD alone in occult bleeding, increasing the diagnostic yield from 41% to 67% while saving time to diagnosis and perhaps cost (95). Finally, capsule endoscopy is also becoming more readily available with success rates of identifying an occult bleeding source 76% of the time (96). Despite a best effort, many

medwedi.ru

536

Part Two: The Alimentary Tract—Other Conditions

patients will continue to bleed from an unidentified source. These patients should have regular follow-up to monitor hemoglobin levels and to offer reassurance.

SUMMARY GI hemorrhage continues to be responsible for as many as 2% of all hospital admissions, with an overall mortality rate approaching 5% to 12%. Bleeding proximal to the ligament of Treitz is termed ‘‘upper GI hemorrhage,’’ while that distal to this anatomic site is referred to as lower GI hemorrhage. Endoscopy provides the mainstay of identifying the source of bleeding for suspected upper tract hemorrhage, while a combination of maneuvers, including endoscopy, radionuclide scanning, and arteriography, may prove necessary to pinpoint the source of bleeding from a lower tract site. Capsule endoscopy is emerging as an important diagnostic aid for bleeding arising from the small intestine, a region of the gut that heretofore was difficult to evaluate. Fortunately, GI tract hemorrhage can be managed without operative intervention in the vast majority of patients using various endoscopic and/or angiographic techniques. In the small subset of patients requiring surgery, the underlying cause will dictate the specific procedure required. In the unusual patient in whom the source of bleeding remains occult, continued surveillance ultimately identifies the underlying cause in the majority of individuals. Appropriate therapy can then be employed based on the natural history of this cause.

REFERENCES 1. Disease A, Adult, California/epidemiology, Female, Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1995; 90:206–210. 2. Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage; a population-based study. Am J Gastroenterol 1997; 92: 419–424. 3. Pardo A, Durandez R, Hernandez M, et al. Impact of physician specialty on the cost of nonvariceal upper GI bleeding care. Am J Gastroenterol 2002; 97:1535–1542. 4. Kovacs TO, Jensen DM. Recent advances in the endoscopic diagnosis and therapy of upper gastrointestinal, small intestinal, and colonic bleeding. Med Clin North Am 2002; 86:1319–1356. 5. Gilbert DA, Silverstein FE, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. III. Endoscopy in upper gastrointestinal bleeding. Gastrointest Endosc 1981; 27:94–102. 6. Rockall TA, Logan RF, Devlin HB, Northfield TC. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 1995; 311:222–226. 7. Strate LL, Orav EJ, Syngal S. Early predictors of severity in acute lower intestinal tract bleeding. Arch Intern Med 2003; 163:838–843. 8. Guglielmi A, Ruzzenente A, Sandri M, et al. Risk assessment and prediction of rebleeding in bleeding gastroduodenal ulcer. Endoscopy 2002; 34:778–786. 9. Cameron EA, Pratap JN, Sims TJ, et al. Three-year prospective validation of a pre-endoscopic risk stratification in patients with acute upper-gastrointestinal haemorrhage. Eur J Gastroenterol Hepatol 2002; 14:497–501.

10. Simoens M, Gevers AM, Rutgeerts P. Endoscopic therapy for upper gastrointestinal hemorrhage: a state of the art. Hepatogastroenterology 1999; 46:737–745. 11. Cooper GS, Chak A, Way LE, Hamrnar PJ, Harper DL, Rosenthal GE. Early endoscopy in upper gastrointestinal hemorrhage: associations with recurrent bleeding, surgery, and length of hospital stay. Gastrointest Endosc 1999; 49:145–152. 12. Cipolletta L, Bianco MA, Rotondano G, Marmo R, Piscopo R. Outpatient management for low-risk nonvariceal upper GI bleeding: a randomized controlled trial. Gastrointest Endosc 2002; 55:1–5. 13. Cello JP. Endoscopic management of esophageal variceal hemorrhage: injection, banding, glue, octreotide, or a combination? Semin Gastrointest Dis 1997; 8:179–187. 14. Van Dam J, Brugge WR. Endoscopy of the upper gastrointestinal tract. N Engl J Med 1999; 341:1738–1748. 15. Cappell MS, Friedel D. The role of esophagogastroduodenoscopy in the diagnosis and management of upper gastrointestinal disorders. Med Clin North Am 2002; 86:1165–1216. 16. Chalasani N, Kahi C, Francois F, et al. Improved patient survival after acute variceal bleeding: a multicenter, cohort study. Am J Gastroenterol 2003; 98:653–659. 17. Ioannou G, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage. Cochrane Database Syst Rev 2003; 1. 18. Bruha R, Marecek Z, Spicak J, et al. Double-blind randomized, comparative multicenter study of the effect of terlipressin in the treatment of acute esophageal variceal and/or hypertensive gastropathy bleeding. Hepatogastroenterology 2002; 49:1161–1166. 19. Akahoshi T, Hashizume M, Shimabukuro R, et al. Long-term results of endoscopic histoacryl injection sclerotherapy for gastric variceal bleeding: a 10-year experience. Surgery 2002; 131:S176–S181. 20. Cheng L, Wang Z, Li C, et al. Experience in sclerotherapy for esophagogastric variceal bleeding. Chin Med J (Engl) 2002; 115:919–922. 21. D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency sclerotherapy versus medical interventions for bleeding oesophageal varices in cirrhotic patients. Cochrane Database Syst Rev 2002; 1. 22. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995; 123:280–287. 23. Banares R, Albillos A, Rincon D, et al. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology 2002; 35:609–615. 24. Bratovic I, Lacevic N. Management of esophageal varices. Med Arch 2002; 56:11–12. 25. Lui HF, Stanley AJ, Forrest EH, et al. Primary prophylaxis of variceal hemorrhage: a randomized controlled trial comparing band ligation, propranolol, and isosorbide mononitrate. Gastroenterology 2002; 123:735–744. 26. Jalan R, Bzeizi KI, Tripathi D, Lui HF, Redhead DN, Hayes PC. Impact of transjugular intrahepatic portosystemic stent-shunt for secondary prophylaxis of oesophageal variceal haemorrhage: a single-centre study over an 11-year period. Eur J Gastroenterol Hepatol 2002; 14:615–626. 27. LaBerge JM, Somberg KA, Lake JR, et al. Two-year outcome following transjugular intrahepatic portosystemic shunt for variceal bleeding: results in 90 patients. Gastroenterology 1995; 108:1143–1151. 28. Wilcox CM, Clark WS. Causes and outcome of upper and lower gastrointestinal bleeding: the Grady Hospital experience. South Med J 1999; 92:44–50. 29. Chung IK, Kim EJ, Hwang KY, et al. Evaluation of endoscopic hemostasis in upper gastrointestinal bleeding related to Mallory-Weiss syndrome. Endoscopy 2002; 34:474–479. 30. Veldhuyzen van Zanten SJ, Bartelsman JF, Schipper ME, Tytgat GN. Recurrent massive haematemesis from Dieulafoy vascular malformations—a review of 101 cases. Gut 1986; 27: 213–222.

Chapter 25: Gastrointestinal Hemorrhage 31. Tseng CC, Wolfe MM. Nonsteroidal anti-inflammatory drugs. Med Clin North Am 2000; 84:1329–1344. 32. Castillo-Rojas G, Ballesteros MA, Ponce de Leon S, MoralesEspinosa R, Cravioto A, Lopez-Vidal Y. Bleeding peptic ulcers and presence of Helicobacter pylori by various tests: a case-control study. Eur J Gastroenterol Hepatol 2002; 14: 1113–1118. 33. Laine LA. Helicobacter pylori and complicated ulcer disease. Am J Med 1996; 100:52S–57S; discussion 57S–59S. 34. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002; 346:2033–2038. 35. Chan FK. Helicobacter pylori, NSAIDs and gastrointestinal haemorrhage. Eur J Gastroenterol Hepatol 2002; 14:1–3. 36. Mamdani M, Rochon PA, Juurlink DN, et al. Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002; 325:624. 37. Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338:727–734. 38. Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998; 338:719–726. 39. Khuroo MS, Yattoo GN, Javid G, et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med 1997; 336:1054–1058. 40. Lee KK, You JH, Wong IC, et al. Cost-effectiveness analysis of high-dose omeprazole infusion as adjuvant therapy to endoscopic treatment of bleeding peptic ulcer. Gastrointest Endosc 2003; 57:160–164. 41. Morgan D. Intravenous proton pump inhibitors in the critical care setting. Crit Care Med 2002; 30:S369–S372. 42. Conrad SA. Acute upper gastrointestinal bleeding in critically ill patients: causes and treatment modalities. Crit Care Med 2002; 30:S365–S368. 43. Kaviani MJ, Hashemi MR, Kazemifar AR, et al. Effect of oral omeprazole in reducing re-bleeding in bleeding peptic ulcers: a prospective, double-blind, randomized, clinical trial. Aliment Pharmacol Ther 2003; 17:211–216. 44. Guglielmi A, Ruzzenente A, Sandri M, et al. Risk assessment and prediction of rebleeding in bleeding gastroduodenal ulcer. Endoscopy 2002; 34:778–786. 45. Lau JY, Chung SC, Leung JW, Lo KK, Yung MY, Li AK. The evolution of stigmata of hemorrhage in bleeding peptic ulcers: a sequential endoscopic study. Endoscopy 1998; 30:513–518. 46. Sacks HS, Chalmers TC, Blum AL, Benier J, Pagano D. Endoscopic hemostasis. An effective therapy for bleeding peptic ulcers. JAMA 1990; 264:494–499. 47. Frossard JL, Spahr L, Queneau PE, et al. Erythromycin intravenous bolus infusion in acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial. Gastroenterology 2002; 123:17–23. 48. Lin HJ, Hsieh YH, Tseng GY, Perng CL, Chang FY, Lee SD. A prospective, randomized trial of endoscopic hemoclip versus heater probe thermocoagulation for peptic ulcer bleeding. Am J Gastroenterol 2002; 97:2250–2254. 49. Lin HJ, Tseng GY, Perng CL, Lee FY, Chang FY, Lee SD. Comparison of adrenaline injection and bipolar electrocoagulation for the arrest of peptic ulcer bleeding. Gut 1999; 44:715–719. 50. Jensen DM, Kovacs TO, Jutabha R, et al. Randomized trial of medical or endoscopic therapy to prevent recurrent ulcer hemorrhage in patients with adherent clots. Gastroenterology 2002; 123:407–413. 51. Longstreth GF, Feitelberg SP. Successful outpatient management of acute upper gastrointestinal hemorrhage: use of practice guidelines in a large patient series. Gastrointest Endosc 1998; 47:219–222.

537

52. Spiegel BM, Ofman JJ, Woods K, Vakil NB. Minimizing recurrent peptic ulcer hemorrhage after endoscopic hemostasis: the cost-effectiveness of competing strategies. Am J Gastroenterol 2003; 98:86–97. 53. Monig SP, Lubke T, Baldus SE, Schafer H, Holscher AH. Early elective surgery for bleeding ulcer in the posterior duodenal bulb. Own results and review of the literature. Hepatogastroenterology 2002; 49:416–418. 54. Fennerty MB. Pathophysiology of the upper-gastrointestinal tract of the critically ill-patient: rationale for the therapeutic benefits of acid suppression. Crit Care Med 2002; 30: S351–S355. 55. Cook DJ, Fuller HD, Guyat GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients; Canadian critical Care Trials Group. N Engl J Med 1994; 330:377–381. 56. Cash BD. Evidence-based medicine as it applies to acid suppression in the hospitalized patient. Crit Care Med 2002, 30: S373–S378. 57. Clouse RE, Costigan DJ, Mills BA, Zuckerman GR. Angiodysplasia as a cause of upper gastrointestinal bleeding. Arch Intern Med 1985; 145:458–461. 58. Warkentin TE, Moore JC, Morgan DG. Gastrointestinal angiodysplasia and aortic stenosis. N Engl J Med 2002; 347:858–859. 59. Green MH, Duell RM, Johnson CD, Jamieson NV. Haemobilia. Br J Surg 2001; 88:773–786. 60. Balsarkar DJ, Joshi MA. Rupture of splenic artery pseudoaneurysm presenting with massive upper gastrointestinal bleed. Am J Surg 2002; 183:197–198. 61. Moawad M, Ray S, Joseph JV. Massive upper gastrointestinal haemorrhage due to intragastric rupture of a splenic artery aneurysm. Int J Clin Pract 2002; 56:482–483. 62. Lemos DW, Raffetto JD, Moore TC, Menzoian JO. Primary aortoduodenal fistula: a case report and review of the literature. J Vasc Surg 2003; 37:686–689. 63. Duncan JR, Renwick AA, Mackenzie I, Gilmour DG. Primary aortoenteric fistula: pitfalls in the diagnosis of a rare condition. Ann Vasc Surg 2002; 16:242–245. 64. Nguyen NT, Rivers R, Wolfe BM. Early gastrointestinal hemorrhage after laparoscopic gastric bypass. Obes Surg 2003; 13: 62–65. 65. Braley SC, Nguyen NT, Wolfe BM. Late gastrointestinal hemorrhage after gastric bypass. Obes Surg 2002; 12:404–407. 66. Angtuaco TL, Reddy SK, Drapkin S, Harrell LE, Howden CW. The utility of urgent colonoscopy in the evaluation of acute lower gastrointestinal tract bleeding: a 2-year experience from a single center. Am J Gastroenterol 2001; 96:1782–1785. 67. Jensen DM, Machicado GA, Jutabha R, Kovacs TO. Urgent colonoscopy for the diagnosis and treatment of severe diverticular hemorrhage. N Engl J Med 2000; 342:78–82. 68. Jensen DM, Machicado GA. Diagnosis and treatment of severe hematochezia. The role of urgent colonoscopy after purge. Gastroenterology 1988; 95:1569–1574. 69. Ohyama T, Sakurai Y, Ito M, Daito K, Sezai S, Sato Y. Analysis of urgent colonoscopy for lower gastrointestinal tract bleeding. Digestion 2000; 61:189–192. 70. Strate LL, Syngal S. Timing of colonoscopy: impact on length of hospital stay in patients with acute lower intestinal bleeding. Am J Gastroenterol 2003; 98:317–322. 71. Lefkovitz Z, Cappell MS, Lookstein R, Mitty HA, Gerard PS. Radiologic diagnosis and treatment of gastrointestinal hemorrhage and ischemia. Med Clin North Am 2002; 86: 1357–1399. 72. DeBarros J, Rosas L, Cohen J, Vignati P, Sardella W, Hallisey M. The changing paradigm for the treatment of colonic hemorrhage: superselective angiographic embolization. Dis Colon Rectum 2002; 45:802–808. 73. Patel TH, Cordts PR, Abcarian P, Sawyer MA. Will transcatheter embolotherapy replace surgery in the treatment of gastrointestinal bleeding?(2)(2). Curr Surg 2001; 58:323–327. 74. Smith R, Copely DJ, Bolen FH. 99mTc RBC scintigraphy: correlation of gastrointestinal bleeding rates with scintigraphic findings. AJR Am J Roentgenol 1987; 148:869–874.

medwedi.ru

538

Part Two: The Alimentary Tract—Other Conditions

75. Howarth DM, Tang K, Lees W. The clinical utility of nuclear medicine imaging for the detection of occult gastrointestinal haemorrhage. Nucl Med Commun 2002; 23:591–594. 76. Ponzo F, Zhuang H, Liu FM, et al. Tc-99m sulfur colloid and Tc-99m tagged red blood cell methods are comparable for detecting lower gastrointestinal bleeding in clinical practice. Clin Nucl Med 2002; 27:405–409. 77. Ludeman L, Warren BF, Shepherd NA. The pathology of diverticular disease. Best Pract Res Clin Gastroenterol 2002; 16: 543–562. 78. McGuire HH Jr, Haynes BW Jr. Massive hemorrhage for diverticulosis of the colon: guidelines for therapy based on bleeding patterns observed in fifty cases. Ann Surg 1972; 175:847–855. 79. McGuire HH Jr. Bleeding colonic diverticula. A reappraisal of natural history and management. Ann Surg 1994; 220:653–656. 80. Ina K, Kusugami K, Ohta M. Bacterial hemorrhagic enterocolitis. J Gastroenterol 2003; 38:111–120. 81. Wilcox CM, Chalasani N, Lazenby A, Schwartz DA. Cytomegalovirus colitis in acquired immunodeficiency syndrome: a clinical and endoscopic study. Gastrointest Endosc 1998; 48:39–43. 82. Pardi DS, Loftus EV Jr, Tremaine WJ, et al. Acute major gastrointestinal hemorrhage in inflammatory bowel disease. Gastrointest Endosc 1999; 49:153–157. 83. Gibbs DH, Opelka FG, Beck DE, Hicks TC, Timmcke AE, Gathright JB Jr. Postpolypectomy colonic hemorrhage. Dis Colon Rectum 1996; 39:806–810. 84. Mulcahy HE, Patel RS, Postic G, et al. Yield of colonoscopy in patients with nonacute rectal bleeding: a multicenter database study of 1766 patients. Am J Gastroenterol 2002; 97:328–333. 85. Chalasani N, Wilcox CM. Etiology and outcome of lower gastrointestinal bleeding in patients with AIDS. Am J Gastroenterol 1998; 93:175–178. 86. Eaton AC. Emergency surgery for acute colonic haemorrhage—a retrospective study. Br J Surg 1981; 68:109–112.

87. Baker R, Senagore A. Abdominal colectomy offers safe management for massive lower GI bleed. Am Surg 1994; 60: 578–581; discussion 582. 88. Douard R, Wind P, Panis Y, et al. Intraoperative enteroscopy for diagnosis and management of unexplained gastrointestinal bleeding. Am J Surg 2000; 180:181–184. 89. Landi B, Cellier C, Gaudric M, et al. Long-term outcome of patients with gastrointestinal bleeding of obscure origin explored by push enteroscopy. Endoscopy 2002; 34:355–359. 90. Ell C, Remke S, May A, Helou L, Henrich R, Mayer G. The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding. Endoscopy 2002; 34:685–689. 91. Zuckerman GR, Prakash C, Askin MP, Lewis BS. AGA technical review on the evaluation and management of occult and obscure gastrointestinal bleeding. Gastroenterology 2000; 118:201–221. 92. Niv Y, Sperber AD. Sensitivity, specificity, and predictive value of fecal occult blood testing (Hemoccult II) for colorectal neoplasia in symptomatic patients: a prospective study with total colonoscopy. Am J Gastroenterol 1995; 90:1974–1977. 93. Rockey DC, Koch J, Cello JP, Sanders LL, McQuaid K. Relative frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult-blood tests. N Engl J Med 1998; 339:153–159. 94. Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia. N Engl J Med 1993; 329:1691–1695. 95. Chak A, Cooper GS, Canto MI, Pollack BJ, Sivak MV Jr. Enteroscopy for the initial evaluation of iron deficiency. Gastrointest Endosc 1998; 47:144–148. 96. Hartmann D, Schilling D, Bolz G, et al. Capsule endoscopy versus push enteroscopy in patients with occult gastrointestinal bleeding. Z Gastroenterol 2003; 41:377–382.

26 The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain Kathryn A. Richardson, Ryan M. Wolfort, and Richard H. Turnage

INTRODUCTION Abdominal pain is the principal symptom of most acute abdominal diseases. In particular, the acute onset of severe abdominal pain in a patient who was previously well suggests a disease of surgical importance, especially if the pain has persisted for six hours or more. The term ‘‘acute abdomen’’ is often applied to such cases; however, this term should not be equated with the need for operation. It does, however, necessitate ‘‘a serious and thorough attempt at diagnosis’’ (1). The onset of severe abdominal pain is caused by ischemia, inflammation of an abdominal organ or tissue, or acute distention of a hollow smooth muscle-lined structure such as the ureter or intestine or by stretching of the peritoneum or the capsule of a solid organ. This chapter relates the anatomy and physiology of acute abdominal pain to the clinical presentation of patients with diseases commonly associated with this symptom. Furthermore, the influence of extremes of age, immunosuppression with steroids or acquired immunodeficiency syndrome (AIDS), and spinal cord injury on the clinical presentation of patients with acute abdominal diseases is reviewed.

TYPES OF ABDOMINAL PAIN Abdominal pain may be categorized as visceral, somatoparietal, or referred based on distinct clinical features and the underlying neuroanatomy.

The pain is more intense and more precisely localized than visceral pain. It is lateralized because only one side of the nervous system innervates a given part of the parietal peritoneum. The pain is exacerbated by movement or coughing, and hence patients will usually lie still in an attempt to limit their pain.

Referred Pain Referred pain occurs when pain is perceived in an area of the body remote from its site of origin. It is intense, sharp, and perceived to be superficial in nature. Referred pain occurs as the visceral stimulus intensifies. Well-known examples of referred pain are shown in Figure 2A and include shoulder pain upon inflammation of the diaphragm, scapular pain associated with acute biliary tract disease, or testicular or labial pain caused by retroperitoneal inflammation. Referred pain is caused by the convergence of visceral afferent neurons innervating an injured or inflamed organ, with somatic afferent fibers arising from a different anatomic region. This convergence occurs at the level of second-order neurons at the same level in the spinal cord as illustrated in Figure 2B.

ANATOMY AND PHYSIOLOGY OF ABDOMINAL PAIN Visceral and Somatoparietal Nociceptors The neuroreceptors involved in nociception are the peripheral ends of two distinct types of afferent nerve fibers: A-delta fibers and C-fibers.

Visceral Pain Visceral pain is caused by stimulation of visceral nociceptors by inflammation, distention, or ischemia. The pain is dull and poorly localized to the epigastrium, periumbilical region, or the lower mid-abdomen depending upon the dermatomal distribution of the nerves supplying the diseased organ. This is illustrated in Figure 1. The pain is poorly localized because the innervation of most viscera is multisegmental and contains fewer nerve receptors than highly sensitive organs such as the skin. It is perceived in the midline because the abdominal organs transmit sensory afferents to both sides of the spinal cord. Visceral pain is often described as cramping, burning, or gnawing and may be accompanied by secondary autonomic effects such as sweating, restlessness, nausea, vomiting, perspiration, and pallor. The patient may move about in an effort to lessen the discomfort.

Somatoparietal Pain Somatoparietal pain is due to stimulation of somatic sensory spinal nerves innervating the parietal peritoneum (T7–L1).

A-Delta Fibers The A-delta fibers are myelinated nerves that are 3 to 4 mm in diameter and transmit signals at a rate of 6 to 30 m/sec. They are primarily distributed in skin and muscle. A-delta fibers mediate the sharp, sudden, and well-localized pain that follows acute injury or inflammation. These fibers transmit somatoparietal pain sensation from the anterior and lateral abdominal walls to the central nervous system via spinal nerves from segments T7 through L1. Somatoparietal pain from the posterior abdominal wall is transmitted to the central nervous system via spinal nerves from segments L2 to L5. The pain is precisely localized by the specific spinal level (T7–L1) and the side of activated A-delta fibers (right or left).

C-Fibers C-fibers are unmyelinated nerves that are primarily involved in the transmission of visceral pain in association with the autonomic nervous system. These fibers are more slowly transmitting than the A-delta fibers (0.5–2 m/sec)

medwedi.ru 539

540

Part Two: The Alimentary Tract—Other Conditions

to provide sensory innervation to the hypogastrium and lower anterior abdominal wall. The iliohypogastric nerve runs parallel to the 12th thoracic nerve to pierce the transversus abdominis muscle near the iliac crest. After coursing between the transversus abdominis and the internal oblique muscle for a short distance, the nerve pierces the latter to travel under the external oblique fascia toward the external inguinal ring. It emerges through the superior crus of the external inguinal ring to provide sensory innervation to the anterior abdominal wall in the hypogastrium. The ilioinguinal nerve courses parallel to the iliohypogastric but closer to the iliac crest. Unlike the iliohypogastric, the ilioinguinal nerve courses with the spermatic cord to emerge from the external inguinal ring with its terminal branches providing sensory innervation to the skin of the inguinal region and the scrotum or labium.

Peripheral Neural Pathways for Visceral Pain

Figure 1 Anatomic locations where visceral abdominal pain is perceived. The location in which visceral pain is perceived is related to the embryologic site of origin of the organ from which the pain stimulus emanates. Activation of nociceptors in the foregut (stomach, duodenum, liver, spleen, and gallbladder) causes the perception of pain in the epigastrium (T5–T9). Stimulation of nociceptors in the midgut (small intestine, appendix, and right colon) causes the perception of pain in the periumbilical region (T8–L1). Pain stimuli from the hindgut-derived organs (left colon and proximal rectum) is perceived in the hypogastrium (T12–L1).

and produce a sensation of pain that is dull, burning, and poorly localized. The sensation of pain mediated by these fibers is also more gradual in onset and longer in duration than the sensation transmitted by A-delta fibers. C-fibers are located in the walls of hollow viscera, mesentery, parietal peritoneum, and the capsule of solid organs. In addition to transmitting the sensation of pain to the central nervous system, stimulation of C-fibers activates local regulatory reflexes mediated by the enteric nervous system and long spinal reflexes mediated by the autonomic nervous system.

Peripheral Neural Pathways for Somatoparietal Pain The 7th to 12th thoracic nerves follow a curvilinear course in the intercostal spaces to emerge from under the costal cartilages and lower ribs. From here, they course medially between the internal oblique and the transversus abdominis muscles to reach the anterior midline. The seventh and eighth thoracic nerves course horizontally or slightly upward to reach the epigastrium whereas the lower nerves follow an increasingly caudal trajectory. As these nerves course medially, they provide motor branches to the abdominal wall musculature and sensory branches to the anterolateral abdominal wall. The anterior ramus of the 10th thoracic nerve reaches the skin at the level of the umbilicus, and the 12th thoracic nerve provides sensory innervation to the skin of the hypogastrium. The anatomic course of the nerves innervating the abdominal wall as well as the corresponding dermatomes are shown in Figure 3A and B. The ilioinguinal and iliohypogastric nerves arise from the anterior rami of the 12th thoracic and first lumbar nerves

The visceral afferent fibers transmitting nociception from the abdominal viscera to the central nervous system follow the distribution of the autonomic nervous system, principally the sympathetic nervous system. Only the middle and upper esophagus and the pelvic organs receive visceral sensory afferents along parasympathetic nerves. The sensory innervation of abdominal organs is related to the embryologic site of origin of the organ. Pain originating in structures derived from the embryonic foregut is perceived in the epigastrium, pain originating in midgut-derived structures is felt in the periumbilical region, and pain originating in structures derived from the embryonic hindgut is perceived in the hypogastrium. The relationship between the site of visceral pain and the embryologic origin of the injured or diseased organ is shown in Table 1 and Figure 1.

Central Neuroanatomy of Visceral and Somatoparietal Pain The sensory afferent nerves from both the abdominal viscera and the abdominal wall enter the spinal cord through the posterior nerve root. The cell bodies for the visceral and somatoparietal afferent nerves are located in the dorsal root ganglia of the spinal nerves. The relationship between the splanchnic and spinal nerves and the corresponding dorsal root ganglion is illustrated in Figure 4. Upon entering the spinal cord, the visceral afferent fibers branch into the dorsal horn and into Lissauer’s tract over several spinal segments before terminating on the dorsal horn cells in Rexed lamina V. Somatic nerves also enter the spinal cord through the dorsal nerve root and branch to synapse with second-order neurons in lamina I. From the dorsal horn, second-order neurons either transmit nociceptive impulses to other neurons (i.e., interneurons or relay cells) or transmit nociceptive impulses via fibers that cross through the anterior commissure to ascend the spinal cord in the contralateral spinothalamic and spinoreticular tract. Ultimately, these fibers project to the thalamic nuclei and the reticular formation nuclei of the pons and medulla. The pons sends third-order neurons to the somatosensory cortex, where the discriminative aspects of pain are perceived. The medulla sends neurons to the limbic system and frontal cortex, where the emotional aspects of pain are interpreted and the associated phenomena of nausea, vomiting, and other physiologic responses are precipitated. Afferent pain impulses are modified by inhibitory neuronal pathways within the dorsal horns of the spinal cord. These inhibitory neurons originate in the mesencephalon,

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

541

Figure 2 The surface anatomy (A) and neuroanatomy (B) of referred abdominal pain is perceived. The location of the referred abdominal pain is based on the convergence of visceral afferent neurons innervating an injured or inflamed organ 1 with somatic afferent fibers arising from the anatomic region in which the referred pain is perceived 3. These visceral and somatic afferent neurons synapse with second-order neurons in the spinal cord 2 and the brain interprets the pain to be somatic in origin and localizes it to the shoulder. Source: From Refs. 2, 3.

periventricular gray matter, and caudate nucleus and descend within the spinal cord to the level of the substantia gelatinosa where they release endogenous opioids and enkephalins, which inhibit ascending nociceptive pain impulses. Inhibitory interneurons also act upon the cell bodies of nerves in Rexed lamina V of the dorsal horn, which receive impulses from both somatic and visceral afferent nerve fibers. Together, these inhibitory pathways allow cerebral modification of afferent pain impulses.

PATHOPHYSIOLOGIC STIMULI FOR SOMATIC AND VISCERAL NOCICEPTORS Somatoparietal nociceptors respond to sudden increases in tissue pressure, the cutting or tearing of tissue, and acute changes in tissue temperature or pH (such as that associated with inflammation). The principal mechanical stimulus for visceral nociceptors is a sudden change in the geometry of the bowel or capsule of a solid organ. This may occur by distention of an acutely obstructed intestine, ureter or fallopian tube, or the stretching of Glisson’s capsule in patients with acute hepatitis or congestive heart failure. Unlike somatoparietal nociceptors, the cutting, tearing, or crushing of abdominal viscera does not stimulate visceral sensory afferents. Visceral nociceptors also respond to chemical stimuli, particularly those associated with inflammation and ischemia. It is postulated that these proinflammatory states induce the release of vasoactive substances (i.e., bradykinin, histamine, serotonin, and eicosanoids), gastrointestinal neurotransmitters and hormones (i.e., substance P and calcitonin-gene–related peptide), and various end products of metabolism (i.e., potassium and hydrogen ions),

which then stimulate visceral afferent sensory neurons. These substances may also potentiate the effects of mechanical stimuli by lowering the threshold for a given mechanical stimulus to excite the C-fiber nociceptor.

EVALUATION OF PATIENTS WITH ACUTE ABDOMINAL PAIN The acute onset of severe abdominal pain necessitates prompt diagnosis. In some cases, the clinical findings are so compelling that there is little doubt as to the etiology, much less the course of action. In others, the precise diagnosis is not readily apparent. In these instances, an earnest effort, based upon a thorough history and physical examination, must be made to determine the cause of the patient’s symptoms. An orderly and systematic approach to diagnosis will facilitate the development of a relevant differential diagnosis and guide the appropriate use of laboratory and imaging studies. The components of the differ ential diagnosis should be considered according to those conditions that are most common and those that present the greatest threat to the patient’s life.

History The goal of the clinician’s examination is to recognize the subtle signs and symptoms of abdominal diseases early in their evolution, well prior to the development of peritonitis. An accurate, detailed history provides the initial, and perhaps most important, step toward elucidating the cause of the patient’s abdominal pain. In large part, an accurate differential diagnosis may be based upon the location and

medwedi.ru

542

Part Two: The Alimentary Tract—Other Conditions

Figure 3 (A) The anatomic course of the thoracic (T7–12) and lumbar (L1–L2) spinal nerves that provide somatoparietal pain sensation to the abdominal wall. The thoracic and lumbar spinal nerves follow a curvilinear course around the torso to provide motor innervation to the flat muscles of the abdominal wall and sensory innervation to the skin, muscle, and parietal peritoneum of the anterolateral abdominal wall. (B) The dermatomes providing sensation to the abdominal wall originate from the seventh thoracic nerve to the second lumbar nerve. The seventh thoracic nerve innervates the epigastrium, the 10th thoracic nerve innervates the region of the umbilicus, and the 12th thoracic and first lumbar nerves provide sensory innervation to the hypogastrium. There is considerable overlap between these dermatomes such that division of one of the nerves alone to a given dermatome will result in minimal deficit. Source: From Refs. 4, 5.

character of the patient’s pain and the chronologic relationship between the pain and other symptoms.

Chronology and Pattern of Abdominal Pain It is important to understand the evolution of the patient’s illness from the moment of onset until the time of examination. Patients with significant abdominal pain will often be able to precisely time the onset of their symptoms. The awakening from a sound sleep by the onset of acute abdominal pain is almost always of great significance. Pain that is sudden in onset, severe, and well localized frequently results from an acute intra-abdominal ischemic or inflammatory process that will require surgical management. In these instances, the pain does not abate with time but retains its severe character as is illustrated by ‘‘Line A’’ in Figure 5. In some instances, the patient will collapse at the onset of their pain. Examples of these conditions include perforation of a duodenal or gastric ulcer, ruptured ectopic pregnancy, ruptured abdominal or splanchnic artery aneurysm, and acute mesenteric ischemia. Other patients will present with a more gradual onset and evolution of their abdominal pain as illustrated by ‘‘Line B’’ in Figure 5. Patients with acute appendicitis will often present with an early vague periumbilical visceral pain followed by localization of severe somatoparietal pain at McBurney’s point. This gradual evolution of pain and associated symptoms is also apparent in cases of acute cholecystitis, acute pancreatitis, and acute diverticulitis.

Obstruction of a hollow viscus such as the small intestine or the ureter causes colicky or cramping pain that is best described by a crescendo–decrescendo pattern with relative freedom from pain between cramps; a pattern illustrated by ‘‘Line C’’ in Figure 5. The change of colicky visceral pain to a constant somatoparietal pattern in patients with intestinal obstruction strongly suggests infarction of the obstructed intestine. The pain caused by obstruction of the cystic duct in cases of biliary ‘‘colic’’ is steady and not paroxysmal, and hence the term ‘‘biliary colic’’ is a misnomer. In this instance, the lack of a dense muscular wall and hence strong steady contractions prevent the cramping associated with obstruction of other hollow viscera.

Location of Abdominal Pain Precise localization of the patient’s abdominal pain is extremely valuable in developing an accurate differential diagnosis. Even patients with severe diffuse pain can often identify a site of greatest discomfort or the site from which the pain originates. The patient may also be able to differentiate the initial medially located, vague visceral pain from the subsequent sharp, well-localized somatoparietal pain. It is important to recall the common sites in which visceral and referred pain from injured or inflamed organs are perceived (Figs. 1 and 2). Understanding the normal anatomic location of various organs, as well as their aberrant locations, may be

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

543

Table 1 Relationship Between the Site of Visceral Pain and the Embryonic Origin of the Diseased or Injured Organ Embryonic site of origin

Surface location

Dermatomal distribution and nerves

Foregut

Epigastrium

T5–T9 spinal levels, celiac plexus, greater splanchnic nerves

Midgut

Periumbilical

T8–L1 spinal levels, lesser and least splanchnic nerves

Hindgut

Hypogastrium

Urogenital system and gonads

Hypogastrium

T11–L1 and S3–S5 spinal levels, inferior mesenteric plexus, lowest splanchnic nerve, hypogastric plexus T10–L 2 spinal levels

Intra-abdominal organs Esophagus, stomach, duodenum, spleen, liver, gall bladder, portion of the pancreas Jejunum, ileum, appendix, cecum, ascending colon, and the right half of the transverse colon Distal half of the transverse colon, descending colon, sigmoid colon and rectum Kidneys, ureter, bladder, uterus, vagina, gonads

Representative diseases Peptic ulcer disease, biliary colic, acute pancreatitis SBO, acute appendicitis, Meckel’s diverticulitis Acute diverticulitis, ischemic colitis, ulcerative colitis Acute salpingitis, pyelonephritis, ureteral colic

Abbreviation: SBO, small bowel obstruction.

suggestive of the organ from which somatoparietal pain impulses originate. Common causes of pain in each of the regions of the abdomen are shown in Figure 6E. It should be recalled that the flow of fluid within the peritoneal cavity is governed by various ligaments or mesenteries, which subdivide the peritoneal cavity into interconnected compartments or spaces. This results in well-defined pathways by which fluid flows within the peritoneal cavity (Fig. 7). From this knowledge, it is understandable how the acrid fluid of a perforated duodenal ulcer may flow down the right paracolic gutter to inflame the parietal peritoneum in the right lower abdomen and cause symptoms suggestive of acute appendicitis. Furthermore, peritoneal fluid normally flows from the pelvis superiorly toward lymphatic channels within the

Figure 4 The sensory afferent nerves from both the abdominal viscera and the anterolateral abdominal wall enter the spinal cord through the posterior nerve root. The cell bodies for both the visceral and the somatoparietal afferent nerves are located in the posterior root ganglion. Source: From Ref. 6.

inferior surface of the diaphragm. Thus infections originating in the pelvis may cause symptoms in other parts of the abdomen, e.g., the right upper abdominal pain associated with Fitz-Hugh-Curtis syndrome from acute salpingitis.

Aggravating and Alleviating Factors The factors that exacerbate or relieve a patient’s pain may provide additional, supportive information to that gleaned from review of the character and location of the pain. Patients with peritonitis will often relate that any sudden movement will exacerbate their pain, such as that produced by coughing. These patients will often lie motionless on the examining table in an attempt to minimize their discomfort. Patients with acute pancreatitis will relate a lessening of their discomfort upon assuming an upright, or even bent over, posture.

Figure 5 Patterns of acute abdominal pain. (A) This unremitting severe pain pattern is characteristic of perforation of the duodenum or stomach from ulcer disease, ruptured ectopic pregnancy, and ruptured visceral artery aneurysm or abdominal aortic aneurysm. (B) The pattern of pain associated with acute pancreatitis, acute cholecystitis, and acute appendicitis is more gradual in onset and evolution. (C) This crescendo–decrescendo pattern of severe pain with intervening periods of absence of pain is characteristic of the colicky pain of simple small intestinal obstruction and obstruction of the ureter by a calculus. (D) Many uncomplicated conditions are associated with the gradual onset and spontaneous resolution of abdominal pain such as acute gastroenteritis.

medwedi.ru

544

Part Two: The Alimentary Tract—Other Conditions

Figure 6 Common diagnoses associated with pain and localized tenderness in the right upper quadrant (A), the left upper quadrant (B), the right lower quadrant (C), and the left lower quadrant (D), and diffuse, generalized abdominal pain and tenderness (E). These diagnoses are grouped according to the organ or organ system in which they occur. Abbreviations: SMA, superior mesenteric artery; SMV, superior mesenteric vein.

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

Figure 7 Intraperitoneal circulation of fluid from the pelvis toward the lymphatic channels in the inferior surface of the diaphragm. From these pathways it is apparent how an infection within the pelvis, such as acute salpingitis, may spread to involve the peri-hepatic spaces to cause FitzHugh-Curtis syndrome. Fluid may also move from superior locations toward the pelvis in response to gravity. For example, the acrid fluid of a perforated duodenal ulcer may spread down the right paracolic gutter to present as peritonitis in the right lower abdomen. Source: From Ref. 7.

545

with a pelvic abscess from perforated appendicitis may present with diarrhea and tenesmus. The failure to pass flatus is an important symptom in patients suspected of having intestinal obstruction. However, it should be noted that patients with a partial small intestinal obstruction, or a high-grade colonic obstruction, may present with a profuse watery diarrhea that is likely to mislead the uninformed examiner who believes that any bowel motions exclude the possibility of obstruction. It is the failure to pass flatus in these cases that supports the diagnosis of intestinal obstruction. Patients with severe abdominal inflammatory conditions may have a fever but the presence of rigors and high fever (103–104 F), particularly early in the course of a patient’s illness, is uncommon. It is of utmost importance to inquire about the menstrual history of premenopausal women presenting with acute abdominal pain. The precise date of the last period must be determined and any irregularity noted. The symptoms associated with a ruptured follicular cyst (Mittelschmerz) usually occur at midcycle whereas rupture of a corpus luteum cyst occurs at the time of the menses. Patients with a tubal pregnancy will almost invariably report some menstrual irregularity in the weeks preceding the onset of their pain.

Past Medical History and Family and Social History

Associated Symptoms It is unusual for abdominal pain to be the only symptom of an acute abdominal disease of surgical importance. Information regarding constitutional symptoms (e.g., fever, chills, and weight loss), digestive function (e.g., anorexia, nausea, vomiting, flatus, diarrhea, and constipation), jaundice, dysuria, menstruation, and pregnancy must be obtained. It is of particular importance to elucidate the temporal relationship between these symptoms and the onset of the patient’s pain. Forexample, patients with acute appendicitis will nearly always develop nausea and vomiting after the onset of their abdominal pain. In fact, the diagnosis of acute appendicitis would be unlikely in those instances in which nausea and vomiting preceded the development of pain. The presence of anorexia and the character and volume of the emesis should be noted. As alluded to earlier, activation of visceral nociceptors is often associated with autonomic effects including vomiting. Even patients with acute obstruction of the ureter or the cystic duct by a stone will have early and sudden emesis of bilious or clear fluid; a similar phenomenon occurs in patients with acute ovarian torsion. In patients with intestinal obstruction, the character of the emesis changes over time from bilious fluid early to a brownish, feculent fluid later in the evolution of this disease. The emesis of patients with proximal small intestinal obstruction is frequent, copious, and early in onset after the development of the patient’s pain, and whereas patients with more distally located obstructions will have less frequent emesis. Anorexia is a more constant symptom than vomiting in patients with acute abdominal diseases. The acute loss of appetite is always significant, especially when accompanied by the development of abdominal pain. An acute change in bowel habits is also likely to be of significance in patients presenting with acute abdominal pain. Patients

Careful review of the patient’s chronic or previous medical problems will often shed light on the current situation. Previous history of partial small bowel obstruction (SBO), renal calculi, or inflammatory bowel disease should alert the clinician to the possibility of a recurrence of their disease. Medication use, both prescriptive and over the counter, must be ascertained, particularly given the association between nonsteroidal anti-inflammatory drug use and ulcer disease. A careful review of the patient’s family history may yield important information regarding the cause of their abdominal pain, particularly in children. Sickle cell disease in people of African descent is a good example. The patient’s social history, especially the use of illicit drugs, may be important in determining the etiology of their disease. For example, cocaine use is associated with ischemic perforation of the intestine.

Physical Examination A thorough physical examination is of paramount importance in developing an accurate differential diagnosis and determining the presence of peritonitis and the need for urgent or emergent operation. The physical findings must be interpreted in the context of the patient’s medical history. For example, elderly or immunocompromised patients will often lack clear physical signs of peritonitis, even in the presence of a perforated bowel (a topic considered subsequently).

Systemic Examination The physical examination begins by observing the patient’s general appearance, posture, position in bed, degree of discomfort, and facial expression. A patient lying still in bed with hips and knees flexed, and reluctant to move with a distressed facial expression suggests the presence of peritonitis whereas those patients who writhe about in bed seeking a comfortable position are more likely to have colic from an obstructed ureter or intestine or acute mesenteric ischemia.

medwedi.ru

546

Part Two: The Alimentary Tract—Other Conditions

The patient’s heart rate, ventilatory rate, temperature, and blood pressure should be measured; tachycardia and tachypnea may result from pain, sepsis, or hypovolemia. An irregularly irregular pulse, suggestive of atrial fibrillation, should greatly heighten one’s suspicion that the patient’s abdominal pain is due to an embolus to the superior mesenteric artery (SMA) with resultant acute mesenteric ischemia. Noteworthily, a normal pulse rate does not preclude the presence of significant abdominal diseases. Careful auscultation of the lungs may provide evidence of lower lobe pneumonia, an important extra-abdominal cause of abdominal pain. Examination of the extremities may demonstrate mottling of the skin of the lower extremities, consistent with poor tissue perfusion from hypovolemia or septic shock.

Abdominal Examination Examination of the abdomen begins by the examiner asking the patient to precisely locate the site of greatest discomfort. The tendency to immediately palpate this region must be avoided; gentleness is essential to a successful examination. The clinician proceeds from the least painful maneuver initially to that of greatest discomfort. Examination of the abdomen begins with inspection for evidence of chronic diseases (e.g., cirrhosis with ascites and dilated periumbilical veins) or abdominal distention suggestive of a distal intestinal obstruction. Previous laparotomy incision sites and hernias must be noted and recently incarcerated hernias should be viewed with particular concern because of their association with strangulated intestinal obstruction. Auscultation of the abdomen in patients with peritonitis will demonstrate diminished bowel sounds consistent with the associated paralytic ileus. Patients with early small intestinal obstruction may have characteristic ‘‘rushes and tinkles.’’ Noteworthily, rarely if ever, are the auscultatory findings so compelling as to be diagnostic of a particular abdominal disease. Percussion and palpation of the abdomen should proceed from the quadrant of the abdomen farthest from the area of greatest tenderness. Gentle percussion will readily distinguish between tympanitic gas-filled dilated loops of obstructed bowel and the shifting dullness of ascites. Percussion of the abdomen will also localize the point of maximal tenderness and often provide the first physical evidence of localized or diffuse peritonitis. The presence (or absence) of voluntary or involuntary guarding (i.e., muscular rigidity) and the specific site of maximal tenderness upon gentle palpation should be elicited. This does not require deep palpation and should be done in such a way as to minimize discomfort to the patient. Extension of the inflammatory process to involve the parietal peritoneum is associated with voluntary guarding, in its earliest stages, and involuntary guarding as the process progresses. It is rare for a patient to have peritonitis without at least some detectable tenderness upon palpation of the abdomen or, in those cases in which the inflamed organ is within the pelvis, tenderness upon rectal or pelvic examination. The most common scenario is localized tenderness with or without voluntary guarding. The presence of diffuse involuntary guarding (or a rigid or ‘‘board-like’’ abdomen) suggests perforation of the stomach, duodenum, or colon. Peritonitis may also be detected by eliciting focal abdominal pain by gently shaking the bed, striking the patient’s heel or asking the patient to breathe deeply or to cough.

Intra-abdominal or retroperitoneal masses may be palpable in patients without significant guarding. The presence of a pulsatile mid-abdominal mass and back pain suggests a ruptured abdominal aortic aneurysm. Also, inflammatory masses may be appreciated in some patients with acute appendicitis or acute cholecystitis, although often voluntary guarding at the site of peritoneal inflammation precludes identification of the mass. ‘‘Rebound’’ pain may be elicited by pressing the fingers gently but deeply over an inflamed focus within the abdomen after which the pressure is suddenly released. This maneuver is associated with sudden and, sometimes, severe pain on the ‘‘rebound.’’ Like Silen, ‘‘we do not recommend the performance of this test, for it elicits no more than can be ascertained by careful, gentle pressure and may cause unexpected and unnecessary pain’’ (1). Inflammation in the region of the psoas muscle, as may occur in patients with retrocecal appendicitis, causes pain during contraction or passive stretching of this muscle. This sign may be elicited by placing the patient in a supine position and flexing the right hip against resistance. Alternatively, the so-called psoas sign may be induced by placing the patient in the left lateral decubitus position with the examiner passively extending the right hip. Inflammation involving the fascia of the obturator internus muscle within the pelvis causes pain upon internal and external rotation of the flexed right hip, the so-called obturator sign.

Genital, Rectal, and Pelvic Examinations Examination of patients with acute abdominal pain is incomplete without digital examination of the pelvis and rectum. These techniques will identify pelvic inflammation that may not be apparent upon examination of the anterior abdominal wall. For example, patients with acute appendicitis in whom the appendix lies in the pelvis will often have minimal tenderness upon palpation of the anterior abdominal wall but will frequently have tenderness on rectal and pelvic examination. Similarly, patients with tuboovarian inflammation will often have tenderness limited to the pelvis and hence demonstrable only by pelvic or rectal examination.

Laboratory Tests Laboratory tests are obtained to narrow the differential diagnosis and to identify acute and chronic medical problems that may represent a threat to the patient’s welfare or otherwise alter the treatment plan. These tests should be obtained only after a thorough history and physical examination have been performed. Tests commonly utilized include a complete blood count with a differential count of the leukocytes and determination of serum electrolytes, blood urea nitrogen, creatinine, and glucose concentrations. A urine or serum pregnancy test should be performed in all women of reproductive age. Serum liver function tests (e.g., serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin) as well as serum amylase determination are obtained, particularly in patients with upper abdominal or right-sided abdominal pain. A serum albumin should be obtained in patients with historical or physical evidence of chronic disease such as cirrhosis. Lastly, an electrocardiogram should be obtained on middle-aged and older men and women presenting with abdominal pain to detect myocardial ischemia or infarction. Inferior wall myocardial infarction is an important cause of acute upper abdominal pain because of the risk it presents to the patient’s life if not detected.

547

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

It must be noted that ‘‘overreliance on laboratory tests . . . will very often mislead the clinician, especially if the history and physical examination are less than diligent and complete’’ (1). For example, patients with acute appendicitis will often have a normal white blood cell (WBC) count and differential, especially early in the course of their disease, i.e., at the very time one wishes to detect it. Similarly, patients with acute intra-abdominal or retroperitoneal hemorrhage will initially have a normal blood hemoglobin level because of the acute nature of their bleeding.

Imaging Studies Similar to laboratory tests, diagnostic imaging studies are performed to narrow the differential diagnosis and to identify acute and chronic medical problems. An upright chest radiograph (posterior–anterior and lateral views) should be performed to exclude thoracic causes of acute abdominal pain, especially lower lobe pneumonia. In addition, these images will readily demonstrate the presence of pneumoperitoneum. Abdominal radiographs (supine and upright) are commonly obtained on patients presenting with acute abdominal pain. Although they are diagnostic in a minority of cases, they may provide corroborating evidence of abdominal diseases such as an appendicolith in patients with appendicitis, ‘‘sentinel’’ loops of dilated, gas-filled bowel in patients with acute pancreatitis, or an ileus in patients with peritonitis. In patients with intestinal obstruction, these images will be diagnostic. Ultrasonography (US) is a particularly important diagnostic tool in patients suspected of having biliary, hepatic, or pelvic diseases. The sensitivity and specificity of US to detect various diseases presenting with acute abdominal pain are shown in Table 2. Sonography, particularly with Doppler, is also very accurate in detecting aortic aneurysms, and less accurate in detecting visceral artery aneurysms. US is limited by its dependence upon the skill of the physician performing and interpreting the examination as well as the frequent occurrence of ileus (and hence gas-filled loops of bowel) in patients with abdominal diseases. Computed tomography (CT) of the abdomen and pelvis with enteral and parenteral contrast is the most versatile diagnostic tool for evaluating patients with acute abdominal pain. CT, utilizing the lung windows, will detect pneumoperitoneum with great sensitivity. CT has also been shown to have an excellent sensitivity and specificity for detecting acute inflammation associated with acute appendicitis, acute diverticulitis, acute pancreatitis, and acute cholecystitis. CT will detect with great accuracy the presence of both aortic Table 2 The Sensitivity and Specificity of Ultrasonography in Detecting Common Abdominal Diseases Presenting with Acute Abdominal Pain

Cholelithiasis (biliary colic) Acute cholecystitis Acute appendicitis Abdominal aortic aneurysm Ovarian torsion Acute salpingitis Ruptured ectopic pregnancy

Sensitivity (%)

Specificity (%)

References

88–100

92–95

8,9

94 55 100 92–95 92–95 92–95

78 95 100 97–98 97–98 97–98

9 10 11 12 12 12

aneurysms and visceral artery aneurysms. Lastly, recent studies have shown that CT is quite accurate in detecting the presence of small intestinal obstruction in equivocal cases. The sensitivity and specificity of CT in detecting various abdominal diseases presenting with acute abdominal pain are shown in Table 3. It should be emphasized that although CT is a valuable adjunct to the clinical history and physical examination, it does little to change the therapeutic algorithm in patients with the signs and symptoms of diffuse peritonitis, uncomplicated acute appendicitis, or even intestinal obstruction.

PROTOTYPICAL EXAMPLES OF ACUTE ABDOMINAL PAIN As alluded to earlier, acute abdominal pain is caused by inflammation, ischemia, and distention of hollow viscera or the capsule of solid organs. This section describes the clinical findings of patients with acute appendicitis, intestinal obstruction, and acute mesenteric ischemia as prototypes for the presentation of acute abdominal pain in the setting of inflammation, visceral ischemia, and obstruction.

Acute Appendicitis as a Prototype for Pain Due to Inflammation Acute appendicitis represents a spectrum of acute inflammatory changes ranging from simple acute inflammation to transmural necrosis and perforation. The earliest visible findings of appendicitis are prominent serosal blood vessels and edema of the appendiceal wall. As the disease progresses, the appendix becomes distended and covered with a fibrinopurulent exudate. Microscopically, acute appendicitis is characterized by a neutrophilic infiltrate of the muscularis propria with inflammation and ulceration of the mucosa, edema, and microabscesses within the appendiceal wall. Thrombosis of intramural blood vessels leads to focal gangrene and ultimately disintegration of the appendiceal wall. Transmural necrosis causes perforation with local abscess formation or, less commonly, diffuse peritonitis.

History Patients with acute appendicitis initially describe a vague periumbilical or epigastric discomfort. This initial visceral pain, often characterized as an ‘‘upset stomach’’ or a vague cramping or gnawing pain, is due to distention and localized inflammation of the appendix. Patients in whom the appendix is located behind the cecum or the terminal ileum Table 3 The Sensitivity and Specificity of Computed Tomography in Detecting Common Abdominal Diseases Presenting with Acute Abdominal Pain

Acute appendicitis Abdominal aortic aneurysm Ruptured abdominal aortic aneurysm Acute diverticulitis Small bowel obstruction Acute mesenteric ischemia

medwedi.ru

Sensitivity (%)

Specificity (%)

87–100 100

83–99 100

References 13 14

79–88

79–88

14

85–95 90–100 50–73

79–98 57–71 94–100

15–17 18,19 20

548

Part Two: The Alimentary Tract—Other Conditions

may lack this epigastric or periumbilical pain and present initially with pain localized to the right iliac region. Over the next few hours, patients may experience mild nausea and may have a few episodes of emesis. Nausea and anorexia are so common in patients with acute appendicitis that the presence of hunger should raise a question regarding the diagnosis. If vomiting is a predominant symptom or if vomiting precedes the development of abdominal pain, the diagnosis of acute appendicitis should be questioned. Patients will often report an elevated body temperature; however, high fevers with rigors are uncommon and suggest perforation or another disease. Over the next 12 to 24 hours, the pain increases in intensity and is accompanied by a noticeable shift in the location to the right lower abdomen. This localization of abdominal pain is an important diagnostic feature that occurs in more than 80% of patients with acute appendicitis (21). This somatoparietal pain, which results from extension of the inflammatory process to involve the parietal peritoneum, is more intense and more precisely localized than the initial visceral periumbilical or epigastric pain. Older patients often lack this classic migration of pain from the periumbilical region to the right lower quadrant. Also right lower quadrant abdominal pain may be delayed in onset, or even absent, in patients with an inflamed pelvic appendix. Only about 50% to 60% of patients with acute appendicitis will have typical symptoms. Patients with symptoms for more than 24 to 48 hours have an increased incidence of perforation with associated morbidity.

Physical Examination Patients with acute appendicitis often appear ill and will usually be lying relatively still with their legs flexed at the knee and hip. The heart rate is usually normal or only slightly elevated. Tachycardia, when present, suggests perforation or significant intravascular volume depletion. The temperature is usually normal or only slightly elevated. A body temperature much greater than 100.5 F suggests a gangrenous appendix and if the initial symptom of the illness is a high fever (i.e., 103 F or 104 F), or if fever precedes the development of abdominal pain, a diagnosis other than acute appendicitis should be considered. Although absent in the early stages of the disease, localized tenderness over the site of the appendix is an important diagnostic feature. Often this can be demonstrated by light percussion of the abdomen. Palpation may also demonstrate tenderness at McBurney’s point (i.e., the junction of the lateral and middle thirds of a line drawn between the umbilicus and the right anterior superior iliac spine) with voluntary and, in advanced cases, involuntary guarding. Gently rocking the bed or striking the heel of the foot will reproduce or exacerbate this discomfort. Patients with early appendicitis in whom the acute inflammatory process has yet to involve the parietal peritoneum will often lack the abdominal wall tenderness and guarding characteristic of more advanced disease. Similarly, patients with a retrocecal appendix as well as those patients in whom the appendix lies within the pelvis may also lack the tenderness and guarding of the abdominal wall musculature. In instances of retrocecal appendicitis, a ‘‘psoas sign’’ may be elicited and in those patients in whom the appendix is located deep within the pelvis, evidence of inflammation involving the obturator internus fascia may be manifested by an ‘‘obturator sign’’ as described earlier. Silen notes that ‘‘whatever the constellation of signs and symptoms, the

clinical diagnosis of acute appendicitis cannot be made unless tenderness (no matter how slight) can be demonstrated in some location’’ (1).

Laboratory Tests and Imaging Studies There are no laboratory tests with which to secure the diagnosis of acute appendicitis; the principal value of these tests comes from excluding other causes of acute abdominal pain. Most patients with appendicitis will have a modest leukocytosis with 11,000 to 17,000 cells per cubic millimeter; the differential cell count may reveal an elevated percentage of granulocytes. It must be noted that many patients with acute appendicitis will have a normal WBC count and differential. Because the diagnosis of acute appendicitis can be reliably based on a characteristic clinical presentation in as many as 50% of cases, there is little support for routine radiographic imaging of all patients suspected of having acute appendicitis. However, in those cases in which the clinical presentation is confusing, US and CT may be extremely valuable. In particular, these studies have nearly supplanted diagnostic strategies of admission, observation, and serial examination of patients suspected to have acute appendicitis but with atypical examinations. A CT of a patient with acute appendicitis is shown in Figure 8; this image demonstrates a distended appendix with peri-appendiceal and peri-cecal fat stranding consistent with acute inflammation.

Acute Mesenteric Embolus as a Prototype for Pain Due to Intestinal Ischemia Pathophysiology The sudden occlusion of the SMA by an embolus causes 30% to 50% of cases of acute mesenteric arterial ischemia (22,23). About half of these emboli lodge in the SMA just distal to the proximal jejunal and middle colic branches, 35% break apart and embolize distally into the splanchnic vasculature, and

Figure 8 Computed tomography of the abdomen in a patient with acute appendicitis. The white arrow points to the distended appendix and the stippled arrow points to the peri-appendiceal inflammation marked by stranding in the mesentery of the cecum and peri-appendiceal tissues. Source: Courtesy of Maureen Heldman, Dept. of Radiology, LSU Health Sciences Center, Shreveport, Louisiana, U.S.A.

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

15% lodge at the ostium (24). When the mean arterial pressure in the SMA is less than 70 mmHg, there is a linear relationship between tissue perfusion and mean arterial pressure during which time tissue viability is maintained through increased oxygen extraction. Below 40 mmHg this mechanism fails, and the bowel becomes progressively more ischemic as anaerobic metabolism replaces aerobic. At this point, the degree of tissue injury is directly related to the duration and anatomic extent of ischemia (25). Structural injury to the villi occurs, with as little as 15 minutes of ischemia; three hours of ischemia causes sloughing of the intestinal mucosa. Restoration of blood flow at this point leads to the regeneration of a new epithelium from crypt cells (26); however, six hours of ischemia leads to transmural necrosis, progressing to perforation and sepsis. Numerous proinflammatory mediators are involved in the pathophysiology of this injury, particularly neutrophils, oxygen-derived free radicals, cytokines, and eicosanoids. Visceral C-fibers are sensitive to many of these proinflammatory and vasoactive substances as well as the metabolic end products of anaerobic metabolism that accumulate in the splanchnic microvascular beds during ischemia. These metabolic and proinflammatory mediators may also lower the pain threshold for mechanical stimuli, a phenomenon of importance because acute mesenteric ischemia often causes vigorous peristaltic activity, which diminishes to inactivity as the period of ischemia increases.

History The ‘‘classic’’ symptoms of patients with an SMA embolus are the sudden onset of excruciating periumbilical pain with bowel evacuation that becomes bloody with time. The onset is usually dramatic given the sudden nature of the event and the lack of preestablished arterial collaterals. Silen warns that often ‘‘early symptoms are present and are relatively mild in 50% of cases for three to four days before medical attention is sought’’ (1). In most cases, emboli originate from a left atrial or ventricular mural thrombus in patients with a history of heart disease such as congestive heart failure, endocarditis, recent myocardial infarction, or cardiac arrhythmias, particularly atrial fibrillation. This association of SMA embolus with acute or chronic cardiac conditions, especially atrial fibrillation and recent myocardial infarction, is so great that a patient with these conditions presenting with the acute onset of severe abdominal pain must be thought to have an SMA embolus until proven otherwise.

Physical Examination Early in the course of the illness, the abdomen of patients with SMA embolus is soft, nontender, and nondistended. In fact, the association of these mild physical findings with severe pain, out of proportion to the examination, is a hallmark of this illness. As the disease progresses, the abdomen becomes distended. Prominent tenderness and rigidity are absent until very late in the course of the disease. Fever, leukocytosis, hypotension, and tachycardia are late (too late!) manifestations of this disease.

549

they lack the sensitivity and specificity to be helpful in the evaluation of patients suspected of having SMA embolus. Early in the course of the disease, plain abdominal radiographs are normal whereas in advanced cases, there may be dilated loops of small intestine consistent with an ileus and the appearance of ‘‘thumbprinting’’ of the small intestine and right colon due to marked edema within the bowel wall. CT will show only nonspecific signs of bowel ischemia including bowel wall edema, luminal dilation, and stranding within the mesentery. Less common, but more ominous, findings of intestinal necrosis include intramural gas and mesenteric or portal venous gas. Patient movement, overlying bowel gas from the associated ileus, and complex anatomy limit the efficacy of duplex US in the evaluation of patients suspected of having an SMA embolus. Arteriography is the only certain means of diagnosing an SMA embolus preoperatively during which it will usually demonstrate a rounded filling defect with nearly complete obstruction to arterial flow. This diagnostic study will differentiate those patients with nonocclusive mesenteric ischemia from those with a structural lesion amenable to operative repair. Patients with obvious peritonitis should undergo immediate laparotomy without prior arteriography.

Small Intestinal Obstruction as a Prototype for Pain Due to Obstruction Pathogenesis Mechanical obstruction to the normal flow of intestinal contents through the gastrointestinal tract may be categorized by the degree of obstruction (i.e., partial or complete), the absence or presence of ischemia (simple or strangulated), and the site of obstruction (i.e., small intestine or colon). The most common cause of mechanical SBO is intraabdominal adhesions following laparotomy; other important causes include hernias and neoplasms. Early after the onset of acute small intestinal obstruction, there are periods of intense intestinal myoelectric activity and peristalsis manifested clinically by colicky mid-abdominal visceral-type pain. The frequency of these contractions is inversely related to the distance from the ligament of Treitz, with more proximal jejunal obstructions having a greater frequency of peristalsis. As the duration of obstruction increases, the intestinal myoelectric activity diminishes and the interdigestive migrating myoelectrical complex pattern is replaced by ineffectual and seemingly disorganized clusters of contractions (27–29). Proximal to the obstruction, the bowel becomes distended as large amounts of fluid and swallowed air accumulate within the lumen. Impaired mucosal water and electrolyte absorption and enhanced secretion cause the net movement of isotonic fluid from the vasculature into the intestinal lumen (30). This phenomenon, in combination with losses from vomiting and reduced oral intake, causes profound intravascular volume depletion that is manifested clinically by tachycardia, tachypnea, oliguria, and, in advanced cases, hypotension.

History Laboratory Tests and Imaging Studies On admission to the hospital, most patients with acute mesenteric ischemia will have a leukocytosis and about 50% will have metabolic acidosis (23). Elevated levels of serum phosphate and amylase are often noted; however,

Patients with SBO typically present with the acute onset of periumbilical cramping pain, vomiting, obstipation, and abdominal distention. The colicky abdominal pain characteristic of SBO is visceral in nature and its location reflects the midgut embryologic origin of the small intestine.

medwedi.ru

550

Part Two: The Alimentary Tract—Other Conditions

Typically, patients with proximal obstruction will describe paroxysms of periumbilical pain occurring at four- to fiveminute intervals whereas patients with more distal obstructions will experience paroxysms of pain less frequently. With increasing time, the cramping colicky pain subsides as the motility in the distended intestine is inhibited. The development of continuous, severe pain strongly suggests ischemia of the obstructed intestine. Closed-loop obstructions, which are associated with a high rate of strangulation, present with the sudden onset of severe unremitting periumbilical pain. Proximal obstructions are associated with profuse vomiting and severe, frequent cramping pain with minimal abdominal distention whereas patients with more distally located obstructions have less frequent vomiting, more abdominal distention, and a greater period of time between paroxysms of pain. The emesis of patients with SBO is usually feculent because of the increased bacterial count in the lumen of the obstructed gut. Although obstipation is an important symptom of intestinal obstruction, patients with partial obstruction may continue to pass flatus and stool. Even patients with complete SBO will evacuate the intestine distal to the point of obstruction. The duration of obstruction is best judged by the time lapsed since the passage of flatus because the transit time of swallowed air is much less than that of solid or liquid intestinal contents.

Physical Examination The systemic manifestations of intestinal obstruction are related to hypovolemia and the systemic response to inflammation (i.e., tachycardia, tachypnea, altered mental status, oliguria, and hypotension). The latter findings, particularly when unresponsive to volume repletion, strongly suggest the presence of intestinal ischemia and necrosis. Auscultation of the abdomen will usually demonstrate periods of high-pitched or musical bowel sounds that correspond to cramping abdominal pain separated by intervals of relative quiet. Borborygmi may be audible in these patients and may correspond with paroxysms of cramping pain. With prolonged obstruction, bowel sounds may be absent. Palpation of the abdomen of patients with simple intestinal obstruction will usually demonstrate minimal tenderness and no guarding. Significant tenderness and guarding, especially if localized, strongly suggests strangulated obstruction. Patients with closed-loop obstructions will often have pain that is out of proportion to the physical findings, much like that of patients with acute mesenteric ischemia. A tender mass at the site of an inguinal, femoral, or umbilical hernia suggests that this is the cause of the obstruction; erythema of the overlying skin suggests intestinal ischemia.

Laboratory Tests and Imaging Studies Patients with SBO will often have a slight leukocytosis on their complete blood count. Neutrophilia with a predominance of immature cellular forms is more common in patients with strangulated obstruction than in patients with simple obstruction; however, the predictive value of this parameter is too low to be useful as a sole determinant of strangulation. Serum electrolyte abnormalities (especially involving sodium, potassium, and chloride), acid–base disturbances (especially metabolic acidosis secondary to intravascular volume depletion), and altered renal function are common in patients with intestinal obstruction. Serum levels of amylase, lipase, lactate dehydrogenase, phosphate, and potassium may be elevated in patients with strangulated bowel; however, these parameters lack sufficient predictive value to allow differentiation between simple and strangulated obstruction at a stage prior to frank intestinal necrosis and peritonitis. Plain abdominal radiographs taken with the patient in the supine position and in the upright (or lateral decubitus) position will usually confirm the diagnosis of intestinal obstruction, localize the site of obstruction to the small intestine or colon, and provide evidence of the degree of obstruction. Noteworthily, up to 30% of patients with SBO will have equivocal or normal abdominal radiographs. False negative studies are particularly likely in patients with proximal or closed-loop obstructions. In these patients, abdominal CT scanning with enteral and intravenous contrast will usually differentiate mechanical obstruction from paralytic ileus and helps in determining the site and degree of obstruction.

ABDOMINAL PAIN IN SPECIAL PATIENT GROUPS This section describes the effect of age, immunosuppression with corticosteroids and AIDS, and spinal cord injury on the clinical features of acute abdominal diseases as well as the relative frequency of various diseases within the differential diagnosis of acute abdominal pain.

The Effect of Age on the Presentation of Patients with Acute Abdominal Disease A patient’s age significantly influences the relative frequency with which various diseases occur in patients presenting with acute abdominal pain. The influence of age on the differential diagnosis of acute abdominal pain is shown in Table 4. The most common causes of severe abdominal pain in young children include gastroenteritis, intussusception, pyelonephritis, and midgut volvulus; although appendicitis occurs in this age group, it is uncommon. Acute appendicitis becomes an important cause of severe abdominal pain in children greater than four years of age. Abdominal trauma from child abuse,

Table 4 Causes of Acute Abdominal Pain in Various Age Groups Less than 3 years of age Gastroenteritis Intussusception Pyelonephritis Midgut volvulus

4–11 years Gastroenteritis Appendicitis Abdominal trauma from child abuse Mesenteric lymphadenitis Urinary tract infection

Source: From Refs. 2, 31–36.

12–18 years Appendicitis Gastroenteritis Mittelschmerz Acute salpingitis Ovarian torsion Ruptured ectopic pregnancy

18–65 years Nonspecific abdominal pain Appendicitis Acute biliary disease

Greater than 66 years Biliary tract disease Nonspecific abdominal pain Malignancy Bowel obstruction Peptic ulcer disease Incarcerated hernias Appendicitis

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

with resultant intra-abdominal injury, is also an important cause of severe abdominal pain during childhood. As young girls enter adolescence, gynecologic causes of abdominal pain become prominent, with Mittelschmerz, acute salpingitis, ovarian torsion, and ectopic pregnancy assuming a prominent role in the differential diagnosis. During adulthood, nonspecific abdominal pain is a common cause of abdominal pain as are appendicitis, biliary tract disease, and urinary tract diseases (31,37,38). The most common causes of severe abdominal pain in the elderly are biliary tract diseases, nonspecific abdominal pain, and malignancies. Appendicitis occurs but to a lesser extent than in younger individuals. The very young and very old tend to present with more advanced and complicated disease than do patients in the middle years. In a survey of nearly 3400 children undergoing appendectomy, the median rate of perforation for children between the ages of 0 and 4 years was 66% compared with 37% for children 5 to 17 years of age (39). The rate of perforated appendicitis averages 10% in young and middle-aged adults (2) and nearly 70% in the elderly (40). At least in part, the high rate of advanced and complicated acute abdominal disease in the very young and the elderly comes from the difficulty in recognizing the clinical manifestations of these diseases in these populations. In very young children with acute appendicitis, vomiting, lethargy, and irritability are important symptoms whereas localized right lower abdominal tenderness is detected in less than 50% of young children (41). In contrast to adults, diarrhea is a relatively common finding in young children with acute appendicitis. In one study, one-third of all children less than three years of age with acute appendicitis presented with diarrhea (42). In older children, the clinical presentation of acute appendicitis is similar to that of adults and includes abdominal pain and tenderness, anorexia, nausea and vomiting, fever, and leukocytosis. Most older patients with acute appendicitis will have abdominal pain and right lower quadrant tenderness upon presentation to the hospital; however, more than half of these patients will have had symptoms for more than 48 hours—an observation consistent with the nearly 70% rate of perforation and 40% rate of intra-abdominal abscess formation (40). The difficulty in correctly diagnosing the cause of acute abdominal pain in elderly patients at the initial examination is corroborated by a study that reported the sensitivity and specificity of the diagnosis at the time of admission to be 68% and 76%, respectively, for patients older than 65 years of age and 82% and 86% for younger patients (43).

The Effect of Immunosuppression on the Presentation of Patients with Abdominal Disease Suppression of an individual’s immune function by chronic diseases such as AIDS or exogenous agents such as corticosteroids alters the clinical presentation of patients with acute abdominal conditions and introduces a variety of unusual diseases into the differential diagnosis.

Steroids Exogenous corticosteroids suppress the inflammatory cascades activated by tissue injury by inhibiting the release of arachidonic acid (and hence numerous proinflammatory eicosanoids) and cytokines (including interleukin-1 and interleukin-2). These agents also decrease leukocyte adherence, chemotaxis, and hence recruitment into sites of tissue injury and profoundly reduce the inflammation, collagen

551

synthesis, and wound contraction associated with the healing of injured tissues (44). Patients receiving exogenous corticosteroids who develop localized or generalized peritonitis will often lack the usual signs and symptoms of such inflammation. The absence of significant abdominal pain, tenderness, and fever in patients with acute abdominal diseases, even gastrointestinal perforation, who are receiving steroid therapy significantly delays appropriate diagnosis and operative management and contributes to the significant mortality risks associated with these diseases (45). The mechanism by which steroid therapy attenuates the clinical features of acute abdominal diseases is unclear. However it is postulated that by inhibiting the release of various proinflammatory substances such as prostaglandins and cytokines, corticosteroids reduce the stimulus for visceral nociception (46). The use of corticosteroids in patients is associated with a much higher incidence of intestinal perforation and peritonitis when compared with the general population (45,47,48). Furthermore, corticosteroid use is an important risk factor for dehiscence of intestinal anastomoses in a retrospective analysis of 754 patients (49).

AIDS Abdominal pain is a frequent complaint of patients with AIDS; however, in most instances, this pain is self-limiting and is not clinically significant. Severe acute abdominal pain, usually in combination with other gastrointestinal symptoms, occurs in about 12% to 15% of patients with AIDS (50,51). Others have estimated that severe gastrointestinal symptoms of AIDS occur in as many as 50% of patients (52). In most cases, this pain is related to HIV infection and its associated opportunistic infections and neoplasms (51). Examples of these HIV-related diseases and symptom complexes are shown in Table 5 and Figure 9. Although these diseases are important causes of severe abdominal pain in patients with AIDS, the efficacy of current therapy with protease inhibitors and antiretroviral medications (highly active antiretroviral treatment) has increased the relative frequency of common causes of acute abdominal pain in the general population, such as appendicitis, acute cholecystitis, and acute diverticulitis. Common causes of HIV-specific severe abdominal pain include non-Hodgkin’s lymphoma, which may obstruct the gastrointestinal tract or cause distention of the hepatic or splenic capsule secondary to infiltration of these organs by this tumor. Perforation of the gastrointestinal tract may result from cytomegalovirus (CMV)-induced vasculitis causing submucosal thrombosis with mucosal ischemia, ulceration, and eventually transmural necrosis (54). Infectious enteritis, with CMV, Mycobacterium avium, or cryptosporidium is a particularly common cause of severe abdominal pain and diarrhea in patients with AIDS. Primary peritonitis (i.e., peritonitis in the absence of gastrointestinal perforation) is well described in patients with AIDS, the cause of which includes numerous infectious agents including histoplasmosis, tuberculosis, M. avium, and toxoplasmosis. Lastly, pancreatitis is a frequent cause of abdominal pain in patients with AIDS and results most often from drugs (e.g., dideoxyinoside, pentamidine, trimethoprim-sulfamethoxazole) and infections with CMV, mycobacteria, and Cryptococcus. The clinical presentation of acute abdominal diseases in patients with AIDS is similar to that of the general population with a few exceptions. It is not unusual for these patients to develop an acute disease process, such as acute

medwedi.ru

552

Part Two: The Alimentary Tract—Other Conditions

Table 5 Causes of Abdominal Pain in Patients with AIDS Organ Stomach Gastritis Ulcer Obstruction Mass Small intestine Enteritis Obstruction Perforation Colon Colitis Obstruction Perforation Appendicitis Liver, spleen Infiltration Biliary tract Cholecystitis Papillary stenosis Pancreas Inflammation Tumor Mesentery, peritoneum

Etiology CMV, cryptosporidium, Helicobacter pylori CMV Cryptosporidium, CMV, lymphoma Lymphoma, Kaposi’s sarcoma, CMV Cryptosporidium, CMV, Mycobacterium avium Lymphoma, Kaposi’s sarcoma CMV, lymphoma CMV, enteric bacteria, herpes simplex virus Lymphoma, Kaposi’s sarcoma, intussusception CMV, lymphoma, Herpes simplex virus Kaposi’s sarcoma, cryptosporidium, CMV Lymphoma, CMV, M. avium CMV, cryptosporidium, microsporidium CMV, cryptosporidium, Kaposi’s sarcoma CMV, Kaposi’s sarcoma, pentamidine, didanosine Lymphoma, Kaposi’s sarcoma M. avium, cryptococcus, Kaposi’s sarcoma, lymphoma, histoplasmosis, tuberculosis, coccidioidomycosis, toxoplasmosis

Abbreviation: CMV, cytomegalovirus. Source: From Ref. 53.

appendicitis, in the setting of chronic abdominal pain and low-grade fevers. Flum et al. noted that 91% of their patients with AIDS and acute appendicitis had the combination of right lower-quadrant abdominal pain and tenderness (55). Patients with AIDS may also lack the systemic leukocytosis that is associated with many severe acute abdominal

conditions, including complicated appendicitis (54,55). The diagnostic strategies and indication for operation in patients with AIDS who develop severe acute abdominal pain are the same as for patients without HIV infection. CT is of particular value in determining the presence of intestinal perforation with secondary peritonitis as well as the local inflammation characteristic of acute appendicitis.

The Effect of Spinal Cord Injury on the Presentation of Patients with Abdominal Disease Acute abdominal diseases are an important cause of death of spinal cord–injured patients. The mortality rate for acute abdominal diseases in patients with spinal cord injuries is 10% to 15%. This high mortality rate is similar to that of immunocompromised or elderly patients and is attributable to delays in identification and treatment of the various abdominal conditions, especially perforation of the bowel (56–58). As alluded to earlier, the most common symptom of patients with acute abdominal diseases is pain. Unfortunately, patients with spinal cord injuries may or may not have this important symptom. The presentation of acute abdominal diseases in spinal cord–injured patients is dependent upon the neurologic level and completeness of the injury as well as the degree of continuity of the reflex arc below the level of the injury (59). Normal somatic sensation to the anterolateral abdominal wall originates from T7 to L1; hence, patients with complete spinal cord lesions above T7 will have no somatoparietal sensation in the abdominal wall (57). Painful stimuli from the abdominal viscera reach the spinal cord via the thoracic sympathetic, splancnhnic, hypogastric, or pelvic nerves, with the sympathetic outflow from most of the viscera originating from the T5 level or below (60). The visceral sensory fibers of the rectum and bladder are carried via the S2 to S4 parasympathetic system. Patients with injury above the level of the splanchnic outflow tract at T6 are referred to as having ‘‘high’’ spinal cord injuries, whereas those patients with injuries below this level are regarded as having ‘‘low’’ cord lesions (59). Patients with

Figure 9 Common clinical presentations and related diagnoses in patients with AIDS. Of note: Because antiretroviral treatment strategies have become more successful, AIDS-specific diseases have declined in the differential diagnosis of abdominal pain in this population and the diseases present in the general population have assumed a greater position. Abbreviation: CMV, cytomegalovirus.

Chapter 26: The Anatomy, Physiology, and Differential Diagnosis of Acute Abdominal Pain

high cord injuries have a loss of sensory, motor, and reflex functions within the viscera and abdominal wall (61). In these instances, patients with an acute intra-abdominal process may present with increased spasticity (often generalized and including abdominal musculature), vague abdominal pain, referred shoulder tip pain, altered bowel function with abdominal distension, nausea and vomiting, autonomic dysreflexia and/or a feeling ‘‘that there is something wrong’’ (57,59,61,62). Patients with spinal cord injuries below the level of the splanchnic outflow tract (i.e., T6) are much likely to manifest an acute abdominal disease with abdominal pain than are patients with high cord injuries (56,59,62). Activation of visceral nociceptors by distention of hollow viscera or inflammation may cause spinal reflex sweating and increased spasticity of the limbs, sphincters, or adjacent abdominal muscles. This autonomic dysreflexia is a problem unique to patients with a spinal cord injury at the T6 level and above. In one study, autonomic dysreflexia was present in 84% of the patients with high spinal cord lesions (58). The inability of inexperienced clinicians to recognize subtle symptoms of acute abdominal disease is felt to be an important cause of delays in diagnosis and therapy and hence negative outcomes. Juler and Eltoral report that often the only clue to the presence of significant abdominal diseases is a change in the degree of spasticity (59). Longo et al. have suggested that any deviation from a normal lifestyle in a patient with a spinal cord lesion should alert the clinician to the possibility of serious abdominal diseases (63). It is of interest and importance that laboratory tests and imaging studies are often not diagnostic in patients with spinal cord injuries. Many spinal cord–injured patients will have a urinary tract infection, pressure sores, or respiratory illnesses, which complicates interpretation of the patient’s vague symptoms. Furthermore, several studies have demonstrated that as many as 33% to 50% of patients with spinal cord injuries will not mount a leukocytosis in the presence of significant abdominal diseases. These investigators also noted that standard abdominal imaging studies such as abdominal radiographs, US, or CT suggested the correct diagnosis in only 62% to 77% of patients with acute abdomen diseases (56,62).

SUMMARY The clinical condition characterized by the acute onset of abdominal pain, usually in association with other findings such as nausea, vomiting, anorexia, and abdominal distention, has been given the designation ‘‘acute abdomen.’’ Both intra-abdominal and extra-abdominal pathologic lesions can be responsible for this condition, many of which have lifethreatening potential. Such being the case, the underlying diagnosis must be promptly made and appropriate treatment measures expeditiously instituted. To accomplish these goals in the most judicious fashion, the treating physician must obtain an accurate database and be able to extrapolate these data within a fund of knowledge encompassing the anatomy, embryology, neurophysiology, and natural history of each potential cause. This database is derived from the history and physical findings, supported by the various laboratory tests and radiologic studies obtained. The differential diagnosis of the acute abdomen can be challenging, even to the most astute physician, but is ultimately successful when approached from this frame of reference.

553

REFERENCES 1. Silen W. Cope’s Early Diagnosis of the Acute Abdomen. 20th ed. New York: Oxford Press, 2000. 2. Glasgow RE, Mulvihill SJ. Abdominal pain, including the acute abdomen. In: Feldman M, Friedman LS, Sleisinger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. Philadelphia: Saunders, 2002:71. 3. Cheung LY, Ballinger WF. Manifestations and diagnosis of gastrointestinal disease. In: Hardy JD, ed. Hardy’s Textbook of Surgery. Philadelphia: JB Lippincott, 1983. 4. Anson BJ, McVay CB. Surgical Anatomy. 5th ed. Philadelphia: WB Saunders, 1971:467. 5. Anderson JE. Grant’s Atlas of Anatomy. 7th ed. Baltimore: Williams & Wilkins Co., 1978:5–42. 6. Currie DJ. Abdominal Pain. New York: Hemisphere Publishing, 1979. 7. Anson BJ, McVay CB. Surgical Anatomy. 5th ed. Philadelphia: WB Saunders, 1971:594. 8. Fang R, Pilcher JA, Putnam AT, Smith T, Smith DL. Accuracy of surgeon-performed gall bladder ultrasound. Am J Surg 1999; 178:475. 9. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient have acute cholecystitis? JAMA 2003; 289:80. 10. Franke C, Bohner H, Yang Q. Ultrasonography for diagnosis of acute appendicitis: results of a prospective multicenter trial. World J Surg 1999; 23:141. 11. LaRoy LL, Cormier PJ, Matalan TA. Imaging of abdominal aortic aneurysms. Am J Roentgenol 1989; 152:785–792. 12. Frederick JL, et al. Routine use of vaginal ultrasonography in the preoperative evaluation of gynecological patients. J Reprod Medicine 1991; 36:779. 13. Sarosi GA Jr, Turnage RH. Appendicitis. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/ Management. Philadelphia: Saunders, 2002:2089. 14. Adam DJ, Bradbury AW, Stuart WP, et al. The value of computed tomography in the assessment of suspected ruptured abdominal aortic aneurysm. J Vasc Surg 1998; 27:431. 15. Ferzoco LB, Raptopoulos V, Silen W. Acute diverticulitis. NEJM 1998; 338:1521. 16. Halligan S, Saunders B. Imaging diverticular disease. Best Pract Res Clin Gastroenterol 2002; 16:595. 17. Ambrosetti P, Jenny A, Becker C, Terrier TF, Morel P. Acute left colonic diverticulitis–compared performance of computed tomography and water-soluble contrast enema: prospective evaluation of 420 patients. Dis Colon Rectum 2000; 43:1363. 18. Peck JJ, Milleson T, Phelan J. The role of computed tomography with contrast and small bowel obstruction in the management of small bowel obstruction. Am J Surg 1999; 177:375. 19. Daneshmand S, Hedley CG, Stain SC. The utility and reliability of CT scan in the diagnosis of small bowel obstruction. Am Surg 1999; 65:922. 20. Kirkpatrick ID. Biphasic CT with mesenteric CT angiography in the evaluation of acute mesenteric ischemia: initial experience. Radiology 2003; 229:91. 21. Wagner JM, McKinney WP, Carpenter JL. Does this patient have appendicitis? JAMA 1996; 276:1589. 22. Bradbury AW, Brittenden J, McBride K, Ruckley CV. Mesenteric ischaemia: a multidisciplinary approach. Br J Surg 1995; 82:1446. 23. Kaleya RN, Boley SJ. Acute mesenteric ischemia. Crit Care Clin 1995; 2:479. 24. Batellier J, Kieny R. Superior mesenteric artery embolism: eighty-two cases. Ann Vasc Surg 1990; 4:112. 25. Udassin R, Vromen A, Haskel Y. The time sequence of injury and recovery following transient reversible intestinal ischemia. J Surg Res 1994; 56:221. 26. Kummerlen C, Seiler N, Galluser M, et al. Polyamines and the recovery of intestinal morphology and function after ischemic damage in rats. Digestion 1994; 55:168.

medwedi.ru

554

Part Two: The Alimentary Tract—Other Conditions

27. Camilleri M. Jejunal manometry in distal subacute mechanical obstruction: significance of prolonged simultaneous contractions. Gut 1989; 30:468. 28. Frank JW, Sarr MG, Camiller M. Use of gastroduodenal motility to differentiate mechanical and functional intestinal obstruction: an analysis of clinical outcome. Am J Gastroenterol 1994; 89:339. 29. Summers RW, Yanda R, Prihodaq M, et al. Acute intestinal obstruction: an electromyographic study in dogs. Gastroenterology 1983; 85:1301. 30. Shields R. The absorption and secretion of fluid and electrolytes by the obstructed bowel. Br J Surg 1965; 52:774. 31. Miettinen P, Pasanen P, Lahtinen J, Alhava E. Acute abdominal pain in adults. Ann Chir Gynaecol 1996; 85:5. 32. Moir CR. Abdominal pain in infants and children. Mayo Clin Proc 1996; 71:984. 33. Hatch E. The acute abdomen in children. Pediatr Clin North Am 1985; 32:1151. 34. Neblett WW, Pietsch JB, Holcomb GW. Acute abdominal conditions in children and adolescents. Surg Clin North Am 1988; 68:415. 35. Bugliosi TF, Meloy TD, Vukov LF. Acute abdominal pain in the elderly. Ann Emerg Med 1990; 19:1383. 36. Bender J. Approach to the acute abdomen. Med Clin North Am 1989; 73:1413. 37. Hawthorn IE. Abdominal pain as a cause of acute admission to hospital. J R Coll Surg Edinburgh 1992; 39:389. 38. Caterino S, Cavallini M, Meli C, et al. Acute abdominal pain in emergency surgery. Clinical epidemiologic study of 450 patients. Ann Ital Chir 1997; 68:807. 39. Newman K, Ponsky T, Kittle K, et al. Appendicitis 2000: variability in practice, outcomes, and resource utilization at thirty pediatric hospitals. J Pediatric Surg 2003; 38:372. 40. Hui TT, Major KM, Avital I, Hiatt JR, Margulies DR. Outcome of elderly patients with appendicitis: effect of computed tomography and laparoscopy. Arch Surg 2002; 137:995. 41. Rothrock SG, Pagane J. Acute appendicitis in children: emergency department diagnosis and management. Ann Emerg Med 2000; 36:39. 42. Horwitz JR, Gursoy M, Jaksic T, et al. Importance of diarrhea as a presenting symptom of appendicitis in very young children. Am J Surg 1997; 173:80. 43. Kizer KW, Vassar MJ. Emergency department diagnosis of abdominal disorders in the elderly. Am J Emerg Med 1998; 16:357. 44. Levenson SM, Demetriou AA. Metabolic factors. In: Cohen IK, Diegelmann RF, Lindblad WJ, eds. Wound Healing, Biochemical and Clinical Aspects. Saunders: Philadelphia, 1992:248. 45. Menegaux F, Chenard X, Wechsler B, Boutin Z, Chigot JP. Diffuse peritonitis in steroid-treated patients. Dig Surg 1998; 15:247. 46. Parham P. Elements of the immune system and their roles in defense. In: The Immune System. 1st ed. London: Elvesier Science, 2000:16–20.

47. Wolfe F, Hawley DJ. The comparative risk and predictors of adverse gastrointestinal events in rheumatoid arthritis and osteoarthritis: a prospective 13 year study of 2131 patients. J Rheumatol 2000; 27:1668. 48. Weiner HL, Rezai AR, Cooper PR. Sigmoid diverticular perforation in neurosurgical patients receiving high-dose corticosteroids. Neurosurgery 1993; 33:40. 49. Golub R, Golub RW, Cantu R Jr, Stein HD. A multivariate analysis of factors contributing to leakage of intestinal anastomoses. J Am Coll Surg 1997; 184:364. 50. Barone JE, Gingold BS, Arvanitis ML, et al. Abdominal pain in patients with acquired immune deficiency syndrome Ann Surg 1986; 204:619. 51. Parente F, Cernuschi M, Antinori S, et al. Severe abdominal pain in patients with AIDS: frequency, clinical aspects, causes and outcome. Scand J Gastroenterol 1994; 29:511. 52. Fauci AS, Masur H, Gelman EP, et al. Gastrointestinal manifestations of the acquired immune deficiency syndrome: an update. Ann Intern Med 1985; 102:800. 53. Wilcox CM. Gastrointestinal consequences of infection with human immunodeficiency virus. In: Feldman M, Friedman LS, Sleisinger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/ Management. Philadelphia: Saunders, 2002:487. 54. Mueller GP, Williams RA. Surgical infections in AIDS patients. Am J Surg 1995; 169:34S. 55. Flum DR, Steinberg SD, Sarkis AY, Wallack MK. Appendicitis in patients with acquired immunodeficiency syndrome. J Am Coll Surg 1997; 184:481. 56. Neumayer LA, Bull DA, Mohr JD, Putnam CW. The acutely affected abdomen in paraplegic spinal cord injury patients. Ann Surg 1990; 212:561. 57. Sheridan R. Diagnosis of the acute abdomen in the neurologically stable spinal-cord injury patient. J Clin Gastroenterol 1992; 15:325. 58. Strauther GR, Longo WE, Virgo KS, Johnson FE. Appendicitis in patients with previous spinal cord injury. Am J Surg 1999; 178:403. 59. Juler GL, Eltoral IM. The acute abdomen in spinal cord injury patients. Paraplegia 1985; 23:118. 60. McMinn RMH. Introduction to regional anatomy. In: McMinn RMH, ed. Last’s Anatomy. Regional and Applied. 9th ed. Edinburgh: Churchill Livingstone, 1994. 61. Bar-On Z, Ohry A. The acute abdomen in spinal cord injury individuals. Paraplegia 1995; 33:704. 62. Miller BJ, Geraghty TJ, Wong C-H, Hall DF, Cohen JR. Outcome of the acute abdomen in patients with previous spinal cord injury. ANZ J Surgery 2001; 71:407. 63. Longo WE, Ballantyne GH, Modlin IM. Colorectal disease in spinal cord patients. An occult diagnosis. Dis Colon Rectum 1990; 33:131.

27 Neoplastic Disorders of the Gastrointestinal Tract Carlos A. Murillo, Kenneth J. Woodside, Lindsey N. Jackson, and B. Mark Evers

INTRODUCTION Collectively, cancers of the gastrointestinal (GI) tract represent a common problem worldwide. Incidence of cancers along the longitudinal axis of the GI tract is variable, with adenocarcinomas of the colon and rectum representing the third most frequent cause of cancer deaths in men and women in the United States, whereas cancers of the small bowel are rare. On the other hand, gastric cancers have decreased in frequency in the United States over the last century; however, they remain a common problem in certain parts of the world such as Asia. This chapter will discuss cancers arising in the GI tract and particularly focus on the pathophysiology and molecular biology contributing to the development of these cancers.

CELLULAR AND MOLECULAR BIOLOGY OF GI CANCERS Oncogenes and Tumor Suppressor Proteins Oncogenes Oncogenes are mutant versions of normal genes, called proto-oncogenes, involved in cellular growth and proliferations. Typically, these genes are abnormally activated growth factors [transforming growth factor-b (TGF-b), insulin-like growth factor, and epidermal growth factor (EGF), Wnt] or their receptors (HER2/neu/c-erb-B2 and c-met), intracellular signaling molecules (K-ras), or transcription factors (c-myc, b-catenin). Tumor suppressor genes, in contrast, normally inhibit cellular growth and act as a counterbalance to proto-oncogenes (Fig. 1). As such, oncogenes can produce phenotypic changes with mutation of only one copy, while tumor suppressor genes usually require mutation or loss of expression of both copies for malignant transformation to occur (2). Typically, multiple mutations of different types are acquired over time, resulting in malignant conversion; single gene mutations are not adequate for tumorigenesis. K-ras One of the better-described oncogenes is K-ras. K-ras mutations are found in about 40% of primary colorectal carcinomas (3,4) and 85% of pancreatic cancers (5). K-ras and the related family members N-ras and H-ras are G proteins found on the inner surface of the plasma membrane and are involved in the control of cell differentiation and proliferation (5,6). Point mutations at certain codons result in loss of the ability to convert guanosine triphosphate to guanosine diphosphate. These mutated G proteins constitutively transmit proliferation signals. In patients with colorectal carcinoma, variable results are noted when attempting to correlate tumor aggressiveness

with specific K-ras mutations (7–9), although mutant K-ras inactivation in advanced colorectal carcinoma cells does result in decreased malignant activity (10). Growth Factor Receptors HER2/neu/c-erb-B2 mutations are found in gastric cancers. The HER2/c-erb-B2 oncogene is the human homolog of the rat neuroblastoma neu oncogene, which closely resembles the EGF receptor (1). In gastric cancer, gene amplification of c-erb-B2 results in overexpression and abnormal cell growth, and probably results in increased metastatic potential and invasiveness (11–13). The hepatocyte growth factor (HGF) receptor is encoded by the c-met proto-oncogene. Overexpression or mutation of this tyrosine kinase receptor is also noted in gastric tumors (14,15). In addition, stromal production of HGF may further promote tumor growth (16–18). b-Catenin and Wnt Pathway Recently, alterations in b-catenin, a molecule involved in cytoskeleton anchoring, and other Wnt pathway members (Fig. 2) have been explored in GI and other carcinomas as well as in familial adenomatous polyposis (FAP) patients (20–24). While the exact mechanism is still somewhat unclear, accumulation of b-catenin seems to result in increased malignant potential, probably through downstream mediators such as c-myc or cyclin D (19,24,25).

Tumor Suppressor Proteins Adenomatous Polyposis Coli Studies of familial colorectal cancer syndromes have been instrumental in identifying a number of genetic defects that contribute to the pathogenesis of this disease process. The adenomatous polyposis coli (APC) gene has been demonstrated as an important tumor suppressor protein for the development of colorectal cancers. FAP occurs as a consequence of inherited mutation of the APC gene and then subsequent mutation or loss of the remaining normal copy. Mutations of the APC gene appear to be one of the earliest changes in sporadic tumor development as well, and possibly an initiating event in a majority of nonfamilial cases. APC is located on chromosome 5p21 and encodes a protein of up to 2843 residues (26,27). The APC protein is expressed in the cytoplasm of a number of tissues, and contains sequences similar to intermediate filament proteins such as myosin and keratin. The vast majority of APC mutations in sporadic and FAP cancers result in truncated proteins. About half of the mutations involve a region spanning less than 10% of the gene. While both wild-type and mutant forms are cytoplasmic, mutant proteins are soluble whereas wild-type proteins are not. Moreover, it appears that certain mutant versions may interfere with the function of the normal

medwedi.ru 555

556

Part Two: The Alimentary Tract—Other Conditions

Figure 1 Normal regulation of cellular proliferation depends upon equilibration between the growth-promoting influence exerted by proto-oncogenes and the growth-inhibiting activity of tumor suppressor genes. Cancer occurs as a consequence of the uncontrolled cellular proliferation that follows disruption of this balance through genetic alterations that activate oncogenes and inactivate tumor suppressor genes. Source: From Ref. 1.

protein in cells heterozygous for the mutation by formation of partially insoluble aggregates in a dominant-negative fashion (28). The protein product of the APC gene associates with a- and b-catenins, which are cadherin-binding proteins (29). b-Catenins bind directly to APC, and a-catenins bind directly to b-catenins and are associated with APC. These catenins then bind directly to E-cadherin, a protein associated with cell–cell adhesions, forming adherens junctions. Thus, mutant APC genes may contribute to abnormal cell signaling and promote cancer formation (20,30). APC has also been associated with cytoplasmic microtubule assembly. Proteins within cells with APC mutations have been documented to lack a carboxy terminal structure that mediates microtubule assembly. Mutant APC proteins also serve to bind to wild-type proteins, and inactivate the wild-type proteins in a dominant-negative fashion and prevent microtubule attachment (29). The APC protein appears to play an integral role in cell–cell adhesion and indirectly in the transcription of genes during development. By sequestering b-catenin, APC prevents it from associating with E-cadherin through a- and g-catenin (plakoglobulin); E-cadherin has an extracellular domain that protrudes from the cell surface and participates in cell-to-cell adhesion by binding to E-cadherins, which extend from neighboring cells (29,31). A small region of exon 15 of the APC gene is designated as the mutation cluster region, because it is

Figure 2 Oncogenes and tumor suppressors in the wnt signaling pathway. Source: From Ref. 19.

the site for 60% of all sequence mutations within the APC gene (32). p53 The p53 tumor suppressor gene, located on chromosome 17, is involved in approximately half of all colorectal carcinomas, making it the most common tumor suppressor protein (33). The p53 gene encodes for a phosphoprotein that affects the cell cycle by arresting cells in the G1 phase of the cell cycle, thus allowing for repairs of DNA strands before the S phase of the cell cycle (34). Mutations of the p53 gene are missense mutations producing altered function proteins rather than silent, truncated proteins. The loss of the p53 gene is probably the key event that allows progression of a severely dysplastic adenoma into a carcinoma (Fig. 3) (36). Mutations of the p53 gene are thought to be lateoccurring events in the sequence progression of carcinoma formation and are more common in invasive cancers (37). Functional p53 exists in the cell as a tetramer; alterations at the interface conjoining the subunits disable the protein (38). Interestingly, p53 is a tumor suppressor gene, and certain mutant forms have the capacity to behave like oncogenes. Certain mutant forms of p53 require only one mutated allele to abrogate p53 function, because p53 mutants have the additional property of increased stability in the cell compared with the wild-type protein. Consequently, because they are not as easily broken down, the mutant protein tends to accumulate in the cell (39). In cells containing a p53 mutation, elevated concentrations of the p53 product can often be detected (40). Deleted in Colon Cancer Deleted in colon cancer (DCC) is a tumor suppressor gene of 29 exons spanning over a million base pairs on the long arm of chromosome 18 (18q) (41). It encodes at 1447-amino acid transmembrane protein whose extracellular domain resembles the neural cell adhesion molecule family of proteins (42). DCC probably participates in signaling pathways that control cell proliferation and differentiation, a finding that is further supported by the fact that many mature epithelial cells express DCC in a restricted fashion limited to the proliferative compartment. Recent studies have raised doubts concerning the role of DCC, thus suggesting that, although DCC appears to play a role in neural development, it is likely not the tumor suppressor from 18q that was thought to promote colorectal carcinoma (43,44). Loss of heterozygosity in 18q occurs in more than 70% of colorectal cancers, and the altered region includes the DCC locus in over 90% of carcinomas with 18q allelic loss. Studies comparing the incidence of DCC allelic loss among adenomas and carcinomas indicate that loss in this region is a relatively late event in the progression of cancer (45). There has also been evidence to suggest that tumors with allelic

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

557

Figure 4 The PI3K pathway. Abbreviations: PTEN, phosphatash and tension; p85/p110, PI3K heterodimer; P, phosphorylation site; PIP2, phosphatidylinositol 4,5-phosphate; PIP3, phosphatidylinositol 3,4,5-phosphate; PDK, phosphatidylinositide-dependent kinase; GSK-3, glycogen synthase kinase-3; FKHR-L1, forkhead transcription factor; BAD, Bcl-2 antagonist of cell death; TNF-a, tumor necrosis factor-a. Source: From Ref. 53.

Figure 3 Colorectal carcinogenesis. Abbreviations: APC, adenomatous polyposis coli; DCC, deleted in colon cancer. Source: From Ref. 35.

loss at 18q metastasize more readily and behave more aggressively (46). Thus, DCC mutations may be of prognostic value. Recent observations on the function of DCC in intracellular signaling have provided a renewed interest in the potential contribution of DCC in the activation of colorectal cancer. In particular, studies suggest that when engaged by netrin ligands, DCC may activate downstream signaling pathways (47). Moreover, in cancers where netrin is absent or at low levels, DCC can promote apoptosis (47). Finally, recent functional studies have shown that inhibition of cell death induced by DCC in the mouse intestine leads to tumor formation. DPC4/SMAD4 Another candidate tumor suppressor gene is called DPC4 (deleted in pancreatic carcinoma), also known as SMAD4. Similar to DCC, DPC4/SMAD4 is located on chromosome 18q (48). Germline DPC4 mutations have been noted in a subset of patients with juvenile polyposis syndrome. DPC4 mutations have been noted in only approximately 10% to 15% of colorectal carcinomas and much less frequently in other GI tumors such as gastric cancers (49). Based on the frequencies of mutations in DPC4, this gene appears not to be a primary tumor suppressor gene targeted for inactivation by 18q loss of heterozygosity in colorectal

cancer (49). Nevertheless, inactivation of this gene is likely to have an important role in the tumor process, because it encodes a protein that functions to transduce TGF-b growth regulatory signals, and TGF-b has significant growth inhibitory effects on colonic epithelial cells (50). Phosphatase and Tensin Phosphatase and tensin (PTEN) homolog deleted on chromosome 10 (p10), also called MMAC1 or TEP1, is a tumor suppressor gene identified on human chromosome 10q23 (51). PTEN plays a major role in cell cycle arrest and apoptosis, as well as other cellular processes such as cell adhesion, migration, and differentiation (52). Disruption of PTEN in mice results in early embryonic lethality, whereas animals heterozygous for this allele develop a broad array of tumors including intestinal tumors. Recent studies show that the phosphatidylinositol-3 kinase (PI3K) product is a critical target of PTEN, by directly dephosphorylating the D3-phosphate group of the lipid second messenger (PI3, 4, 5-triphosphate), thus suggesting that PTEN can serve as a negative regulator of the signaling events mediated by PI3K (Fig. 4) (54). Although heterozygous PTEN mice are viable, they show hyperplastic-dysplastic changes and spontaneous tumor formation in various tissues including the colon (55). In humans, PTEN germline mutations have been found in autosomal-dominant cancer syndromes with overlapping clinical features: Cowden disease and Bannayan–Zonana syndrome (56). Even though each of these syndromes manifests distinct phenotypes such as thyroid carcinoma, breast cancers, meningiomas, or macrocephaly, they are all characterized by multiple hamartomas in the intestine.

medwedi.ru

558

Part Two: The Alimentary Tract—Other Conditions

p16 p16 is a tumor suppressor gene found at chromosome 9p21 (57). It is transcribed from the CDK N2a gene that also encodes the p19 Ark protein; the two products are obtained through alternative splicing of RNA (58). Like p53, it functions to inhibit cell cycle progression in the presence of genetic mutation at critical junctions, thus controlling neoplastic growth. It is thought that the p16 product suppresses tumors by inhibiting CDK/cyclin phosphorylation of the retinoblastoma (Rb)/E2F complex (59). The downstream effect of the normal p16 protein activity is the inhibition of transcription of genes that are responsible for growth and differentiation through hyperphosphorylated Rb protein. p16 is known to act in a regulatory feedback circuit with CDK-4, D-type cyclins, and Rb protein (60). The p16 gene appears to be inactivated through three basic mechanisms: point mutation with loss of heterozygosity within CDK N2a, homozygous deletion, and through methylation of the prime motor region (59). p16 mutations have been described in both diffuse and intestinal type gastric cancers.

Mismatch Repair Genes In about 80% of patients with hereditary nonpolyposis colorectal carcinoma (HNPCC), the propensity toward development of colorectal tumors results from an inherited mutation in one or more DNA mismatch repair genes (61). Loss of function of these genes leads to replication errors accumulating at a rate of 1000-fold in normal cells for each cell cycle, consequently resulting in the acceleration of cancer progression (62). The mismatch repair genes specific to HNPCC and sporadic cases of colorectal cancer target specific point mutations and microsatellite repeats. Cells with this type of error are said to be replication error–positive (RERþ) and to possess microsatellite instability (MSI). The most common genes affected are MSH2 and MLH1, followed by PMS1, PMS2, and MSH6 (62). In addition, one candidate tumor suppressor gene that is found to be consistently associated with RERþ colorectal neoplasms is the gene encoding the type 2 TGF-b receptor (63). Colorectal neoplasms with this mutation have a growth advantage that is clearly not a by-product of the generalized instability in these tumors. TGF-bR2 may play an important role in mediating differentiation and apoptosis of gut epithelial cells.

Stromal Influences Angiogenesis Angiogenesis, the process of new capillary formation (Fig. 5), is required for tumor growth and metastasis. Initially, small tumors may survive on established blood supply. However, as a tumor grows larger, metabolic demand requires microvessel ingrowth and neovascularization to supply nutrients and oxygen. These tumors induce phenotypic changes in vascular endothelial cells, initiating a new blood supply and allowing more rapid growth (65). This vascular ingrowth is associated with, but probably disproportionate to, the normal microvessel formation stimulated by hypoxia (66–68). Conversely, when blood supply does not keep up with metabolic demand, central necrosis or apoptosis, a common finding in larger tumors, may result (69,70). Intuitively, these tumors also have increased metastatic potential, as the process of angiogenesis involves enzymatic alteration of the basement membrane, cell migration, and proliferation.

Figure 5 The process of tumor angiogenesis. In a complex series of events, angiogenic factors provide a signal for quiescent mature blood vessels to develop new vascular sprouts that subsequently undergo remodeling and maturation. Source: From Ref. 64.

A number of cytokines have been implicated in angiogenesis, including TGF-b1, vascular endothelial growth factor (VEGF), HGF, and small molecules such as platelet activating factor and nitric oxide (NO). TGF-b1 regulates multiple processes from malignant transformation and immunomodulation to microvessel formation and matrix remodeling with multiple layers of regulation. VEGF, in contrast, is a direct-acting angiogenic hormone that is required for endothelial cell survival in new blood vessels, and is associated with tumor progression (71–73). Furthermore, malignant transformation has been associated with increased VEGF expression (74,75). The resulting increase in VEGF results in increased expression of growth factor receptors and matrix metalloproteinases (MMP). Vascular permeability increases and MMP-induced degradation of the extracellular matrix allows endothelial cell migration and proliferation, resulting in vascular budding and microvessel formation (Fig. 6) (65). Bevacizumab, a humanized monoclonal anti-VEGF antibody, has shown increased response rates and survival times when used with irinotecan, 5-fluorouracil (5-FU), and leucovorin (77,78), and is the first VEGF-related agent approved by the Food and Drug Administration for use in metastatic colorectal cancer. There are three VEGF receptors (VEGF-R), all of which are transmembrane tyrosine kinase receptors. VEGF-R1 activation promotes endothelial cell migration but not proliferation, while VEGF-R2 activation is required for endothelial cell differentiation and development (79–81). VEGF-R3 binds

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

559

Figure 6 Tumor angiogenesis is mediated by factors secreted from tumor cells or infiltrating stromal cells. Source: From Ref. 76.

other members of the VEGF family. Although VEGF-R1 has a higher affinity for VEGF than VEGF-R2, in endothelial cells overexpressing VEGF-R1, VEGF induces receptor phosphorylation, but not mitogenesis (65), suggesting that VEGF-R2 is the more likely candidate for therapeutic intervention. A number of tyrosine kinase inhibitors have entered clinical trials in an attempt to exploit the necessity of VEGF for microvessel ingrowth (Table 1) (82). Furthermore, VEGF-R2 binding is enhanced by the presence of its coreceptor, neuropilin-1 (83). A soluble neuropilin-1 has been shown to have antitumor activity in a rat prostate carcinoma model (84).

Epithelial–Mesenchymal Crosstalk Carcinogenesis is a multicellular process, where alterations in the surrounding microenvironment are part of tumor progression. Surrounding stromal cells have recently gained attention for their role in the proliferation and progression of epithelial carcinoma cells (85–88). Increased expression of proangiogenic factors, such as TGF-b and VEGF, and factors involved in extracellular matrix remodeling, such as multiple endocrine neoplasia type-1 (MMP-1), tissue inhibitors of MMPs (TIMP-1), and plasminogen activator inhibitor type-1 (PAI-1) and, again, TGF-b, have been noted in colonic carcinoma (Fig. 7) (85,87,89). In addition, proinflammatory cytokines such as interleukin-8 (IL-8) are also upregulated

Table 1 Tyrosine Kinase Inhibitors in Clinical Trials Inhibitor PTK787/ZK222584 AZD6474 CP-547, 632 SU11248

Target VEGF-R1 and VEGF-R2 VEGF-R2, EGF-R VEGF-R2, EGF-R, PDGF-R VEGF-R1 and VEGF-R2, PDGF-R, Flt-3

Clinical trial phase 3 2 2 3

Abbreviations: EGF-R, epidermal growth factor receptor; Flt-3, fms-like tyrosine kinase 3; PDGF-R, platelet-derived growth factor receptor; VEGFR1, vascular endothelial growth factor receptor 1; VEGF-R2, VEGF receptor 2. Source: From Ref. 82.

Figure 7 Immunohistochemical analysis for proteins related to angiogenesis, invasion, and metastasis. Representative immunohistochemical sections are shown for VEGF, TIMP-1, and PAI-1. Paired sections of normal mucosa and colon cancer from the same patients are displayed (magnification, 400). Abbreviation: VEGF, vascular endothelial growth factor. Source: From Ref. 89.

(89), which have angiogenic and mitogenic properties (90). Also, stromal cells may exhibit enhanced proliferation (89), suggesting that the active role these cells play in carcinogenesis results in abnormal growth of both the tumor and the stroma.

Inflammatory Components Contributing to GI Cancers Inflammation and GI Cancers The link between chronic inflammation and cancer was first reported by the French surgeon Jean Nicholas Marjolin who, in 1828, described the occurrence of squamous cell carcinoma in a post-traumatic, chronically inflamed wound (91). In 1863, Rudolf Virchow identified leukocytes in tumor stroma and suggested that malignancy originated at sites of chronic inflammation, challenging the popular opinion that lymphoreticular infiltrate was simply a reaction to the neoplastic process (90). The occurrence of cancers arising after prolonged inflammation has been described in every organ system of the body. Many of these cancers are attributable to infectious, mechanical, or chemical agents that elicit a chronic immune response. Recent evidence implicates a role for such an inflammatory response in the development of GI cancer. While the overall incidence of gastric cancer in the United States has significantly decreased over the past 50 years, gastric cancer remains the second most common cancer-related mortality in developing countries (92). The single most identifiable factor contributing to the development of gastric adenocarcinomas, particularly the intestinal

medwedi.ru

560

Part Two: The Alimentary Tract—Other Conditions

decrease the risk of developing colorectal cancer in IBD patients, (ii) the risk of colorectal cancer increases with duration of illness, and (iii) the risk of colorectal cancer increases with severity of inflammation (94). Other differences in colorectal cancer development in patients with IBD include a younger age at tumor development, mucinous or signet ring histology, higher incidence of two or more primary tumors, and more proximal distribution of tumors (94).

Chronic Inflammation and the Tumor Microenvironment

Figure 8 The relationship between chronic Helicobacter pylori infection and gastric cancer. Abbreviation: NO, nitric oxide. Source: From Ref. 94.

type, which generally involves the distal stomach (93), is chronic infection with the bacterium Helicobacter pylori (H. pylori), which has led to its recent classification as a class I carcinogen by the World Health Organization (WHO) (92). Case-controlled studies have estimated an approximately 2- to 17-fold increased risk of patients seropositive for H. pylori to develop gastric cancer when compared with seronegative patients (Fig. 8) (95). Inflammatory bowel disease (IBD), including both ulcerative colitis (UC) and Crohn’s disease, has a wellestablished association with the development of colorectal cancer. In contrast to conditions such as FAP and HNPCC, which have a well-defined genetic basis and follow an ‘‘adenoma–carcinoma’’ sequence of development, it appears that chronic inflammation predisposes to the development of colorectal cancer in the setting of IBD, following an ‘‘inflammation-dysplasia-carcinoma’’ model (Fig. 9) (94,96). This is supported by the following facts: (i) anti-inflammatory agents

The chronic inflammatory response represents a fine balance between active inflammation, repair, and destruction that occurs in response to a persistent stimulus over a prolonged period of time. Activation of leukocytes in response to such an ongoing stimulus leads to the production of chemokines, cytokines, and reactive oxygen species (ROS), resulting in accumulated tissue destruction and subsequent attempts at healing via remodeling, angiogenesis, and connective tissue replacement. Accumulation of cellular damage with loss of cell cycle control mechanisms is thought to be the final common pathway leading to tumor initiation (91,97). Tumor stroma is far more likely to contribute to tumor growth, invasion, and immunosuppression than it is to mount an effective antitumor response. Gastric and colorectal cancer stroma shares a common composition of macrophages, dendritic cells, lymphocytes, fibroblasts, connective tissue, and a fibrin-gel matrix (98). Examination of tumor cells and surrounding stroma has demonstrated that a mitogenic relationship exists between the two, whereby tumor cells express receptors for mediators produced by stromal elements (98). Of the stromal elements, the tumor-associated macrophages are the chief effectors of chronic inflammation in the pathogenesis of gastric and colorectal cancer, producing a large array of inflammatory mediators. These inflammatory mediators include growth and angiogenic factors (PDGF, TGF-b, and EGF), cytokines and chemokines [IL-1, IL-8,

Figure 9 Proposed model of how inflammation-associated with colitis promotes the development of colonic dysplasia and cancer. Abbreviation: MMR, mismatch repair. Source: From Ref. 96.

Chapter 27:

and tumor necrosis factor-a (TNF-a)], and proteolytic enzymes (proteases, elastase, collagenase, hydrolases, phosphatases, matrix metalloproteinase-9, and lipases) that degrade the extracellular matrix, promoting invasiveness, and cytotoxic agents which likely contribute to host cell genomic damage and promote carcinogenesis, such as ROS, hydrogen peroxide (H2O2), and NO (91,97,99). Macrophages also produce migration inhibitory factor (MIF), which contributes to mononuclear cell immobilization at the site of active, chronic inflammation; however, MIF also has the dual role of suppressing transcriptional activation of the tumor suppressor gene p53, which may also contribute to carcinogenesis (91,97,100). H2O2, a by-product of macrophage activation, has the ability to activate the nuclear factor-kB (NF-kB) pathway, leading to translocation of the activated complex to the nucleus, where it acts as a transcription factor for products inhibiting apoptosis (100). TNF-a also activates the NF-kB complex, effectively inhibiting apoptosis (100). TNF-a, IL-1, and IL-6, produced by activated leukocytes, are major mediators of inflammation and tumorigenesis (101–103). Together they induce production of adhesion molecules, growth factors, eicosanoids, NO, and chemotactic and angiogenic factors such as VEGF, and upregulate pathways that subsequently inhibit apoptosis, thus supporting tumor initiation, growth, and invasion. Receptors are found both on stromal elements and tumor cells, suggesting both autocrine and paracrine local effects (91,98). Experimental deletion of selected cytokines and chemokines in animal models confers resistance to carcinogenesis, supporting their role in the development of cancer (104,105). Neoplasia developing in the setting of chronic inflammation is a multihit process, resulting from the accumulation of genetic mutations (Fig. 10). These mutations may largely be due to the effects of ROS such as superoxide anions, H2O2, hydroxyl and hydroperoxyl radicals, and reactive nitrogen species such as NO, collectively known as reactive oxygen and nitrogen species (RONS), that are elaborated by activated inflammatory cells (91,106). The toxic effects of RONS include DNA strand breaks, mismatches, mutations, and the formation of adducts with DNA (100,107). NO is specifically responsible for the nitrosylation of proteins involved in apoptosis, such as caspases-3, -8, and -9, resulting in inactivation and prevention of cell death in response to injury (107). H2O2 is capable of damaging the protein complexes responsible for DNA mismatch repair, resulting in inactivation and accumulation of sequence errors (106).

Neoplastic Disorders of the Gastrointestinal Tract

561

Signaling Pathways Linking Inflammation and GI Cancer Many derangements in cell signaling occur during the transformation of a normal cell to a malignant phenotype. It is useful to identify cell-signaling pathways that may inhibit apoptosis and promote tumor growth, which are similarly upregulated in multiple cancer cell lines. Three prominent pathways include cyclooxygenase-2 (COX-2), NF-kB, and PI3K pathways. COX-2, also known as prostaglandin G/H synthase, is the rate-limiting enzyme catalyzing the conversion of arachidonic acid to a variety of inflammatory and physiological mediators, including prostaglandins and thromboxane. The COX-2 isoform of this enzyme belongs to a class of genes known as immediate early or early growth response genes inducible by inflammatory cytokines and growth factors, including IL-1 and TNF-a, and its products are predominantly proinflammatory prostaglandins and eicosanoids involved in regulation of the immune response (Fig. 11) (109). COX-2 is not normally expressed in the human intestine, but its activity is significantly elevated in the majority of human colorectal and gastric cancers (110). A significant and early COX-2 overexpression is associated with UC, both in inflamed and in noninflamed mucosa, and with UCassociated dysplasia and neoplasia (110). This has led to interest in defining its specific mechanism of action in chronic inflammation and neoplasia to determine if its inhibition may act as an adjunct to current chemotherapy. Large epidemiologic studies have demonstrated a 30% to 50% reduction in adenomatous polyp formation, incident disease, and death from colorectal cancer by inhibiting COX-2 activity with nonsteroidal anti-inflammatory medications (111). NF-kB is a ubiquitously expressed transcription factor that plays a pivotal role in cellular responses to environmental changes, such as stress, inflammation, and infection. NF-kB is activated in response to infectious agents or cytokines, including TNF-a, IL-1, ROS, and lipopolysaccharide (112). Its products include growth factors, cytokines, cell adhesion molecules, immunoreceptors, and cell survival proteins, making it an important and complex regulator of the immune response (112,113). Constitutive activation of NF-kB has been described in inflammatory conditions such as gastritis and IBD, as well as many solid tumors, including GI cancers. The activation of NF-kB by proinflammatory stimuli and its ability to inhibit apoptosis have led to the assumption that the NF-kB pathway provides a mechanistic link between inflammation and cancer (114).

Figure 10 Inflammation and the landscape theory. Chronic inflammation, as seen in inflammatory bowel disease, causes damage of stromal cells, and subsequent healing allows these damaged cells to be exposed to growth factors. This combination of cell damage and proliferation may lead to the development of an abnormal microenvironment, where stromal elements encourage the production of transformed cells. Abbreviations: COX-2, cyclooxygenase-2; NF-kB, nuclear factor kB; ROS, reactive oxygen species. Source: From Ref. 100.

medwedi.ru

562

Part Two: The Alimentary Tract—Other Conditions

Figure 11 COX-2–derived PGE2 promotes tumor development. Abbreviations: COX-2, cyclooxygenase-2: VEGF, vascular endothelical growth factor. Source: From Ref. 108.

Another pathway playing a critical role in the balance between cell survival and apoptosis is the PI3K pathway. PI3K, a ubiquitous lipid kinase activated by a wide variety of extracellular stimuli, including inflammatory cytokines (e.g., TNF-a) and growth factors, is involved in the regulation of diverse cellular processes such as cell growth and survival, actin cytoskeletal rearrangement, membrane ruffling, and vesicular trafficking (115); therefore, signaling through this pathway plays a pivotal role in the regulation of cellular growth, transformation, and tumorigenesis. Increased PI3K activity has been identified in as many as 86% of human colorectal cancers, with increasing activity correlating with increasing tumorigenic potential of the cancer cell lines examined (115,116). The promotion of cell survival by PI3K and its subsequent contribution to tumorigenesis is thought to occur via the inhibition of proapoptotic signals and the induction of survival signals (116).

Hormone and Hormone Receptors The receptors for GI hormones are cell surface G protein– coupled receptors (117). These receptors regulate a number of cellular processes including growth, differentiation, and development. The binding of GI hormones to their G protein–coupled receptors can result in a varied cellular response through complex activation of the hormone– receptor complex (118). In a manner analogous to other hormone responsive tumors such as breast cancers and prostate cancers, GI cancers can also possess receptors for various intestinal hormones, and the binding of these hormones to their receptors can lead to increased growth of these cancers. Experimental studies have shown that colorectal and gastric cancers that possess receptors for selected GI hormones are responsive to the effects of these hormones, resulting in enhanced proliferation (119). GI hormones are cellular messengers that regulate intracellular signaling within intestinal tract cells affecting secretion, motility, absorption, digestion, and cell proliferation (120). GI hormones are produced and secreted by endocrine cells located throughout the GI mucosa and pancreas. Although these hormones were initially discovered as solely endocrine in nature, recent studies have demonstrated that these hormones can act in either a paracrine or autocrine fashion (120). GI hormones that have been shown to play a role in the growth of gastric or colorectal cancers include gastrin, bombesin/gastrin-releasing peptide, and neurotensin (120). In addition, the hormone,

somatostatin, has been shown to inhibit the proliferation of various GI cancers through both direct and indirect mechanisms (121,122). Although the amount of proliferation contributed by GI hormones on tumor growth may be relatively small, the identification of GI cancers with these receptors may be important in streamlining chemotherapy to include agents that block these receptors, which, in conjunction with other standard chemotherapeutic agents, may be useful in selected cancers.

NEOPLASTIC DISEASES OF THE STOMACH, SMALL BOWEL, AND COLORECTUM Gastric Neoplasms The majority of gastric neoplasms are malignant, with 90% to 95% of these cases identified as adenocarcinomas (123). Other malignant neoplasms include lymphomas and sarcomas. Benign gastric neoplasms include leiomyomas and lipomas.

Benign Gastric Tumors Gastric polyps are usually an incidental finding on endoscopy and are detected in approximately 2% to 3% of upper GI endoscopies (124). Hyperplastic polyps are among the most frequently observed polyps; these polyps are usually small and benign. Adenomatous polyps have a risk for malignancy that is associated with size; the greater the size, the more likely an invasive cancer is present (125). Resection is required for polyps, either by endoscopic polypectomy or, if too large, gastric resection. Other benign conditions of the stomach include leiomyomas, which are smooth muscle tumors of benign origin, lipomas, and ectopic pancreas.

Adenocarcinoma of the Stomach Incidence/Epidemiology Adenocarcinoma of the stomach is the second most common cancer worldwide, when specific geographic variations are included (126). Notably, higher rates are noted in Japan and in some parts of South America, whereas lower rates occur in Western Europe and the United States (127,128). In the United States, gastric adenocarcinoma is the 10th most common cancer, with an incidence that has been decreasing over the last 70 years (129). Gastric cancer is twice as common in men as in women, and is higher among

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

563

African-American men than Caucasian men. As with other cancers, the incidence increases with age, peaking in the seventh decade. Other factors, which contribute to gastric adenocarcinoma, include environmental exposure as well as other cultural or genetic factors. Although adenocarcinoma localized to the distal stomach has declined, the incidence in other more proximal sites, including the gastric cardia, have increased, possibly as a result of differences in pathogenic factors. Etiology Diet has been postulated to play a role in the geographic differences noted in gastric adenocarcinoma. Diets low in animal protein and fat, high in complex carbohydrates, high in salted meats and fish, and high in nitrates or H. pylori in the drinking water are associated with an increased risk for gastric adenocarcinoma (130). In contrast, the consumption of raw vegetables, fruits, and high-fiber foods is associated with a lower risk of gastric cancer. Other factors associated with an increased risk of gastric adenocarcinoma include low socioeconomic status (except in Japan), cigarette smoking, male gender, and H. pylori infection. The presence of immunoglobulin G antibodies to H. pylori appears to correlate with the local incidence and mortality rates of gastric cancer (131). Infection with the cagA strain produces a greater mucosal inflammation than cagAnegative strains and results in a greater risk of gastric cancer (132). Host genetic factors also play a role in development, as noted by increased risk of hypochlorhydria induced by H. pylori associated with increased IL-1 gene cluster polymorphisms, thus resulting in increased gastric cancer (133). Therefore, the familial clustering of H. pylori infection associated with inherited genetic polymorphisms linked to hypochlorhydria may explain the increased risk in individuals of certain families (134). Pernicious anemia is associated with an increased risk for developing gastric adenocarcinoma (135,136). This condition represents an autoimmune gastritis of the oxyntic mucosa and increases the risk of gastric cancer as a result of increased chronic inflammation. The presence of adenomatous gastric polyps carries a distinct risk for the development of gastric adenocarcinoma in the polyp. Similar to polyps in the colon, increasing size of the polyp is associated with increased risk of invasive cancer (125). Several genetic alterations have been reported to occur in gastric adenocarcinomas and include the overexpression of the c-met proto-oncogene (the receptor for the HGF) and the K-sam and c-erb-B2 oncogenes (Fig. 12). Inactivation of the tumor suppressor genes, p53 and p16, have been noted in both diffuse- and intestinal-type cancers, whereas APC gene mutations tend to be more frequent in the intestinal-type gastric cancers (138–140). In addition, a reduction or loss of the cell adhesion molecule, E-cadherin, is noted in about 50% of diffuse-type gastric cancers and MSI is noted in approximately 20% to 30% of intestinal-type cancers (133,138,141). Pathology The most useful and widely used classification system for gastric adenocarcinomas divides those cancers into two types: intestinal and diffuse (123,142). The intestinal type arises in the setting of precancerous conditions such as gastric atrophy or intestinal metaplasia; men are more commonly affected than women, and the incidence of intestinal type increases with age. This variant is well differentiated,

Figure 12 A model for the progression of molecular lesions in gastric cancer. The two histological subtypes of gastric adenocarcinoma, diffuse and intestinal gastric cancer, originate from different combinations of molecular lesions. Abbreviations: APC, adenomatous polyposis coli; DCC, deleted colon cancer; TGF-b, transforming growth factor-b. Source: From Ref. 137.

with a tendency to form glands, and metastatic spread is generally hematogenous to distant organs. The intestinal type is typically noted in the distal stomach with ulcerations; this form is declining in incidence in the United States (143). In contrast, the diffuse type involves widespread thickening of the stomach, especially in the cardia and often affects younger patients. It often presents as linitis plastica, a particularly virulent form of gastric cancer characterized by nondistensible and thickened stomach walls. In addition, the diffuse form of gastric cancer is composed of signet ring cells (123). The route of spread is generally by transmural extension and through lymphatic invasion. This form is more common in women, affects a slightly younger age group, and is associated with blood type A, suggesting a genetic etiology (142). Clinical Manifestations The symptoms associated with gastric adenocarcinoma can be relatively nonspecific and, therefore, may not be diagnosed at an early stage. Early symptoms include epigastric discomfort and indigestion, which may be mistaken for gastritis or peptic ulcer. More advanced disease presents with weight loss, anorexia, fatigue, or vomiting. Proximal tumors can present as dysphagia with involvement of the GE junction. More distal cancers may present as a gastric outlet obstruction. Diffuse mural involvement, such as that which occurs with linitis plastica, may result in early satiety (144,145). Clinically significant GI bleeding is rare, but as many as 15% of patients may develop hematemesis and 40% of patients are anemic (146). Classic physical findings associated with very advanced gastric cancers and metastatic spread include a palpable abdominal mass, a palpable supraclavicular (Virchow’s) or periumbilical (Sister Mary Joseph’s) lymph node, peritoneal metastasis palpable by

medwedi.ru

564

Part Two: The Alimentary Tract—Other Conditions

rectal examination (Blumer’s shelf), or a palpable ovarian mass (Krukenberg’s tumor) (147). Diagnosis Once suspected, gastric adenocarcinoma may be diagnosed by a barium upper GI contrast study or, preferably, upper GI endoscopy with biopsy and cytology, which approaches a diagnostic accuracy of 90% to 95% (148). Once identified, the staging of gastric cancer is performed by endoscopic ultrasound (EUS), which provides a staging accuracy of approximately 75% (149). Staging by computed tomography (CT) scan provides complementary information regarding lymphadenopathy and extragastric organ involvement. Treatment Surgical treatment remains the only hope for cure. It is estimated that surgical resection for cure is possible in only 25% to 30% of the cases (150). If the tumor is confined to the distal stomach, subtotal gastrectomy is performed, with resection of surrounding lymph nodes. In contrast, tumors in the more proximal stomach require total gastrectomy. The role of extended lymphadenectomy in combination with the primary resection remains controversial. The various types of surgical procedures that are employed to manage gastric cancer are shown in Figure 13. The routes of lymphatic spread are shown in Figure 14. Gastric adenocarcinomas are partially responsive to chemotherapy. Single-agent treatment with 5-FU, doxorubicin, mitomycin C, or cisplatin provides a response rate of approximately 20% to 30% (153,154). When used in combination, response rates of 35% to 50% can be obtained. Radiation therapy is relatively ineffective and is used in only special cases for predominately palliative reasons (155). Prognosis Overall, the five-year survival rate of gastric adenocarcinoma is less than 10% (156). Prognostic factors include anatomic location and nodal status. That is, distal gastric cancers without lymph node involvement have a better prognosis than proximal gastric cancers with or without lymph node involvement. Other prognostic factors include depth of penetration and tumor cell aneuploidy. Linitis plastica and infiltrating lesions are associated with an overall worse prognosis. The TMN system of classifying gastric carcinoma emphasizes the extent of spread through the gastric wall and the presence or absence of regional lymph node involvement (Fig. 15). It is the major system of staging this disease in the United States.

Gastric Lymphoma The stomach is the most common site for lymphomas of the GI system. However, they are still relatively infrequent, accounting for less than 15% of gastric malignancies (123). Patients often present with vague symptoms including epigastric pain, early satiety, and fatigue; more than half of patients present with anemia. Similar to adenocarcinoma, lymphomas occur in an older age group, with more cases noted in men (158). The majority of gastric lymphomas are non-Hodgkin’s lymphomas, with the most common histologic diagnosis of diffuse large B-cell lymphoma followed by extranodal marginal cell lymphoma [mucosa-associated lymphoid tissue (MALT)] (Table 2). MALT lymphomas are strongly associated with H. pylori infection (Fig. 16) (159).

Figure 13 Surgical options for treatment of gastric adenocarcinoma. (A) Subtotal gastrectomy with gastrojejunal reconstruction. (B) Total gastrectomy followed by esophagojejunostomy. (C) Esophagogastrectomy with intrathoracic or cervical reconstruction. Source: From Ref. 151.

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

565

TNM Classification of Carcinoma of the Stomach

Category

Criteria

PRIMARY TUMOR (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria T1 Tumor invades lamina propria or submucosa T2 Tumor invades muscularis propria or subserosa . T2a Tumor invades muscularis propria T2b Tumor invades subserosa T3 Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures T4 Tumor invades adjacent structures

Figure 14 Routes of lymphatic spread for carcinoma of stomach. Source: From Ref. 152.

Gastric lymphomas usually arise as ulcers or as exophytic masses. Diagnosis may be obtained by upper GI endoscopy or upper GI barium studies. Proper staging of gastric lymphoma involves endoscopic ultrasonography, chest and abdominal CT scans, and, in some cases, bone marrow biopsy. The treatment of diffuse large B-cell lymphoma of the stomach is with combination chemotherapy with or without radiotherapy. Five-year survival rates of 40% to 60% have been reported using this treatment modality. For MALT lesions, the eradication of H. pylori infection appears to induce regression of the tumor. However, longer-term studies are required before this can be substantiated (158,161).

Gastric Sarcomas Leiomyosarcomas constitute about 1% of all gastric cancers and usually occur as an intramural mass with central ulceration. Symptoms can include bleeding accompanied by a palpable mass. Surgical resection results in a five-year survival rate of about 50% (162).

Neoplasms of the Small Intestine Incidence/Epidemiology Small bowel neoplasms are exceedingly rare, constituting only 5% of all GI neoplasms and only 1% to 2% of all malignant tumors of the GI tract (163). The mean age at onset is approximately 59 years and, similar to other cancers, there appears to be a geographic distribution, with the highest cancer rates among the Maori of New Zealand and ethnic Hawaiians (164). Numerous risk factors and associated conditions have been described with relation to small bowel neoplasms and include patients with FAP, HNPCC, Peutz– Jeghers syndrome, Crohn’s disease, gluten-sensitive enteropathy (i.e., celiac sprue), and biliary diversion (e.g., previous cholecystectomy). Controversial factors that may contribute to small bowel cancers include smoking, heavy alcohol consumption, and consumption of red meat or salt-cured foods. Although the molecular genetics of small bowel neoplasms

REGIONAL LYMPH NODES (N) NX Regional lymph node(s) cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1 to 6 regional lymph nodes N2 Metastasis in 7 to 15 regional lymph nodes N3 Metastasis in more than 15 regional lymph nodes DISTANT METASTASIS (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis STAGE GROUPING Stage 0 Tis Stage 1A Tl Stage IB Tl T2a/b Stage II Tl T2a/b T3 Stage III T2a/b T3 T4 Stage IIIB T3 Stage IV T4 Tl-3 Any T

N0 N0 N1 N0 N2 N1 N0 N2 N1 N0 N2 N1_3 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Figure 15 TNM classification of carcinoma of the stomach. Source: From Ref. 157.

have not been entirely characterized, similar to colorectal cancers, mutations of the K-ras gene are commonly found (165). Allelic losses, particularly involving tumor suppressor genes, APC, p53, DCC, and DPC4 (SMAD4) genes, have been noted in some small bowel cancers (166–168).

Pathology Benign neoplasms of the small bowel account for the majority of small bowel neoplasms. These benign lesions include adenomas, leiomyomas, lipomas, and angiomas (169).

medwedi.ru

566

Part Two: The Alimentary Tract—Other Conditions

Table 2 Frequency of Organ Involvement GI lymphoma Diffuse large cell lymphoma MALT lymphoma Burkitt’s lymphoma Peripheral T-cell lymphoma Mantle cell lymphoma Follicular lymphoma

Stomach 55 40 3 0 <1 <1

Abbreviations: GI, gastrointestinal; MALT, mucosa-associated lymphoid tissue. Source: From Ref. 159.

Adenomas account for approximately 15% of all benign small bowel tumors and are of three primary types: true adenomas, villous adenomas, and Brunner gland adenomas (170). Leiomyomas are benign tumors of smooth muscle origin and are the most common symptomatic benign neoplasm of the small bowel. Lipomas are most common in the ileum and usually present as a single intramural lesion. Hamartomas of the small bowel occur as part of the Peutz–Jeghers syndrome, an inherited syndrome, which includes mucocutaneous melanotic pigmentation and GI polyps. Although once considered as purely benign disease, adenomatous changes have been reported in 3% to 6% of hamartomas (171). Hemangiomas are developmental malformations and are most commonly found in the jejunum. Hemangiomas of the small bowel may occur as part of an inherited disorder known as Rendu-Osler-Weber syndrome (172). Malignant neoplasms of the small intestine include adenocarcinomas, leiomyosarcomas, lymphomas, and carcinoid tumors (Fig. 17). Adenocarcinomas constitute approximately 50% of malignant tumors of the small bowel and can occur as a result of long-standing Crohn’s disease (174,175). Carcinoid tumors of the small bowel arise from enterochromaffin cells found in the crypts of Lieberku¨hn (176). Leiomyosarcomas, more commonly referred to as malignant gastrointestinal stromal tumors (GISTs), arise from mesenchymal tissue and constitute approximately 20% of malignant neoplasms of the small bowel (177). Malignant lymphomas involve the small bowel primarily or as a manifestation of systemic disease. Adenocarcinomas occur most frequently in the duodenum, carcinoid is the most common

tumor of the distal small bowel, and lymphomas typically arise in the ileum. Due to specific variations in the pathology and treatment, carcinoid tumors and GISTs will be discussed separately.

Clinical Manifestations Symptoms associated with small bowel neoplasms are often vague and nonspecific and may include dyspepsia, anorexia, malaise, and dull abdominal pain. The majority of patients with benign neoplasms remain asymptomatic, and the neoplasms are only discovered at autopsy or as incidental findings at laparotomy or upper GI radiologic studies. Of the remainder, pain, most often related to obstruction, is the most frequent complaint. Bleeding (usually occult) is the next most common symptom. In contrast to benign lesions, malignant neoplasms almost always produce symptoms, with the most common symptoms being pain and weight loss. Obstruction develops in 15% to 35% of patients and is usually the result of tumor infiltration and adhesions (178). Adenocarcinomas typically produce the constricting apple-core lesions that are observed most commonly in the colon. GI bleeding manifested by anemia and guaiac-positive stools occurs to varying degrees with malignant lesions and is more common with leiomyosarcomas. A palpable mass may be felt in 10% to 20% of patients and perforations (usually secondary to lymphomas or sarcomas) develop in approximately 10% (178).

Diagnosis Due to the insidious nature of many small bowel neoplasms, most can go unrecognized until they grow to a size that causes obstruction or bleeding. In most series, a correct preoperative diagnosis is made in only 20% to 50% of symptomatic patients. An upper GI tract series with small intestinal follow through is accurate in approximately 50% to 70% of patients with malignant neoplasms of the small intestine (179). Enteroclysis increases the diagnostic accuracy to approximately 90% (180). Other diagnostic modalities that may be useful include small bowel endoscopy, radiotelemetry capsules, CT scan, or ultrasound. Despite the useful diagnostic modalities that are currently available, the diagnosis of small bowel tumors is still often achieved only at

Figure 16 MALT lymphoma. (A) Lymphoma infiltrates gastric submucosa (200). (B) Lymphoepithelial lesions are associated with MALT change (400). (C) Helicobacter pylori are often found associated with MALT change and MALT lymphomas (1000). Abbreviation: MALT, mucosa-associated lymphoid tissue. Source: From Ref. 159.

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

567

Figure 17 Small bowel neoplasms constitute 5% of all GI neoplasms and only 1% to 2% of all malignant tumors of the GI tract. (A) Large circumferential mucinous adenocarcinoma of the jejunum. (B) Small bowel leiomyosarcoma (malignant GI stromal tumor) with hemorrhagic necrosis. Abbreviation: GI, gastrointestinal. Source: From Ref. 152.

the time of surgical exploration performed either as an elective procedure or as an emergency.

Treatment The primary treatment for neoplasms of the small bowel is surgical resection. Segmental resection with primary anastomosis is most commonly used for benign small bowel neoplasms. The entire small bowel should be searched for other lesions because they are oftentimes multiple. The treatment of adenocarcinomas and lymphomas of the small bowel is wide resection, including the regional lymph nodes (Fig. 18). This may require pancreaticoduodenectomy (Whipple operation) for duodenal lesions. Often, surgical resection for cure is not possible; therefore, palliative resection should be performed to prevent further complications. If this is not possible, bypass of the involved segment may provide relief of symptoms (182). Adjuvant radiation and chemotherapy have little role in the treatment of patients with adenocarcinomas of the small bowel (183). In contrast, radiotherapy and chemotherapy combined with surgical excision provide the best survival rates for patients with lymphomas (183).

Prognosis The survival rates and prognosis are excellent for patients with benign tumors of the intestine, if surgical resection is

Figure 18 Surgical management of carcinoma of the small bowel. (A) Malignant tumors should be resected with a wide margin of normal bowel and a wedge of mesentery to remove the immediate draining lymph nodes. (B) End-to-end anastomosis of the small bowel and repair of the mesentery. Source: From Ref. 157.

able to treat the bleeding and obstruction. Only half of the patients operated on for malignant tumors have lesions amenable to curative resection (163). One-third have a distant metastasis at the time of initial surgery, and the overall survival rate after surgical treatment of malignant tumors is only 25%. Adenocarcinoma has the poorest prognosis, with an overall survival rate of 15% to 20% (184).

GI Stromal Tumors In the mid-20th century, stromal tumors of the GI tract were thought to be neoplasms of smooth muscle origin, and were most often classified as leiomyoma, leiomyosarcoma, or leiomyoblastoma (177,185,186). Starting in the early 1980s, GISTs were identified as a distinct entity from smooth muscle tumors arising from the myometrium as noted by the variable expression of muscle markers (actins and desmins). However, GIST tumors were not accepted widely until the 1990s when immunohistochemistry staining of these GI tumors showed a common marker, CD34 (187). Electron microscopy and immunohistochemistry studies of GISTs showed a common overlap of smooth muscle and neural characteristics that led to a common speculation that these tumors were not of smooth muscle origin, but rather from populations of spindle cells present in the gut wall, the intestinal cells of Cajal (ICC) (188). Myenteric plexus subtypes of ICC that are found in the stomach and intestines share common features with GIST, including frequent expression of CDr34, embryonic smooth muscle myosin heavy chain, and intermediate filament nestin (189,190). ICC cells fail to develop without the receptor tyrosine kinase (KIT) or its ligand, stem cell factor (SFC), indicating that KIT–SFC axis is essential to the development of ICC cells. This observation led to the discovery that GISTs also strongly express KIT (Fig. 19) (192,193). This provided a new marker to identify GIST tumors and supported the hypothesis that GIST tumors share a common stem cell with ICC. In fact, several studies have shown that up to 95% of GIST tumors strongly stain for KIT (194,195). However, several recent studies have found a small subset of GIST tumors are KIT negative (196). Most GISTs are comprised of a fairly uniform population of spindle cells (70%), but some are predominantly epithelial (20%). The remainder consists of a mixture of spindle and epithelial cells. The spindle cells are often arranged in short fascicles. Occasional tumors have neuroendocrine-like features that resemble paraganglioma or carcinoid tumors. Approximately 95% of GISTs stain positively for KIT. Other common markers include Bcl-2 (80%), CD34 (70%), musclespecific actin (50%), smooth muscle actin (35%), S-100 (10%), and desmin (5%) (197–199).

medwedi.ru

568

Part Two: The Alimentary Tract—Other Conditions

and mitotic index for risk stratification of patients with primary tumors. These guidelines were developed based on a retrospective review of 200 cases noting that the five-year disease-specific survival of approximately after removal of tumors larger than 10 cm was approximately 20%, whereas tumors smaller than 5 cm had a five-year survival approximately 60% (182,201). Mitotic index has been linked to prognosis in a large number of studies and should be included in the evaluation of GISTs (202). Tumor location is also very important in assessing tumor prognosis; patients with gastric tumors have a better prognosis than those with tumors arising from the small bowel or the rectum (203,204). Up to 30% of newly diagnosed GISTs are malignant or are at a high risk for malignancy. Progression of these tumors follows a well-characterized course that includes recurrence at the site of resection, intra-abdominal spread on serosal surfaces, and the development of liver metastases (205). Lymphatic spread is uncommon, and disease progression outside of the abdomen is seen only in advanced cases. Recurrence is reported to be 20%, even for low-risk GISTs. Several groups have reported an association between aggressive clinical behavior of GIST tumors and the presence of an exon 11 mutation in the KIT protein (201). The juxtamembrane region of KIT (exon 11) functions to inhibit receptor dimerization in the absence of SFC (192). The reported incidence of exon 11 mutations ranges from 20% to 92% (192,201). Treatment is primarily surgical. Segmental small bowel resection is required; wide margins and extensive lymph node dissection are not necessary. The adjuvant treatment of GISTs may be favorably impacted by recent reports demonstrating an effect on GIST tumor progression using imatinib mesylate (Gleevec). Imatinib somewhat selectively inhibits Abl-family tyrosine kinases, including the KITreceptor tyrosine kinase, resulting in reduced cellular proliferation and increased apoptosis (191). While initially utilized for chronic myelogenous leukemia, its use in GIST tumors is likely to improve outcomes, as up to 90% of these tumors have KIT mutations. While long-term survival has not been established with imatinib, tumor bulk reduction and stabilization have been documented (Fig. 20), with an 88% one-year survival (206). The current five-year survival rates for GISTs are variable, ranging from 7% to 56%.

Figure 19 Histopathology and immunohistochemistry of a GIST. (A) GIST with spindle cell phenotype. Note the compact and highly cellular pattern. The cells have paler eosinophilic cytoplasm than smooth muscle neoplasms, with indistinct cell margins and minimal tumor stroma. The nuclei are typically uniform in appearance and spindle or ovoid in shape. The arrow points to an apoptotic tumor cell (400 magnification). (B) KIT immunostaining of a GIST. Most GISTs show diffuse strong cytoplasmic staining (200 magnification). Abbreviation: GIST, gastrointestinal stromal tumor. Source: From Ref. 191.

Carcinoid Tumors

GISTs arise predominantly in the stomach (60%) and small intestine (25%), but may also occur in the rectum (5%), esophagus (2%), and other abdominal organs (5%). The age range for GISTs is broad (second to ninth decade of life), with a peak incidence in the seventh decade of life. Tumors generally measure from 2 to 30 cm in diameter, and are frequently found due to mass-related effects or anemia from mucosal ulceration. However, some GISTs are found incidentally during radiologic or endoscopic studies for other diseases or at the time of surgical resection or autopsy specimens. Retrospective studies into the incidence of GISTs place the frequency around 5000 new cases per year within the United States (200). Consensus guidelines for GIST prognosis were generated during a National Institutes of Health/National Cancer Institute workshop in 2001, and emphasized the tumor size

GI carcinoid tumors are rare neuroendocrine neoplasms arising from the enterochromaffin cells of the crypts of Lieberku¨hn (207,208). While there are reports of these tumors arising from almost every organ derived from the primitive gut, they are most likely to arise in the pulmonary system or intestinal tract. In the adult gut, they are most likely to arise in the appendix, ileum, or rectum (209,210). In addition, small bowel carcinoid tumors are multicentric in up to a quarter of patients and are associated with synchronous malignancies (e.g., colonic adenocarcinoma) in up to a fifth of patients (208,211–213). The incidence of clinically detectable carcinoid is thought to be about 2 per 100,000 people, but autopsy series place the actual incidence at up to 1.2% (208–210). Carcinoid tumor classification is based on embryological origin within the primitive gut (Table 3) (176). Foregut tumors arising form the respiratory tract, esophagus, stomach, upper duodenum, or pancreas produce low levels of serotonin, but secrete 5-hydroxytryptophan (5-HTP),

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

569

Figure 20 CT of a 60-year-old woman with a metastatic GIST. (A) Before imatinib, (B) after 4 month of treatment with imatinib, and (C) after 14 months of treatment. (B) and (C) demonstrate the cystic-like degeneration of the metastatic lesions that occurs with imatinib treatment. Abbreviations: CT, computed tomography; GIST, gastrointestinal stromal tumor. Source: From Ref. 191.

histamine, or adrenocorticotrophic hormone (215–219). Midgut tumors arise from the distal duodenum, jejunum, ileum, appendix, ascending colon, or liver, and may produce high levels of serotonin (215). Usually, hepatic filtration limits systemic effects; however these tumors may produce the classical carcinoid syndrome (see below) when metastatic to the liver or other systemic organs. Hindgut tumors arise from the distal colon and rectum, and are more likely to produce somatostatin, peptide YY, 5-HTP, or other hormones (215). Grossly, these tumors are usually firm submucosal nodules, with the majority less than 1 cm in diameter. Serosal invasion elicits an intense desmoplastic reaction that can lead to intestinal kinking and bowel obstruction. Tumors are composed of small, round, well-differentiated neuroendocrine cells with regular nuclei in one of five growth patterns: insular, trabecular, glandular, undifferentiated, or mixed (220). While tumor size is usually the best predictor of malignant potential, the location, depth of invasion, and growth pattern remain influential (221). With the exception

of appendiceal carcinoid tumors, these neoplasms are associated with a 2% metastatic rate for lesions less than 1 cm, with tumors greater than 2 cm having an 80% to 90% metastatic rate (222). Intermediate lesions (1–2 cm) have approximately a 50% metastatic rate. Appendiceal tumors are less likely to present as metastatic. While theories vary, this low rate is likely a function of the early onset of obstructive symptoms (i.e., appendicitis) associated with even relatively small appendiceal tumors (Fig. 21). These tumors most likely present either incidentally or with obstructive symptoms. Often, the diagnosis is only made postoperatively. Work-up usually consists of computed tomography and, as many carcinoid tumors are associated with synchronous lesions of other histological types, additional cancer screening (e.g., colonoscopy in patients with small intestinal carcinoid tumors). While positron emission tomography (PET) scanning, selective angiography, and other modalities have shown some use in the past, radiolabeled somatostatin-analog scintigraphy is the current

Table 3 Characteristics of Foregut, Midgut, and Hindgut Gastrointestinal Carcinoid Tumors Foregut Site of primary

Cell of origin

Typical histology

Usual syndrome

Possible mediators

Midgut

Esophagus Stomach Proximal duodenum Liver Gallbladder Bile ducts Pancreas Epithelial endocrine cell Enterochromaffin-like cell in stomach Well differentiated, often multiple, occurs in MEN-1 Often invasive in sporadic carcinoid Atypical with prolonged purple flush headache, lacrimation, bronchoconstriction 5-HTP, histamine, others

Hindgut

Distal duodenum Jejunum Ileum Appendix Right colon Transverse colon

Descending colon Sigmoid colon Rectum

Epithelial endocrine cell Subepithelial endocrine cell in appendix Well differentiated, often multiple Nodal metastases very common except from appendix Typical short pink/red flushes with diarrhea, cardiac fibrosis, wheezing, dyspnea, pellagra Serotonin, kinins, others

Epithelial endocrine cell

Abbreviations: MEN-1, multiple endocrine neoplasia type-1; 5-HTP, 5-hydroxytryptophan. Source: From Ref. 213.

medwedi.ru

Well differentiated Nodal metastases common Syndrome very rare

570

Part Two: The Alimentary Tract—Other Conditions

Table 4 Summary of Surgical Recommendations for Treatment of Midgut Carcinoid Tumors Size Jejunum and ileum <1 cm

60

>2 cm

85

Appendix <1 cm 1–2 cm

<0.1 <2

>2 cm

50

40

1–2 cm

60

>2 cm

85

Mesenteric metastases Up to SMA/SMVc Surrounding SMA/ SMV Hepatic metastases <50% replacement Unsuitable for resection

staging technique of choice, both for the localization of primary and metastatic lesions. With this technique, sensitivities approach 90% (224–229). In addition, intraoperative localization of the radiolabeled probe can be accomplished with a gamma-detecting probe (230–236). Surgical resection remains the cornerstone of therapy for carcinoid tumors (Table 4). For gastric carcinoid tumors associated with chronic atrophic gastritis, Zollinger–Ellison syndrome, or multiple endocrine neoplasm type I (i.e., type I and II tumors associated with hypergastrinemia), smaller lesions are resected endoscopically, with larger lesions requiring formal operative resections (237). Sporadic (type III) tumors are more aggressive, and usually require a subtotal or radical gastrectomy (237–239). Duodenal lesions are rare, but in small studies, endoscopic resection seems adequate for lesions less than 1 cm, with larger lesions requiring transduodenal excision (1–2 cm lesions) or pancreaticoduodenectomy (greater than 2 cm). In the small intestine, small (less than 1 cm) lesions without regional lymph node involvement may be removed with segmental intestinal resection, with larger lesions requiring wide excision of the bowel and mesentery. Palliative

40

1–2 cm

Right and transverse colon <1 cm

Figure 21 (A) Longitudinal ultrasound image of the right lower quadrant showing a dilated, noncompressible appendix (arrowheads) with striated wall-thickening and intraluminal gas echoes in a patient with the clinical symptoms of obstructive appendicitis. (B) Photograph of the gross specimen sectioned at the appendiceal base demonstrating a rounded, subcentimeter carcinoid tumor (arrowheads), which produced the luminal obstruction. Source: From Ref. 223.

Nodes (%)

Treatment Segmental resection with nodal clearance Segmental resection with nodal clearance Segmental resection with nodal clearance Appendicectomy Appendicectomy or right hemicolectomya Right hemicolectomy with nodal clearance Hemicolectomyb with nodal clearance Hemicolectomy with nodal clearance Hemicolectomy with nodal clearance Resection of mesenteric nodal mass Nodal resection not possible

Liver resection if >25% normal liver preserved Consider transplantationd

a

Depending on operative findings/histology; if hemicolectomy, wide nodal clearance. b Right hemicolectomy or extended right hemicolectomy depending on site. c Superior mesenteric artery/superior mesenteric vein. d If no extrahepatic disease and poor response to other treatments. Source: From Ref. 213.

resection and debulking may be required in patients with severe desmoplastic reactions resulting in bowel obstruction (240,241). For appendiceal lesions, tumors less than 1 cm are resected by simple appendectomy, while lesions greater than 2 cm require right hemicolectomy. Intermediate (1–2 cm) lesions are more controversial, but are often resected by simple appendectomy if the surgical margins are clear (221). While endoscopic resection has been attempted for colonic lesions, colonic resection with locoregional lymphadenectomy is usually performed (242). In contrast, smaller rectal lesions are often managed with local excision or endoscopic resection. Larger lesions (greater than 2 cm) often require low anterior resection or abdominoperineal resection (221,243–245). As these tumors are often hormonally active, surgical debulking, hepatic wedge resections, radiofrequency ablation, and other techniques are often utilized for symptomatic relief, often in combination with somatostatin-analog therapy. Advanced disease is often treated with somatostatin-analog therapy, as chemotherapy is of limited utility (221). External beam radiation is not beneficial for local control, although it is utilized for palliation of brain and bone metastases and spinal cord compression (246).

Chapter 27:

As indicated above, patients with metastatic carcinoid tumors may develop the carcinoid syndrome (209,210,215, 221,222,241). In fact, the systemic manifestations associated with this syndrome may be the first indication that a carcinoid tumor is present. Characterized by episodic cutaneous flusing, asthma, intestinal hyperperistalsis, and diarrhea, as well as a variety of hemodynamic alterations that may result in vasomotor collapse, this constellation of symptoms almost always indicates the presence of metastases, particularly those involving massive liver implants. Occasionally a patient with this syndrome may also exhibit right-sided heart failure secondary to endocardial and valvular fibrosis, presumably caused by the abnormally high vasoactive amines in the blood entering the right heart. Elucidation of the biochemical mediators responsible for the carcinoid syndrome has still not been completely resolved, but an abnormality in serotonin metabolism has been clearly implicated. Normally, about 1% of dietary tryptophan, the immediate precursor of serotonin, is metabolized to produce this substance. In the presence of a functioning carcinoid tumor, 50% or more of tryptophan may be diverted into the serotonin pathway. Under usual physiologic conditions, any excess in serotonin production is metabolized in the liver to 5-hydroxy-indoleacetic acid (5-HIAA) and excreted in the urine. In patients with metastatic implants of carcinoid tumor, this normal metabolism is altered with substantial amounts of serotonin itself being released into the systemic circulation. It is as a result of this circumstance and perhaps the release of other unidentified vasoactive substances that give rise to the clinical manifestations of the carcinoid syndrome. Notwithstanding the deranged serotonin metabolism in the presence of metastatic implants, available liver parenchyma still attempts to convert as much serotonin as possible to 5-HIAA. Consequently, urinary levels of this substance are greatly elevated and provide a chemical marker for the diagnosis of a functioning carcinoid tumor. Treatment of the carcinoid syndrome can be extremely challenging. Because diffuse hepatic metastases are generally present, hepatic resection is usually not possible. Radiotherapy has no proven benefit , and chemotherapy elicits positive responses in no more than a third of patients with no associated survival benefit. Thus, symptom control of the syndrome’s clinical manifestations is often the most that can be offered these patients and under the best circumstances this is far from optimal. While various pharmacologic agents have been tried, octreotide (a synthetic somatostatin anaologue) is the best agent currently available for palliation of the symptoms, especially flushing and diarrhea. This drug is administered subcutaneously, but requires repeated injections because its effects are only sustained for six to eight hours. While a third of patients receiving this drug may gain effective palliation for several years, the response in most is only marginal.

Colorectal Neoplasms Incidence Colorectal cancer is a common disease, and is the third most common site of both new cancer cases and cancer deaths in men and women in the United States (247). In 2004, the estimated number of new cases of colorectal cancer is approximately 147,000, with approximately 57,000 deaths predicted from this disease. The average lifetime risk of developing colorectal cancer is approximately 6% in North America, with over 90% of the cases occurring in patients

Neoplastic Disorders of the Gastrointestinal Tract

571

Table 5 Familial Risk and Colon Cancer Familial setting General U.S. population One first-degree relativea with colon cancer Two first-degree relativesa with colon cancer First-degree relativea with colon cancer diagnosed 50 yr One second- or third-degree relativeb,c with colon cancer Two second- or third-degree relativeb,c with colon cancer One first-degree relativea with adenomatous polyp

Approximate lifetime risk of colon cancer 6% Two- to three-fold increase Three- to four-fold increase Three- to four-fold increase 1.5-fold increase Two- to three-fold increase Two-fold increase

a

First-degree relatives include parents, siblings, and children. Second-degree relatives include grandparents, aunts, and uncles. c Third-degree relatives include great-grandparents and cousins. Source: From Ref. 250. b

over the age of 50 (248). Over the last decade, the death rate from colorectal cancer has decreased, possibly due to heightened awareness and the increased emphasis on screening and surveillance. This disease is eminently treatable if identified at an early stage when polyps can be simply removed through the colonoscope, or an early cancer is detected while it is still contained within the colonic wall. A number of advances have been made in our understanding of the pathogenesis and treatment of colorectal cancers. It is now generally considered that the majority of colorectal cancers start as a polyp and then, over a time span of years, a small percentage of these polyps proceed to cancer (249). The majority of colorectal cancers are sporadic in nature, affecting an older population, and usually presenting as an isolated colon or rectal lesion. Other colorectal cancers may be hereditary in nature or characterized by a positive family history (Table 5) (25). Younger age at onset and the presence of other tumors, not only in the intestine but in other organs as well, may also be contributory. The genetic etiology for these hereditary forms of colorectal cancer has been delineated, and this information has provided a critical understanding of the molecular changes associated with developing colorectal cancer (Table 6).

Polyps of the Colon Polyps of the colon and rectum represent a protrusion into the lumen of the bowel above the surface of the intestinal epithelium. Polyps are classified generally by their gross appearance (Fig. 22) and can be either pedunculated (on a stalk) or sessile (flat). They are further classified by their histologic appearance as a tubular adenoma, villous adenoma (with long finger-like projections), or tubulovillous adenoma (a combination of tubular and villous components) (249). In addition to the various adenomas, polyps can also be classified as nonadenomatous and include hyperplastic, inflammatory, lymphoid, and juvenile polyps. Complications of polyps include bleeding, partial bowel obstruction, or, more likely, their propensity to develop colorectal cancer. Nonadenomatous Polyps Nonadenomatous polyps account for approximately 90% of all polyps detected in the colon and rectum (254). As noted

medwedi.ru

Malignancy risk

Other clinical features

GI features Hundreds to thousands of colorectal polyps; duodenal adenomas and gastric polyps, usually fundic gland Osteomas, desmoid tumors, epidermoid cysts, and congenital hypertrophy of retinal epithelium

Turcot’s syndrome

Hereditary adenomatous polyposis syndromes Familial adenomatous polyposis/Gardner’s syndrome Cowden’s disease

Familial juvenile polyposis

Hereditary hamartomatous polyposis syndromes Peutz–Jeghers syndrome

Ruvalcaba—MyhreSmith syndrome (Bannayan–Zonana syndrome)

Colorectal polyps, which Polyps most commonly Juvenile polyps mostly Small number of Hamartomatous GI may be few or of colon and stomach in the colon but polyps throughout polyps, usually resemble classic throughout GI tract GI tract but most lipomas, familial adenomatous defined by 10 common in small hemangiomas, or polyposis juvenile polyps intestine lymphangiomas Muir-Torre variant: Brain tumors, including Mucocutaneous lesions, Congenital Pigmented lesions Dysmorphic facial sebaceous cerebellar thyroid adenomas and abnormalities in at of skin; benign features, adenomas, medulloblastoma and goiter, fibroadenomas least 20%, including and malignant macrocephaly, keratoacanthomas, glioblastomas and fibrocystic disease malrotation, genital tumors seizures, sebaceous of the breast, uterine hydrocephalus, intellectual epitheliomas, and leiomyomas, and cardiac lesions, impairment, and basal cell macrocephaly Meckel’s pigmented epitheliomas diverticulum, and macules of shaft mesenteric and glans of penis lymphangioma Colorectal carcinoma 10% risk of thyroid 9–25% risk of " risk of GI Malignant GI tumors 70–80% lifetime risk Colorectal cancer risk and brain tumors cancer and up to 50% colorectal cancer; malignancy and identified, but of colorectal cancer; approaches 100%; risk of adenocarcinoma " risk of gastric, pancreatic cancer lifetime risk for 30–60% lifetime " risk of periampullary malignancy, thyroid of breast in affected duodenal, and and adenoma malignancy risk of endometrial carcinoma, central women pancreatic cancer malignum of cervix; unknown cancer; " risk of nervous system tumors, unknown risk of ovarian cancer, and hepatoblastoma breast cancer gastric carcinoma, transitional cell carcinoma of the ureters and renal pelvis, small bowel cancer, and sebaceous carcinomas

Small number of colorectal polyps

HNPCC

Table 6 Hereditary Cancer Syndromes

572 Part Two: The Alimentary Tract—Other Conditions

Genetic basis

Screening recommendations

Clinical testing of APC gene available

APC (chromosome 5q)

AD

Clinical testing of Research testing of APC and MLH1 genes PTEN gene available available

Families being Research testing of Research testing of collected for research STK11 gene available PTEN gene studies only available

Abbreviations: GI, gastrointestinal; APC, adenomatous polyposis coli; STK, serine/threonine kinase-11; PTEN, phosphatase and tensin; HNPCC, hereditary nonployposis colorectal cancer.

Genetic testing

medwedi.ru

PMS1 (chromosome 2q) PMS2 (chromosome 7q) Clinical testing of MLH1 and MSH2 genes available

MSH2 (chromosome 2p)

MLH (chromosome 3p)

AD

Annual physical Screening by age Upper GI endosNo known published exam with special 12 yrs if symptoms copy, small bowel recommendations attention to thyroid have not yet arisen radiography, and mammography at age Colonoscopy with colonoscopy every 30 or 5 yrs before multiple random 2 yrs; pancreatic earliest breast cancer biopsies every ultrasound and case in the family several years (expert hemoglobin levels Routine colon cancer opinion only) annually; gynecologic surveillance (expert exam, cervical smear, opinion only) and pelvic ultrasound annually; clinical breast exam and mammography at age 25 yrs; clinical testicular exam and testicular ultrasound in males with feminizing features (expert opinion only) AD AD AD inheritance in some AD AD families subset of families with mutation in SMAD4 (DRC4) (chromosome 10q) APC mutations identified STK11 (chromosome PTEN (chromosome PTEN (chromosome predominantly in 19p) 10q) 10q) in some families with cerebellar families medulloblastoma MLH1, PMS2 mutations identified in families with predominance of glioblastomas

Colonoscopy at age Flexible proctosigmoid- Same as for familial 20–25 yrs; repeat oscopy at age adenomatous every 1–3 yrs; 10–12 yrs; repeat every polyposis also transvaginal 1–2 yrs until age 35; consider imaging ultrasound or after age 35, of the brain endometrial aspirate repeat every 3 yrs at age 20–25 yrs; Upper GI endoscopy repeat annually every 1–3 yrs starting (expert opinion only) when polyps first identified

Chapter 27: Neoplastic Disorders of the Gastrointestinal Tract

573

574

Part Two: The Alimentary Tract—Other Conditions

above, these polyps can be further characterized into hyperplastic, inflammatory, lymphoid, and juvenile polyps and are considered to be non-neoplastic. The majority of these non-neoplastic polyps are hyperplastic polyps that are formed due to abnormal maturation of the epithelial cells (254). These hyperplastic polyps are not malignant and are not associated with any measurable increase in malignant potential. Inflammatory polyps arise from chronic inflammation associated with UC or Crohn’s disease (255). These polyps are associated with increased malignant potential, given the chronic inflammatory state. Lymphoid polyps simply represent increased aggregates of lymphoid tissue and are also nonmalignant (254). Juvenile polyps are usually termed hamartomatous and are caused by abnormal development of the lamina propria. Juvenile polyps may manifest as bleeding or obstruction in young children (256). Adenomatous Polyps Adenomatous polyps (adenomas) represent neoplastic polyps with a malignant potential (254). These polyps are more common in the distal colon and rectum and can be either pedunculated or sessile (Fig. 22). As noted above, adenomas can be classified as tubular adenomas, villous adenomas, or tubulovillous adenomas (254). Tubular adenomas are the most common and account for 70% to 85% of all adenomas. These polyps are often smaller and pedunculated and generally have a lower malignant potential than the villous adenomas, which are usually larger, sessile, and can contain

areas of dysplasia or cancer. The malignant potential of tubulovillous adenomas is less than true villous components but more so than pure tubular adenomas. Patients with polyps may present with rectal bleeding (either hematochezia or occult bleeding), obstruction, or as incidental findings by surveillance, colonoscopy, or barium studies. Less than 5% of all adenomas will develop into cancers (254). Factors that are predictive of cancer formation include the size of the polyp and the grade of dysplasia. High-grade dysplasia is associated with an approximately 27% rate of eventual cancer transformation. Polyps less than 1 cm in size have a risk of cancer approximating 1% to 3%, polyps between 1 and 2 cm have a 10% risk of cancer, and polyps greater than 2 cm have approximately a 40% risk of finding in situ or invasive cancer (254). Colonoscopy remains the most accurate method for diagnosing colorectal polyps. Not only is this technique associated with higher accuracy than barium enema, but also with an added advantage of the ability to perform a biopsy or to remove the polyp entirely. A general consensus is that patients over the age of 50 should have a screening colonoscopy performed. Destruction or removal of the polyp through the colonoscope is the major goal of treatment. With pedunculated adenomas, this can be accomplished usually by snare polypectomy, and for sessile polyps, piecemeal resection may be required. For localized cancers that have not spread beyond the muscularis mucosa and do not involve vascular

Figure 22 (A) Anatomic landmarks of pedunculated and sessile adenomas. (B) Pedunculated adenomatous polyp, microscopic appearance at low-power magnification. The head of the polyps is lined with dysplastic epithelium, whereas the stalk is lined with nondysplastic epithelium. (C) Sessile adenomatous polyp, microscopic appearance at low-power magnification. This small tubular adenoma is called sessile because of its broad base, the preservation of the muscularis mucosa underneath, and the absence of a stalk. Source: From Refs. 252, 253. Courtesy of M. Markowitz Haber, MD, Hahnemann University Hospital.

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

575

or lymphatic invasion, polypectomy can be definitive therapy if the margins are free of cancer cells and the polyp is completely excised. If invasive cancer is noted in the stalk, then formal colonic resection is indicated. Patients found to have adenomatous polyps are at increased risk for subsequent development of adenomas or adenocarcinomas (254). Therefore, in general, follow-up colonoscopy is recommended in three years. Earlier colonoscopies may be recommended for patients with multiple polyps or large sessile adenomas that have been removed. Patients who have had less than three small (less than 1 cm) tubular adenomas removed are at no increased risk for malignancy and can be followed with colonoscopy in five years.

Hereditary Cancer Syndromes The inherited forms of colorectal cancer account for approximately 6% of all cases (257). The analysis of genetic abnormalities that can occur with these inherited syndromes has greatly increased our understanding of the molecular defects leading to colorectal cancers (Table 7). The inherited syndromes will be briefly described, emphasizing the genetic defects as well as treatment. Familial Adenomatous Polyposis FAP is a syndrome with well-defined clinical, pathological, and epidemiological characteristics. FAP is inherited in an autosomal-dominant fashion and marked by multiple (greater than 100) colorectal adenomas (Fig. 23) (27). Patients have a 100% chance of developing a cancer by an average age of 39, if the colon is not removed. The penetrance is between 80% and 100%. The gene attributed to FAP is the APC tumor suppressor gene, which is localized to the long arm of chromosome 5 (5q21) (26,27). The APC gene is integrally involved in cellular adhesion, communication, and microtubular assembly (the genetic aspects of APC have been previously Table 7 Gene Mutations That Cause Colon Cancer Mutation type Germline

Somatic

Genetic polymorphism

Genes involved APC MMR Oncogenes myc ras src erbB2 Tumor suppressor genes TP53 DCC APC MMR genes hMSH2 hMLH1 hPMS1 hPMS2 hMSH6 hMSH3 APC

Type of disease caused Familial adenomatous polyposis HNPCC (Lynch syndrome) Sporadic disease

Familial colon cancer in Ashkenazi Jewish persons

Abbreviations: APC, adenomatous polyposis coli; DCC, deleted in colorectal carcinoma; HNPCC, hereditary nonpolyposis colorectal cancer; MMR, mismatch repair. Source: From Ref. 252.

Figure 23 The macroscopic appearance of familial adenomatous polyposis. Source: From Ref. 252.

discussed). Patients with FAP inherit one mutant copy of APC and, when a loss of function mutation develops in the other APC gene, polyps are formed. Variable phenotypes exist based upon location of the APC mutation. Adenomatous polyps usually appear in the second decade of life in patients with FAP. These polyps are distributed evenly throughout the colon with a slight predominance in the more distal segments. Gastric and duodenal polyps can occur in a significant number of FAP patients and, therefore, upper GI endoscopy is required in these patients to assess for polyp formation in the upper GI tract. The primary treatment for patients with FAP is total proctocolectomy with either a permanent ileostomy or ileoanal pouch anastomosis (258). Most of the gastric polyps in these patients represent fundic gland hyperplasia rather than adenomatous polyps and have limited malignant potential. In contrast, duodenal polyps are adenomatous and require removal. In some patients with periampullary lesions, this may require a pancreatoduodenectomy (Whipple procedure). It has been proposed that genetic testing may assist in the decision between a total proctocolectomy and an abdominal colectomy with ileorectal anastomosis. Patients with mutations of the APC gene occurring proximal to codon 1250 have a decreased number of polyps and a somewhat decreased risk of developing rectal cancer. Randomized trials suggest that treatment with selective COX-2 inhibitors may decrease the number and size of polyps in patients with FAP (111). However, at the current time, patients with FAP should undergo a total proctocolectomy, and if this is not performed due to patient preference or site of APC mutation, then close follow-up surveillance is required of the remaining rectal mucosa because this is at increased risk for developing cancer. Further trials are required to better understand the role of COX-2 inhibitors as well as more limited resections in this disease process. Gardner’s Syndrome Gardner’s syndrome occurs also as a result of an APC mutation and, similar to FAP, is associated with colorectal polyposis. However, in deference, patients with Gardner’s syndrome exhibit extraintestinal manifestations including

medwedi.ru

576

Part Two: The Alimentary Tract—Other Conditions

osteomas, soft tissue tumors (e.g., lipomas, sebaceus cysts, and fibrosarcomas), desmoid tumors, and mesenteric fibrosis (259). These differences are thought to be due to a different location of the APC mutation as well as the presence of modifying genes and environmental factors. The malignant potential in patients with Gardner’s syndrome is similar to that of patients with FAP and, therefore, proctocolectomy is the preferred treatment in these patients as well. Turcot’s Syndrome This syndrome is likewise associated with APC gene mutation in approximately two-thirds of the cases of patients with Turcot’s syndrome, and the remaining cases are due to mutations in the DNA mismatch repair genes. This syndrome is associated with colorectal polyposis as well as central nervous system malignancies such as medulloblastomas, glioblastomas, or ependymomas (260). Hereditary Nonpolyposis Colorectal Cancer HNPCC or Lynch syndrome was first described by Warthin in 1913 when he described a ‘‘cancer family syndrome’’ where family members acquired colorectal or endometrial cancers (261). HNPCC is the most common hereditary colorectal cancer and accounts for approximately 5% of all cases of colorectal cancer (261). HNPCC is inherited in an autosomal-dominant fashion and is highly penetrant. In 1991, the International Collaborative Group on HNPCC formulated three minimum criteria for diagnosis: (i) at least three relatives (one of which is a first-degree relative) should have histologically verified colorectal cancer, (ii) at least two successive generations should be affected, and (iii) one of the relatives must be diagnosed before the age of 50 (261). The underlying mechanism for HNPCC tumor formation has been extensively studied, and current theories implicate a defective DNA mismatch repair system producing MSI in HNPCC tumors (262). DNA mismatch repair systems are protein complexes designed to correct deletions or abnormalities that occur along the DNA genome as a result of physical damage, misincorporation of nucleotides during DNA replication, or recombination. Colorectal cancers in patients with HNPCC have a high frequency of microsatellite loci as compared with sporadic tumors (57% vs. 3%, respectively) (262). Tumors with high numbers of MSI sequences have a 100-fold increase in their mutation rate compared to low numbers of sequences, which could explain the acceleration of the adenoma-to-carcinoma sequence resulting in the early appearance of tumors in patients with HNPCC. Tumors with high numbers of MSI are defined as RERþ tumors. Recent studies have linked RERþ phenotype tumors to a defective mismatch repair system. Mutation of mismatch repair genes includes HMSH-2, HMSH-3, HMSH-6, HMLH-1, HPMS-1, and HPMS-2 (261). HNPCC patients have an earlier onset of colorectal cancer (usually in the mid-1940s) compared with sporadic cancers but the prognosis is better. HNPCC patients have an increased survival compared to sporadic cancers due to the tendency to form diploid neoplasms, which confers a protective measure through an unknown mechanism (263). Although more than one adenoma may be present, the diffuse polyposis noted with FAP is not found in patients with HNPCC. The adenomatous polyps associated with HNPCC are usually located predominately in the more proximal colon (cecum and ascending colon). It is important to note that patients with HNPCC are also at higher risk for developing other cancers including cancers of the ovary, ureter,

pancreas, stomach, and endometrium. Individuals in families with HNPCC should undergo a colonoscopy every two years from the age of 21 to 40 years and every year after the age of 40 because their risk is quite high, and genetic testing is not as useful as in patients with FAP. It is also important to note that women in HNPCC families should have pelvic examinations every one to three years beginning at the age of 18. Annual pelvic examination as well as transvaginal ultrasonography and endometrial biopsy have been recommended in women beginning at age 25. Peutz–Jeghers Syndrome This syndrome is associated with intestinal hamartomatous polyps in combination with mucocutaneous pigmentation involving characteristically the lips, buccal mucosa, and skin (264). This syndrome is inherited in an autosomal-dominant fashion with high penetrance and is usually diagnosed in patients in their mid-20s. Symptoms usually include recurrent bouts of small bowel intussusception, obstruction, and GI bleeding. Once thought to be entirely benign, these hamartomatous polyps, in rare instances, can become malignant. In fact, adenomatous changes have been reported in 3% to 6% of hamartomas (264). Germline defects in the tumor suppressor serine/ threonine kinase-11 gene are implicated in the Peutz– Jeghers syndrome (59). The syndrome is associated with an increase (2–10%) risk of cancer of the intestinal tract, with cancers reported throughout the intestinal tract from the stomach to the rectum. There is also an increased risk of extraintestinal malignancies including cancer of the breast, ovary, cervix, fallopian tubes, thyroid, lung, gallbladder, bile ducts, pancreas, and testes (59). Juvenile Polyposis Juvenile polyposis is a rare syndrome characterized by 10 or more non-neoplastic hamartomatous polyps composed of cystic dilatations of glandular structures within the fibroblastic stroma of the lamina propria throughout the GI tract (256). This syndrome is inherited in an autosomal-dominant fashion. Mutations in the SMAD4, PTEN, or VMP-1 genes are associated with juvenile polyposis (265). Patients can present with rectal bleeding, abdominal pain, or intussusception. Extraintestinal manifestations include pulmonary arteriovenous malformations. The risk of malignancy is reported to be approximately 10% (256). Cowden’s Syndrome This syndrome is a rare autosomal-dominant disease associated with multiple hamartomatous polyps of the skin and mucus membranes (266). There is a high rate of associated malignancy, particularly in the thyroid and breast, and the causative genetic lesion appears to be a mutation in the PTEN tumor suppressor gene.

Adenocarcinoma of the Colon and Rectum Epidemiology Adenocarcinomas are the most common histologic type of malignancies occurring in the large intestine and account for approximately 98% of all malignancies (247). These cancers are thought to arise predominantly from polyps and then progress from severe dysplasia to invasive cancer over a period of years. There is a distinct geographic distribution, with highest rates of colorectal cancer found in the industrialized countries such as the United States, Canada, New Zealand, and countries of Northwestern Europe. This

Chapter 27:

geographic distribution is thought to be due primarily to environmental factors such as diet. Similar incidence of adenocarcinoma has been noted in both men and women in the colon; however, rectal cancer appears to be somewhat more prevalent in men. Sporadic colorectal cancers affect an older population, with peak incidence from 60 to 79 years of age. As noted above, environmental influences can play a role in the development of colorectal adenocarcinoma. The Western style diet consisting of red meat, with high dietary fat and low fiber content, has been proposed as a possible environmental influence. In addition, colorectal adenomas have been associated with tobacco use; increased consumption of ethanol and inherited predisposition have already been noted to increase the risk of adenocarcinoma. Individuals who have a first-degree relative with colorectal cancer have an approximately two- to threefold increase in risk for malignancy, and this risk rises to five- or sixfold if two firstdegree relatives are involved. Another component that increases the risk of colorectal cancer is IBD. Adenocarcinoma of the colon and rectum is 10 to 20 times more common in patients with IBD involving the colon (255). The two most important predictors of malignancy include the duration of the disease and the extent of colonic involvement. The identification of dysplasia in the setting of IBD is also a useful indicator of early cancer. Pathobiology Most of the colorectal cancers are adenocarcinomas exhibiting differing degrees of glandular differentiation. The gross pathologic findings are different depending upon the location in the colon and rectum. For example, right-sided lesions tend to grow to a larger size and manifest as polypoid, exophytic masses that oftentimes bleed. In contrast, carcinomas of the distal colon tend to lead to obstruction. Colorectal cancers tend to spread by direct extension and can invade surrounding organs. In addition, cancers spread through the lymphatic system as well as to systemic organs (usually liver). Colorectal cancers can also metastasize to the lung, bone marrow, and brain. A well-described model for the development of colorectal cancer, the ‘‘adenoma-tocarcinoma’’ multistep process (Fig. 3), was originally described by Fearon and Vogelstein (267,268). This sequence of tumor progression involves mutations of various proto-oncogenes and tumor suppressor genes leading eventually to carcinoma. This model is important because it demonstrates that the development of cancer cannot be simply ascribed to one particular mutation; multiple mutations are required for the progression to cancer. Common genetic abnormalities include mutation of the APC tumor suppressor gene, which leads to the accumulation of b-catenin within the nucleus leading to regulation of gene expression that promotes malignancy. Other abnormalities include mutation of the Ras proto-oncogene and loss of function mutations in various other tumor suppressor genes such as p53 or PTEN (3,269). Clinical Manifestations Symptoms of colorectal cancer are oftentimes nonspecific, and these cancers (particularly right-sided lesions) may remain clinically silent for a number of years. The symptoms that manifest are usually characteristic to the segment of colon or rectum that is involved. Due to the more capacious nature of the proximal colon, cancers can grow to a larger size and manifest as rectal bleeding, usually occult, with patients presenting with iron deficiency anemia. In the descending and sigmoid colon, smaller cancers are identified

577

Neoplastic Disorders of the Gastrointestinal Tract

due to the smaller lumen and manifest with obstructive symptoms such as abdominal pain and distention. Diagnosis Methods for diagnosis include physical examination, which may identify an abdominal mass in a small percentage of cases. In addition, digital rectal examination may identify a rectal cancer and is useful for the detection of frank or occult blood. Diagnosis may be aided by either barium Table 8 Staging Classification of Colorectal Cancera TNM System Primary tumor Tx T0 Tis T1 T2 T3/T4 Serosa present T3

Primary tumor cannot be assessed No evidence of tumor in resected specimen (prior polypectomy or fulguration) Carcinoma in situ Invades into submucosa Invades into muscularis propria Depends on whether serosa is present

Invades through muscularis propria into subserosa Invades serosa (but not through) Invades pericolic fat within the leaves of the mesentery T4 Invades through serosa into free peritoneal cavity, or through serosa into a continguous organ No serosa (distal two-thirds of rectum, posterior left or right colon) T3 Invades through muscularis propria T4 Invades other organs (vagina, prostate, ureter, kidney) Regional lymph node involvement NX Nodes cannot be assessed (e.g., local excision only) N0 No regional node metastases N1 1–3 positive nodes N2 4 or more positive nodes N3 Central nodes positive Distant metastasis MX Presence of distant metastases cannot be assessed M0 No distant metastases M1 Distant metastases present Dukes’ Staging System Correlated with TNM Dukes A T1, N0, M0 (stage I) T2, N0, MO (stage I) Dukes B T3, N0, M0 (stage II) T4, N0, M0 (stage II) Dukes C T (any), N1, M0; T (any), N2, M0 (stage III) Dukes D T (any), N (any), M1 (stage IV) Modified Astler-Coller (MAC) System Correlated with TNM MAC A T1, N0, M0 (stage I) MAC B1 T2, N0, M0 (stage I) MAC B2 T3, N0, M0 (stage II) MAC B3 T4, N0, M0 (stage II) MAC C1 T2, N1, M0; T2, N2, M0 (stage MAC C2 T3, N1, M0; T3, N2, M0 (stage T4, N1, M0; T4, N2, M0 (stage MAC C3 T4, N1, M0; T4, N2, M0 (stage a

III) III) III) III)

In all pathologic staging system, particularly those applied to rectal cancer, the abbreviation m and g may be used; m denotes microscopic transmural penetration; g or m þ g denotes transmural penetration visible on gross inspection and confirmed microscopically. Source: From Ref. 271.

medwedi.ru

578

Part Two: The Alimentary Tract—Other Conditions

radiographic studies or colonoscopy. Colonoscopy is the procedure of choice, given the fact that it is more accurate than barium studies and allows for simultaneous biopsy. Once a cancer of the colorectum is identified, procedures that may aid in tumor staging include CT scan of the abdomen, which will help to determine the extent of tumor spread. Chest x-ray should be performed to assess for lung metastasis. Patients with rectal cancer require EUS to determine the depth of invasion, which can aid in determining the most appropriate therapy (270). Tumor Staging Colorectal cancers are staged using the older Dukes’ method and, more preferably, the universal tumor node metastatic (TNM) classification system (Table 8) (272). Staging is based

upon tumor invasion through the wall of the colon, lymph node involvement, and distant metastases. Treatment Surgery, which includes total resection of the cancer along with the associated lymphatic drainage, is the mainstay of treatment and the only option that offers a reasonable chance of cure or long-term survival (273). The extent of resection depends on the location of the cancer (Fig. 24). Resection may be achieved by standard open techniques or laparoscopic resection. A recent multi-institutional analysis demonstrated that comparable oncologic results could be achieved with either a laparoscopic resection or open techniques (275). Cancers in the rectum may be treated by sphincter-saving procedures if there is enough distance

Figure 24 Operative procedures used for resection of colon adenocarcinoma based on location of the lesion. Source: From Ref. 274.

Chapter 27:

Neoplastic Disorders of the Gastrointestinal Tract

579

Table 9 Screening Recommendations for Colorectal Cancer and Polyps Risk category Average risk

Family history

HNPCC

FAP

UC

Screening method Choose one of the following: 1. Fecal occult blood testing annually 2. Flexible sigmoidoscopy every 5 yrs 3. Fecal occult blood testing annually and flexible sigmoidoscopy every 5 yrsa 4. Double-contrast barium enema every 5–10 yrsb 5. Colonoscopy every 10 yrsc Choose one of the following: 1. Colonoscopy every 10 yrs 2. Double-contrast barium enema every 10 yrs Colonoscopy every 1–3 yrs Genetic counseling Consider genetic testing Flexible sigmoidoscopy or colonoscopy every 1 or 2 yrs Genetic counseling Consider genetic testing Colonoscopy with biopsies for dysplasia every 1–2 yrs

Age to begin screening 50 yrs

40 yrs or 10 yrs before cancer was diagnosed in the youngest affected family member, whichever is earlier in years 21 yrs

Puberty

7–8 yrs after the diagnosis of pancolitis 12–15 yrs after the diagnosis of sides colitis

a

Some experts recommend combining annual fecal occult blood testing with flexible sigmoidoscopy every five years. Rigid proctoscopy is recommended as an adjunctive examination to allow adequate visualization of the distal rectum. Furthermore, flexible sigmoidoscopy may be necessary to evaluate a tortuous or spastic sigmoid colon. c Most current recommendations favor colonoscopy to flexible sigmoidoscopy—see Ref. 278. Abbreviations: FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; UC, ulcerative colitis. Source: From Ref. 279. b

(at least 2 cm) from the distal margin. For low-lying rectal cancers close to the dentate line, an abdominal perineal resection and permanent colostomy may be required. Adjuvant chemotherapy utilizing usually 5-FU and leucovorin can improve a disease-free survival in patients with stage III disease. The addition of either irinotecan or oxaliplatin to the 5-FU/leucovorin regimen can improve response rates in patients with metastatic disease (276). Patients with rectal cancer may benefit from radiation therapy, either prior to or after resection. Radiation therapy is useful in reducing tumor size and decreasing the risk of local recurrence (273). Prognosis The overall five-year survival rate for patients with colorectal cancer is dependent upon stage of disease at the time of diagnosis. Patients with stage I disease, which is limited to the mucosa, have a greater than 90% five-year survival rate (277). Metastatic spread to the regional lymph nodes is associated with a five-year survival rate of 35% to 65% and with distant metastasis noted, the five-year survival rate is less than 5% (273,277). After a curative resection, surveillance colonoscopy should be performed at three years and, if negative, at five-year intervals. Additional follow-up measures include semiannual physical examinations and yearly blood chemistries. Although controversial, serum CEA levels that are rising suggest recurrent colorectal cancer. There is no clear consensus on the use of other radiographic studies such as chest x-rays or CT scans.

Colorectal Cancer Screening and Chemoprevention The prevention of colorectal cancer is eminently achievable if screening procedures are followed. Current screening recommendations for colorectal cancer are shown in Table 9. In addition to screening, there have been different recommendations for chemoprevention based upon experimental data. These findings are still relatively new and controversial

and will require future trials. Several studies have demonstrated a potential benefit of calcium and folic acid in lowering the risk of colorectal cancer (280,281). Randomized trials assessing the chronic intake of aspirin or other nonsteroidal anti-inflammatory drugs have been shown to be associated with a reduction in the relative risk of developing colorectal cancer. This effect was thought to be secondary to the inhibition of the COX-2 enzyme. However, recent studies evaluating the efficacy of selected COX-2 inhibitors have shown potentially lethal complications related to increased risk of myocardial infarctions or strokes (282). Further studies are needed to establish the potential role of chemoprevention in colorectal cancer prevention. For now, the most effective method of preventing colorectal cancer is through screening procedures that involve assessment of fecal occult blood, as well as some form of colonic mucosal visualization such as colonoscopy or sigmoidoscopy.

SUMMARY Neoplastic disorders of the GI tract are a common problem throughout the world, and their management continues to comprise significant challenges in the practice of digestive surgery, especially when malignancy is present. Until recently, treatment of these conditions has been primarily surgical, and a successful outcome has been dependent almost exclusively on early diagnosis and the ability to completely resect these lesions before malignant degeneration occurs, or if the latter circumstance exists before metastatic disease has resulted. With the rapid advances in molecular biology and genetics that have evolved over the past decade, we now have a much better understanding of the molecular mechanisms responsible for neoplastic development and how a benign lesion may ultimately become a malignancy. This chapter has highlighted the important advances that have occurred in our understanding of GI tract neoplasia and how these advances are already being

medwedi.ru

580

Part Two: The Alimentary Tract—Other Conditions

employed to effectively manage GI malignancies that previously could only be treated surgically and often in a palliative fashion. While surgery continues to be the mainstay in managing GI neoplasia whether benign or malignant, it is not beyond the realm of possibility that many GI tumors which can only be treated surgically now will be effectively managed without this modality in the years to come as the mystery of the cell and why cancer occurs continues to unfold.

REFERENCES 1. Kim M, Evers BM. Oncogenes and tumor suppressor genes in GI cancer. In: Evers BM, ed. Molecular Mechanisms in Gastrointestinal Cancer. Austin: Landes Company, 1999:95–109. 2. Thomas RP, Evers BM. The molecular biology of gastrointestinal neoplasia. New Surgery 2001; 1:10–16. 3. Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 1987; 327: 293–297. 4. Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 1987; 327:298–303. 5. Howe JR, Guillem JG. The genetics of colorectal cancer. Surg Clin North Am 1997; 77:175–195. 6. Waldmann V, Rabes HM. What’s new in ras genes? Physiological role of ras genes in signal transduction and significance of ras gene activation in tumorigenesis. Pathol Res Pract 1996; 192:883–891. 7. Laurent-Puig P, Olschwang S, Delattre O, et al. Survival and acquired genetic alterations in colorectal cancer. Gastroenterology 1992; 102:1136–1141. 8. Kern SE, Fearon ER, Tersmette KW, et al. Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected]. JAMA 1989; 261:3099–3103. 9. Senagore AJ, Biener JT. A newly identified pattern of K-ras mutations at codons 12 and 13 is associated with long-term survival in colorectal cancer. Surgery 1997; 122:765–770. 10. Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 1993; 260:85–88. 11. Wu MS, Shun CT, Wang HP, et al. Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection. Gastroenterology 1997; 112:1457–1465. 12. Mizutani T, Onda M, Tokunaga A, Yamanaka N, Sugisaki Y. Relationship of C-erbB-2 protein expression and gene amplification to invasion and metastasis in human gastric cancer. Cancer 1993; 72:2083–2088. 13. Shun CT, Wu MS, Lin JT, et al. Relationship of p53 and c-erbB2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Hepatogastroenterology 1997; 44:604–609. 14. Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E. Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem Biophys Res Commun 1992; 189:227–232. 15. Kuniyasu H, Yasui W, Yokozaki H, Kitadai Y, Tahara E. Aberrant expression of c-met mRNA in human gastric carcinomas. Int J Cancer 1993; 55:72–75. 16. Matsumoto-Taniura N, Matsumoto K, Nakamura T. Prostaglandin production in mouse mammary tumour cells confers invasive growth potential by inducing hepatocyte growth factor in stromal fibroblasts. Br J Cancer 1999; 81: 194–202. 17. Nakamura T, Matsumoto K, Kiritoshi A, Tano Y, Nakamura T. Induction of hepatocyte growth factor in fibroblasts by tumorderived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res 1997; 57:3305–3313. 18. von Schweinitz D, Faundez A, Teichmann B, et al. Hepatocyte growth-factor-scatter factor can stimulate post-operative

19. 20.

21.

22.

23.

24.

25.

26.

27. 28. 29. 30. 31.

32.

33. 34. 35.

36.

37.

38.

39. 40.

41.

tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer 2000; 85:151–159. Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14: 1837–1851. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 1998; 58:1130–1134. Iwao K, Nakamori S, Kameyama M, et al. Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res 1998; 58:1021–1026. Brennan K, Gonzalez-Sancho JM, Castelo-Soccio LA, Howe LR, Brown AM. Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize beta-catenin independently of Frizzled proteins. Oncogene 2004; 23:4873–4884. Jackson MW, Agarwal MK, Agarwal ML, et al. Limited role of N-terminal phosphoserine residues in the activation of transcription by p53. Oncogene 2004; 23:4477–4487. Cong F, Zhang J, Pao W, Zhou P, Varmus H. A protein knockdown strategy to study the function of beta-catenin in tumorigenesis. BMC Mol Biol 2003; 4:10. Aihara R, Mochiki E, Nakabayashi T, Akazawa K, Asao T, Kuwano H. Clinical significance of mucin phenotype, betacatenin and matrix metalloproteinase 7 in early undifferentiated gastric carcinoma. Br J Surg 2004. Burt RW, Groden J. The genetic and molecular diagnosis of adenomatous polyposis coli. Gastroenterology 1993; 104:1211–1214. Cunningham C, Dunlop MG. Molecular genetic basis of colorectal cancer susceptibility. Br J Surg 1996; 83:321–329. Mimori-Kiyosue Y, Tsukita S. Where is APC going? J Cell Biol 2001; 154:1105–1109. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87:159–170. Bienz M. APC: the plot thickens. Curr Opin Genet Dev 1999; 9:595–603. Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997; 275:1787–1790. Miyoshi Y, Nagase H, Ando H, et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1992; 1:229–233. Morris DJ. Primary human herpesvirus 6 infection in an adult. N Engl J Med 1993; 329:1817–1819. Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature 1991; 351:453–456. Goodman AA. Polypoid diseases. In: Corman ML, ed. Colon and Rectal Surgery. 4th ed. Philadelphia: Lippincott-Raven, 1998:566–624. Kikuchi-Yanoshita R, Konishi M, Ito S, et al. Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res 1992; 52:3965–3971. Borresen-Dale AL, Lothe RA, Meling GI, Hainaut P, Rognum TO, Skovlund E. TP53 and long-term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival. Clin Cancer Res 1998; 4:203–210. Stommel JM, Marchenko ND, Jimenez GS, Moll UM, Hope TJ, Wahl GM. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. Embo J 1999; 18: 1660–1672. Vousden KH, Prives C. P53 and prognosis: new insights and further complexity. Cell 2005; 120:7–10. Westhof G, Bader W, Greiner-Mai E, Hatzmann W. Comparison of cytosolic p53 protein levels in the female genital tract and breast, and their tumors. Tumour Biol 2000; 21: 123–134. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319:525–532.

Chapter 27: 42. Pierceall WE, Cho KR, Getzenberg RH, et al. NIH3T3 cells expressing the deleted in colorectal cancer tumor suppressor gene product stimulate neurite outgrowth in rat PC12 pheochromocytoma cells. J Cell Biol 1994; 124:1017–1027. 43. Fazeli A, Dickinson SL, Hermiston ML, et al. Phenotype of mice lacking functional deleted in colorectal cancer (Dcc) gene. Nature 1997; 386:796–804. 44. Rieger-Christ KM, Brierley KL, Reale MA. The DCC Protein — Neural Development and the Malignant Process. Front Biosci 1997; 2:d3438–d3448. 45. Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994; 331:213–221. 46. Frank CJ, McClatchey KD, Devaney KO, Carey TE. Evidence that loss of chromosome 18q is associated with tumor progression. Cancer Res 1997; 57:824–827. 47. Mehlen P, Fearon ER. Role of the dependence receptor DCC in colorectal cancer pathogenesis. J Clin Oncol 2004; 22: 3420–3428. 48. Hua Z, Zhang YC, Hu XM, Jia ZG. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. World J Gastroenterol 2003; 9:2764–2767. 49. Woodford-Richens KL, Rowan AJ, Gorman P, et al. SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway. Proc Natl Acad Sci USA 2001; 98: 9719–9723. 50. Calonge MJ, Massague J. Smad4/DPC4 silencing and hyperactive Ras jointly disrupt transforming growth factor-beta antiproliferative responses in colon cancer cells. J Biol Chem 1999; 274:33,637–33,643. 51. Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15:356–362. 52. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000; 100:387–390. 53. Jackson LN, Evers BM. Chronic inflammation and pathogenesis of GI and pancreatic cancers. Cancer Treatment and Research Series. New York: Springer Publishing Company. 54. Hirsch E, Katanaev VL, Garlanda C, et al. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 2000; 287:1049–1053. 55. Sugatani T, Alvarez U, Hruska KA. PTEN regulates RANKLand osteopontin-stimulated signal transduction during osteoclast differentiation and cell motility. J Biol Chem 2003; 278:5001–5008. 56. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004; 22: 2954–2963. 57. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993; 366:704–707. 58. Roussel A, Canaan S, Egloff MP, et al. Crystal structure of human gastric lipase and model of lysosomal acid lipase, two lipolytic enzymes of medical interest. J Biol Chem 1999; 274:16,995–17,002. 59. Liggett WH Jr, Sidransky D. Role of the p16 tumor suppressor gene in cancer. J Clin Oncol 1998; 16:1197–1206. 60. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 1998; 95:8292–8297. 61. D’Emilia JC, Rodriguez-Bigas MA, Petrelli NJ. The clinical and genetic manifestations of hereditary nonpolyposis colorectal carcinoma. Am J Surg 1995; 169:368–372. 62. Peltomaki P, Vasen HF. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997; 113:1146–1158.

Neoplastic Disorders of the Gastrointestinal Tract

581

63. Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998; 8:1243–1252. 64. Litvak DA. Angiogenesis and GI cancer. In: Evers BM, ed. Molecular Mechanisms in Gastrointestinal Cancer. Austin: R.G. Landes Company, 1999:95–109. 65. McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist 2000; 5(suppl 1):3–10. 66. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxiainitiated angiogenesis. Nature 1992; 359:843–845. 67. Minchenko A, Bauer T, Salceda S, Caro J. Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest 1994; 71:374–379. 68. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxiainducible factor 1. Mol Cell Biol 1996; 16:4604–4613. 69. Brem S, Brem H, Folkman J, Finkelstein D, Patz A. Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res 1976; 36:2807–2812. 70. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995; 1:149–153. 71. Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995; 1:1024–1028. 72. Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci USA 1997; 94:8761–8766. 73. Torimura T, Sata M, Ueno T, et al. Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol 1998; 29:986–991. 74. Kieser A, Weich HA, Brandner G, Marme D, Kolch W. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 1994; 9: 963–969. 75. Grugel S, Finkenzeller G, Weindel K, Barleon B, Marme D. Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J Biol Chem 1995; 270:25,915–25,919. 76. Folkman J. Angiogenesis—Retrospect and outlook. In: Steiner R, Weisz PB, Langer R, eds. Angiogenesis: Key Principles, Science, Technology, Medicine. Basel: Birkha¨user Verlag, 1992:4–13. 77. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–2342. 78. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21:60–65. 79. Borg JP, deLapeyriere O, Noguchi T, Rottapel R, Dubreuil P, Birnbaum D. Biochemical characterization of two isoforms of FLT4, a VEGF receptor-related tyrosine kinase. Oncogene 1995; 10:973–984. 80. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996; 87:3336–3343. 81. Shalaby F, Ho J, Stanford WL, et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 1997; 89:981–990. 82. Sivakumar B, Harry LE, Paleolog EM. Modulating angiogenesis: more vs less. JAMA 2004; 292:972–977. 83. Soker S, Miao HQ, Nomi M, Takashima S, Klagsbrun M. VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem 2002; 85:357–368.

medwedi.ru

582

Part Two: The Alimentary Tract—Other Conditions

84. Gagnon ML, Bielenberg DR, Gechtman Z, et al. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: in vivo expression and antitumor activity. Proc Natl Acad Sci USA 2000; 97:2573–2578. 85. Bhowmick NA, Chytil A, Plieth D, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303:848–851. 86. Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology 2000; 119:854–865. 87. De Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol 2003; 200:429–447. 88. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442–454. 89. Sugiyama Y, Farrow B, Murillo C, et al. Analysis of differential gene expression patterns in colon cancer and cancer stroma using microdissected tissues. Gastroenterology 2005; 128: 480–486. 90. Xie K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 2001; 12:375–391. 91. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001; 357:539–545. 92. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420:860–867. 93. Stoicov C, Saffari R, Cai X, Hasyagar C, Houghton J. Molecular biology of gastric cancer: Helicobacter infection and gastric adenocarcinoma: bacterial and host factors responsible for altered growth signaling. Gene 2004; 341:1–17. 94. Stolte M, Meining A. Helicobacter pylori and gastric cancer. Oncologist 1998; 3:124–128. 95. Parsonnet J, Vandersteen D, Goates J, Sibley RK, Pritikin J, Chang Y. Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst 1991; 83:640–643. 96. Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 2004; 287:G7–G17. 97. Lichtenstein GR. Reduction of colorectal cancer risk in patients with Crohn’s disease. Rev Gastroenterol Disord 2002; 2(suppl 2):S16–S24. 98. Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark Evers B. Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004; 239:763–771. 99. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunol Today 1992; 13:265–270. 100. Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol 2002; 10:153–169. 101. Cotran RS, Kumar V, Collins T. Pathologic Basis of Disease. 6th ed. Philadelphia: W.B. Saunders Company, 1999. 102. McCawley LJ, Matrisian LM. Tumor progression: defining the soil round the tumor seed. Curr Biol 2001; 11:R25–R27. 103. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315:1650–1659. 104. Suganuma M, Okabe S, Marino MW, Sakai A, Sueoka E, Fujiki H. Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice. Cancer Res 1999; 59:4516–4518. 105. Moore RJ, Owens DM, Stamp G, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999; 5:828–831. 106. Gasche C, Chang CL, Rhees J, Goel A, Boland CR. Oxidative stress increases frameshift mutations in human colorectal cancer cells. Cancer Res 2001; 61:7444–7448. 107. Hussain SP, Amstad P, Raja K, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 2000; 60:3333–3337. 108. Mann JR, DuBois RN. Cyclooxygenase-2 and gastrointestinal cancer. Cancer J 2004; 10:145–152.

109. Sheng H, Shao J, Kirkland SC, et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 1997; 99:2254–2259. 110. Agoff SN, Brentnall TA, Crispin DA, et al. The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. Am J Pathol 2000; 157:737–745. 111. Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002; 94:252–266. 112. Gustin JA, Ozes ON, Akca H, et al. Cell type-specific expression of the IkB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kB activation. J Biol Chem 2004; 279:1615–1620. 113. Schwartz SA, Hernandez A, Mark Evers B. The role of NF-kB/ IkB proteins in cancer: implications for novel treatment strategies. Surg Oncol 1999; 8:143–153. 114. Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitisassociated cancer. Cell 2004; 118:285–296. 115. Wang Q, Li N, Wang X, Kim MM, Evers BM. Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3’-kinase inhibition in the KM20 human colon cancer cell line. Clin Cancer Res 2002; 8:1940–1947. 116. Khaleghpour K, Li Y, Banville D, Yu Z, Shen SH. Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma. Carcinogenesis 2004; 25:241–248. 117. Marinissen MJ, Gutkind JS. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 2001; 22:368–376. 118. Wilkie TM. Treasures throughout the life-cycle of G-proteincoupled receptors. Trends Pharmacol Sci 2001; 22:396–397. 119. Watson SA, Crosbee DM, Dilks KL, Robertson JF, Hardcastle JD. Interactions between oestradiol and danazol on the growth of gastrointestinal tumour cells. Anticancer Res 1993; 13:97–102. 120. Thomas RP, Hellmich MR, Townsend CM Jr, Evers BM. Role of gastrointestinal hormones in the proliferation of normal and neoplastic tissues. Endocr Rev 2003; 24:571–599. 121. Fisher WE, Wu Y, Amaya F, Berger DH. Somatostatin receptor subtype 2 gene therapy inhibits pancreatic cancer in vitro. J Surg Res 2002; 105:58–64. 122. Hu C, Yi C, Hao Z, et al. The effect of somatostatin and SSTR3 on proliferation and apoptosis of gastric cancer cells. Cancer Biol Ther 2004; 3:726–730. 123. Coit DG, Brennan MF. Gastric neoplasms. In: Moody FG, Carey LC, Jones RS, Kelly KA, Nahrwold DL, Skinner DB, eds. Surgical Treatment of Digestive Disease. Chicago: Year Book Medical Publishers, 1990:212–235. 124. Abraham SC, Nobukawa B, Giardiello FM, Hamilton SR, Wu TT. Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene. Am J Pathol 2001; 158:1005–1010. 125. Papa A, Cammarota G, Tursi A, et al. Histologic types and surveillance of gastric polyps: a seven year clinico-pathological study. Hepatogastroenterology 1998; 45:579–582. 126. United States Cancer Statistics Working Group. United States Cancer Statistics: 1999 Incidence. Atlant GA: Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute, 2002. 127. Ries LAG, Hankey BF, Miller BA, et al. Cancer Statistics Review, 1973–1988 (NIH publication No. 91–2789). Bethesda: National Institutes of Health, 1988. 128. Haensel W. Migrant studies. In: Schottenfeld D, Fraumeni JF, eds. Cancer Epidemiology and Prevention. Philadelphia: W.B. Saunders, 1982:194–207. 129. Graham S, Haughey B, Marshall J, et al. Diet in the epidemiology of gastric cancer. Nutr Cancer 1990; 13:19–34. 130. 128. Dunham LJ, Bailar JC 3rd. World maps of cancer mortality rates and frequency ratios. J Natl Cancer Inst 1968; 41: 155–203.

Chapter 27: 131. Munoz N. Is Helicobacter pylori a cause of gastric cancer? An appraisal of the seroepidemiological evidence. Cancer Epidemiol Biomarkers Prev 1994; 3:445–451. 132. Blaser MJ, Perez-Perez GI, Kleanthous H, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 1995; 55:2111–2115. 133. Figueiredo C, Machado JC, Pharoah P, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 2002; 94:1680–1687. 134. El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000; 404:398–402. 135. Hitchcock CR, Schneiner SL. Early diagnosis of gastric cancer. Surg Gynecol Obstet 1961; 113:655. 136. Stemmermann GN, Fenoglio-Preiser C. Gastric carcinoma distal to the cardia: a review of the epidemiological pathology of the precusors to a preventable cancer. Pathology 2002; 34: 494–503. 137. Tahara E. Molecular biology of gastric cancer. World J Surg 1995; 19:484–490. 138. Gunther T, Schneider-Stock R, Pross M, et al. Alterations of the p16/MTS1-tumor suppressor gene in gastric cancer. Pathol Res Pract 1998; 194:809–813. 139. Hong SI, Hong WS, Jang JJ, et al. Alterations of p53 gene in primary gastric cancer tissues. Anticancer Res 1994; 14: 1251–1255. 140. Tamura G, Maesawa C, Suzuki Y, et al. Mutations of the APC gene occur during early stages of gastric adenoma development. Cancer Res 1994; 54:1149–1151. 141. Joo YE, Rew JS, Choi SK, Bom HS, Park CS, Kim SJ. Expression of e-cadherin and catenins in early gastric cancer. J Clin Gastroenterol 2002; 35:35–42. 142. Aird I, Bentall HH, Roberts JA. A relationship between cancer of stomach and the ABO blood groups. Br Med J 1953; 1: 799–801. 143. Munoz N, Connelly R. Time trends of intestinal and diffuse types of gastric cancer in the United States. Int J Cancer 1971; 8:158–164. 144. Alexander H, Kelsen D, Tepper J. Cancer of the stomach. In: De Vita V, Hellman S, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia: J.B. Lippincott, 1993:818–848. 145. Wanebo HJ, Kennedy BJ, Chmiel J, Steele G Jr, Winchester D, Osteen R. Cancer of the stomach. A patient care study by the American College of Surgeons. Ann Surg 1993; 218: 583–592. 146. Antman KH, Skarin AT, Mayer RJ, Hargreaves HK, Canellos GP. Microangiopathic hemolytic anemia and cancer: a review. Medicine (Baltimore) 1979; 58:377–384. 147. Warren S. Studies on tumor metastases: IV. Metastases of cancer of stomach. N Engl J Med 1933; 209:825. 148. Monico S, Giansanti M, Fugiani P. Cytodiagnosis of gastric cancer by brushing: 1978–1983. Tumori 1987; 73:147–150. 149. Lightdale CJ, Botet JF, Brennan MF, Shiu MH, Coit DG. Endoscopic ultrasonography (EUS) compared to computerized tomography (CT) for pre-operative staging of gastric cancer. Gastrointest Endosc 1989; 35:154–155(A). 150. Bizer LS. Adenocarcinoma of the stomach: current results of treatment. Cancer 1983; 51:743–745. 151. Mulholland MW. Gastric neoplasms. In: Greenfield LJ, et al., eds. Surgery: Scientific Principles and Practice. Philadelphia: JB Lippincott, 1993. 152. Coller FA, Kay EB, McIntyre RS. Regional lymphatic metastases of carcinoma of the stomach. Arch Surg 1941; 43:748. 153. Coombes RC, Schein PS, Chilvers CE, et al. A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group. J Clin Oncol 1990; 8: 1362–1369.

Neoplastic Disorders of the Gastrointestinal Tract

583

154. Grau JJ, Estape J, Alcobendas F, Pera C, Daniels M, Teres J. Positive results of adjuvant mitomycin-C in resected gastric cancer: a randomised trial on 134 patients. Eur J Cancer 1993; 29A:340–342. 155. Takahashi T. Studies on preoperative and postoperative telecobalt therapy in gastric cancer. Xii. Nippon Igaku Hoshasen Gakkai Zasshi 1964; 24:129–132. 156. Hallissey MT, Jewkes AJ, Dunn JA, Ward L, Fielding JW. Resection-line involvement in gastric cancer: a continuing problem. Br J Surg 1993; 80:1418–1420. 157. AJCC Cancer Staging Manual. 6th ed. New York: SpringerVerlag, 2001. 158. Stephens J, Smith J. Treatment of primary gastric lymphoma and gastric mucosa-associated lymphoid tissue lymphoma. J Am Coll Surg 1998; 187:312–320. 159. Koniaris LG, Drugas G, Katzman PJ, Salloum R. Management of gastrointestinal lymphoma. J Am Coll Surg 2003; 197: 127–141. 160. Rosin D, Rosenthal RJ, Bonner G, Grove MK, Sesto ME. Gastric MALT lymphoma in a Helicobacter pylori-negative patient: a case report and review of the literature. J Am Coll Surg 2001; 192:652–657. 161. Raderer M, Valencak J, Osterreicher C, et al. Chemotherapy for the treatment of patients with primary high grade gastric B-cell lymphoma of modified Ann Arbor Stages IE and IIE. Cancer 2000; 88:1979–1985. 162. Bandoh T, Isoyama T, Toyoshima H. Submucosal tumors of the stomach: a study of 100 operative cases. Surgery 1993; 113:498–506. 163. Cunningham JD, Aleali R, Aleali M, Brower ST, Aufses AH. Malignant small bowel neoplasms: histopathologic determinants of recurrence and survival. Ann Surg 1997; 225:300–306. 164. Neugut AI, Jacobson JS, Suh S, Mukherjee R, Arber N. The epidemiology of cancer of the small bowel. Cancer Epidemiol Biomarkers Prev 1998; 7:243–251. 165. Arber N, Neugut AI, Weinstein IB, Holt P. Molecular genetics of small bowel cancer. Cancer Epidemiol Biomarkers Prev 1997; 6:745–748. 166. Blaker H, von Herbay A, Penzel R, Gross S, Otto HF. Genetics of adenocarcinomas of the small intestine: frequent deletions at chromosome 18q and mutations of the SMAD4 gene. Oncogene 2002; 21:158–164. 167. Rashid A, Hamilton SR. Genetic alterations in sporadic and Crohn’s-associated adenocarcinomas of the small intestine. Gastroenterology 1997; 113:127–135. 168. Bresalier RS, Ben-Menachem T. Tumors of the small intestine. In: Alpers DH, Kaplowitz N, Laine Lea, eds. Textbook of Gastroenterology. Philadelphia: Lippincott Williams & Wilkins, 2003:1643–1662. 169. Ashley SW, Wells SA Jr. Tumors of the small intestine. Semin Oncol 1988; 15:116–128. 170. Morgan BK, Compton C, Talbert M, Gallagher WJ, Wood WC. Benign smooth muscle tumors of the gastrointestinal tract. A 24-year experience. Ann Surg 1990; 211:63–66. 171. McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am J Gastroenterol 2000; 95:596–604. 172. Morgan DR, Mylankal K, el Barghouti N, Dixon MF. Small bowel haemangioma with local lymph node involvement presenting as intussusception. J Clin Pathol 2000; 53: 552–553. 173. Evers BM. Small intestine. In: Townsend CM Jr, Beauchamp RD, Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 17th ed. Philadelphia: Elsevier Saunders, 2004:1323–1380. 174. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet 1998; 352:799–805. 175. Neugut AI, Marvin MR, Rella VA, Chabot JA. An overview of adenocarcinoma of the small intestine. Oncology (Huntingt) 1997; 11:529–36, 45, 49–50. 176. Williams ED, Sandler M. The classification of carcinoid tumours. Lancet 1963; 1:238–239.

medwedi.ru

584

Part Two: The Alimentary Tract—Other Conditions

177. Antonioli DA. Gastrointestinal autonomic nerve tumors. Expanding the spectrum of gastrointestinal stromal tumors. Arch Pathol Lab Med 1989; 113:831–833. 178. Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF. Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol 2000; 7:705–712. 179. Crosby JA, Catton CN, Davis A, et al. Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann Surg Oncol 2001; 8:50–59. 180. Nolan DJ. The small intestine. In: Grainger RG, Allison DJ, Adam A, Dixon AK, eds. Diagnostic Radiology: A Textbook of Medical Imaging. Vol. 2. 4th ed. New York: Churchill Livingstone, 2001:1075–1098. 181. Thompson JC. Atlas of Surgery of the Stomach, Duodenum and Small Bowel. St. Louis: Mosby-Year Book, 1992:299. 182. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231:51–58. 183. Demetri GD. Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development. Hematol Oncol Clin North Am 2002; 16:1115–1124. 184. Martin RG. Malignant tumors of the small intestine. Surg Clin North Am 1986; 66:779–785. 185. Appelman HD. Smooth muscle tumors of the gastrointestinal tract. What we know now that Stout didn’t know. Am J Surg Pathol 1986; 10(suppl 1):83–99. 186. Franquemont DW. Differentiation and risk assessment of gastrointestinal stromal tumors. Am J Clin Pathol 1995; 103:41–47. 187. Miettinen M, Virolainen M, Maarit Sarlomo R. Gastrointestinal stromal tumors—value of CD34 antigen in their identification and separation from true leiomyomas and schwannomas. Am J Surg Pathol 1995; 19:207–216. 188. Perez-Atayde AR, Shamberger RC, Kozakewich HW. Neuroectodermal differentiation of the gastrointestinal tumors in the Carney triad. An ultrastructural and immunohistochemical study. Am J Surg Pathol 1993; 17:706–714. 189. Sakurai S, Fukasawa T, Chong JM, Tanaka A, Fukayama M. Embryonic form of smooth muscle myosin heavy chain (SMemb/MHC-B) in gastrointestinal stromal tumor and interstitial cells of Cajal. Am J Pathol 1999; 154:23–28. 190. Tsujimura T, Makiishi-Shimobayashi C, Lundkvist J, et al. Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol 2001; 158:817–823. 191. Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumours. Br J Surg 2003; 90:1178–1186. 192. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; 279:577–580. 193. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152:1259–1269. 194. Hornick JL, Fletcher CD. Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol 2002; 117:188–193. 195. Miettinen M, Sarlomo-Rikala M, Lasota J. KIT expression in angiosarcomas and fetal endothelial cells: lack of mutations of exon 11 and exon 17 of c-kit. Mod Pathol 2000; 13:536–541. 196. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004; 22:3813–3825. 197. Wardelmann E, Neidt I, Bierhoff E, et al. c-kit mutations in gastrointestinal stromal tumors occur preferentially in the spindle rather than in the epithelioid cell variant. Mod Pathol 2002; 15:125–136. 198. Suster S, Fletcher CD. Gastrointestinal stromal tumors with prominent signet-ring cell features. Mod Pathol 1996; 9: 609–613.

199. Rudolph P, Gloeckner K, Parwaresch R, Harms D, Schmidt D. Immunophenotype, proliferation, DNA ploidy, and biological behavior of gastrointestinal stromal tumors: a multivariate clinicopathologic study. Hum Pathol 1998; 29:791–800. 200. Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era. Cancer 2005; 103:821–829. 201. Singer S, Rubin BP, Lux ML, et al. Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors. J Clin Oncol 2002; 20:3898–3905. 202. Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J. Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. Am J Surg Pathol 2000; 24:1339–1352. 203. Emory TS, Sobin LH, Lukes L, Lee DH, O’Leary TJ. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. Am J Surg Pathol 1999; 23:82–87. 204. Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002; 33:466–477. 205. Miettinen M, El-Rifai WLHLS, Lasota J. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 2002; 33:478–483. 206. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:472–480. 207. Rude RK, Oldham SB, Singer FR. Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf) 1976; 5:209–224. 208. Moertel CG, Sauer WG, Dockerty MB, Baggenstoss AH. Life history of the carcinoid tumor of the small intestine. Cancer 1961; 14:901–912. 209. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997; 79:813–829. 210. Godwin JD 2nd. Carcinoid tumors. An analysis of 2,837 cases. Cancer 1975; 36:560–569. 211. Oyajobi BO, Mundy GR. Receptor activator of NF-kB ligand, macrophage inflammatory protein-1a, and the proteasome: novel therapeutic targets in myeloma. Cancer 2003; 97:813–817. 212. Gerstle JT, Kauffman GL Jr, Koltun WA. The incidence, management, and outcome of patients with gastrointestinal carcinoids and second primary malignancies. J Am Coll Surg 1995; 180:427–432. 213. Sutton R, Doran HE, Williams EM, et al. Surgery for midgut carcinoid. Endocr Relat Cancer 2003; 10:469–481. 214. Evers BM, Ishizuka J, Townsend CM Jr, Thompson JC. The human carcinoid cell line, BON. A model system for the study of carcinoid tumors. Ann NY Acad Sci 1994; 733: 393–406. 215. Hirata Y, Sakamoto N, Yamamoto H, Matsukura S, Imura H, Okada S. Gastric carcinoid with ectopic production of ACTH and beta-MSH. Cancer 1976; 37:377–385. 216. Kolby L, Wangberg B, Ahlman H, et al. Gastric carcinoid with histamine production, histamine transporter and expression of somatostatin receptors. Digestion 1998; 59:160–166. 217. Roberts LJ 2nd, Bloomgarden ZT, Marney SR Jr, Rabin D, Oates JA. Histamine release from a gastric carcinoid: provocation by pentagastrin and inhibition by somatostatin. Gastroenterology 1983; 84:272–275. 218. Soga J. Carcinoids of the small intestine: a statistical evaluation of 1102 cases collected from the literature. J Exp Clin Cancer Res 1997; 16:353–363. 219. Strodel WE, Talpos G, Eckhauser F, Thompson N. Surgical therapy for small-bowel carcinoid tumors. Arch Surg 1983; 118:391–397. 220. Roberts LJ 2nd, Marney SR Jr, Oates JA. Blockade of the flush associated with metastatic gastric carcinoid by combined histamine H1 and H2 receptor antagonists. Evidence for an important role of H2 receptors in human vasculature. N Engl J Med 1979; 300:236–238.

Chapter 27: 221. Woodside KJ, Townsend CM Jr, Mark Evers B. Current management of gastrointestinal carcinoid tumors. J Gastrointest Surg 2004; 8:742–756. 222. Evers BM. Small bowel. In: Townsend CM Jr, ed. Sabiston Textbook of Surgery. 17th ed. Philadelphia: Elsevier Saunders, 2004:1323–1380. 223. Pickhardt PJ, Levy AD, Rohrmann CA Jr, Kende AI. Primary neoplasms of the appendix: radiologic spectrum of disease with pathologic correlation. Radiographics 2003; 23:645–662. 224. Shi W, Johnston CF, Buchanan KD, et al. Localization of neuroendocrine tumours with [111In] DTPA-octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging. QJM 1998; 91:295–301. 225. Westlin JE, Janson ET, Arnberg H, Ahlstrom H, Oberg K, Nilsson S. Somatostatin receptor scintigraphy of carcinoid tumours using the [111In-DTPA-D-Phe1]-octreotide. Acta Oncol 1993; 32:783–786. 226. Krenning EP, Kwekkeboom DJ, Oei HY, et al. Somatostatinreceptor scintigraphy in gastroenteropancreatic tumors. An overview of European results. Ann NY Acad Sci 1994; 733:416–424. 227. Lamberts SW, Bakker WH, Reubi JC, Krenning EP. Somatostatinreceptor imaging in the localization of endocrine tumors. N Engl J Med 1990; 323:1246–1249. 228. Kwekkeboom DJ, Krenning EP. Somatostatin receptor scintigraphy in patients with carcinoid tumors. World J Surg 1996; 20:157–161. 229. Ohrvall U, Eriksson B, Juhlin C, et al. Method for dissection of mesenteric metastases in mid-gut carcinoid tumors. World J Surg 2000; 24:1402–1408. 230. Woltering EA, Barrie R, O’Dorisio TM, O’Dorisio MS, Nance R, Cook DM. Detection of occult gastrinomas with iodine 125-labeled lanreotide and intraoperative gamma detection. Surgery 1994; 116:1139–1147. 231. Benjegard SA, Forssell-Aronsson E, Wangberg B, Skanberg J, Nilsson O, Ahlman H. Intraoperative tumour detection using 111 In-DTPA-D-Phe1-octreotide and a scintillation detector. Eur J Nucl Med 2001; 28:1456–1462. 232. Dominioni L, Dionigi R, Benevento A, Garancini S, Roncari G. Localisation of carcinoid tumour with radiolabelled octreotide and intraoperative gamma detection. Lancet 1994; 344:1783. 233. Hajnal JV, Bydder GM, Young IR. Use of fluid attenuated inversion recovery sequence in magnetic resonance imaging. Lancet 1994; 344:1783. 234. Ahlman H, Wangberg B, Tisell LE, Nilsson O, Fjalling M, Forssell-Aronsson E. Clinical efficacy of octreotide scintigraphy in patients with midgut carcinoid tumours and evaluation of intraoperative scintillation detection. Br J Surg 1994; 81:1144–1149. 235. Schirmer WJ, O’Dorisio TM, Schirmer TP, Mojzisik CM, Hinkle GH, Martin EW. Intraoperative localization of neuroendocrine tumors with 125I-TYR(3)-octreotide and a handheld gamma-detecting probe. Surgery 1993; 114:745–752. 236. Benevento A, Dominioni L, Carcano G, Dionigi R. Intraoperative localization of gut endocrine tumors with radiolabeled somatostatin analogs and a gamma-detecting probe. Semin Surg Oncol 1998; 15:239–244. 237. Schindl M, Kaserer K, Niederle B. Treatment of gastric neuroendocrine tumors: the necessity of a type-adapted treatment. Arch Surg 2001; 136:49–54. 238. Rindi G, Bordi C, Rappel S, La Rosa S, Stolte M, Solcia E. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior. World J Surg 1996; 20: 168–172. 239. Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E. Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology 1993; 104:994–1006. 240. Stinner B, Kisker O, Zielke A, Rothmund M. Surgical management for carcinoid tumors of small bowel, appendix, colon, and rectum. World J Surg 1996; 20:183–188.

Neoplastic Disorders of the Gastrointestinal Tract

585

241. Memon MA, Nelson H. Gastrointestinal carcinoid tumors: current management strategies. Dis Colon Rectum 1997; 40:1101–1118. 242. Ballantyne GH, Savoca PE, Flannery JT, Ahlman MH, Modlin IM. Incidence and mortality of carcinoids of the colon. Data from the Connecticut Tumor Registry. Cancer 1992; 69: 2400–2405. 243. Koura AN, Giacco GG, Curley SA, Skibber JM, Feig BW, Ellis LM. Carcinoid tumors of the rectum: effect of size, histopathology, and surgical treatment on metastasis free survival. Cancer 1997; 79:1294–1298. 244. Burke M, Shepherd N, Mann CV. Carcinoid tumours of the rectum and anus. Br J Surg 1987; 74:358–361. 245. Sauven P, Ridge JA, Quan SH, Sigurdson ER. Anorectal carcinoid tumors. Is aggressive surgery warranted? Ann Surg 1990; 211:67–71. 246. d’Entremont TS, Sun W. Recent advances in colorectal cancer therapy. Cancer Biol Ther 2003; 2:6–13. 247. Schupak KD, Wallner KE. The role of radiation therapy in the treatment of locally unresectable or metastatic carcinoid tumors. Int J Radiat Oncol Biol Phys 1991; 20:489–495. 248. Mayer RJ. Tumors of the large and small intestine. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, eds. Harrison’s Principles of Internal Medicine. Vol. 2. 13th ed. New York: McGraw-Hill, 1994:1424–1431. 249. Mayer RJ. Gastrointestinal tract cancer. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds. Harrison’s Principles of Internal Medicine. Vol. 1. 14th ed. New York: McGraw-Hill, 1998:568–578. 250. Burt RW. Colon cancer screening. Gastroenterology 2000; 119:837–853. 251. Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology 1985; 89:328–336. 252. Mahmoud N, Rombeau J, Ross HM, Fry RD. Colon and rectum. In: Townsend CM Jr, Beauchamp RD, Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 17th ed. Philadelphia: Elsevier Saunders, 2004:1401–1481. 253. Kim EC, Lance P. Colorectal polyps and their relationship to cancer. Gastroenterol Clin North Am 1997; 26:1–17. 254. Willenbucher RF. Inflammatory bowel disease. Semin Gastrointest Dis 1996; 7:94–104. 255. Hoffenberg EJ, Sauaia A, Maltzman T, Knoll K, Ahnen DJ. Symptomatic colonic polyps in childhood: not so benign. J Pediatr Gastroenterol Nutr 1999; 28:175–181. 256. Box JC, Watne AL. Inherited syndromes of colon polyps. Semin Surg Oncol 1995; 11:394–398. 257. Nandakumar G, Morgan JA, Silverberg D, Steinhagen RM. Familial polyposis coli: clinical manifestations, evaluation, management and treatment. Mt Sinai J Med 2004; 71: 384–391. 258. Perniciaro C. Gardner’s syndrome. Dermatol Clin 1995; 13: 51–56. 259. Dean PA. Hereditary intestinal polyposis syndromes. Rev Gastroenterol Mex 1996; 61:100–111. 260. Cunningham C, Dunlop MG. Genetics of colorectal cancer. Br Med Bull 1994; 50:640–655. 261. Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75:1027–1038. 262. Boland CR. Molecular genetics of hereditary nonpolyposis colorectal cancer. Ann NY Acad Sci 2000; 910:50–61. 263. Half EE, Bresalier RS. Clinical management of hereditary colorectal cancer syndromes. Curr Opin Gastroenterol 2004; 20:32–42. 264. Fogt F, Brown CA, Badizadegan K, Zimmerman RL, Odze R. Low prevalence of loss of heterozygosity and SMAD4 mutations in sporadic and familial juvenile polyposis syndrome-associated juvenile polyps. Am J Gastroenterol 2004; 99:2025–2031.

medwedi.ru

586

Part Two: The Alimentary Tract—Other Conditions

265. Schreibman IR, Baker M, Amos C, McGarrity TJ. The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol 2005; 100:476–490. 266. Fearon ER, Hamilton SR, Vogelstein B. Clonal analysis of human colorectal tumors. Science 1987; 238:193–197. 267. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002; 52:23–47. 268. Frattini M, Balestra D, Suardi S, et al. Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res 2004; 10:4015–4021. 269. Wiersema MJ, Harewood GC. Endoscopic ultrasound for rectal cancer. Gastroenterol Clin North Am 2002; 31:1093–1105. 270. Scott-Conner CE, Christie DW. Cancer staging using the American Joint Committee on Cancer TNM System. J Am Coll Surg 1995; 181:182–188. 271. Greenfield LJ, et al., eds. Surgery: Scientific Principles and Practice. 2nd ed. Philadelphia: Lippincott Raven, 1997. 272. Finlay GJ. Genetics, molecular biology and colorectal cancer. Mutat Res 1993; 290:3–12. 273. Gimbel MI, Paty PB. A current perspective on local excision of rectal cancer. Clin Colorectal Cancer 2004; 4:26–37.

274. Chang A. Colorectal cancer. In: Greenfield LJ, et al., eds. Surgery: Scientific Principles and Practice. Philadelphia: JB Lippincott, 1993:1024. 275. A comparison of laparoscopically assisted and open colectomy for colon cancer. . 276. Grem JL. Current treatment approaches in colorectal cancer. Semin Oncol 1991; 18:17–26. 277. Chessin DB, Guillem JG. Surgical issues in rectal cancer: a 2004 update. Clin Colorectal Cancer 2004; 4:233–240. 278. Liebermann DA, Weiss DG. Screening for colorectal cancer. Am J Gastroenterol 2002; 97:1837–1838. 279. Winawer SJ. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112:594–642. 280. Martinez ME. Primary prevention of colorectal cancer: lifestyle, nutrition, exercise. Recent Results Cancer Res 2005; 166:177–211. 281. Oakley GP, Mandel JS. Folic acid fortification remains an urgent health priority. BMJ 2004; 329:1376. 282. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors Parecoxib and Valdecoxib after cardiac surgery. N Engl J Med 2005; 352:1081–1091.

28 Mechanical Disorders of the Stomach, Duodenum, and Intestine Sean P. Harbison and Daniel T. Dempsey

INTRODUCTION Under normal circumstances, the stomach and the intestine function to provide the body with adequate hydration and nutrition. Accomplished through various absorptive mechanisms throughout the gastrointestinal (GI) tract, this function occurs optimally only in the setting of proper peristaltic activity to move food through the alimentary tube and may be pathologically altered by two basic mechanisms: mechanical or functional. The first is a narrowing of the bowel lumen by either intrinsic or extrinsic means. An incomplete narrowing, or partial obstruction, may progress to total obstruction of the lumen, resulting in a complete bowel obstruction. The second mechanism is one of ineffective peristalsis, a state referred to as ‘‘adynamic ileus’’ or ‘‘pseudo-obstruction,’’ depending on the clinical scenario. In both instances, normal GI physiology is altered. Discussion of this alteration forms the basis of this chapter.

MECHANICAL DISORDERS OF THE STOMACH AND DUODENUM Gastric Outlet Obstruction Etiology and Pathophysiology

hypertrophy of the muscularis propria and may result in gastric enlargement. More sophisticated techniques of assessing myoelectric activity and motor function of the obstructed stomach may guide diagnosis and treatment in the future (5,6). Historically, the saline load test was often used as an index of the degree of obstruction. If 400 mL or greater remained in the stomach 30 minutes after gastric instillation of 750 mL saline solution, the result is considered positive. Because liquids may empty by gravity, whereas solids require intact gastric motor function, the saline load test should be abandoned in favor of more quantitative assessments, such as nuclear scintigraphy. Significant nutritional defects may be present, especially in the patient who has had symptoms for weeks or months. Clinically significant protein and calorie deficits are indicated by 15% weight loss (measured after return to euvolemic status), serum albumin 3 g/dL, assessment of dietary history, and functional evaluation (e.g., muscle fatigability). Deficiencies in calcium, iron, magnesium, trace elements, and vitamins may also be evident (7).

Diagnosis and Treatment

Gastric outlet obstruction in the adult is most often caused by cancer, but also frequently by peptic ulcer disease (1). In acute ulcer disease, the pyloric channel may be obstructed by edema. Alternatively, normal antropyloric peristaltic function may be disrupted solely by the inflammatory process. Contained perforation of the ulcer with extrinsic compression by mass effect is less common. Chronic peptic ulcer disease produces obstructive scarring of the pyloric channel. Adenocarcinomas of the distal stomach and pancreas are the most common malignancies associated with gastric outlet obstruction. Other less common etiologies include idiopathic hypertrophic pyloric stenosis, proximal duodenal webs, posttraumatic (including postoperative) stricture, and a variety of primary or secondary gastric motor disorders (2) (Box 1). Volume and electrolyte depletion from vomiting may be severe in patients with gastric outlet obstruction. The characteristic finding is hypokalemic, hypochloremic metabolic alkalosis with extracellular fluid volume depletion (3). Because of the sodium and potassium depletion, sodium is avidly absorbed and exchanged at the expense of hydrogen ion in the distal renal tubule. This results in paradoxical aciduria (an acidic urinary pH in the setting of alkalemia) (4). The effects of gastric outlet obstruction on gastric motor function are poorly understood. Acute gastric outlet obstruction presumably results in overdistention of the stomach and loss of motor tone. Chronic obstruction causes

The clinical presentation of gastric outlet obstruction may be acute or chronic. The most common symptoms are nausea, nonbilious vomiting, epigastric pain, and bloating. The last two symptoms usually occur postprandially. Patients with nonmalignant obstruction do feel hunger and do not report early satiety, perhaps because the capacitance function of the proximal stomach is not affected and the disease process does not disturb autonomic innervation. Epigastric fullness and tympany may be evident on physical examination and a ‘‘succession splash’’ may be Box 1 Causes of Chronic Gastric Retention Without Mechanical Obstruction Drugs Diabetes Gastric surgery Pain, trauma Peritonitis Contiguous inflammation (e.g., pancreatitis) Neuromuscular diseases Central nervous system disease Pseudo-obstruction Collagen vascular disease Idiopathic cause Source: From Ref. 2.

medwedi.ru 587

588

Part Two: The Alimentary Tract—Other Conditions

elicited in some patients. The latter finding is the audible sound of fluid heard in the left upper quadrant on auscultation of the abdomen during its gentle movement. A palpable mass usually indicates malignancy. Tachycardia and orthostatic hypotension reflect volume depletion. Cardiac irritability and muscle weakness may reflect electrolyte abnormalities, particularly those associated with potassium losses from vomiting. The history and physical examination suggest the diagnosis. Vital signs, urinary output, and measurements of serum electrolytes should guide the repletion of fluid and electrolyte deficits with isotonic saline and potassium chloride solutions (the latter should be given only after reassurance regarding adequate renal function). Repletion of magnesium, as well as calcium and iron (both of which are absorbed in the stomach and duodenum), may be necessary. Diagnosis is confirmed and etiology is sought by endoscopy, scintigraphy, and upper GI tract radiologic evaluation. Total parenteral nutrition should be initiated if the patient is severely malnourished or will receive nothing by mouth for at least seven days. Whether preoperative gastric decompression, often practiced for five to seven days, hastens postoperative return of gastric function is unknown. Because postoperative return of normal gastric emptying is not always prompt, temporary gastrostomy and feeding jejunostomy may be useful adjunct procedures. Definitive treatment of mechanical gastric outlet obstruction depends on the underlying cause. All patients with peptic ulcer disease should be treated with intravenous antisecretory drugs and evaluated for Helicobacter pylori infection. Although as many as 46% of these patients (presumably those with ‘‘acute’’ ulcer) show improvement after a few days of nasogastric suction and intravenous fluid therapy, the risk of recurrent obstruction in the ‘‘pre–Helicobacter era’’ was greater than 50% (7,8). Most patients with gastric outlet obstruction caused by peptic ulcer disease should therefore be considered for definitive operation (hemigastrectomy and reconstruction with vagotomy or gastrojejunostomy with vagotomy). Gastric outlet obstruction is most commonly caused by types II and III ulcers, which are associated with increased acid production. Lesser procedures (parietal cell vagotomy with dilation, endoscopic balloon dilation, etc.) have been used with variable results (9–11). Whether the success of aggressive treatment of H. pylori in patients infected with this bacterium will alleviate obstruction and obviate surgery remains to be seen. It is noteworthy that the eradication of H. pylori has been shown to reduce recurrence of ulcer diathesis significantly. Patients with malignant gastric outlet obstruction should undergo curative resection or palliative gastrojejunostomy. Vagotomy should be considered if survival longer than six months is anticipated. Laparoscopic vagotomy and gastrojejunostomy offer a useful option in some patients with benign or malignant obstruction (12). Webs and hypertrophic pyloric stenosis may be treated with endoscopic dilatation or operative stricturoplasty.

Duodenal Obstruction Etiology and Pathophysiology Duodenal obstruction in the adult may cause symptoms similar to gastric outlet obstruction. However, the vomitus may be bilious, and the alkalosis tends to be less pronounced because alkaline duodenal contents are vomited along with gastric acid. Postprandial pain may be significant, presumably because of postcibal secretion into an

obstructed duodenal loop, which may be intermittently closed at the upper end by the pylorus, creating a closed loop. Pyloric relaxation and retrograde discharge of contents from the distended duodenal loop relieve the pain (and often result in bilious vomiting with food). The most common causes of duodenal obstruction in the adult are cancer (pancreatic, duodenal, and recurrent colon cancers), duodenal ulcer disease (gastrinoma should be considered in the case of a duodenal ulcer distal to the bulb), pancreatitis, and congenital problems [webs, intraluminal diverticula (windsock deformity), etc.]. In the patient with trauma or receiving anticoagulation, duodenal hematoma should be considered. Rare causes of duodenal obstruction include the ‘‘superior mesenteric artery (SMA) syndrome’’ (obstruction of the third portion of the duodenum due to the SMA traversing at a narrowed angle from the aorta) (13), radiation fibrosis, idiopathic retroperitoneal fibrosis, gallstones (Bouveret’s syndrome), and paraduodenal hernia. Duodenal atresia, annular pancreas, and Ladd’s bands (associated with malrotation of the midgut) are important causes in the pediatric patient (see Chapter 59). Although they are unusual in the adult, Ladd’s bands should always be considered because midgut volvulus and infarction remain a possibility even in the adult patient (14,15).

Diagnosis and Treatment The diagnosis of duodenal obstruction is suggested by the history and confirmed by endoscopic gastroduodenoscopy and/or radiologic evaluation of the upper GI tract. Ladd’s bands with malrotation may be ruled out if the latter evaluation shows the cecum in its normal right lower quadrant location. Computed tomographic scan should be done if malignancy is suspected, and endoscopy may be indicated in certain cases. Angiography or magnetic resonance imaging may be necessary to assess the frontal and lateral SMA–aortic angle in the rare case of suspected SMA syndrome (15). The treatment of duodenal obstruction is dictated by the cause, but should be guided by duodenal physiology. Whereas gastric outlet obstruction entails one functional problem (emptying of the stomach), duodenal obstruction presents at least two, emptying of the stomach ‘‘and’’ emptying of duodenal contents. Duodenal distention causes pain and nausea but also causes gastric hypomotility. In these patients, physiologic stimuli (e.g., eating) deliver normal volumes of bile and pancreatic juice to the duodenum; these, along with duodenal secretions, cause duodenal distention in the setting of normal pyloric function. Gastrojejunostomy for duodenal obstruction relies on retrograde transpyloric decompression of the duodenum into what may be a poorly functioning stomach and yields poor results and should be avoided in the patient with benign disease. Duodenojejunostomy, duodenoduodenostomy, and stricturoplasty are much more physiologically sound and yield better results. They are easily applied to most patients with benign duodenal obstruction (e.g., webs, distal ulcers, SMA syndrome, and annular pancreas). Furthermore, they are not ulcerogenic, so vagotomy or long-term acid suppression is not required unless the cause of obstruction is peptic ulcer disease. Loop gastrojejunostomy may be appropriate, however, for the patient with duodenal obstruction from pancreatic carcinoma where the bile has been diverted above the duodenum and the pancreatic duct is obstructed by the tumor. These patients admittedly have limited survival and should be maintained on acid-suppressive therapy. Malrotation in the adult

Chapter 28: Mechanical Disorders of the Stomach, Duodenum, and Intestine

with symptoms should be treated promptly with operative division of Ladd’s bands and cecal fixation in the right lower quadrant.

Gastric Volvulus Etiology and Pathophysiology Most clinically significant cases of gastric volvulus are associated with paraesophageal hiatal hernia or some other diaphragmatic defect and are referred to as ‘‘supradiaphragmatic’’ or ‘‘secondary volvulus’’ (16,17). Less commonly, the twist is not associated with a diaphragmatic defect (‘‘subdiaphragmatic’’ or ‘‘primary volvulus’’) and is thought to be caused by unusually lax gastric attachments or a high left hemidiaphragm (e.g., occurring after left pulmonary resection or left phrenic nerve injury). Usually, the stomach rotates on this long axis (organoaxially), giving rise to the term ‘‘upside-down stomach.’’ This is the volvulus usually seen with paraesophageal hiatal hernia. Volvulus along the shorter transverse axis (mesenteroaxial) or a combination of these two rotations may also be seen (Fig. 1). The important pathophysiologic features of gastric volvulus are vascular compromise, poor gastric emptying, and compression of adjacent viscera. The twist may obstruct the distal stomach, so that ingestion of food and air causes prolonged gastric distention. This often compresses adjacent organs (e.g., esophagus, heart, and lung), causing postprandial symptoms (e.g., dysphagia, arrhythmia, and dyspnea). The volvulus, closed-loop, distention, and (in supradiaphragmatic cases) narrow-neck hernia sac result in ischemia and gastric infarction in some patients.

Diagnosis and Treatment Although some patients with acute gastric volvulus have severe epigastric and chest pain, retching, diaphoresis, and tachycardia, most have chronic, intermittent symptoms (18). Usually these symptoms are related to eating and include pain, dysphagia, bloating, palpitations, and the sensation that belching or vomiting would give relief, but without the ability to do so. Plain radiographs of the chest

589

and abdomen usually appear abnormal and may reveal a distended gastric air bubble in the abdomen or thorax. Meglumine diatrizoate (Gastrograffin) swallow is diagnostic and should be done before the passage of a nasogastric tube, because acute gastric volvulus may appear much like spontaneous esophageal rupture (Boerhaave’s syndrome). Treatment depends on the clinical scenario. If gastric ischemia or infarction is suspected, emergency operation is indicated. If symptoms settle with gastric decompression, or if they are chronic and severe, prompt elective operation should be planned. Repair of the diaphragmatic defect is essential. Ideally, the sac is removed, but if this cannot be accomplished safely, the stomach must be completely disconnected from the peritoneum of the hernia sac. Gastropexy or gastrostomy should be added (19).

Disorders of Gastric Motility Etiology and Pathophysiology Although the pathophysiology of most GI motility disorders is incompletely understood (20), it is important to consider gastroduodenal motor dysfunction in the differential diagnosis of many of the more common disorders discussed previously. GI motility disorders are generally classified as idiopathic, neuropathic, myopathic, metabolic, or iatrogenic (e.g., medication related) (21). Some syndromes are thought to have heterogeneous pathogenesis. A simpler but less organized classification divides disorders into primary and secondary (22). Clinically, secondary gastropareses are more common than primary. Chronic idiopathic gastroparesis causes a measurable delay in gastric emptying of solids, and to a lesser extent liquids, on scintiscan. Electrogastrography may demonstrate abnormal myoelectric activity, and pressure measurements demonstrate decreased antral contractile activity. Dyscoordinated antropyloric function may also be present. Diabetic gastroparesis is thought to be neuropathic, resulting from diabetes-induced damage to the extrinsic autonomic gastric innervation. Postprandial antral hypomotility and pylorospasm are characteristic findings on gastric manometry (23).

Figure 1 Barium studies characteristic of mesenteroaxial (A) and organoaxial gastric volvulus (B).

medwedi.ru

590

Part Two: The Alimentary Tract—Other Conditions

Amyloidosis and systemic sclerosis may produce GI dysmotility by damaging both intrinsic nerves and muscularis propria. Postoperative gastroparesis is iatrogenic, and its etiology is multifactorial. In many patients, a preexisting motility problem may not be identified, and an operation such as truncal vagotomy and drainage, truncal vagotomy and antrectomy, or gastric resection worsens the problem. If GI continuity is reestablished with a Roux-en-Y procedure, in which the anastomosed segment has measurable motility and myoelectric abnormalities, gastric emptying may be worsened even further (24). This is especially true if there is a large vagotomized gastric remnant. Duodenogastric reflux is a poorly understood phenomenon that may be pathologic in small numbers of patients (25). Measurements show increased gastric reflux of duodenal bile on scintigraphy and abnormal antral alkalinization although gastric emptying is usually normal.

Diagnosis and Treatment Primary or secondary gastroparesis or pathologic duodenogastric reflux should be considered in patients with symptoms of gastric or duodenal obstruction, in whom no lesion is found. It should be noted, however, that these motor disorders might be associated with lesions more commonly associated with obstruction, namely ulcers and previous operation. The single most useful test in evaluating these gastric motility disorders is a radioisotope gastric emptying study (26). By means of a simple, noninvasive technique, gastric emptying of solids and liquids, as well as duodenogastric reflux and gastroesophageal reflux, may be quantitated. The treatment of these disorders is largely medical (e.g., promotility agents, dietary counseling, and bile salt–binding resins), and surgery is palliative. Irreversible operations should therefore be avoided. An ill-conceived operation or reoperation often makes the problem worse. Some success in electrically stimulating the stomach has been reported. Definitive results are not yet clear and the most effective methods of gastric pacing are still being elucidated (27).

MECHANICAL DISORDERS OF THE SMALL BOWEL Small Bowel Obstruction There are three broad categories of small bowel obstruction according to the origin of the lesion: (i) intrinsic (the lesion arises from within the bowel wall), (ii) extrinsic (the lesion is external to the bowel wall and compresses from without), and (iii) obturation (the lumen is obstructed by material such as feces, bezoars, parasites, or gallstones). Extrinsic lesions are by far the most common cause, with adhesions and hernias accounting for approximately 70% to 75% of all cases of small bowel obstruction (27,28). Intrinsic lesions causing small bowel obstruction are congenital, inflammatory, or neoplastic. An inflamed Meckel’s diverticulum may cause obstruction or act as a lead point for intussusception. Volvulus may occur if congenital malrotation exists, or the intestine may twist around a fibrotic remnant of the yolk sac. Acute inflammatory conditions of the bowel, such as Crohn’s disease and diverticulitis, may also cause obstruction through local edema and stricture formation. In addition, complicated cases of Crohn’s disease or diverticulitis resulting in perforation, abscess formation, and fistulization can extrinsically obstruct the bowel lumen through a mass effect. Stricture

may occur from chronic ischemia, Crohn’s disease, or radiation damage. Obstructions may also result from small bowel neoplasms. Among malignant small bowel neoplasms causing obstruction, adenocarcinoma is the most common, although epidemiologic reports suggest that carcinoid is the most common tumor of the small bowel (29). Carcinoid tumors are most frequently found in the distal small bowel, whereas adenocarcinoma tends to occur proximally. Another infrequent cause of intrinsic small bowel obstruction is intramural hematoma occurring in the patient with trauma or, rarely, spontaneously in persons receiving anticoagulation. Even if not initially obstructing, these lesions may eventually produce symptoms related to stricture formation. Extrinsic lesions are the most common cause of small bowel obstruction. Congenital lesions, such as annular pancreas or Ladd’s band related to congenital malrotation, are rare in the adult. Postoperative or inflammatory adhesions are by far the most common cause of small intestinal obstruction, followed by herniae (30). External compression of the small bowel from various neoplastic conditions, including diffuse carcinomatosis and extraintestinal neoplasms, less frequently result in obstruction. Other miscellaneous etiologies include volvulus and SMA syndrome. The final, and least common, type of obstruction is related to obliteration of the small bowel lumen by foreign bodies, including gallstones (‘‘gallstone ileus’’), bezoars, parasites, and balloons of intraluminal tubes.

Etiology Adhesions Intraperitoneal adhesions are the most common cause of intestinal obstruction in Western society, and they are the most likely cause in the patient who has previously undergone abdominal surgery. The physiologic mechanisms of adhesion formation have not been completely elucidated. However, it is evident that intraperitoneal irritation by surgery or previous intra-abdominal infection, such as pelvic inflammatory disease, may initiate the process (30). Ischemia plays a role, in addition to inflammation, because the ischemic peritoneum is particularly susceptible to adhesion formation (31). Dense fibrous bands form between loops of bowel or between bowel and parietal peritoneum. These bands may result in progressive decrease in luminal diameter by external compression, may create a fixed defect through which the bowel may herniate, or may provide an axis around which loops of bowel volvulize. The last two situations in particular may compromise blood supply, creating a closed loop of bowel with predilection to ischemia and strangulation. This represents a surgical emergency that necessitates immediate operative intervention. Hernia Hernia comprises the second most common cause of bowel obstruction in the Western world. Hernias can be classified as external, in which there is an abnormal protrusion of intra-abdominal tissue through a defect in the abdominal wall, or, less commonly, internal, in which the intraabdominal tissue protrudes through an abnormal opening in mesentery or the peritoneum. In either case, the defect may be acquired or congenital. The most frequently encountered hernias are inguinal and umbilical. A hernia is defined as ‘‘reducible’’ if its contents are returned freely to the abdominal cavity, ‘‘incarcerated’’ if the contents are unable to be reduced,

Chapter 28: Mechanical Disorders of the Stomach, Duodenum, and Intestine

and ‘‘strangulated’’ if the incarcerated contents become ischemic with compromised blood supply. The less frequently encountered hernias are those with a higher incidence of strangulation (femoral, obturator, paraduodenal, etc.). Intussusception/Volvulus ‘‘Intussusception’’ is defined as a telescoping of one segment of bowel into another (Fig. 2). It occurs mostly in infants, with 80% of cases being observed in the first two years of life (32). It has been hypothesized that inflamed lymphoid tissue in the terminal ileum may act as a lead point by causing focal wall-motion abnormalities, with subsequent kinking of bowel and invagination of this segment into the more distal bowel by a peristaltic wave. Although lead points are found in only 5% of pediatric cases (33), as many as 80% of adult cases have a discrete lead point, usually a neoplasm (34). Thus, intussusception in the adult is an indication for operation and resection, whereas careful hydrostatic reduction with barium enema is often used successfully in children. Volvulus, by contrast, is more commonly seen in adults. It results when the intestine twists on its mesentery. Vascular compromise occurs from direct occlusion of mesenteric vessels, or from creation of a closed-loop obstruction, with resultant increases in wall tension, venous obstruction, and eventual arterial insufficiency (35). Volvulus may occur in either the small bowel or the large bowel; however, the pathogeneses are different. Volvulus of the small bowel in the adult is comprised of mobile loops of small bowel, which may twist around a fixed object. The adhesive band may be inflammatory (e.g., postoperative adhesion), congenital (e.g., omphalomesenteric duct), or iatrogenic (e.g., jejunostomy tube). A less common cause of small bowel volvulus results from a particularly narrowed

Figure 2 Barium enema study demonstrating ileocolic intussuception. The terminal ileum is seen as a filling defect within the proximal colon.

591

mesentery found with congenital malrotation, which is rare but does occur in adults (16). In contrast, the colon is usually fixed in the retroperitoneum, and is susceptible to torsion around its mesentery only in an area that may be freely mobile, namely the cecum or more commonly the sigmoid.

Pathophysiology Absorption/Secretion The GI tract accumulates 6 to 8 L of salivary, gastric, pancreatic, and intestinal secretions per day (36), with most of this fluid reabsorbed along the intestinal tract. The normal secretory and absorptive capacities of the bowel are markedly altered in bowel obstruction. Classic studies on small bowel obstruction revealed a net decrease in the absorptive capacity and a net increase in the secretory activity. In early intestinal obstruction, there is a decrease in absorption with little change in secretion. With progressive dilatation, secretion is augmented and absorption remains decreased (37,38), resulting in marked intraluminal fluid accumulation, and distention, a condition further exacerbated by luminal gas, distention, and swallowed air. These effects are potentiated in the closed-loop type of obstruction. Distention causes increased secretion and initiates a positivefeedback loop that induces high intraluminal pressures, with risk of ischemia and perforation. Fluid accumulates not only intraluminally, but also within the wall of the distended gut (edema) and eventually in the peritoneum (39). Fluid loss from various sources can be quite substantial, resulting in profound hypovolemia, electrolyte disturbance, and shock. Volume replacement is an essential aspect of preoperative management of the patient with obstruction, and it can usually be accomplished with a balanced salt solution such as lactated Ringer’s solution or normal saline, with the addition of 20 to 30 mEq/L potassium chloride (if urine output is adequate). Depending on the magnitude of dehydration, several liters of fluid may be required to restore fluid and electrolyte balance. Clinical response to fluid resuscitation is measured by heart rate, blood pressure, central venous pressures, and maintenance of adequate urinary output ( > 30 mL/hr). In elderly patients or those with underlying renal or cardiac disease, pulmonary artery catheters may be useful for monitoring resuscitation. Intestinal Blood Flow Intestinal blood flow is directly related to intraluminal pressures (40–44). Clinically, the longer a mechanical obstruction exists, the greater the degree of distention, with a concomitant increase in intraluminal pressures. Multiple classic experiments have demonstrated decreases in mucosal blood flow with progressive increase in intraluminal pressures. However, these experimentally induced pressures are often much greater than those encountered in the setting of a simple mechanical small bowel obstruction. Sustained intraintestinal pressures of 5 to 15 mmHg, representing only a mild elevation beyond normal intraluminal pressure, have been reported in experimental models of simple small bowel obstruction. In contrast, pressures greater than 15 to 30 mmHg are required to impair capillary flow. The ability of the gut to distend as well as decompress proximally prevents tremendous pressure increases. When this ability is lost, as in the closed-loop obstruction, intraluminal pressures increase, with values as high as 43 mmHg reported (45). Thus, it is reasonable to conclude that simple obstruction will usually not compromise bowel viability, whereas

medwedi.ru

592

Part Two: The Alimentary Tract—Other Conditions

closed-loop obstruction is more likely to result in the loss of regional blood flow, with subsequent ischemic changes and tissue death. Direct compression of vascular elements, whether by volvulus, intussusception, hernia, or adhesive bands, is an obvious source of ischemia. Most of these strangulations are essentially venous in character, and classic experiments demonstrated that death is more rapid from simple venous occlusion than from simultaneous arterial and venous ligation (46). In the setting of venous occlusion, the patient may have a large amount of blood lost into the bowel, resulting in profound shock that necessitates both blood and fluid resuscitation. At the time of surgery, all nonviable portions of the intestine must be resected, with viable margins assessed by Doppler signals or the use of fluorescein dye. The choice of primary closure versus ostomy depends on the clinical situation and the judgment of the surgeon. Bacterial Overgrowth, Translocation, and Antibiotic Prophylaxis In the healthy human, the proximal GI tract is relatively bacteria free, with a resident bowel flora of streptococci, lactobacilli, diphtheroids, and fungus in only small quantities, less than 104 organisms/mL (47). In the terminal ileum, coliform and bacteroides may be isolated, but again in low concentrations (105–108 organisms/mL) compared with the normal colonic flora concentration of 109 to 1012 organisms/g of stool. Peristalsis continually clears bacteria from the bowel lumen. In the setting of obstruction, this mechanism fails and bacterial stasis and overgrowth occur, with the accumulation of primarily coliform and anaerobic bacteria (48,49). Alterations in the mucosal layer of the intestinal tract may also play a role in bacterial adherence and overgrowth in obstructed intestine. It has been postulated that these changes result in a loss of barrier function of the intestinal mucosa, especially in the setting of vascular compromise which allows for bacterial translocation across the intestinal wall, leading to systemic infection and possibly sepsis (50). The role of antibiotics in bowel obstruction remains controversial (27). Generally, the longer the obstruction has been present, allowing distention of the bowel wall and the overgrowth of intestinal flora, the more likely that antibiotic prophylaxis will be of value. As the likelihood of ischemia increases, as determined by history, physical examination, and laboratory values, the threshold for using prophylactic antibiotics decreases, especially if resection is anticipated. Generally, if bowel distention has been present for longer than 24 hours, broad-spectrum antibiotics should be administered before surgery and continued for two to three days after the operation. Motility Alterations Clinically, small bowel obstruction is heralded by the onset of intermittent, crampy abdominal pain interrupted by periods of quiescence. Several studies have revealed an increase in motor activity in bowel proximal to the point of obstruction (51). This is postulated to result from a reflex response of the myenteric receptor to distention, creating increased cholinergic-stimulated myoelectric activity. The hypermotility begins initially in the segment just proximal to the obstruction, progresses cephalad with time, and is characterized by irregular electrical spike-burst activity accompanied by a loss of the normal migrating motor complex (MMC) observed in the GI tract during the fasting state (52,53). In unobstructed bowel, the MMC (‘‘housekeeper

potential’’) originates cyclically in the stomach and progresses to the terminal ileum, propelling retained foodstuffs and bacteria through the gut between meals. Distal to the site of obstruction, there are also alterations in motility manifested by a loss of the MMC, with an accompanied increase in irregular myoelectrical spike bursts. This distal activity is less vigorous than the myoelectric bursts seen proximally, perhaps related to postulated long neural inhibitory reflexes or modulation of intramural mechanoreceptors by the lack of GI contents passing through the distal segment (54). It seems as though peristaltic activity remains both proximal and distal to the obstruction, but is grossly abnormal. In the setting of partial small bowel obstruction, the normal MMC is also lost and replaced by periods of intense spike-burst activity with longer periods of quiescence. This activity remains confined to the area of obstruction and does not progress orally in the setting of complete small bowel obstruction. Normal MMC patterns are reestablished two to three days after release of the partial obstruction. These changes occur in the acute period. Prolonged obstruction leads to progressively decreased motor activity and eventually paralysis.

Diagnosis and Treatment The principal signs and symptoms of intestinal obstruction are abdominal colic, distention, vomiting, lack of flatus or defecation (obstipation), and, with prolonged symptoms, dehydration with decreasing urinary output and eventual shock. The severity of these complaints depends on the degree of the obstruction and the region of intestine involved. More proximal sites of obstruction result in the early onset of clear or bilious vomiting as a result of the rapid accumulation of salivary, gastric, biliary, and pancreatic secretions. In addition, distention is less prominent due to distal decompression, and secretions may be almost completely expelled with emesis. In lower intestinal obstructions, vomiting is less pronounced and may initially be absent. With prolonged distal obstruction, as normal peristalsis and clearance of resident bowel flora are abolished and bacterial overgrowth occurs, the vomitus may take on a characteristic feculent odor and consistency. Distention becomes more pronounced, especially with complete obstruction, as swallowed air and GI secretions accumulate proximal to the obstruction. The normal GI tract secretes approximately 6 to 8 L fluid per day, making it easy to appreciate the massive dilatation that can occur during a short period in the absence of normal clearance mechanisms. Pain is also a characteristic symptom of intestinal obstruction and is usually crampy and intermittent in nature, corresponding to the vigorous contractions of the peristaltic bowel as it attempts to push fluid and gas beyond the point of obstruction. This activity translates into the hyperactive, high-pitched sounds observed on auscultation. A metallic tinkling of bowel sounds results from the large air–fluid interface present in obstructed bowel. Between periods of peristalsis, the abdomen is quiet and the pain is less pronounced. The onset of continuous abdominal pain with subsequent peritoneal signs is more ominous, indicating the possibility of strangulation and ischemia. Most patients with bowel obstruction report some change in bowel habits, preceding the onset of other symptomatology. These changes may be subtle, such as changes in frequency of defecation, or dramatic, such as complete cessation of fecal passage and flatus as seen with complete

Chapter 28: Mechanical Disorders of the Stomach, Duodenum, and Intestine

obstruction. In addition, patients with colorectal carcinoma may report progressive narrowing of stool caliber, as well as change in color indicative of passage of blood. From a laboratory standpoint, any patient with suspected intestinal obstruction should have a complete blood cell count, electrolyte profile, blood urea nitrogen, and creatinine determination performed. Other useful studies are arterial blood gas, serum lactate, and amylase determinations. The patient with obstruction usually has profound dehydration and may exhibit any combination of electrolyte and acid–base imbalances. Hemoconcentration as a result of dehydration usually increases hemoglobin and hematocrit. Patients with high obstruction usually have hypochloremic, hypokalemic metabolic alkalosis as a result of hydrogen, sodium, and chloride losses with emesis. Volume contraction is a contributing factor to the alkalosis that may be present to a variable extent. In addition, a metabolic acidosis may be seen as a result of combined presence of dehydration and ketosis of starvation. A profound acidosis indicated by decreased bicarbonate, low pH, and increased lactate levels heralds the presence of a strangulated segment of bowel. Although modest elevation in white blood cell count may be seen with intestinal obstruction, marked leukocytosis with an accompanying leftward shift suggests ischemia. The serum amylase activity may be elevated in intestinal obstruction as a result of leakage of amylase and lipase into the peritoneal space, usually from a compromised intestinal wall. Urinalysis generally shows increased specific gravity due to volume deficit and ketosis. In the large majority of cases with compromised small bowel, the obstruction is complete. Thus important aids in the diagnosis of intestinal obstruction are plain radiographs and limited contrast studies. An obstruction series should include upright and supine abdominal films. In a patient too debilitated to sit upright or stand, lateral decubitus films suffice. Of course, pneumoperitoneum or pneumatosis indicates the need for operation. The presence of air–fluid levels in the bowel, often in a stepladder configuration, is the

593

hallmark of small intestinal obstruction (Fig. 3). Because peristalsis remains functional beyond the obstruction, gas is expelled from that point distally. Thus, proximal distention and gasless distal bowel suggest complete small bowel obstruction, mandating early operation. Small intestine or colonic distention suggests paralytic ileus or distal obstruction possibly with an incompetent ileocecal valve. The pattern of air–fluid levels suggests the level of obstruction. High duodenal obstruction may yield a double-bubble sign, indicating gas in both the stomach and proximal duodenum. Valvulae conniventes are pronounced in jejunal rather than ileal obstruction. Haustra may be distinguished from valvulae because they do not traverse the entire bowel lumen on plain radiography. Location of the air–fluid levels may also provide a clue to their origin, with the small bowel usually remaining more central on radiography, and the colon being confined to the peripheral region of the abdomen. It may be difficult to differentiate mechanical small bowel obstruction from paralytic ileus or to distinguish complete from partial obstruction (55). In this setting, contrast radiography using water-soluble contrast may rule out or confirm the presence of an obstructing lesion (either partial or complete and allow estimation of transit times of small bowel contents). Both computed tomography (CT) and small bowel follow-through have been used for abdominal imaging. Several studies suggest CT should be the firstline contrast study, because it is more accurate (80–95%) and can potentially identify mass lesions as well as ischemia (56,57). CT has been shown to be less accurate in identifying low-grade obstruction. The use of water-soluble contrast (Gastrograffin) introduces concentrated liquid into the intestine and draws fluid into the lumen. This may be of therapeutic help to actually resolve a partial obstruction (58). Intestinal transit times are greatly increased in paralytic ileus. Antegrade barium studies should be avoided if imminent operation is deemed necessary. The hyperactive bowel sounds and intense colicky abdominal

Figure 3 Characteristic upright abdominal radiograph of small bowel obstruction revealing distended small bowel, multiple air–fluid levels, and paucity of air within the colon (A). Bowel gas patterns in paralytic ileus are similar, expect that air is seen throughout both small and large bowel (B).

medwedi.ru

594

Part Two: The Alimentary Tract—Other Conditions

pain characteristic of small bowel obstruction are absent in the patient with paralytic ileus unless the source of ileus is related to peritoneal irritation caused by pancreatitis, cholecystitis, pneumonitis, or trauma. Differentiating these two entities is important because an ileus is managed nonoperatively, while bowel obstruction may require operative intervention. In addition to demonstrating air–fluid levels and possibly confirming the site of obstruction, plain radiographs may be helpful in other respects. For example, foreign bodies, as well as renal, biliary calculi or fecaliths, may be visualized radiographically, which helps to sort out underlying pathology in less clear cases. Gallstones seen radiographically may themselves be the obstructing lesions in gallstone ileus. Because the gallstone enters the bowel through a cholecystoenteric (usually duodenal) fistula and usually obstructs the narrowest part of the small bowel (terminal ileum), pneumobilia and multiple loops of distended small bowel are pathognomonic of gallstone ileus (59). Decompression of the intestine has classically been show to increase survival (Fig. 4) (59). The early management of suspected partial or complete bowel obstruction includes the passage of intestinal tubes. Shorter tubes, such as nasogastric and nasoduodenal tubes, function by aspirating swallowed air and upper GI tract secretions, thereby minimizing further intestinal distention. In most cases, nasogastric tubes are as effective as long, nasointestinal tubes (60). Some authors have had success in treating small bowel obstruction with endoscopically placed long intestinal tubes. Longer enteric tubes may be placed fluoroscopically or endoscopically to decompress distal intestinal contents, facilitating the relief of intestinal obstruction. The preferred method of decompressing a complete obstruction is operative because of the higher risks of strangulation with complete obstruction. These longer tubes may be used in a more prolonged, palliative fashion in individuals with

terminal illnesses, for example, those with extensive intraabdominal malignancies (61,62). The following principles guide the management of small bowel obstruction: 1.

2. 3.

Clinical judgment (even if that of experienced surgeons) is a notoriously ‘‘bad’’ predictor of which patients with small bowel obstruction will have compromised bowel. The great majority of cases of compromised bowel in small bowel obstruction occur in the setting of complete obstruction. The patient with clear evidence of partial small bowel obstruction (but not fever, tachycardia, leukocytosis, tenderness, or unremitting pain) does not have compromised bowel.

For years, general surgeons have trained with the adage, ‘‘Never let the sun rise or set on an intestinal obstruction.’’ This was born out of the tremendous morbidity and mortality associated with the delay in diagnosis and definitive therapy of a strangulated obstruction, and is still a reliable dictum. With the advent of nasogastric decompression and aggressive resuscitation, it has become increasingly acceptable to manage incomplete obstruction and, in a few rare instances, complete obstruction nonoperatively. For instance, few surgeons are anxious to operate on an anastomotic obstruction in a patient in stable condition during the postoperative period. Bowel compromise is unusual in this setting, and most cases of postoperative small bowel obstruction (many of which may be persistent ileus) resolve uneventfully with appropriate nonoperative treatment. However, the clinician must ever be alert for the conversion of a simple obstruction to a strangulating obstruction, heralded by an increase in abdominal pain and associated peritoneal signs, increasing white blood cell count, fever, and acidosis.

Figure 4 Classic experiments designed to prevent bowel distention by diverting esophagostomy (A) demonstrated increased survival in the canine model of complete ileal obstruction. Survival among control animals (surgical creation of complete ileal obstruction) averaged seven days, whereas survival in the experimental group averaged 35 days (B). Source: From Ref. 59.

Chapter 28: Mechanical Disorders of the Stomach, Duodenum, and Intestine

The surgeon must also bear in mind that most obstructions (complete and partial) have etiologies that are readily corrected by operation: adhesions, hernias, neoplasms, and volvulus. Two obvious and common exceptions are intussusception in an infant treated with barium enema and sigmoid volvulus in an elderly person treated initially with sigmoidoscopic decompression. The important principles of operative management of small bowel obstruction are simply stated: (i) relieve the obstruction; (ii) remove compromised (ischemic, perforated) bowel; and (iii) avoid spillage of GI contents.

Motility Disorders of the Small Intestine Etiology and Pathophysiology Paralytic ileus is the most common acute motor disorder of the small intestine. It is usually associated with an acute intraperitoneal or retroperitoneal pathologic process or operation. The pathophysiology of acute paralytic ileus is unclear, but perturbations of the enteric nervous system, the endocrine system, and GI muscle are almost certainly involved. Chronic intestinal pseudo-obstruction is a rare condition with multiple possible causes (63). It should be considered in patients with symptoms of recurrent small bowel obstruction, especially if these remain unexplained at operation. Marked chronic enlargement anywhere along the GI tract (megaduodenum, megajejunum, or megacolon) may occur. Mechanical obstruction must be ruled out, even in patients with known pseudo-obstruction, because vascular compromise and perforation may ensue if a mechanical obstruction is missed.

595

MECHANICAL DISORDERS OF THE COLON Colonic Obstruction Etiology and Pathophysiology Most mechanical colon obstructions are caused by cancer, volvulus, or diverticulitis, in decreasing order of frequency (35). In contrast to small bowel obstruction, most large bowel obstructions (60–65%) are a result of intrinsic neoplasms, usually in the left side of the colon (66). Postulated reasons for this phenomenon include the steadily decreasing caliber of the intra-abdominal colon as it progresses from right to left, combined with the more solid character of stool in the left colon. In addition, there is a higher frequency of circumferential tumor within the left colon. Inflammatory processes, most commonly diverticulitis, account for approximately 10% of all large bowel obstructions. Uncommon intrinsic etiologies of obstruction include inflammatory bowel disease, ischemic stricture, postradiation stricture, and intussusception. The most common external cause (and second most common cause overall) of large bowel obstruction is volvulus, accounting for approximately 10% to 15% of large bowel obstructions. Volvulus usually affects the sigmoid (75%) or cecum (20%) (Fig. 5). Transverse colon volvulus is rare (5%). Sigmoid volvulus results when the colon is elongated and distended by such factors as chronic constipation or high fiber intake, making the bowel more likely to volvulize on itself (67). Finally, obstructing lesions, such as rectal foreign bodies and stool impaction, can cause large bowel obstruction. Less common extrinsic etiologies of colonic obstruction include hernias, carcinomatosis, extraintestinal tumor, and recurrent rectal carcinoma.

Diagnosis and Treatment The clinical presentation of small bowel motility disorders may be remarkably similar to that of patients with mechanical small bowel obstruction. Signs and symptoms include distention, pain, obstipation, vomiting, and dehydration. Plain radiographs may show small bowel distention with air–fluid levels. Colonic distention is common. Upper GI tract series and small bowel follow-through with thin barium are useful to rule out mechanical obstruction. CT with contrast may aid in diagnosis but has been shown to be not as accurate in low-grade obstruction. Results of esophageal manometry are usually abnormal in patients with chronic intestinal pseudo-obstruction, as are those of radioisotopic scintigraphic transit scans. The ingestion of nonabsorbable radiopaque markers may be helpful in identifying the site of functional obstruction along the alimentary tract. Treatment of acute paralytic ileus consists of nasogastric decompression (long intestinal tubes do not pass without peristalsis), intravenous fluids, nutritional support, mobilization (ambulation if possible), and therapy for any associated underlying diseases (e.g., pancreatitis). Operation is rarely indicated unless perforation is likely (55). Treatment of chronic intestinal pseudo-obstruction is largely medical and includes promotility agents; dietary, nutritional, and psychologic counseling; intermittent antibiotics for bacterial overgrowth; and treatment of diarrhea or constipation (64). Long-term parenteral alimentation may be necessary. Acute exacerbations are treated with intravenous hydration, tube decompression, and antibiotics as needed. Operation is palliative and a last resort; it is indicated if mechanical obstruction is suspected, to place decompressive gastrostomy and jejunostomy tubes, and to manage complications (e.g., stercoral perforation) (65).

Diagnosis and Treatment Patients with a completely obstructing colon cancer or colon volvulus have progressive distention and obstipation. Nausea and vomiting are variable, depending on the competence of the ileocecal valve. Peritoneal signs suggest compromised bowel or perforation. Acute colon obstruction not uncommonly complicates acute diverticulitis. Despite resolution of the acute attack, progressive colonic distention may be an indication for operation in acute diverticulitis. Alternatively, chronic partial obstruction of the sigmoid from chronic diverticular disease is associated with cramps, distention, and difficult defecation. Operation for obstruction is more often indicated in chronic diverticulitis. The diagnostic workup of colon obstruction consists of plain radiography (obstruction series), sigmoidoscopy, and limited barium enema or CT with rectal contrast. Plain films suggest the diagnosis. Operation is indicated if cecal diameter is 12 cm or greater due to increased risk of ischemia and/or perforation. Sigmoidoscopy rules out rectal pathology and may be diagnostic of obstructing rectosigmoid cancer or diverticulitis. Air insufflation should be negligible. Careful barium enema or CT documents obstruction and should be terminated when complete obstruction or extravasation is seen. CT is currently considered to be the contrast study of choice due to its high accuracy. Sigmoidoscopy is successful in reducing sigmoid volvulus in approximately 85% of cases, with emergency laparotomy and sigmoid resection with end-colostomy reserved if endoscopy is unsuccessful or ischemia is suspected. Because of the high rate of recurrence, elective sigmoid resection, usually with primary anastomosis, should

medwedi.ru

596

Part Two: The Alimentary Tract—Other Conditions

Figure 5 The ‘‘bent inner tube’’ sign of sigmoid volvulus. The distended loop of sigmoid colon is directed to the right upper quadrant, with its base located in the left lower quadrant (A). In contrast, the ‘‘coffee bean deformity’’ of cecal volvulus is directed toward the left upper quadrant, with its base in the right lower quadrant (B).

be scheduled after successful reduction. Unlike sigmoid volvulus, which presents as a large bowel obstruction, cecal volvulus is seen as small bowel obstruction. Colonoscopic detorsion is ineffective in this instance, and laparotomy should be undertaken to reduce the volvulus and prevent recurrence through a definitive procedure such as cecal resection, cecostomy, or cecopexy. Resection with primary anastomosis is acceptable if irreversible cecal damage has occurred. Obstructing colon cancer may be managed initially with decompressing colostomy, resection, and end colostomy (e.g., Hartmann’s procedure), or less often with resection and primary anatomists following on-table mechanical cleansing of the obstructed colon. Intractable acute obstruction from acute diverticulitis is managed with Hartmann’s operation, whereas chronic obstruction from chronic diverticular disease is treated with resection and primary anastomosis.

tract, with the largest radius. When the cecum distends and pressure increases in this setting, wall tension increases and the risk of perforation becomes substantial (Fig. 7) (69). Cecal diameters greater than 12 cm on abdominal radiographs are of great concern and may necessitate decompression with either a transverse colostomy or a cecostomy. Alternatively, colonoscopy can be used in the appropriate patient for decompression in individuals with Ogilvie’s syndrome. Intravenous neostigmine has also been shown to be very effective for acute colonic pseudoobstruction (71).

Colonic Dysmotility Etiology and Pathophysiology Colonic dysmotility may mimic mechanical obstruction from tumor, diverticulosis, stool, or volvulus. Presentation may be acute (e.g., Ogilvie’s syndrome or toxic megacolon) or chronic (e.g., colonic inertia or idiopathic megacolon). Most deaths from colonic dysmotility occur in the acute group from perforation or fulminant colitis. The pathophysiology of acute colonic ileus is unclear, but motor function is often abnormal in the setting of fulminant mucosal inflammation. Medications (e.g., narcotics) or operations (e.g., hip replacement) may precipitate colonic ileus. Chronic colon dysfunction may be congenital (e.g., adult Hirschsprung’s disease) or acquired (e.g., laxative abuse). In practice, most cases of acute and chronic colonic dysfunction are idiopathic (68). Experimental evidence has revealed bowel distention, not sustained increases in intraluminal pressures, to be the hallmark of simple obstruction (44). This carries important implications in colonic obstruction or acute colonic ileus, especially in a patient with a competent ileocecal valve and with the massive dilatation that frequently accompanies Ogilvie’s syndrome (Fig. 6). Laplace’s law dictates that wall tension is the product of radius and internal pressure. The cecum is the widest portion of the GI

Figure 6 The massive colonic dilatation associated with Ogilvie’s syndrome.

Chapter 28: Mechanical Disorders of the Stomach, Duodenum, and Intestine

Cecum

seen in healthy subject. Total abdominal colectomy and ileoproctostomy are indicated if colonic hypomotility is confirmed in the patient with severe symptoms and relatively normal gastric emptying and small bowel transit. Adult Hirschsprung’s disease may respond to internal sphincterotomy or distal proctectomy with coloanal anastomosis. Frozen-section confirmation of proximal resection margins is necessary to confirm ganglion cells.

Desc. colon 4.5 cm. T = 340 cm.

9.75 cm.

Τ = 735 cm.

597

T = π D pr

SUMMARY Figure 7 As the colon dilates in cases of obstruction or ileus, wall tension is greatest in the region of largest diameter, as dictated by Laplace’s law. The risk of perforation increases with increasing wall tension. Source: From Ref. 70.

Diagnosis and Treatment Diagnostic evaluation in the patient with colonic dilatation is focused on answering three questions: (i) Is there distal obstruction? (ii) Is this a manifestation of colonic dysmotility, and if so, was the hypomotility caused by mucosal disease? (iii) Is the viability of the colon compromised? This evaluation is done by physical examination, plain abdominal radiography, protosigmoidoscopy, and limited retrograde barium study. Complete distal obstruction requires urgent operative decompression. If distal obstruction is ruled out, acute distention may be caused by mucosal disease (e.g., ‘‘megacolon’’ from inflammatory bowel disease, or Clostridium difficile colitis), ischemia, or some other poorly understood cause (e.g., opioids, stroke, and reflex dysmotility after major orthopedic surgery). In the setting of clinical toxicity, megacolon associated with mucosal disease should be treated by subtotal colectomy and ileostomy. Segmental ischemia may be treated with partial colectomy. In either case, margin viability cannot be assessed by gross inspection and frozen section confirmation is important. Diagnostic evaluation in the adult patient with chronic colonic dysfunction is designed to rule out colonic obstruction, global motility disorder, and adult short-segment Hirschsprung’s disease, and to confirm colonic dysfunction. On plain radiographs, patients with colonic obstruction or dysfunction and a competent ileocecal valve show colonic dilatation and little small bowel and rectal gas. In contrast, those with incompetent valves may have radiographic evidence of small bowel and colonic distention. Paralytic ileus results in air–fluid levels evenly distributed throughout the GI tract, and at times, it may be extremely difficult to differentiate from colonic obstruction in the setting of an incompetent ileocecal valve. Barium enema or CT with contrast can be useful in these circumstances to exclude the colon as a site of obstruction. Colonoscopy may also be used in this setting; it has the advantage of facilitating cecal decompression or identifying a site of discrete obstruction. Other important tests include anorectal manometry, ingestion of radiopaque markers, scintigraphy, and defecography. In colonic inertia or idiopathic megacolon, anorectal manometry shows normal relaxation of the internal sphincter in response to rectal distention (provided that normal sensory threshold exists). This feature is absent in adult short-segment Hirschsprung’s disease. A deep mucosal biopsy sample of the distal rectum in the latter disease may show a paucity of ganglion cells, but this may also be

Mechanical disorders of the GI tract result when either an obstructive process or a derangement in motility alters the normal digestive and absorptive functions of the stomach, duodenum, or intestine. Depending on the site of obstruction, these patients often have a predictable history and physical examination. An understanding of the underlying pathophysiologic changes common to these disorders allows early correction of underlying metabolic derangements and paves the way for ultimate surgical intervention designed to restore normal GI function.

REFERENCES 1. Shone DN. Malignancy is the most common cause of gastric outlet obstruction in the era of H2 blockers. Am J Gastro 1995; 90:1769–1770. 2. Graham DY. Ulcer complications and their nonoperative treatment. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal Disease. 5th ed. Philadelphia: WB Saunders, 1993:698. 3. Adrogue HJ, Madias NE. Management of life-threatening acid–base disorders. N Engl J Med 1998; 338:107. 4. Galla JH. Pathophysiology of metabolic alakalosis. Hosp Pract 1987:95–118. 5. Parkman HP, et al. Electrogastrography and gastric emptying scintigraphy are complementary for assessment of dyspepsia. J Clin Gastroenterol 1997; 24:214. 6. Galil MA, Critchle M, Mackie CR. Isotope gastric emptying tests in clinical practice; expectation, outcome and utility. Gut 1993; 34(7):916–919. 7. Jaffin BW, Kaye MD. The prognosis of gastric outlet obstruction. Ann Surg 1985; 201:276. 8. Matthews JB, Silen W. Operations for peptic ulcer disease and early postoperative complications. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal Disease. 5th ed. Philadelphia: WB Saunders, 1993:713. 9. Mentes AS. Parietal cell vagotomy and dilatation for peptic duodenal stricture. Ann Surg 1990; 212:597. 10. Lindor KD, Ott BJ, Hughes RW Jr. Balloon dilatation of upper digestive tract strictures. Gastroenterology 1985; 89:545. 11. Kuwada SK, Alexander GL. Long-term outcome of endoscopic dilation of non-malignant pyloric stenosis. Gastrointest Endosc 1995; 41:15. 12. Brune IB, et al. Laparoscopic gastrojejunostomy and endoscopic biliary stent placement for palliation of incurable gastric outlet obstruction with cholestasis. Surg Endosc 1997; 11:L834. 13. Balatazar U, Dunn J, Floresguerra C, et al. Superior mesenteric artery syndrome: an uncommon cause of intestinal obstruction. South Med J 2000; 93(6):606–608. 14. Fukuya T, Brown BP, Lu CC. Midgut volvulus as a complication of intestinal malrotation in adults. Dig Dis Sci 1993; 38:438. 15. Raissi B, Taylor BM, Taves DH. Recurrent superior mesenteric artery (Wilkie’s) syndrome. Can J Surg 1996; 39:410. 16. Watkins BP, Patel NY, Gundersen SB. Midgut vovulus. J Am Coll Surg 2003; 196(6):986. 17. Wasselle JA, Norman J. Acute gastric volvulus: pathogenesis, diagnosis, and treatment [review]. Am J Gastroenterol 1993; 88:1780.

medwedi.ru

598

Part Two: The Alimentary Tract—Other Conditions

18. Harriss DR, et al. Paraesophageal hiatal hernia: when to operate. J R Coll Surg Edin 1992; 37:97. 19. Daniels I, Chisolm EM. Changing patterns in the management of gastric vovulus over 14 years. Br J Surg 2000; 87(9): 1251–1252. 20. Kusano M, et al. Further classification of dysmotility-like dyspepsia by interdigestive gastroduodenal manometry and plasma motilin level. Am J Gastroenterol 1997; 92:481. 21. Schuffler MD, Sinahan MN. Intestinal obstruction and pseudo-obstruction. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal Disease. 5th ed. Philadelphia: WB Saunders, 1993:898. 22. Malagelada J-R, Azpiroz F, Mearin F. Gastroduodenal motor function in health and disease. In: Sleisinger MH, Fordtran JS, eds. Gastrointestional Disease. 5th ed. Philadelphia: WB Saunders, 1993:486. 23. Koch KL. Diabetic gastropathy: gastric neuromuscular dysfunction in diabetes mellitus: a review of symptoms pathophysiology and treatment. Dig Dis Sci 1999; 44(6):1061–1075. 24. Schirmer BD. Gastric atony and the Roux syndrome. Gastroenterol Clin North Am 1994; 23:327. 25. Wilson P, et al. Pathologic duodenogastric reflux associated with persistence of symptoms after cholecystectomy. Surgery 1995; 117:421. 26. Parkman HP, Miller MA, Fisher RS. Role of nuclear medicine in evaluating patients with suspected gastrointestinal motility disorders. Semin Nucl Med 1995; 25:289. 27. Levine BA, Aust JB. Surgical disorders of the small intestine. In: Sabiston DC Jr, ed. Essentials of Surgery. Philadelphia: WB Saunders, 1987. 28. Wangensteen OH. Historical aspects of the management of acute intestinal obstructions. Surgery 1969; 65:363. 29. DiSario JA, et al. Small bowel carcinoma: epidemiological and clinical characteristics from a population based registry. Am J Gastroenterol 1994; 89:699. 30. Tanphiphat C, Chittmittrapat S, Prosopsunti K. Adhesive small bowel obstruction. Am J Surg 1987; 154:283. 31. Kalff JC, Schraut WH, Simmons RL, et al. Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann Surg 1998; 228(5):652–663. 32. Stevenson RJ. Non-neonatal intestinal obstruction in children. Surg Clin North Am 1985; 65:1217. 33. Ziegler MM. Gastrointestinal problems after the first month of life. In: Hardy JD, ed. Hardy’s Textbook of Surgery. Philadelphia: JB Lippincott, 1988. 34. Nagorney DM, Starr MG, McIlrath DC. Surgical management of intussusception in the adult. Ann Surg 1981; 193:230. 35. Lopez-Kostner F, Hool GR, Lavery IC. Management and causes of acute large bowel obstruction. Surg Clin North Am 1997; 77(6):1265–1290. 36. Guyton AC. Textbook of Medical Physiology. Philadelphia: WB Saunders, 1986. 37. Shields R. The absorption and secretion of fluid and electrolytes by the obstructed bowel. Br J Surg 1965; 25:774. 38. Wright HK, O’Brien JJ, Tilson MD. Water absorption in experimental closed segment obstruction of the ileum in man. Am J Surg 1971; 121:96. 39. Chappuis CW, Cohn I Jr. Intestinal Obstruction. In: Fielding LP, Welch JP, Moore FD, eds. Clinical Surgery International. Vol. 13. Edinburgh: Churchill Livingstone, 1987:32. 40. Enochsson L, Nylander G, Ohman U. Effects of intraluminal pressure on regional blood flow in obstructed and unobstructed small intestine in the rat. Am J Surg 1982; 144:558. 41. Gatch WD, Trusler HM, Ayers KD. Effects of gaseous distention on bowel obstruction: incarceration of intestine by gas traps. Arch Surg 1927; 14:1215. 42. Oppenheimer MJ, Mann FC. Intestinal capillary circulation during distention. Surgery 1943; 13:548. 43. Shikata J, Shida T, Amino K. Experimental studies on the hemodynamics of the small intestine following increased intraluminal pressure. Surg Gynecol Obstet 1983; 156:155.

44. Ohman U. Studies on small intestinal obstruction. I. Intraluminal pressure in low small bowel obstruction in the cat. Acta Chir Scand 1975; 141:413. 45. Burgett GE, Martzliff K, Suckon G. The closed intestinal loop: relation of intra loop (jejunum) pressure to the clinical condition of the animal. Arch Surg 1936; 21:289. 46. Wangensteen OH. The early diagnosis of acute intestinal obstruction with comments on pathology and treatment. Dis Colon Rectum 1982; 25:65. 47. Gurbach SL. Intestinal microflora. Gastroenterology 1971; 60:1110. 48. Sykes PA, Boulter KH, Schofield PF. The microflora of the obstructed bowel. Br J Surg 1976; 63:721. 49. Gupta S, Reddy KRRM, Samyal SC. Bacterial flora in acute small bowel obstruction. Chemotherapy 1980; 26:446. 50. Deitch EA, et al. Obstructed intestine as a reservoir for systemic infection. Am J Surg 1990; 159:394. 51. Summers RW, et al. Acute intestinal obstruction: an electromyo-graphic study in dogs. Gastroenterology 1983; 85:1301. 52. Prihoda M, Glatt A, Summers RW. Mechanisms of motility changes during acute intestinal obstruction in the dog. Am J Physiol 1984; 247:G37. 53. Enochsson L, et al. Myoelectric motility patterns during mechanical obstruction and intestinal obstruction and paralysis of the small intestine in the rat. Scand J Gastroenterol 1987; 22:969. 54. Carlson RS, Wangensteen OH. Motor activity of the distal small bowel in intestinal obstruction. Proc Soc Exp Biol Med 1930; 27:676. 55. Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg 2003; 138(2):206–214. 56. Peck JJ, Milleson T, Phelan J. The role of computed tomography with contrast and small bowel follow through in management of small bowel obstruction. Am J Surg 1999; 177(5):375–378. 57. Maglinte DD, Heitkamp DE, Howard TJ, et al. Current concepts in imaging of small bowel obstruction. Radiol Clin North Am 2003; 41(2):263–283. 58. Biondo S, Pares D, Mora L, et al. Randomized clinical study of gastrograffin administration in patients with adhesive small bowel obstruction. Br J Surg 2003; 90(5):542–546. 59. Wangensteen OH, Rea J. The distention factor in simple intestinal obstruction. Surgery 1939; 5:327. 60. Fleshner PR, et al. A prospective randomized trial of short versus long tubes in adhesive small bowel obstruction. Am J Surg 1995; 170:366. 61. Wolfson PJ, et al. Use of the long tube in the management of patients with small intestinal obstruction due to adhesions. Arch Surg 1985; 120:1001. 62. Krouse RS, McCahill LE, Easson AM, et al. When the sun can set on an unoperated bowel obstruction: management of malignant bowel obstruction. J Am Coll Surg 2002; 195(1):117–128. 63. Kamm MA. Intestinal pseudo-obstruction. Gut 2000; 47:84. 64. Mazloum BW, Barnes JB, Lee M. Cisapride as a successful treatment for acute intestinal pseudo-obstruction. South Med J 1996; 89(8):828–830. 65. Murr MM, Sarr MG, Camilleri M. The surgeon’s role in the treatment of chronic intestinal pseudoobstruction. Am J Gastroenterol 1995; 90:2147. 66. Lee YM, Law WL, Chu KW, et al. Emergency surgery for obstructing colorectal cancers: a comparison between right-sided and leftsided lesions. J Am Coll Surg 2001; 53(1):120–121. 67. Chiu HH, Jao YT, Mo LR. Recurrent sigmoid volvulus. Gastrointest Endosc 2002; 56(3):419–420. 68. Mc Intyre PB, Pemberton JH. Pathophysiology of colonic motility disorders. Surg Clin North Am 1993; 73(6):1225–1243. 69. Miller LD, Mackie JA, Rhoads JE. The pathophysiology and management of intestinal obstruction. Surg Clin North Am 1962; 42:1285. 70. Wangensteen OH. Intestinal Obstruction. Springfield, Illinois: Charles C. Thomas, 1937:51. 71. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med 1999; 341(3):137–141.

29 Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor Janette Gaw and Walter E. Longo

INTRODUCTION Anorectal diseases are common presenting problems to a surgeon. The symptoms can range from causing an annoyance to causing severe lifestyle limitations and lifethreatening sepsis. A thorough understanding of the normal anatomy and physiology of the anorectum is a prerequisite to understanding the pathophysiology and treatment of anorectal disease.

ANORECTAL ANATOMY Rectum The definition of the anorectum may seem fairly straightforward in that it represents the terminal portion of the gastrointestinal tract. However, anatomical definitions of the anorectum can be confusing because of the multiple landmarks that are used (1). The rectum is partially intraperitoneal and partially extraperitoneal. The proximal third is almost covered by peritoneum except for the mesorectum, while the middle third is covered by peritoneum only anteriorly. The distal third of the rectum is completely extraperitoneal. The level of the anterior peritoneal reflection varies between men and women. For women, it is between 5 and 7.5 cm above the anal verge, and for men, it is between 7 and 9 cm. The rectum starts at the rectosigmoid junction and continues into the anal canal. However, there are multiple definitions of the rectosigmoid junction. It has been described in terms of length as being 15 cm from the anal verge. Other landmarks used include the level of the sacral promontory as well as the peritoneal reflection. In terms of a surgical landmark, the rectum is also described as beginning at the confluence of the teniae coli. It is where the teniae splay out at the rectosigmoid junction to become a continuous layer of longitudinal muscle around the rectum (Fig. 1). However, because this landmark cannot be seen endoscopically, the National Cancer Institute has defined the rectum as the last 12 cm above the anal verge (2). The purpose of the guideline is to create uniformity in reporting results of clinical trials and for interpreting the literature.

The pelvis is covered by the endopelvic fascia (Fig. 1). The endopelvic fascia is composed of two layers, namely the visceral layer and the parietal layer. It is the visceral layer of the pelvis that envelops the rectum as the fascia propria of the rectum. The fascia propria condenses on either side of the rectum below the peritoneal reflection to form the lateral ligaments. The parietal layer of the endopelvic fascia forms the presacral fascia. This fascia covers the sacral veins. These veins can cause hemorrhage when the presacral fascia is surgically violated during rectal mobilization. The fascia propria and the presacral fascia fuse below the level of S4 to form the retrorectal fascia (rectosacral fascia or Waldeyer’s fascia). This is a thick layer that needs to be sharply excised for complete mobilization of the rectum down to the levator floor. Anteriorly, Denonvilliers’ fascia is formed by the condensation of the areolar tissue anterior to the rectum. This separates the rectum from the bladder and the vagina in women, or from the prostate and seminal vesicles in men.

Fascial Structures Understanding the fascial planes is critical in treating anorectal diseases. A good working knowledge is crucial in an oncologically sound resection of rectal neoplasm, which can make a difference in local recurrence rates. Also, these planes delineate spaces that can represent routes of abscess extension, which will be discussed later.

Figure 1 Anorectal anatomy. Source: From Ref. 1.

medwedi.ru 599

600

Part Two: The Alimentary Tract—Other Conditions

Figure 2 Anal canal. Source: From Ref. 1.

Anal Canal The terminology describing the structures and the anatomy of the anal canal is also quite varied (3). The description of surgical anal canal is a clinical one and correlates with a digital examination, but not with histology. It is approximately 4 cm in length from the anal verge to the anorectal ring (Fig. 2). The anorectal ring is defined as the proximal extent of the levator–external anal sphincter complex. As the rectum becomes the anal canal, the gross appearance of the mucosa changes. The smooth mucosa of the rectum becomes plicated with 12 to 14 longitudinal folds known as the columns of Morgagni. The bases of the columns form anal valves. Above each anal valve is an anal crypt that is connected to an anal gland via an anal duct. This defines a cryptoglandular complex and can vary in number from 4 to 10. The anal glands traverse the mucosa and can end in the internal sphincter or intersphincteric

space, or even into the external sphincter (Fig. 3) (1). These cryptoglandular complexes are thought to be responsible for the development of perianal abscesses and fistulae (Fig. 3). Anal glands contain and can also give the ‘‘toothed’’ appearance of the dentate line, also known as the pectinate line. The dentate line is where the intestinal mucosa derived from the endoderm fuses with the ectodermal skin. This is approximately 2 cm from the anal verge and represents a transition in terms of blood supply, innervation, and lymphatic drainage, which is crucial in understanding the oncologic behavior of malignancies that arise from this area. The epithelium in this area also changes in morphology. As the rectum becomes the anal canal, and as the anal canal terminates at the anal verge, the epithelium also changes from intestinal-type to columnar mucosa and then to squamous cell epithelium. The anal transition zone (Fig. 2)

Figure 3 Cryptoglandular theory on anorectal abscess and fistula formation. Source: From Ref. 1.

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

is the area above the dentate line and has a combination of columnar, cuboidal, and squamous cell epithelium. This area is thought to be important in being able to differentiate between solid stool, liquid, and gas (4). It is also known as the cloacogenic zone and is important for classification of neoplasms. Between the dentate line and the anal verge is the anoderm (Fig. 2), which consists of squamous cells that lack typical skin adnexal tissues such as hair follicles and glands. At the anal verge, the skin is arranged in radial folds, and the epithelium changes to one that contains hair and glands. This area is called the anal margin.

Musculature The musculature in the pelvis consists of the muscles lining the sidewalls of the pelvis, the pelvic floor, and the sphincteric complex (1). The external boundary of the pelvis is formed by the obturator internus and the piriformis muscle (Fig. 3). These muscles and their investing fascia serve as routes where infection can spread from the pelvis to extrapelvic structures. For example, an abscess in the deep postanal space can become a horseshoe abscess by tracking along the obturator internus fascia or present as a soft tissue infection in the lower extremity. The pelvic diaphragm is a funnel-shaped structure that supports the pelvic and abdominal structures and contains two hiatal openings through which the gastrointestinal and urogenital tract traverse. The levator ani makes up the posterior portion of the diaphragm and is composed of three separate components: iliococcygeus, pubococcygeus, and puborectalis muscles (Fig. 4). The puborectalis muscle forms part of the external sphincter complex as well. It provides a U-shaped sling that pulls the anorectum anteriorly, resulting in an increased angulation between the rectum and anus. This anorectal angle contributes to the mechanism for continence and relaxes during defecation to straighten the rectum. The perineal body is anterior to the anus and helps support the pelvic floor as well. It is a tendinous intersection formed by the superficial and deep transverse perinea muscle, external sphincter muscle, and bulbocavernosus muscle.

Figure 4 Pelvic floor anatomy. Source: From Ref. 1.

601

The internal and external sphincter muscles form the anal sphincter mechanism. The internal sphincter muscle is a smooth muscle and is a continuation of the circular muscles of the rectum. It is innervated by the autonomic nervous system, both sympathetic and parasympathetic. It is continually in a contracted state and contributes to a large portion of the resting anal tone (1). The external anal sphincter is composed of striated skeletal muscles, which is innervated by the somatic nervous system, specifically by the inferior rectal branch of the pudendal nerve. Traditionally, the external sphincter is divided into the subcutaneous, superficial, and deep components (Fig. 2), although this distinction is not as surgically relevant. The subcutaneous portion of the external sphincter is attached to the coccyx by the anococcygeal ligament, while the deep portion of the external sphincter is inserted anteriorly to the perineal body. The external sphincter can be actively contracted for only 30 to 60 seconds. However, it does maintain a resting electrical tone through a reflex arc at the level of the cauda equina and contributes to 25% to 30% of the resting anal tone (1). The intersphincteric groove (Fig. 3) is the space in between the internal and external sphincter and can be palpated below the dentate line. The longitudinal muscles of the rectum join some of the fibers of the puborectalis muscle to descend in this interface and form the corrugator cutis ani, which attaches to the perianal skin.

Para-Anal Spaces There are several potential spaces in the pelvis (Fig. 5), which are important clinically, because they can be routes where infection can travel. Understanding these spaces is critical in being able to recognize these potentially lifethreatening infectious disease processes and in adequately controlling them. The potential spaces include the perianal space, the ischiorectal space, the intersphincteric space, the supralevator space, superficial and deep postanal space, and the rectosacral (or retrorectal) space (5). The perianal space is the area that surrounds the anal verge and extends into the subcutaneous fat of the buttocks laterally. It extends into the intersphincteric space and contains the internal and external hemorrhoidal plexus, the subcutaneous portion of the external sphincter, distal internal anal sphincter, and the corrugator ani. The ischiorectal space is located superiorly to the perianal space in the ischiorectal fossa. It is bordered medially by the anal canal and rectum, laterally by the pelvic sidewall, superiorly by the levator ani, anteriorly by the urogenital diaphragm and the transversus perinei, and posteriorly by the sacrotuberous ligament and the gluteus maximus. Alcock’s canal runs in the superolateral wall and contains the pudendal nerve and the internal pudendal vessels. Also in this space are the inferior rectal vessels and nerves, and the scrotal or labial vessels. The intersphincteric space is the area between the internal and external anal sphincters. Most of the anal glands end in this space, and the space also contains the internal hemorrhoidal plexus. The supralevator space is located above the levator ani and below the peritoneum. The medial border is formed by the rectum, whereas the lateral border is formed by the obturator fascia. The rectosacral (or retrorectal) space is the area where presacral tumors of developmental origin are located. It is defined anteriorly by the fascia propria of the rectum and posteriorly by the presacral fascia. Inferiorly, Waldeyer’s

medwedi.ru

602

Part Two: The Alimentary Tract—Other Conditions

Figure 6 Arterial anatomy. Source: From Ref. 5.

Figure 5 Pararectal and para-anal spaces: (A) coronal view, (B) sagittal view. Source: From Ref. 5.

fascia (also referred to as retrorectal fascia or rectosacral fascia) borders the retrorectal space. This space is continuous superiorly with the retroperitoneum. The superficial and deep postanal spaces communicate with the ischiorectal fossa and are potential sources of horseshoe abscesses. The superficial postanal space is located between the anococcygeal ligament and the skin, whereas the deep postanal space is above this area in between the anococcygeal ligament and the anococcygeal raphe of the pelvic floor.

Blood Supply The blood supply of the rectum is mostly from the superior hemorrhoidal artery (superior rectal artery) and, to a variable degree, the middle hemorrhoidal artery (Fig. 6). The superior hemorrhoidal artery can be considered the terminal branch or a direct continuation of the inferior mesenteric artery. It bifurcates into left and right branches at the level of S3 and forms a rich anastomotic network with the middle hemorrhoidal artery in the rectal submucosa. The contribution of the middle hemorrhoidal artery varies depending on the size of the superior hemorrhoidal artery. Its absence

has been reported in 40% to 88% of the specimens, whereas its presence has been reported in 94% to 100% by some (5). The middle hemorrhoidal arteries originate from the internal iliac arteries (hypogastric arteries) or pudendal arteries. They course through the lateral pelvic wall and reach the rectum at a level above the levator ani and not through the lateral ligaments. The anorectum receives its blood supply from the superior hemorrhoidal artery and the inferior hemorrhoidal artery. The inferior hemorrhoidal artery is a branch of the pudendal artery, which arises from the internal iliac artery. The inferior hemorrhoidal artery passes through the external sphincters and continues upward in the submucosa. The venous drainage of the rectum follows that of the arterial supply. The superior hemorrhoidal vein drains through the inferior mesenteric vein to the portal system. The anorectum drains through the middle and inferior hemorrhoidal veins that drain into the systemic system via the internal iliac veins and then into the inferior vena cava.

Lymphatic Drainage The lymphatic drainage of the rectum and of the anus also follows the arterial supply. The lymphatic drainage of the upper two-thirds of the rectum is exclusively through the superior hemorrhoidal nodes to the inferior mesenteric nodes and then to the para-aortic nodes. The lower third of the rectum, on the other hand, drains through two systems: one system drains upwards, through the superior hemorrhoidal and inferior mesenteric nodes, and the other drains laterally to the internal iliac nodes. The drainage of the anal canal is also through two systems and is demarcated by the dentate line. Above the dentate line, the drainage is to the inferior mesenteric nodes and to the internal iliac nodes. Below the dentate line, it drains through the inferior hemorrhoidal lymphatics to the superficial inguinal nodes.

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

Nerve Supply The anorectum and the pelvis are supplied by the autonomic nervous system and the somatic nervous system (Fig. 7).

Autonomic Nervous System The autonomic nervous system is subdivided into the sympathetic and parasympathetic nervous system. Sympathetic Nervous System The sympathetic innervation of the rectum parallels the blood supply. The lateral columns of T12 to L3 provide sympathetic innervation to the left colon and upper rectum. The preganglionic fibers pass through the white rami communicantes to the sympathetic chain. The fibers after the sympathetic chain travel via the lumbar splanchnic nerves to join the preaortic plexus and synapse at the inferior mesenteric plexus. The postganglionic fibers then travel along the inferior mesenteric artery to the left colon and upper rectum. The sympathetic innervation of the lower rectum and the anal canal is supplied by the terminal branches of the aortic plexus and the lumbar splanchnic nerves. The nerves combine to form the superior hypogastric plexus or the presacral nerve, which then descends into the pelvis. It then divides into two hypogastric nerves, which can be found at the sacral promontory. It continues on caudally to supply the lower rectum, anal canal, bladder, and genitalia. In general, rectal motility and contractility are inhibited by sympathetic stimulation. Sympathetic stimulation of the internal sphincter was classically thought to cause a constriction (6), although there is some evidence that it may cause a relaxation (7).

603

Parasympathetic Nervous System The parasympathetic nervous supply of the anorectum is innervated by the sacral parasympathetic centers in S2 to S4. The nervi ergentes originate from the sacral parasympathetic centers and join the pelvic plexuses of the sympathetic system on the pelvic sidewall. From there, it travels along the presacral nerve to (i) the inferior mesenteric plexus, distributed along the inferior mesenteric artery to the upper rectum, and to (ii) the pelvic plexus supplying the internal sphincter, bladder, and genital organs, and lastly to (iii) periprostatic plexus, which supplies the prostate, seminal vesicles, corpora cavernous, vas deferens, ejaculatory ducts, and bulbourethral glands (8). Stimulation of the parasympathetic system results in an increase in rectal tone, motility, and relaxation of the internal sphincters.

Somatic Nervous System The somatic pudendal nerve (S2–S4) innervates the pelvic floor. The external anal sphincter is controlled by the inferior hemorrhoidal branch of the internal pudendal nerve and the perineal branch of S4. In about a third of the population, there is a direct branch from the fourth sacral nerve to the external sphincter as well (9). The puborectalis muscle is innervated by a direct branch from S3 and S4. The levator ani is supplied on its pelvic side by the fourth sacral nerves, whereas its perineal surface is innervated by the inferior hemorrhoidal branches of the pudendal nerves. Sensation of the anal canal is supplied by the inferior hemorrhoidal branch of the pudendal nerve. Pain can be felt from the anal verge to within 1.5 cm proximal to the dentate line (9). In contrast, the rectum can only sense distention, which is carried back to S2 to S4 by parasympathetic nerves.

NORMAL PHYSIOLOGY OF THE ANUS AND RECTUM The anorectum is mainly responsible for maintaining continence and for evacuation. These are highly complex and coordinated processes, the dysfunction of which can be distressing. Incontinence and constipation can limit patients’ lifestyles severely and have devastating effects on their quality of life. An understanding of normal physiology is essential to properly treat these patients.

Fecal Continence Fecal continence is maintained by several factors, both mechanical and neurologic. These are discussed below.

Stool Volume and Consistency Stool volume and consistency play an important role in maintaining anal continence. Some patients are variably continent to solid, liquid, or gas. By changing the stool consistency and volume, some patients may be made continent.

Rectal Capacity and Compliance

Figure 7 Nerve supply of the anorectum. Source: From Ref. 1.

Another mechanical factor is the reservoir function of the rectum. The valves of Houston slow down the progression of stool and provide a barrier effect. Rectal capacity and adaptive compliance are also important for an effective reservoir. Urgency is usually felt after instilling 200 mL of saline into the rectum. This transiently causes an increase in the intrarectal pressure, but then the pressure returns to baseline and the feeling of urgency disappears. This is called receptive relaxation.

medwedi.ru

604

Part Two: The Alimentary Tract—Other Conditions

Anorectal Angle Another important factor for maintaining continence is the angulation of the anorectal angle. This is normally maintained at 80 to 90 by the continuous tonic activity of the puborectalis muscle (10). Defecation is facilitated by straightening this angle, with the relaxation of the puborectalis muscle. The anorectal angle may also help maintain continence during sudden increases in intra-abdominal pressure such as during coughing, sneezing, or laughing, because these tend to increase the angulation. This flap valve theory has now been challenged as an important factor during increases in intra-abdominal pressure in a normal subject. Instead, a reflex contraction of the external anal sphincter may be what maintains continence during sudden increases in intra-abdominal pressures (11). The flap valve mechanism may play a more important role in subjects, with a decreased anal pressure.

Anal Resting Pressure Anal resting pressure is maintained by the aid of the internal anal sphincter, the external anal sphincter, and the hemorrhoidal complex. The resting pressure is between 40 and 80 mmHg and is higher than the baseline intrarectal pressure. It is this differential in pressure that allows the maintenance of continence. The internal sphincters are the major contributors to this high-pressure zone. Also, the external sphincter maintains a continuous tonic activity that contributes to the resting pressure. Increases in intra-abdominal pressure, rectal distention, and perianal stimulation tend to augment its activity. It should be noted that voluntary contraction of the external anal sphincter can only be maintained between 30 and 60 seconds (1,10). The hemorrhoidal complexes are vascular cushions located in the left lateral, right anterolateral, and right posterolateral areas of the anal canal. They also contribute to anal continence by their ability to expand and contract.

Anorectal Sensibility Anorectal sensibility is the ability to discriminate between gas, liquid, or solid. By allowing awareness, the external sphincter can contract in order to postpone defecation.

is voluntarily contracted while rectal compliance allows accommodation and the urge passes. On the other hand, if it is determined that it is an appropriate time and place, a voluntary increase in abdominal pressures assists the defecation reflex to evacuate the rectum. In addition, a squatting position tends to straighten the puborectalis angle.

COLONIC FUNCTION AND ANORECTAL PHYSIOLOGY TESTING Anorectal physiology testing is an important part of evaluating patients with anorectal dysfunction such as incontinence and constipation. These include anal manometry, electromyography, nerve stimulation, and sensation measurements. However, continence is determined by a variety of factors that interact with each other in a manner that is not completely understood. Measuring a single factor such as manometry alone may not provide a complete picture to evaluate bowel dysfunction. To evaluate the coordinated functions that are involved for defecation, tests such as electromyography, nerve stimulation, defecating proctography, and colonic transit studies are also utilized.

Anal Manometry Anal manometry is used to measure the anal resting and squeeze pressures, rectal capacity and compliance, and the presence of rectoanal inhibitory response. There are many different types of instruments and techniques that may give different results. One of the instruments used is a four-channel probe, with each probe oriented 90 apart. This instrument can provide resting pressure measurement on four quadrants, and maximal squeeze pressure is measured with the patient consciously squeezing down on the probe. This can be used to measure the pressures along the whole anal canal. Also, this probe can be positioned in the proximal anal canal, and a balloon can be deployed to measure rectal capacity, rectal compliance, and the presence of the rectoanal inhibitory response.

Electromyography

Rectoanal Inhibitory Reflex When feces reaches the rectum with colonic mass movements, the rectal wall stretches and this causes reflexive relaxation of the internal sphincter. This is called the rectoanal inhibitory reflex. With the reflexive relaxation of the internal sphincter, the rectal contents can then descend into the anal canal where sampling can occur to determine whether the contents are solid, liquid, or gas. The external sphincter is then contracted to maintain continence. Defective sampling and sensation can lead to incontinence.

The electrical activity of the external anal sphincter and of the pelvic floor can be measured at rest or at maximum squeeze pressure using electromyography. Their response to different reflexes and maneuvers can also be measured. Electromyography can be performed using a variety of electrodes including a concentric needle, monopolar wire electrode, single fiber electrode, and surface anal plug. This type of investigation is usually used to map sphincter function and to evaluate pelvic floor dysfunction.

Nerve Stimulation Defecation Reflex The process of defecation is a highly coordinated and complex process. Distention of the rectum stimulates contractions of the colon and rectum. This is known as the defecation reflex and involves the sacral segments of the spinal cord. When the rectum is distended, the rectoanal inhibitory reflex is initiated and the internal anal sphincter relaxes whereas the external anal sphincter contracts. This allows sampling of the rectal contents to determine whether it is solid, liquid, or gas, while maintaining continence. If it is not a socially acceptable time, the external anal sphincter

Nerve stimulation can be performed at two different levels: over L1 to L4, which supplies the external anal sphincter and the puborectalis, and transanally over the ischial spine to stimulate the pudendal nerve. The pudendal nerve– terminal motor latency is the time between the nerve stimulation and the response of the muscle. A prolonged pudendal nerve–terminal motor latency can be seen in women who have a history of vaginal delivery associated with or without external anal sphincter injury. The pudendal nerve–terminal motor latency can predict the success of a sphincteroplasty for incontinence (12).

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

Mucosal Sensation Mucosal sensation of the anal canal can also be measured by evaluating the electrosensitivity and temperature sensation. These techniques can be used to evaluate patients with incontinence.

Cinedefecography Disorders of defecation can also be evaluated by cinedefecography. This is performed by emptying the patient’s rectum with enemas, followed by instilling liquid barium as well as barium paste into the rectum. The patient then sits on a radiolucent commode and defecates, while the anorectum is observed using fluoroscopy. Static pictures are taken using lateral films. The anorectal angle and the amount of perineal descent can be measured. Other abnormalities that can be observed include rectocele, rectal intussusception, and mucosal prolapse.

Colonic Transit Constipation may be caused by a slow colonic transit time. This can be evaluated using small radiopaque markers (Sitz-marks, Lafayette Pharmaceutical, Inc, Fort Worth, Texas, U.S.A.) that are swallowed for the first three days; a plain abdominal radiograph is taken on day 4 and day 7. This can detect a slow transit time of the whole colon, segments of colon, or a generalized slowing of the entire gastrointestinal tract.

DISORDERED ANORECTAL PHYSIOLOGY Most patients who develop an anorectal problem would complain of ‘‘hemorrhoids.’’ The problem may range from being hemorrhoids to a number of other disease processes including an anorectal malignancy. To differentiate between the various disease processes that can occur, the clinician must be familiar with the pathophysiology, presentation, diagnosis, and treatment of each disease.

Hemorrhoids Hemorrhoids have plagued people throughout history, and there are references to it in the writings of the ancient Egyptians (13) and Hippocrates. In fact, some historians attribute the defeat of Napoleon at Waterloo to his delay in attacking Wellington’s forces because of ‘‘blinding pain’’ from hemorrhoids and his inability to ride on a horse (14). Hemorrhoids are fairly common in the United States today, although the exact prevalence is unknown. One of the reasons that the exact prevalence is not known is because most patients who complain of perianal pain or pruritus attribute it to ‘‘hemorrhoids.’’

Pathophysiology Hemorrhoids are an abnormality of the anal cushions. Anal cushions are present at birth and are submucosal vascular structures. Anal cushions are part of the mechanism for continence and may also protect the anal canal from damage during defecation. There are three groups of anal cushions located in the anal canal: right anterolateral, right posterolateral, and left lateral. The exact pathophysiology as to why hemorrhoids develop from the anal cushions is not known. One possible etiology is mechanical in that repeated straining causes prolapse of the anal cushions (15). Straining is caused by irregular bowel movements, either with constipation or with diarrhea. Another proposed pathophysiology is internal

605

sphincter dysfunction, which leads to venous obstruction, stasis, and engorgement of the hemorrhoids (16). External hemorrhoids are below the dentate line and are covered with anoderm. This is squamous epithelium that is innervated by somatic nerves, and therefore, sensate. Internal hemorrhoids, on the other hand, are above the dentate line, are covered with rectal mucosa, and are insensate.

Diagnosis A thorough history and physical examination is important in distinguishing hemorrhoids from other anorectal disorders. Patients with hemorrhoids usually present with bleeding, which can be either on the toilet paper or in the toilet bowl. They may also complain of a prolapsing mass during defecation that they have to reduce. When the disease is uncomplicated, pain is usually not a symptom. Pain is an indication of a thrombosed external hemorrhoid, strangulated hemorrhoids, abscess, or anal fissure. The patient may also complain of soiling or pruritus from leakage associated with a chronically prolapsed internal hemorrhoid. Physical examination should include a careful inspection of the area for evidence that would suggest another disorder such as perianal Crohn’s disease or malignancy. Palpation and digital examination are also important to evaluating for fullness, tenderness, mass, and tone. Anoscopy is also warranted to evaluate the degree of the disease and to exclude other disorders. Internal hemorrhoids are graded according to its degree of prolapse. First-degree hemorrhoids do not prolapse below the dentate line even with straining. Second-degree hemorrhoids prolapse during straining but reduce spontaneously when the patient stops straining. Third-degree hemorrhoids prolapse with straining and require manual reduction. Fourth-degree hemorrhoids are always prolapsed. If the patient’s history is atypical or the physical examination does not demonstrate the reason for rectal bleeding, a sigmoidoscopy should be performed to rule out proximal disease. A colonoscopy should be considered if the patient is at risk for colorectal cancer.

Treatment The treatment goal for hemorrhoids is symptomatic relief. There are many different available therapies, both nonoperative and operative. The treatment is usually dictated by the degree of hemorrhoidal disease. Practice parameters have been established by the American Society of Colon and Rectal Surgeons (17). The majority of the patients with first- to third-degree internal hemorrhoids can be treated nonoperatively with good results. The first line of treatment is dietary modification, specifically adding more fiber (18) and fluid to the diet. At least 20 to 30 g/day of fiber is recommended to normalize the patient’s stool and to prevent straining with defecation, whether the patient is constipated or diarrheic. Behavioral modification and education are also required. The patients should be advised not to sit on the toilet too long and to avoid reading while on the toilet. Straining should also be avoided. Also, for symptomatic relief, the patients can soak in a warm tub of water. Some patients prefer an ice pack for relief and reduction of edema. Both are acceptable as long as the exposure to either the heat or the cold is not prolonged. There are also many local therapies that are available commercially. These come in several forms including

medwedi.ru

606

Part Two: The Alimentary Tract—Other Conditions

suppositories, foam, and creams. Although these do not eliminate hemorrhoids, they can improve the symptoms. Most of the symptoms resolve with dietary and behavioral modifications; however, for those that fail to improve, there are also a number of nonoperative procedures. These include rubber band ligation, cryotherapy, infrared photocoagulation, electrocoagulation, and sclerotherapy. These methods should be limited to first-degree, second-degree, and some third-degree internal hemorrhoids. These procedures are relatively painless, well tolerated, and have very low morbidity rates. Third-degree hemorrhoids that fail nonoperative procedures, fourth-degree hemorrhoids, and internal hemorrhoids with a large external component require operative management. There are two established types of hemorrhoidectomies: open technique and closed technique. The open technique was described by Milligan et al. (19), and the closed technique was described by Ferguson and Heaton (20). Both procedures involve excision of the abnormal vascular cushions with any associated skin tags followed by ligation of the vascular pedicle. The only difference between the two is whether the mucosa and perianal skin are left open or closed. These two types of procedures seem to be equivalent, although the surgeons here in the United States prefer the modified Ferguson technique (21). The complication rate following both procedures are low but include bleeding, urinary retention, anal stenosis, anal fissure, and incontinence. More recently, another modified type of closed hemorrhoidectomy was described by Sayfon et al. using Ligasure (Valleylab, Boulder, Colorado, U.S.A.) (22), which is an electrothermal system designed originally to seal vessels intraabdominally. The authors report fewer complications and a faster recovery. Another recent method that is gaining attention is a procedure initially described by Longo called the procedure for prolapsed hemorrhoids (23). The procedure is a hemorrhoidopexy and not a hemorrhoidectomy. It involves resecting the prolapsed suprahemorrhoidal rectal tissue and repositioning the hemorrhoids back into the anal canal, thereby relieving symptoms. The advantage of the stapled hemorrhoidopexy is less postoperative pain compared to excisional hemorrhoidectomy. However, it is not clear whether this technique is more appropriately compared to nonoperative techniques such as rubber band ligation (24). Further studies with long-term follow-up are needed. A thrombosed external hemorrhoid can cause severe pain, the treatment of which depends on when the patient presents with it. If left untreated, the clot would either drain through the skin or be resorbed in one to two-weeks time, and the pain resolves without intervention. However, if the patient presents early in the course or if the symptoms do not improve, then an excision should be performed. An incision and drainage is not an adequate procedure, because it not only leaves some clot behind, but also leaves excess skin, which can result in a skin tag when it heals.

Fissure Fissures are longitudinal tears in the lower anal canal that extends from the dentate line to the anal verge. These occur mostly in the mid-posterior area (approximately 90%); a minority of them occur in the mid-anterior position (approximately 10%), while a fraction occur laterally and is associated with other disease processes (25).

Pathophysiology The reason that fissures are thought to occur in the midline is the elliptical shape of the external sphincter, which may provide less support in the anterior and posterior areas, making them susceptible to trauma. However, most fissures do heal on their own whereas some become chronic. The exact etiology is not very well elucidated, but the prevalent thought is that the failure to heal is secondary to ischemia. Klosterhafen et al. performed an anatomic study that suggests there is a paucity of blood supply to the posterior midline (26). Also, even though it is difficult to ascertain whether it is a cause or effect, there is a higher resting anal pressure in patients with fissures (27), which can further compromise the perfusion in this area (28).

Diagnosis The diagnosis of anal fissure can be made with a good history and physical examination. Anal fissures tend to occur after a hard bowel movement. Patients usually describe a sharp, tearing, or knife-like pain, which occurs during each bowel movement and does not resolve immediately. These patients also usually report a small amount of rectal bleeding. Physical examination consists of an inspection of the area with gentle separation of the buttocks. A tear can be visualized and might be associated with a sentinel pile, an edematous skin tag, suggesting chronicity of the fissure. Also, if the fissure is chronic, the internal sphincter muscle fibers may be seen at the base of the fissure. Atypical features such as a lateral position, extension of the fissure proximal to the dentate line, or ulceration beyond the internal sphincter should alert the clinician to other etiologies such as Crohn’s disease, immunodeficiency, tuberculosis, or a malignancy (29).

Treatment Acute anal fissures are treated with stool bulking agents, initially. Symptomatic relief may be obtained with warm sitz baths and topical treatment using anesthetics or hydrocortisone. The conservative treatments outlined above are not as efficacious in the treatment of fissures that are chronic. The treatment of either a nonhealing or a chronic fissure all try to address the underlying pathophysiology of fissures, namely ischemia, secondary to internal sphincter spasm. The cycle of spasm can be broken either by pharmaceutical therapy or by surgical management. Local application of 0.2% glyceryl trinitrate ointment (GTN, nitroglycerin) has been shown to decrease anal pressure (30) and increase blood flow to the anoderm (31,32). The results in the literature of GTN vary between 50% and 85% (29). Up to 40% of the patients complain of headaches, which may lead to noncompliance (29). The recurrence rate after successful healing can be as high as 46% (33). Topical and oral calcium channel–blockers have also been shown to relax the internal anal sphincter and lower the resting anal pressure (34). The oral formulation can result in hypotension and flushing, which would also lead to noncompliance (35). Even though nifedipine topical ointment has been shown to have healing rates up to 95% (36) with less side effects than GTN (37), long-term results are still unknown. Another method to reduce resting anal pressure is by chemically denervating the sphincter with botulinum toxin. The exact dose of the toxin is still being investigated as well as the exact location of injection (external vs. internal anal

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

607

sphincter, posterior vs. anterior) (38). Initial injections have been reported to have approximately 60% healing rate and repeated injections have reports of up 95% healing (39),although the same group reported their long-term results after a 42-month follow-up and found a recurrence rate of 41.5% (40). Surgical therapy should be undertaken if conservative therapy fails. Many types of procedures have been described in the past, but the procedure of choice is a lateral internal sphincterotomy. There are variations to the technique, including a closed technique and an open technique. The closed version involves inserting a scalpel in the intersphincteric groove and cutting the internal sphincter by blind palpation. The open technique involves an incision of the anoderm and cutting the internal sphincter under direct vision. The rate of healing for a lateral internal sphincterotomy is greater than 90%, whereas the recurrence rate is between 1% and 6% (29). Incontinence is a known complication of the procedure, although the rate is fairly low in experienced hands.

Anorectal Abscess and Fistula-in-Ano Anorectal abscess and fistula-in-ano are two types of suppurative anorectal infections. An abscess is considered the acute form and a fistula is the chronic manifestation. The treatment of anorectal infection is usually relegated to the most junior person in a surgical team. Yet, treating these problems properly involves decision-making grounded on the knowledge of anatomy, in order to adequately treat the sepsis and yet preserve continence.

Pathophysiology The most accepted theory on the etiology of anorectal abscesses and fistulae is that of the cryptoglandular theory (Fig. 3). The anal glands may get obstructed, secondary to trauma, anoreceptive sex, diarrhea, or hard stools, and result in an infection. About a third of the treated abscesses can result in a fistula (41,42). In the absence of a cryptoglandular infection, abscesses and fistulae can also be associated with inflammatory bowel disease, tuberculosis, immunodefiency, and malignancy. Anorectal abscesses are classified according to location (Fig. 3), which is helpful to recognize subtle presentations of the disease and to assure complete drainage. The infection can travel along fascial planes to spread to the contralateral side in case of an intersphincteric, supralevator, or ischiorectal abscess. In the case of an ischiorectal abscess, the suppuration can originate or travel through the deep postanal space to form a horseshoe abscess. Fistula-in-ano is classified by Parks et al. (43) according to the location (Fig. 8), which has major implications for treatment. Goodsall’s rule is useful for defining the direction of the fistulous tract in that an anterior external opening will tract radially to the closest crypt, whereas a posterior external opening will most likely tract to the posterior midline (Fig. 9). A lack of appreciation for the complexity of the fistula can result in a recurrence or an inadvertent injury to the sphincters, leading to incontinence.

Figure 8 Classification of fistula-in-ano: (A) intersphincteric, (B) transsphincteric, (C) suprasphincteric, (D) extrasphincteric. Source: From Ref. 44.

external evidence of an abscess may be symptoms of an intersphincteric or supralevator abscess. Physical examination consists of inspection, palpation, and digital examination. Inspection and palpation may demonstrate erythema, warmth, swelling, fluctuance, or drainage. It should be noted again that patients with an intersphincteric or supralevator abscess may not have any external evidence of disease. However, an intersphincteric or supralevator abscess can be felt as a tender mass on digital rectal examination, if the patient would allow it. If the suspicion is high for an abscess and the patient cannot tolerate an examination, then a computed tomography scan or an examination under anesthesia may be warranted. Patients who give a history of previous incision and drainage may have a fistula. Also, soiling of underwear from chronic, purulent drainage may be reported. Patients

Diagnosis Patients with an anorectal abscess usually complain of pain and swelling, although patients can also present with overwhelming sepsis with no localized pain. Patients who complain of gluteal pain may have a supralevator abscess, whereas severe rectal pain and urinary retention with no

Figure 9 Goodsall’s Rule. Source: From Ref. 44.

medwedi.ru

608

Part Two: The Alimentary Tract—Other Conditions

with a fistula may have a telltale red papular external opening, where pus can be expressed. Palpation may demonstrate a fibrous cord of a chronic fistulous tract. Goodsall’s rule is helpful in predicting the internal opening, which may be evident with anoscopy. A metal probe is best reserved for the operating room. For patients with a complex history of recurrent fistula, an additional study to delineate the anatomy, such as a magnetic resonance imaging (MRI) or fistulogram, may be helpful prior to surgery.

Treatment The treatment of anorectal abscesses and fistulae-in-ano depends on the location and classification. The goal is to treat the source of sepsis adequately, without disrupting continence. The treatment of an abscess generally involves an incision and drainage. A delay in diagnosis and treatment can cause life-threatening sepsis (45). The incision should be as close to the anal verge as possible, in order to prevent the development of a long, complex fistula, which is difficult to treat. Even though most abscesses can be drained under local anesthesia, an ischiorectal abscess is best drained under regional or general anesthesia so that the loculations can be broken down more adequately. Also, if there is a horseshoe abscess, the deep postanal space should be drained. To drain an intersphincteric abscess, the internal sphincter needs to be divided along the length of the abscess. The treatment of a supralevator abscess depends on the origin of the abscess. If the source is an upward extension of an ischiorectal abscess or an intersphincteric abscess, then it should not be drained through the rectum. On the other hand, if the abscess is of pelvic origin, then it should not be drained through the skin (Fig. 10). These guidelines are made to prevent the formation of a long extrasphincteric fistula. The definitive treatment for a fistula-in-ano has several goals, which include eliminating the fistula adequately and thereby minimizing the recurrence while preserving continence. The treatment choice depends on the type of fistula. It is therefore crucial to be able to identify the primary internal opening. This can be achieved intraoperatively by passing a metal probe or by injecting methylene blue, milk, or hydrogen peroxide (44). For a simple, low lying fistula, a

fistulotomy can be performed by inserting the probe from the external opening to the internal opening, and then incising the tissue overlying the probe. Marsupialization of the skin edges may also be performed following the fistulotomy. Recurrence rate of a fistulotomy ranges between 0% and 18% (46). High, complex fistulae that incorporate a large amount of external sphincter should be treated with a seton, because a complete fistulotomy would result in incontinence. The internal sphincter may be divided, and the seton is then inserted through the tract encircling the external sphincter. A seton can be a silk suture or a vessel loop. It can be used as a cutting seton, which is tightened at intervals and transforms a high fistula to a low one. Or, the seton can be a draining seton, which is not tightened but merely placed to facilitate drainage. For complex and recurrent fistulae, another option is an anorectal advancement flap. A technique that was proposed in the past decade and has been receiving attention is the use of fibrin glue for the treatment of fistulae (47). The main advantage in this procedure is that the sphincter is not divided, and therefore, there is no risk of incontinence. However, this has been found to be successful in only about 60% of the cases, and fails in the longer and more complex fistulae (48,49), where the risk of incontinence is greatest with a fistulotomy. The definitive treatment of a fistula at the same time as the incision and drainage of the associated abscess is controversial (50). Arguments for a simultaneous fistulotomy include a decrease in the recurrence rate of the abscess and a more complete drainage of the infection. On the other hand, probing for an internal opening in acutely inflamed tissue may create false passages and increase the risk for incontinence. This question may not be as relevant today given that most abscesses are drained under local anesthesia (50).

Rectal Prolapse Rectal prolapse or procidentia is the intussusception and protrusion of the full thickness rectum through the anus. Incomplete prolapse is the internal intussuception of the rectum without protrusion. Mucosal prolapse involves only the distal rectal tissues and is akin to hemorrhoidal disease.

Pathophysiology

Figure 10 Drainage of a supralevator abscess. Source: From Ref. 44.

Rectal prolapse occurs more often in women than in men, and yet it does not seem to be associated with multiparity (51,52). It also seems to occur in patients in nursing homes and in institutionalized patients with mental illness (53). There have been numerous studies trying to elucidate the pathogenesis of rectal prolapse. In 1912, Moschowitz, through his observations during laparotomy, believed that rectal prolapse is a sliding hernia of the anterior wall of the rectum through the fascial investments of the pelvic floor (54). Other anatomic defects described with rectal prolapse in an attempt to understand the etiology include a redundant rectosigmoid, loss of the horizontal position of the rectum, loss of posterior fixation of the rectum, a deep cul de sac, and a defect in the pelvic floor (55). Another theory that was proposed after cinedefecography (56) and a radiopaque marker study (57) is that rectal prolapse is started by an internal intussusception with a lead point. The most accepted theory at this time is the internal intussusception theory, and the anatomic defects appear to be secondary. Patients with rectal prolapse can develop pelvic neuropathy and anal sphincter dysfunction leading to

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

incontinence. In an attempt to further elucidate the pathophysiology of the incontinence associated with rectal prolapse, numerous anorectal physiology studies have been performed. Manometric studies have demonstrated that patients with rectal prolapse and incontinence have lower resting pressures and lower squeeze pressure (58). Electromyographic studies also demonstrate denervation of the pelvic musculature in incontinent patients with rectal prolapse (59). This may be due to pudendal nerve injury from traction (60). These abnormalities may be the reason that incontinence persists in patients even after surgical correction of the prolapse. Up to half of the patients with prolapse may also complain of constipation (60). It is difficult to ascertain whether constipation is a predisposing factor to prolapse secondary to excessive straining, or that constipation is a result of a pelvic outlet obstruction from the intussusception.

Diagnosis The most frequent presentation is a complete prolapse. Patients complain of a protrusion when they defecate. If left untreated, the symptoms can occur with any Valsalva maneuver such as coughing, sneezing, or straining. Patients may also present with incontinence. Incomplete rectal prolapse present with feelings of incomplete evacuation, rectal pressure, and tenesmus. On physical examination, the prolapse may be obvious upon inspection. If not, the patient may have to be examined on the toilet while straining. The mucosa may appear edematous or ulcerated if the tissue is chronically prolapsed. To determine whether the prolapse is full thickness or merely mucosal, the orientation of the mucosal fold should be noted. Mucosal prolapse has radial folds, whereas a complete rectal prolapse has concentric folds. Palpation of the protruding tissue should also demonstrate a double thickness.

Treatment A persistently prolapsed rectum should be reduced in order to avoid strangulation, gangrene, ulceration, and bleeding. This is best accomplished while the patient is relaxed. Rectal prolapse should be corrected surgically to avoid complications and further damage to the pelvic floor and nerves. There are numerous procedures described with different variations. They can be classified into an intraabdominal approach and a perineal approach. The intra-abdominal approaches include rectopexy and/or resection. The rectopexy can be done anteriorly, encircling the rectum (Ripstein procedure), or posteriorly (Wells procedure). The rectum is basically mobilized and then fixed to the sacral hollow or to the promontory. Various materials have been used with different success rates and complication rates. A sigmoid resection is also carried out by some with the argument that a resection causes the rectum to firmly adhere to the sacrum and that all the redundancy is removed and thereby preventing further prolapse. The Frykman–Goldberg procedure combines resection with rectopexy. Because leaving foreign material is not advisable when a bowel resection is carried out, a suture retropexy is done instead. Of course, an intra-abdominal bowel resection with rectopexy is the most physiologically demanding procedure among the choices, and should be limited to healthy patients.

609

Laparoscopic approaches have also gained popularity recently. Laparoscopic rectopexy and laparoscopic resection with rectopexy have been described (61). The possible advantages include a shorter length of stay, shorter period of ileus, and decreased need for narcotics. However, the operative time also tends to be longer. Long-term studies are still needed. For the frail patient with rectal prolapse, there are a variety of perineal approaches available that can be performed under spinal or epidural anesthesia. One procedure is the Thiersch procedure in which the anus is encircled subcutaneously with a steel wire. This results in a high failure rate and can result in skin sloughing, infection, and extrusion. Also, the internal intussusception is not corrected (60). Another procedure is the Delorme procedure, which is a mucosal proctectomy with reefing of the denuded muscle wall. Investigators have reported satisfactory results with this procedure (60). The most widely used perineal approach is the Altmeier procedure, which is a perineal rectosigmoidectomy (62). The long-term results were reported by Kim et al., and the recurrence rate is acceptable at 16% with no mortality (63).

Fecal Incontinence Fecal incontinence is basically uncontrolled release of rectal contents. Complete fecal incontinence is passage of solid material whereas incomplete incontinence is passage of liquid or gas. It is a life-altering problem that has severe social implications. Incontinence seems to affect the elderly in nursing homes and institutionalized psychiatric patients. However, it is important to distinguish between true fecal incontinence versus urgency with passage of liquid stool.

Pathophysiology Continence is affected by several factors including stool quantity, stool consistency, motor and sensory nervous system, rectal capacity and compliance, and the sphincter mechanism. One of the identifiable causes of fecal incontinence is sphincter injury. This may result from anorectal surgery such as dilatation, fistulotomy, hemorrhoidectomy, lateral internal sphincterotomy, or a low anterior resection. Another common cause is an obstetric injury especially after a delivery of a high–birth-weight baby, use of forceps, a third-degree tear, or an episiotomy (64). Rectal irradiation, trauma, and rectal prolapse are also risk factors for incontinence. Central and peripheral neurologic diseases can also lead to incontinence. These include spinal cord injuries, demyelinating diseases, and diabetic neuropathy. A chronic diarrheal disease can overwhelm the sphincter mechanism, leading to incontinence. Alternatively, constipation can also cause overflow diarrhea. However, some patients do not have an identifiable cause and are considered to have idiopathic fecal incontinence. Patients with idiopathic fecal incontinence have one or several physiologic abnormalities. Progressive neuropathic damage to the external sphincter and pelvic floor muscles, and a weakening of the internal sphincter may be the most likely cause of idiopathic fecal incontinence (65). There is some evidence as well that in some cases, the internal anal sphincter has a reduced sensitivity to the neurotransmitter, norepinephrine (66). Other observed abnormalitites include an abnormal external anal electromyogram, a low resting pressure, a decreased squeeze pressure, and a sensory deficit of the anal canal. There might also be an increase in the pudendal nerve latencies. Fecal incontinence may also be

medwedi.ru

610

Part Two: The Alimentary Tract—Other Conditions

caused by an increased rectal pressure, which can overcome the anal pressure, causing leakage of the rectal contents. Some patients may have an obtuse anorectal angle, which in conjunction with an abnormal anal pressure will result in fecal incontinence.

Diagnosis Obtaining a good history is paramount in the assessment of fecal incontinence. The patient should be questioned regarding the frequency, severity, and exacerbating factors. The severity of the incontinence can be estimated by asking how often the patient has to change their underwear, whether they have to use a pad, or if their lifestyle has been severely altered. The patients should also be asked detailed questions regarding vaginal deliveries, prior anorectal surgeries, possible rectal prolpase, previous irradiation, or trauma. A review of comorbid diseases should also be obtained, such as the presence of central and peripheral neurologic diseases or diabetes mellitus. An inspection of the perineum may demonstrate scarring, perianal infections, fistulae, prolapse, or perineal descent. A digital exam can reveal a patulous anus, tumor, or fecal impaction. It can also provide a rough estimate of the patient’s resting and squeeze anal pressures. The rectovaginal septum should be evaluated with a bimanual examination to determine anterior injury. Proctosigmoidoscopy should also be performed to look for tumors, ulcers, and proctitis. As discussed previously, there are several physiologic tests available to evaluate the mechanisms of continence. Anorectal manometry can determine the resting and squeeze pressures in four quadrants. It is useful in evaluating evidence of sphincter trauma. However, these measurements should not be used to ascertain the severity of the incontinence, because the pressures do not correlate well (65). The use of endoanal ultrasonography has also been gaining popularity. A small transducer is inserted into the anal canal and then withdrawn while the internal and external sphincters are evaluated. Defects in the sphincters can be easily detected. On the grounds that not all sphincter defects are clinically significant, these results should be used in conjunction with anal manometry (67). Pudendal nerve damage can be assessed using electromyography. The presence of a prolonged pudendal nerve– terminal motor latency is usually a predictor of a poor outcome to sphincter repair (12,68). Defecography can measure the anorectal angle, pelvic floor, and puborectalis function. Abnormal perineal descent, rectal prolapse, enterocele, and rectocele can also be detected. Rectal compliance and anorectal sensation can also be evaluated. These may be helpful in further delineating the cause of incontinence.

and practice sphincter contractions. The success rate is variable in the literature, but can be as high as 70% (71). Patient selection is an important determining factor. Patients who are unresponsive to conservative treatment and who have specific sphincter defects are the best candidates for surgery. The surgical armamentarium for fecal incontinence includes sphincteroplasty, muscle transpositions, artificial sphincters, and fecal diversion. Sphincteroplasty is performed by identifying the disrupted ends of the sphincter, mobilizing them, and then sewing them in an overlapping fashion. The success rate can be excellent, especially if there is no associated pudendal nerve damage (12,68). If the patient does not have any salvageable sphincter muscles, then a muscle transposition can be performed. The gluteus muscle and the gracilis muscle have been used; however, the gracilis muscle is the one used most often today. The gracilis muscle is mobilized and used to encircle the anus. Because the muscle is incapable of continuous contraction, a pacemaker can be inserted to continuously stimulate the muscle. A magnet is then used to switch off the pacemaker to allow defecation. Artificial anal sphincters are also available. These have the same mechanisms as the artificial urinary sphincters in which an inflatable cuff is inserted around the anal canal. These can be deflated during defecation by using a pump inserted in the scrotum or labia majora. Preliminary results have shown improvement in some patients, although, because it is a foreign material in the perianal area, the development of infection is a concern (72). Patients who have fecal incontinence secondary to a neurologic disorder may benefit from sacral nerve stimulation (73). This technique has been successful in treating urinary incontinence. External stimulation is first performed to evaluate the efficacy in individual patients. If effective, an implantable electrode is inserted surgically with a pulse generator. Fecal diversion with an end colostomy may be the best solution in some patients. It should be considered for patients who failed other treatment modalities and also for debilitated patients with severe incontinence.

Constipation Constipation is a subjective complaint used by patients to describe various symptoms such as hard stools, small stools, infrequent bowel movements, or difficulty defecating. Functional constipation can be defined using the Rome II criteria (74,75). a.

Symptoms include: 1. less than three bowel movements a week, 2. excessive straining, 3. hard stools, 4. feelings of incomplete evacuation, 5. sensation of a blockage, and 6. requiring manual assistance such as digital evacuation and vaginal or perineal support.

b.

Symptoms should occur at least 25% of the time over a 12-week period in the preceding two years.

Treatment The treatment of incontinence depends on its underlying cause. However, a good starting point is supplementing fiber to increase the bulk of the stool. Patients with diarrhea associated with their incontinence may be helped with antidiarrheal medications such as loperamide and diphenoxylate. However, loperamide may be more effective and can also increase internal sphincter tone (69,70). Biofeedback is also useful in patients who are motivated and who can still contract their external sphincter. With the help of a trained technician and visual cues, the patient can be taught to respond to anorectal sensation

Pathophysiology There are many causes of constipation including diet, medications, psychiatric, neurologic, metabolic, and endocrine disorders. However, the most common causes of functional

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

constipation can be classified under obstructed defecation and colonic dysmotility, or a combination of both. Obstructed Defecation There are numerous mechanisms that lead to obstructed defecation. Impaired rectal sensation secondary to central nervous system disorders, or impaired internal sphincter relaxation such as in Hirschprung’s disease and Chagas’ disease can lead to obstructed defecation. Multiple sclerosis and spinal cord lesions can lead to a nonrelaxing pelvic floor during defecation. Anismus or puborectalis paradox is the failure of the puborectalis to relax or the paradoxical contraction of the puborectalis muscle during defecation. This causes a mechanical obstruction by the anorectal angle failing to relax. A mechanical outlet obstruction can also be caused by a rectocele, rectal intussusception, rectal prolapse, and descending perineum. Colonic Dysmotility Idiopathic slow transit constipation is characterized by intractable constipation with a normal-appearing colon and without any evidence of systemic disorders or pelvic floor dysfunction (76). It seems to occur primarily in women and is not responsive to laxatives or fiber. Several causes have been attributed to this disease. Abnormalities have been demonstrated with the colonic myenteric plexus, the interstitial cells of Cajal, and the colonic neuroendocrine system. Psychosocial factors have also been considered as a cause for idiopathic slow transit constipation (76).

Diagnosis Patients commonly present with complaints of constipation. They should be asked specifically what they mean by ‘‘constipation.’’ Questions regarding bowel habits, diet, fiber intake, and laxative use should always be part of history taking. Reports of digitation or vaginal support can be helpful. Again, a list of comorbid diseases and medications is important. Physical examination should include an inspection of the area for evidence of fissures, hemorrhoids, and rectal prolapse. A digital examination should evaluate the rectovaginal septum. The patient must also be asked to expel the examiner’s finger. If the anal canal tightens or fails to relax, then the patient may have anismus. A perineum that descends below the ischial tuberosities when the patient strains is also abnormal. Proctosigmoidoscopy should be performed to evaluate for possible intussusception and for physical changes associated with rectal prolapse. For patients who are at risk for colorectal cancer, an obstructing mass should be excluded with a colonoscopy. A colonic transit time–measurement should be performed as part of the evaluation for constipation. By evaluating where the radiopaque markers linger, this can differentiate between generalized gastrointestinal disorder, colonic dysmotility, and pelvic outlet obstruction. Physiologic studies such as manometry can detect the absence of rectoanal inhibitory reflex that is pathognomonic for Hirschsprung’s disease and Chagas’ disease. Electromyography can help diagnose puborectalis paradox. Cindefecography can detect a rectocele, an abnormal anorectal angle, and a rectal intussusception. More recently, dynamic MRI has been used for pelvic floor imaging (77).

Treatment Patients should initially be advised to increase their fiber intake, fluid intake, and physical activity. When these fail,

611

an attempt to identify the underlying cause should be undertaken. Biofeedback has been shown to be helpful in retraining the pelvic floor muscles in patients with pelvic floor dysfunction. This has been shown to be relatively successful in some cases of anismus (78), with or without associated defecography abnormalities (79). Rectal prolapse, aganglionosis, and symptomatic rectoceles should be corrected with surgery. Constipation secondary to colonic dysmotility without an associated pelvic disorder is successfully treated with a total colectomy and ileorectal anastomosis (80). Patients with a combination of pelvic floor disorder and colonic dysmotility should undergo biofeedback therapy prior to a total colectomy (81). Laparoscopic colectomy for constipation has also been reported (82,83).

NEOPLASMS OF THE ANAL CANAL AND ANAL MARGIN Anal and perianal malignancies of the gastrointestinal tract are rare, representing approximately 1% to 5% of all anorectal tumors. A number of risk factors have been identified, such as prior sexually transmitted diseases, anoreceptive intercourse, and chronic benign anal conditions such as pruritus ani (84). Of particular note is the fact that human papilloma virus (HPV) infection has been shown to confer an increased risk of anal cancer. Evidence supporting this observation includes the fact that many patients have simultaneous anal neoplasia and genital viral infections and that both these entities are associated with HPV genotypes 16 and 18 (85). Other factors, such as carcinogenic compounds (e.g., tobacco), simultaneous infection with other viruses, the immunocompromised state, and genetic mutations, may act in concert with HPV to transform epithelial abnormalities, including dysplastic lesions, into cancer. Although these lesions may occur at any age, the median age is 50 to 60. Males more commonly develop anal ‘‘margin’’ lesions, whereas anal ‘‘canal’’ tumors are nearly equally distributed between males and females. Anal neoplasms are divided into those arising within the anal canal and those found at the anal margin. Secondary invasion from an adenocarcinoma of the rectum, which descends into the anal canal, may also occur. Lesions in the perianal skin act similarly to other cutaneous lesions found elsewhere. Neoplasms of the anal canal and anal margin may be either invasive or in situ. Nevertheless, these anal and perianal lesions present much confusion as to anatomic location and staging. One area of confusion relates to the anatomic location of the anal canal. Most surgeons agree that the proximal end of the anal canal corresponds to the anorectal ring. However, much disagreement exists about its distal limit. This limit has been chosen as the dentate line, the mucocutaneous junction, or the anal verge. Depending on the definition used, the anal margin would correspond to that region caudal to the distal limit of the anal canal. Until a uniform description is agreed on, it is important for authors to state clearly which definitions they are using to report results of treatment. A second area of confusion involves staging. A number of staging techniques have been proposed. Dukes’ stages cannot be applied because the tumor spreads to inguinal and iliac nodes, which are not routinely removed. Popular staging methods include TNM (tumor, node, metastasis) classification and the International Union Against Cancer. Once the diagnosis is confirmed, examination of both groins, colonoscopy, chest X-ray

medwedi.ru

612

Part Two: The Alimentary Tract—Other Conditions

examination, and CT scan of the abdomen and pelvis should be performed to determine the confinement of the tumor to the site of origin or its distant spread. Neoplasms of the ‘‘anal margin’’ are generally slow growing and late to metastasize. Nevertheless, despite their surface location, they are frequently detected late, often years after the onset of symptoms. This circumstance is frequently due to neglect, either by the patient or by the physician, and to the fact that both benign disease and neoplasia may coexist concomitantly, with the latter being missed. Squamous cell carcinoma of the anal margin often resembles lesions found elsewhere in the skin. The lesions commonly have rolled everted edges with central ulceration. Treatment is wide local excision; occasionally a split-thickness skin graft may be required to cover the defect. Recurrent disease is often treated by reexcision. Abdominoperineal resection is reserved for lesions that have destroyed the sphincteric mechanism, rendering the patient incontinent. The five-year survival rate varies from 40% to 100% for most lesions (86). Advanced disease results in a poorer prognosis. Basal cell carcinoma is an extremely rare lesion. Grossly, this lesion is similar to a cutaneous basal cell carcinoma found elsewhere in the body; it is superficial, mobile, and rarely metastasizes. This lesion must be distinguished from basaloid (cloacogenic) carcinoma, which has an entirely different origin and behavior (87). Treatment of this lesion is local excision. Although local recurrence is common, it can be treated by reexcision. This tumor is almost uniformly curable (88). There are two cancerous lesions at the anal margin, which generally involve in situ histopathology, specifically Bowen’s disease and Paget’s disease. Bowen’s disease is an intraepithelial squamous cell carcinoma; only rarely does it invade or metastasize (87). Patients commonly present with nonspecific complaints of anal itching, burning, or bleeding. Examination of the perineum in symptomatic patients usually reveals raised, irregular scaly lesions with eczematoid features. Diagnosis is confirmed by biopsy, which reveals characteristic bowenoid cells, which are multinucleated giant cells giving a ‘‘halo effect.’’ In the absence of invasive malignancy, wide local excision is the treatment of choice. Mapping of the perianal and the anal canal with four-quadrant random biopsies is recommended because Bowen’s cells may extend beyond the gross margin of the lesion (89). If invasion of the anal sphincter has occurred, abdominal perineal resection may be needed to insure its curability. Although Bowen’s disease was once considered to represent a cutaneous manifestation of a predisposition to the development of malignant tumors elsewhere, recent evidence has failed to support the view that this condition is a marker for internal malignancy (90). Paget’s disease of the anus is an intraepithelial adenocarcinoma. Most patients complain of intense pruritus and a perianal rash. Microscopically, perianal Paget’s disease is characterized by Paget’s cells located immediately above the basal layer. Wide excision and mapping is the treatment of choice for this disease. Recurrent lesions are reexcised. In the absence of invasive malignancy, the patient is cured (91). Unlike Bowen’s disease, the incidence of associated malignancies with Paget’s disease approaches 50% or higher and is associated with a poorer prognosis (87). In both lesions, long-term follow-up is necessary to identify recurrence of the disease or progression to invasive malignancy. There are other rare anal margin tumors. The Buschke– Lo¨wenstein tumor, or giant condyloma acuminatum, represents a verrucous carcinoma. It is a well-differentiated

squamous cell carcinoma that can be distinguished from large condylomata only by invasion into local tissues. It may also originate from within the anal canal. Wide local excision with clear margins is the treatment of choice. Abdominoperineal resection is reserved for lesions that involve the anal sphincter (92). Kaposi’s sarcoma is a malignancy whose incidence and aggressiveness increases with immunosuppression. Treatment is palliative; it is reserved for symptomatic lesions and may involve excision, ablation, radiation, or chemotherapy. The prognosis is poor and is usually related to the severity of coexisting opportunistic infections. Leukemia cutis is an extremely painful lesion that involves infiltration of the perianal area by leukemic cells. It may first appear as a fistula, an abscess, or a tender erythematous area with marked cellulitis. These signs usually indicate advanced disease and carry a poor prognosis. Treatment is aimed at aggressive management of septic perianal complications of the leukemia. Mycosis fungoides is a fatal cutaneous malignancy of the lymphoreticular system. Treatment is aimed at managing the systemic disease. The majority of epithelial tumors in the ‘‘anal canal’’ are squamous cell cancers or their histologic variants, such as the cloacogenic (transitional) tumors and the mucoepidermoid lesions. When treatment and outcome are discussed, all three histologic lesions are considered interchangeably. Anal canal carcinomas spread along the superior rectal, internal iliac, or inguinal lymphatic channels. It is estimated that in up to 20% of patients, inguinal lymph node metastases are present at the time of diagnosis and that in up to 30% pelvic lymph node involvement is noted (93). It is for this reason that these lesions must be treated with multimodality therapy. The patients often come to the attention of the physician with a painless lump in the anus, or they may have rectal bleeding, tenesmus, anal pain, fecal incontinence, or inguinal adenopathy; some patients are entirely asymptomatic. Biopsy demonstrates epidermoid carcinoma originating from the stratified squamous epithelium. Treatment of this lesion has changed from radical surgery to multimodality therapy. Local excision alone gives a high local recurrence rate and poor survival. Some advocate this treatment when the tumor involves only the submucosa. Abdominoperineal resection results in poor local control, a permanent colostomy, and, at best, a 50% survival at five years. Originally chemotherapy and radiation were used to enhance local control of disease in patients who subsequently underwent abdominoperineal resection. Among Nigro’s first six patients treated in this fashion, no cancer was found in the operative specimen in five (94). This finding led to chemoradiation, with local excision as the treatment of choice for epidermoid cancer of the anal canal (95). Although there have been several modifications to Nigro’s original protocol, external beam radiotherapy (3000–5000 cGy) with administration of 5-fluorouracil and mitomycin C remains the treatment of choice (96). One can expect local control in 90% of patients and five-year survival rates between 70% and 80%. If metastatic tumor is suspected in the groin, or if it subsequently develops, inguinal lymphadenopathy should be performed. In the absence of palpable nodes, lymphadenectomy should not be performed. Radical radiotherapy produces survival rates that approach those of chemoradiation; however, it carries a high rate of anal complications necessitating fecal diversion. Once the patient has been successfully treated, followup initially involves proctoscopic examination and biopsy of the scar performed four weeks after treatment. This

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

approach allows for desquamanation of nonviable tumor cells. The patient is followed up with a yearly proctoscopic examination with biopsy of the scar and, if necessary, intrarectal ultrasound, including imaging of the anal canal and anal margin. Patterns of failure are manifest by local recurrence, regional spread, or distant metastasis. Local failure is characterized by either persistent disease or recurrent disease. Persistent disease is defined as either partial response or no response to treatment, which implies that the original therapy failed to eradicate disease. Recurrent disease is defined as tumor that returns after an initial period of complete clinical response. Local failure is best managed by abdominoperineal resection (97). Such treatment, however, does not ensure survival for most individuals. There are currently some promising reports on the use of additional chemotherapy and radiation in the management of locally advanced disease. Regional failure involving spread to the inguinal lymph nodes is best treated by groin dissection followed by chemotherapy and radiation therapy. Distant visceral metastases have a poor prognosis, rarely allowing for one to be free of disease, and relapse is often anticipated. Carcinoma in a hemorrhoidectomy specimen poses a challenge. If the pathologist reports a focus of carcinoma in a hemorrhoidectomy specimen, the patient should be reexamined in four weeks under anesthesia with performance of reexcision and mapping of the pedicle from which the hemorrhoid was removed. If biopsies are negative, follow-up at three-month intervals is done for one year. If no adverse development occurs by one year, the patient is considered cured. If either persistent tumor after reexcision of the hemorrhoid specimen or recurrent tumor is identified, chemoradiation is performed (98). The remainder of tumors seen in the anal canal are rare. Anal canal melanoma is suspected when a deeply pigmented lesion is noted in or surrounding the anorectum. However, a number of these lesions may be amelanotic. Up to 40% of lesions will have metastasized at the time of the diagnosis. The virulence and resistance of melanoma to treatment is accounted for by its obscure location and by the fact that it is usually not diagnosed until the tumor has grown to considerable size. This lesion is radioresistant and does not consistently respond to chemotherapy and immunotherapy. The surgical approach to this neoplasm is controversial. The majority of patients with melanoma succumb to distant metastasis. Wide local excision can provide local control, and most patients retain fecal continence. Abdominoperineal resection provides improved local control. Long-term survival has occurred only in patients with tumor that is less than 3 mm in depth (15% five-year survival) following abdominoperineal resection (99,100). Anal canal adenocarcinomas are rare tumors arising from anal glands or chronic fistulas. They are slow growing and invasive. An accurate diagnosis requires a deep biopsy. Because of the rarity of this lesion, no comparative studies allow for rigorous analysis of treatment options. Wide local excision can be performed for small, superficial, and welldifferentiated lesions. Otherwise, abdominoperineal resection is indicated. Postoperative adjuvant therapy may be of some benefit (101). Prognosis depends on the stage of disease and the depth of invasion. Anal sarcomas are extremely rare and may be intraluminal or extraluminal. A variety of histologic types resembling any mesodermal tissue can occur. Abdominoperineal resection is the favored treatment, with five-year survival between 20% and 30% (102).

613

SUMMARY A thorough understanding of the normal anatomy and physiology of the anorectum is essential in treating anorectal disorders. The mechanism of continence and defecation are complex and are still not completely understood. However, with astute history taking and excellent physical examination skills, most of the disorders can be diagnosed. There are several diagnostic tools available today, which require judicious application to individual cases. There are many treatment options available for several of the disorders, and the treatment of choice should be tailored to each patient.

REFERENCES 1. Kaiser AM, Ortega AE. Anorectal anatomy. Surg Clin North Am 2002; 82:1125–1138. 2. Nelson H, Petrelli N, Carlin A, et al. National Cancer Institute Expert Panel. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001; 93(8):583–596. 3. Wendell-Smith CP. Anorectal nomenclature: fundamental terminology. Dis Colon Rectum 2000; 43:1349–1358. 4. Thompson-Fawcett MW, Warren, BF, Mortensen NJ. A new look at the anal transitional zone with reference to restorative proctocolectomy and the columnar cuff. Br J Surg 1998; 85: 1517–1521. 5. Jorge JM. Anorectal anatomy and physiology. In: Beck DE, Wexner SD. Fundamentals of Anorectal Surgery. 2d ed. London: WB Saunders Company, 1998:1–24. 6. Carlstedt A, Nordgren S, Fasth S, Appelgren L, Hulten L. Sympathetic nervous influence on the internal anal sphincter and rectum in man. Int J Colorectal Dis 1988; 3:90–95. 7. Lubowski DZ, Nicholls RJ, Swash M, Jordan MJ. Neural control of internal anal sphincter function. Br J Surg 1987; 74:668–670. 8. Longo WE, Ballantyne GH, Modlin IM. The colon, anorectum, and spinal cord patient: a review of the functional alterations of the denervated hindgut. Dis Colon Rectum 1989; 32:261–267. 9. Nivatgongs S, Gordon PH. Surgical anatomy. In: Gordon PH, Nivatgongs S, eds. Principles and Practice of Surgery for the Colon, Rectum, and Anus. 2d ed. St. Louis: Quality Medical Publishing, 1999:3–39. 10. Schouten WR, Gordon PH. Physiology. In: Gordon PH, Nivatgongs S, eds. Principles and Practice of Surgery for the Colon, Rectum, and Anus. 2d ed. St. Louis: Quality Medical Publishing, 1999:41–86. 11. Bannister JJ, Gibbons C, Read NW. Preservation of faecal continence during rises in intra-abdominal pressure: is there a role for the flap valve? Gut 1987; 28:1242–1245. 12. Wexner SD, Marchetti F, Jagelman DG. The role of sphincteroplasty for fecal incontinence reevaluated: a prospective physiologic and functional review. Dis Colon Rectum 1991; 34:22–30. 13. Nunn J. Ancient Egyptian Medicine. Norman: University of Oklahoma Press, 1996. 14. Karlen A. Napoleon’s Glands and Other Ventures in Biohistory. New York: Little Brown & Co, 1984. 15. Thompson W. The nature of hemorrhoids. Br J Surg 1975; 62:542–552. 16. Hancock BD. Internal sphincter and the nature of hemorrhoids. Gut 1977; 18:651–655. 17. Standards Task Force. American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of hemorrhoids. Dis Colon Rectum 1993; 36:1118–1120. 18. Moesgaard F, Nielsen ML, Hansen JB, Knudsen JT. High-fiber diet reduces bleeding and pain in patients with hemorrhoids. Dis Colon Rectum 1982; 25:454–456. 19. Milligan EC, Morgan CN, Jones LE, Officer R. Surgical anatomy of the anal canal and the operative treatment of hemorrhoids. Lancet 1937; 2:1119–1124.

medwedi.ru

614

Part Two: The Alimentary Tract—Other Conditions

20. Ferguson JA, Heaton JR. Closed hemorrhoidectomy. Dis Colon Rectum 1959; 2:176–179. 21. Arbman G, Krook H, Haapaniemi S. Closed vs. open hemorrhoidectomy—is there any difference? Dis Col Rectum 2000; 43:31–34. 22. Sayfon J, Becker A, Koltun L. Sutureless closed hemorrhoidectomy: a new technique. Ann Surg 2001; 234:21–24. 23. Longo A. Mechanical hemorrhoidectomy using a circular stapler. Refresher course on hemorrhoidal disease therapy. 24th International Congress of Latin Mediterranean. Palermo: Renna s.p.a. Graphic, 1995. 24. Peng BC, Jayne DG, Ho YH. Randomized trial of rubber band ligation vs. stapled hemorrhoidectomy for prolapsed piles. Dis Col Rectum 2003; 46:291–297; discussion 296–297. 25. Fleshman JW. Fissure-in-ano and anal stenosis. In: Beck DE, Wexner SD, eds. Fundamentals of Anorectal Surgery. 2d ed. London: WB Saunders Company, 1998:209–224. 26. Klosterhafen B, Vogel P, Rixen H, Mittermayer C. Topography of the inferior rectal artery. A possible cause of chronic primary anal fissure. Dis Colon Rectum 1989; 32:43–52. 27. Cerdan FJ, de Leon AR, Azpiroz F, Martin J, Balibrea JL. Anal sphincter measures in fissure in ano before and after lateral sphincterotomy. Dis Colon Rectum 1982; 25:198–201. 28. Schouten WR, Briel JW, Auwerda JJ, De Graaf EJ. Ischaemic nature of anal fissure. Br J Surg 1996; 83:63–65. 29. Metcalf AM. Anal fissure. Surg Clin North Am 2002; 82: 1291–1297. 30. Loder PB, Kamm MA, Nicholls RJ, Phillips RK. ‘Reversible chemical sphincterotomy’ by local application of glyceryl trinitrate. Br J Surg 1994; 81:1386–1389. 31. Lund JN, Scholefield JH. A randomised, prospective, doubleblind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissure. Lancet 1997; 349:11–14. 32. Kua KB, Kocher HM, Kelkar A, Patel AG. Effect of topical glyceryl trinitrate on anodermal blood flow in patients with chronic anal fissures. ANZ J Surg 2001; 71:548–550. 33. Pitt J, Williams S, Dawson PM. Reasons for failure of glyceryl trinitrate treatment of chronic fissure-in-ano: a multivariate analysis. Dis Colon Rectum 2001; 44:64–67. 34. Carapeti EA, Kamm MA, Evans BK, Phillips RK. Topical diltiazem and bethanechol decrease anal sphincter pressure without side effects. Gut 1999; 45:719–722. 35. Jonas M, Neal KR, Abercrombie JF, Scholefield JH. A randomized trial of oral vs. topical diltiazem for chronic anal fissures. Dis Colon Rectum 2001; 44:1074–1078. 36. Antropoli C, Perrotti P, Rubino M, et al. Nifedipine for local use in conservative treatment of anal fissures: preliminary results of a multicenter study. Dis Colon Rectum 1999; 42:1011–1015. 37. Ezri T, Susmallian S. Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissure. Dis Colon Rectum 2003; 46:805–808. 38. Utzig MJ, Kroensen AJ, Buhr HJ. Concepts in pathogenesis and treatment of chronic anal fissure—a review of the literature. Am J Gastroenterology 2003; 98:968–974. 39. Minguez M, Melo F, Espi A, et al. Therapeutic effects of different doses of botulinum toxin in chronic anal fissure. Dis Colon Rectum 1999; 42:1016–1021. 40. Minguez M, Herreros B, Espi A, et al. Long-term follow-up (42 months) of chronic anal fissure after healing with botulinum toxin. Gastroenterology 2002; 123:112–117. 41. Vasilevsky CA, Gordon PH. The incidence of recurrent abscesses or fistula in ano following anorectal suppuration. Dis Colon Rectum 1984; 27:126–130. 42. Henrichsen S, Christensen J. Incidence of fistula in ano complicating anorectal sepsis: a prospective study. Br J Surg 1986; 73:371–372. 43. Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-in-ano. Br J Surg 1976; 63:1–12. 44. Vasilevsky CA. Fistula-in-ano and abscess. In: Beck DE, Wexner SD, eds. Fundamentals of Anorectal Surgery. 2d ed. London: WB Saunders Company, 1998:153–173.

45. Bubrick MP, Hitchcock CR. Necrotizing anorectal and perineal infections. Surgery 1979; 86:655–662. 46. Sangwan YP, Rosen L, Riether RD, Stasik JJ, Sheets JA, Khubchandani IT. Is simple fistula-in-ano simple? Dis Colon Rectum 1994; 37:885–889. 47. Hjortrup A, Moesgaard F, Kjaergard J. Fibrin adhesive in the treatment of perineal fistulas. Dis Colon Rectum 1991; 34: 752–754. 48. Sentovich SM. Fibrin glue for anal fistulas: long-term results. Dis Colon Rectum 2003; 46:498–502. 49. Cintron JR, Park JJ, Orsay CP, et al. Repair of fistulas-in-ano using fibrin adhesive: long-term follow-up. Dis Colon Rectum 2000; 43:944–950. 50. Nelson R. Anorectal abscess fistula: what do we know? Surg Clin North Am 2002; 82:1139–1151. 51. Kupfer CA, Goligher JC. One hundred consecutive cases of complete prolapse of the rectum treated by operation. Br J Surg 1974; 17:482–487. 52. Jurgeleit HC, Corman ML, Coller JA, Veidenheimer MC. Symposium: Procidentia of the rectum: Teflon sling repair of rectal prolapse, Lahey Clinic experience. Dis Colon Rectum 1975; 18:464–467. 53. Corman ML. Rectal prolapse, solitary rectal ulcer, syndrome of descending perineum, and rectocoele. In: Colon and Rectal Surgery. 4th ed. Philadelphia: Lippincott Williams & Wilkin, 1998:401–448. 54. Moschowitz AV. The pathogenesis, anatomy and cure of prolapse of the rectum. Surg Gynecol Obstet 1912; 15:7–21. 55. Goldberg SM, Gordon PH. Treatment of rectal prolapse. Clin Gastroenterol 1975; 4:489–504. 56. Broden B, Snellman B. Procidentia of the rectum studied with cineradiography. A contribution to the discussion of causative mechanism. Dis Colon Rectum 1968; 11:330–347. 57. Theuerkauf FJ, Jr., Beahrs OH, Hill JR. Rectal prolapse. Causation and surgical treatment. Ann Surg 1970; 171:819–835. 58. Hiltunen KM, Matikainen M, Auvinen O, Hietanen P. Clinical and manometric evaluation of anal sphincter function in patients with rectal prolapse. Am J Surg 1986; 151: 489–492. 59. Neill ME, Parks AG, Swash M. Physiological studies of the anal sphincter musculature in faecal incontinence and rectal prolapse. Br J Surg 1981; 68:531–536. 60. Madoff RD. Rectal prolapse and intussusception. In: Beck DE, Wexner SD. Fundamentals of Anorectal Surgery. 2d ed. London: WB Saunders Company, 1998:99–114. 61. Kairaluoma MV, Viljakka MT, Kellokumpu IH. Open vs. laparoscopic surgery for rectal prolapse: a case-controlled study assessing short-term outcome. Dis Colon Rectum 2003; 46: 353–360. 62. Altemeier WA, Culbertson WR, Schowengerdt C, Hunt J. Nineteen years’ experience with the one-stage perineal repair of rectal prolapse. Ann Surg 1971; 173:993–1006. 63. Kim DS, Tsang CB, Wong WD, Lowry AC, Goldberg SM, Madoff RD. Complete rectal prolapse: evolution of management and results. Dis Colon Rectum 1999; 42:460–466. 64. Sultan AH, Kamm MA, Hudson CN, Bartram CI. Third degree obstetric anal sphincter tears: risk factors and outcome of primary repair. BMJ 1994; 308:887–891. 65. Nyam DC, Frizelle FA, Pemberton JH. Physiologic derangements of the rectum and anus. In: Miller TA, ed. Modern Surgical Care. 2d ed. St. Louis: Quality Medical Publishing, 1998: 702–727. 66. Speakman CT, Hoyle CH, Kamm MM, Henry MM, Nicholls RJ, Burnstock G. Abnormalities of innervation of internal anal sphincter in fecal incontinence. Dig Dis Sci 1993; 38:1961–1969. 67. Rudolph W, Galandiuk S. A practical guide to the diagnosis and management of fecal incontinence. Mayo Clin Proc 2002; 77:271–275. 68. Laurberg S, Swash M, Henry MM. Delayed external sphincter repair for obstetric tear. Br J Surg 1988; 75:786–788. 69. Palmer KR, Corbett CL, Holdsworth CD. Double-blind crossover study comparing loperamide codeine and diphenoxylate

Chapter 29: Physiologic Derangements of the Anorectum and the Defecatory Pelvic Floor

70.

71. 72.

73.

74.

75.

76. 77.

78.

79.

80.

81.

82.

83.

in the treatment of chronic diarrhea. Gastroenterology 1980; 79:1272–1275. Read M, Read NW, Barber DC, Duthie HL. Effects of loperamide on anal sphincter function in patients complaining of chronic diarrhea with fecal incontinence and urgency. Dig Dis Sci 1982; 27:807–814. MacLeod JH. Management of anal incontinence by biofeedback. Gastroenterology 1987; 93:291–294. O’Brien PE, Skinner S. Restoring control: the Acticon Neosphincter artificial bowel sphincter in the treatment of anal incontinence. Dis Colon Rectum 2000; 43:1213–1216. Rosen HR, Urbarz C, Holzer B, Novi G, Schiessel R. Sacral nerve stimulation as a treatment for fecal incontinence. Gastroenterology 2001; 121:536–541. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(suppl 2): II43–II47. Whitehead WE, Wald A, Diamant NE, Enck P, Pemberton JH, Rao SS. Functional disorders of the anus and rectum. Gut 1999; 45(suppl 2):II55–II59. Wald A. Slow transit constipation. Curr Treat Options Gastroenterol 2002; 5:279–283. Fletcher JG, Busse RF, Riederer SJ, et al. Magnetic resonance imaging of anatomic and dynamic defects of the pelvic floor in defecatory disorders. Am J Gastroenterol 2003; 98:399–411. Gilliland R, Heymen S, Altomare DF, Park UC, Vickers D, Wexner SD. Outcome and predictors of success of biofeedback for constipation. Br J Surg 1997; 84:1123–1126. Lau CW, Heymen S, Alabaz O, Iroatulam AJ, Wexner SD. Prognostic significance of rectocele, intussusception, and abnormal perineal descent in biofeedback treatment for constipated patients with paradoxical puborectalis contraction. Dis Colon Rectum 2000; 43:478–482. Pemberton JH, Rath DM, Ilstrup DM. Evaluation and surgical treatment of severe chronic constipation. Ann Surg 1991; 214:403–411. Nyam DC, Pemberton JH, Ilstrup DM, Rath DM. Long-term results of surgery for chronic constipation. Dis Colon Rectum 1997; 40:273–279. Inoue Y, Noro H, Komoda H, et al. Completely laparoscopic total colectomy for chronic constipation: report of a case. Surg Today 2002; 32:551–554. Schiedeck TH, Schwandner O, Bruch HP. Laparoscopic therapy of chronic constipation. Zentralbl Chir 1999; 124: 818–824.

615

84. Wexner SD, Milsom JW, Dailey TH. The demographics of anal cancers are changing: identification of a high-risk population. Dis Colon Rectum 1987; 30:942. 85. Noffsinger A, Witte D, Fenoglio-Presier CM. The relationship of human papillomaviruses to anorectal neoplasia. Cancer 1992; 70:1276. 86. Greenall MJ et al. Epidermoid cancer of the anal margin. Pathologic features, treatment, and clinical results. Am J Surg 1985; 149:95. 87. Nelson H, Dozois RR. Anal neoplasms. Perspect Colon Rectal Surg 1994; 7:16. 88. Nielsen OV, Jensen SL. Basal cell carcinoma of the anus. A clinical study of 34 cases. Br J Surg 1981; 68:856. 89. Beck DE et al. Perianal Bowen’s disease. Dis Colon Rectum 1988; 31:419. 90. Reymann F et al. Bowen’s disease and internal malignancy. Arch Dermatol 1988; 124:677. 91. Beck DE, Fazio VW. Perianal Paget’s disease. Dis Colon Rectum 1987; 30:263. 92. Chu QD et al. Giant condyloma acuminatum (BuschkeLowenstein tumor) of the anorectal and perianal regions. Dis Colon Rectum 1994; 37:950. 93. Cummings BJ. Treatment of primary epidermoid carcinoma of the anal canal. Int J Colorectal 1987; Dis 2:107. 94. Nigro ND, Vaitkevicius VK, Considine B. Combined therapy for cancer of the anal canal. Dis Colon Rectum 1974; 17:354. 95. Nigro ND et al. Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 1983; 51:1826. 96. Nigro DN, Vaitkevicius VK, Considine B Jr. Dynamic management of squamous cell cancer of the anal canal. Invest New Drugs 1989; 7:83–89. 97. Longo WE et al. Recurrent squamous cell carcinoma of the anal canal. Ann Surg 1994; 200:40. 98. Corman ML. Malignant tumors of the anal canal. In: Corman ML, ed. Principles of Colon and Rectal Surgery. Philadelphia: JB Lip-pincott, 1993. 99. Ross M, Pezzi C, Pezzi T. Patterns of failure in anorectal melanoma. A guide to surgical therapy. Arch Surg 1990; 125:313. 100. Bullard KM, Tutttle TM, Rothenberger DA, et al. Surgical therapy for anorectal melanoma. J Am Coll Surg 2003; 196:206–211. 101. Jensen SL et al. Adenocarcinoma of the anal ducts: a series of 21cases. Dis Colon Rectum 1988; 31:268. 102. Beck DE, Wexner SW Anal neoplasms. Beck DE, Wexner SD, eds. Fundamentals of Anorectal Surgery. New York: McGraw-Hill, 1992.

medwedi.ru

30 Derangements in Gastrointestinal Function Secondary to Previous Surgery Jeannie F. Savas, Thomas A. Miller, and David W. Mercer

INTRODUCTION Although operative procedures on the stomach are less commonly performed today than they were a decade or two ago because of the decreasing incidence of gastric cancer and the ability to manage most forms of acid-peptic disease with various pharmacologic manipulations or antibiotic regimens, gastric procedures are still performed with sufficient frequency that an understanding of those derangements that may be surgically induced is paramount to good surgical practice. Virtually any type of gastric operation is attended by some type of postoperative symptomatology; fortunately, the majority of these physiologic alterations can be managed with little patient inconvenience. Despite a surgeon’s best efforts, however, a small percentage of patients subjected to gastric surgery develop untoward sequelae that can be devastating not only to a patient’s sense of well-being but also to his ability to function in society and continue gainful employment. These physiologic aberrations can result from the loss of normal gastric reservoir function, transection of the vagus nerves, or interruption of normal pyloric sphincter function, or they may be directly related to the procedure performed to restore normal gastrointestinal continuity following treatment of the underlying disease. Similarly, operations on the intestine can perturb normal absorption and digestion by reducing the overall epithelial surface area involved in the digestive process as occurs during intestinal resection, or by altering its normal proximal to distal continuity as may result from various rerouting procedures. Although changes in any portion of the intestine can induce digestive malfunction, alterations in small bowel function are generally more important from the standpoint of clinical relevance. An understanding of the pathophysiology responsible for these various derangements involving the gastrointestinal tract is mandatory if successful management is to be effectively rendered. The focus of this chapter is to discuss these derangements and how the associated physiologic dysfunction can be restored to normal or as near normal as possible.

GASTRIC DYSFUNCTION Derangements Related to Gastric Resection or Interruption of Normal Pyloric Sphincter Function Dumping Syndrome The dumping syndrome refers to the symptom complex that occurs following the ingestion of a meal when a portion of the stomach has previously been removed or the normal pyloric sphincter mechanism has been disrupted. Both an early and late form of this syndrome have been described, with the early form occurring considerably more frequently.

Early Dumping The early form of the dumping syndrome usually occurs within 10 to 30 minutes following the ingestion of a meal, and is associated with both gastrointestinal and cardiovascular symptomatology. The gastrointestinal symptoms include nausea and vomiting, a sense of epigastric fullness, eructations, crampy abdominal pain, and often explosive diarrhea. The cardiovascular symptoms include palpitations, tachycardia, diaphoresis, fainting, dizziness, flushing, and occasionally blurred vision. Characteristically these symptoms occur while the patient is seated at the table eating or shortly after arising. The symptom complex can develop after any operation on the stomach, but is especially common after partial gastrectomy with a Billroth II reconstruction in which as many as 50% to 60% of patients may be victims, especially if more than two-thirds of the stomach has been removed. Less commonly, it is observed after a Billroth I gastrectomy and in patients following vagotomy and drainage procedures, particularly if the type of drainage was a generous gastroenterostomy or a Finney-type pyloroplasty. Only rarely does this full-blown symptom complex supervene, and usually the gastrointestinal symptomatology is more frequently encountered than the vasomotor aberrations. Although the exact sequence of events responsible for this syndrome remains to be defined, there is general agreement that it occurs because of the rapid passage of food of high osmolarity from the stomach into the small intestine (1,2). This occurs because the previous gastric resection or interrupted pyloric sphincteric mechanism no longer allows the stomach to prepare its contents and deliver them to the proximal bowel in the form of small particles in isosmotic solution. Thus the resulting discharge of this hyperosmotic chyme into the small intestine induces a rapid shift of extracellular fluid into the intestinal lumen to achieve isotonicity. The luminal distention that follows and the autonomic responses induced by the resultant decrease in circulating plasma volume are thought to be responsible for many of the symptoms of this syndrome. To what extent the contracted blood volume per se gives rise to the autonomic symptoms following dumping remains to be clarified, because several studies have failed to demonstrate a clear correlation between the severity of symptoms and the magnitude of blood volume derangements (1). On the other hand, a number of studies have demonstrated that the release of several humoral agents is increased in patients with dumping and not in asymptomatic patients after gastrectomy, suggesting that the agents are involved in the pathogenesis of this syndrome. Serotonin, for example, is released from the intestine in response to distention, and serotonin antagonists have

medwedi.ru 617

618

Part Two: The Alimentary Tract—Other Conditions

been shown to benefit some patients with dumping symptoms (3,4). Further evidence exists that plasma levels of a bradykinin-like substance are likewise elevated during dumping attacks and that bradykinin can reproduce many of the vasomotor components of the syndrome when administered exogenously (5). Additionally, neurotensin (6) and vasoactive intestinal peptide (7) levels have been demonstrated to be increased in patients with the dumping syndrome. Plasma enteroglucagon concentrations are also increased after gastrectomy in symptomatic patients following a glucose challenge, in contrast to control subjects without the dumping syndrome (8). In addition, this agent inhibits sodium and water absorption from the small intestine and through such a mechanism could account for the diarrhea that occurs in early dumping. Finally, other agents implicated in early dumping include cholecystokinin, peptide YY, and atrial natriuretic peptide (9–11). Generally, the symptoms associated with dumping are sufficiently obvious that the diagnosis can be made on this basis alone. It must be emphasized, however, that in any group of patients complaining of dumping-like symptoms, a high proportion of individuals with social problems, various neuroses, and occasionally alcoholism may be present (12). Thus if any doubt exists concerning the exact cause of the symptomatology, objective support for the diagnosis should be obtained, especially if a surgical procedure to correct the problem is potentially anticipated. This would include the demonstration of rapid gastric emptying on upper gastrointestinal barium study or by assessment with one of the currently available radionuclide techniques (13). Another diagnostic approach is the use of a provocation test in which a patient is given a meal of 200 mL of a 50% glucose solution in water (14). In patients with the dumping syndrome, instillation of this liquid meal into the residual stomach has been shown to provoke the symptom complex concomitant with a fall in plasma volume. It is of interest that the majority of patients subjected to gastric surgery complain of some dumping-like symptoms in the early months following surgery. Most of these individuals, however, experience spontaneous relief and require no specific treatment (15,16). Of those patients plagued with prolonged symptomatology, dietary measures alone can effect adequate management in most instances. Such measures should include avoiding foods containing large amounts of sugars, frequent feeding of small meals rich in protein and fat, and separating liquids from solids during a meal. If hot drinks elicit symptoms, as occurs in some patients, they should also be avoided. Lying down when symptoms do occur may likewise be beneficial, because gravity can aggravate dumping symptomatology. In some patients, carbohydrate gelling agents such as pectin have been ingested with the meal and shown to be of some success (17); unfortunately, these agents are rather unpalatable and not readily tolerated for long periods of time. Previously, serotonin antagonists were the only pharmacologic agents available that had potential benefit in the relief of dumping symptoms. Both methysergide maleate (Sansert) and cyproheptadine (Periactin) have been helpful in some individuals when given before meals (3). Usually, however, large doses of such agents were required, which produced their own disagreeable side effects. Thus their use in any long-term fashion was limited. In many patients the long-acting somatostatin analog, octreotide acetate (Sandostatin), has been shown to be highly effective in preventing the development of symptoms in the early dumping syndrome, both vasomotor and

gastrointestinal (18). Treatment with this synthetic analog of somatostatin was demonstrated to inhibit the hormonal responses associated with this syndrome and to completely ablate diarrhea (18). In addition, intestinal motility is altered by octreotide acetate (19). This peptide was demonstrated to not only inhibit gastric emptying, but also to induce a fasting or interdigestive small bowel motility pattern in patients with the dumping syndrome such that intestinal transit of an ingested meal was prolonged (19). Thus sandostatin appears to be a very helpful agent in the nonoperative treatment of incapacitating early dumping syndrome by changing the hormonal response elicited by an ingested meal and by altering intestinal transit. Furthermore, the side effects associated with administration of this synthetic peptide are relatively innocuous (18), consisting of occasional mild abdominal cramping immediately following its subcutaneous administration. In the few patients (1% or less) who fail to respond to these treatment measures, operative intervention may become necessary. The physiologic rationale behind surgery should be to improve gastric reservoir function, decrease the rapid gastric emptying, or ideally accomplish both of these goals. Although a wide variety of surgical procedures have been used to manage dumping, the use of isoperistaltic or antiperistaltic jejunal segments has met with the greatest success in dealing with this problem in most centers (Fig. 1). With the former approach, a 10 to 20 cm loop of jejunum is interposed between the stomach and small intestine in an isoperistaltic fashion (20,21). Over time, this loop dilates and thereby promotes reservoir function. It also appears to delay gastric emptying, at least that of liquids. In the antiperistaltic approach, a jejunal segment 10 cm in length is used, in which the jejunum is twisted on its mesentery so that its distal end is anastomosed to the stomach and its proximal end to the small intestine (21,22). The resulting reversal in peristalsis permits the loop to act as a substitute pylorus, enabling it to slow the rate of gastric emptying and thereby allow more time for mixing and grinding of food

Figure 1 Surgical approaches to treat the dumping syndrome. (A) A 10 to 20 cm loop of jejunum is interposed between the stomach and the small intestine in an isoperistaltic fashion. (B) A 10 cm loop of jejunum is twisted on its mesentery so that its distal end is anastomosed to the stomach, and its proximal end to the small intestine in an antiperistaltic fashion. (C) A long-limb Roux-en-Y anastomosis where the jejunojejunostomy is fashioned approximately 60 cm from the gastrojejunostomy.

Chapter 30: Derangements in Gastrointestinal Function Secondary to Previous Surgery

619

before delivery into the small bowel. Published experience with this latter technique is now in excess of 10 years, demonstrating significant alleviation of symptoms in more than 90% of patients (22). Another technique is the creation of a long-limb Roux-en-Y anastomosis to delay gastric emptying (Fig. 1) (23). Many surgeons believe that this is the most durable procedure to prevent dumping. Vogel et al. successfully managed 19 of 22 patients with severe dumping, spanning a period of 13 years, using the Roux-en-Y technique (24). Late Dumping Late dumping occurs two to three hours after a meal and is considerably less common than its early counterpart. Like early dumping, the basic defect in this disorder is also rapid gastric emptying. In this situation, however, it is related specifically to carbohydrates and can be induced by meals containing large amounts of monosaccharides or disaccharides. When these sugars are delivered rapidly to the small intestine, they are quickly absorbed. The resulting hyperglycemia triggers the release of large amounts of insulin to control the rising blood sugar. In the attempt to normalize blood sugar, an actual ‘‘overshooting’’ occurs so that a profound hypoglycemia ensues. Catecholamines released by the adrenal gland are then activated, with the resulting symptoms of diaphoresis, tremulousness, light-headedness, tachycardia, and confusion. This symptom complex is indistinguishable from insulin shock. As with early dumping, patients should be advised to ingest frequent small meals and markedly reduce their carbohydrate intake. Pectin has also been used in the treatment of this disorder, either alone or in combination with acarbose, an a-glucoside hydrolase inhibitor, a compound that delays carbohydrate absorption through impairment of intraluminal starch and sucrose digestion (17,25). If these nonoperative approaches fail, the use of an antiperistaltic loop of jejunum between the residual gastric pouch and intestine has also been shown to effectively manage this problem (Fig. 1). Not only does this loop delay gastric emptying, but it also results in a flattening of the glucose tolerance curve and an alleviation of the hypoglycemic symptomatology (26). The Roux-en-Y procedure has also proved helpful in managing late dumping (24).

Small Stomach Syndrome If an excessive amount of the stomach has been removed, leaving only a small gastric pouch, some patients may develop the small stomach syndrome. This syndrome is characterized by extreme discomfort following the ingestion of even small amounts of food. Because of this unpleasant sensation and the fact that vomiting often occurs if any attempt is made to increase oral intake, patients with this disorder are frequently malnourished. The exact cause of this disorder is uncertain, but it probably develops because of the inability of the proximal stomach to dilate and receive a bolus of food without increasing intragastric pressure (2). Normally the vagus nerve, which has been transected in most of these patients, initiates distention of the stomach to allow accommodation of ingested food, a process known as receptive relaxation. If this vagally mediated action has been interrupted, such relaxation does not occur, and the intragastric pressure increases with distention on reception of food. Unfortunately, treatment of this problem has remained extremely difficult. Although frequent small

Figure 2 Surgical management of the short stomach syndrome.

feedings and various liquid and enteral diets have been tried to alleviate symptoms, such nonoperative approaches have usually been unsuccessful. A number of operative approaches have also been used with varying degrees of success. These have included procedures to enlarge the gastric reservoir through the creation of various pouches interposed between the stomach and intestine (Fig. 2) (27). Jejunal interposition with the use of an isoperistaltic limb has also been used to treat this disorder with reasonable success in alleviating symptoms and improving the underlying malnutrition problems (28). In view of the difficulty in managing this disorder, the best approach is to prevent its development rather than to attempt to treat it when it occurs.

Metabolic Disturbances Metabolic problems may develop following any type of gastric procedure, but they are more common and serious after partial gastrectomy than after vagotomy, and the incidence following gastrectomy is much greater if a Billroth II rather than a Billroth I approach has been used in reconstruction (29). As with dumping, the severity of these disturbances is directly related to the extent of the gastric resection. Anemia is clearly the most common metabolic derangement. Two major types have been identified: (i) that related to a deficiency of iron and (ii) that related to an impairment in vitamin B12 metabolism. Of the two, iron deficiency is the more common, and more than 30% to 50% of patients carefully evaluated demonstrate this type of anemia following gastrectomy. The exact cause has remained elusive, but it appears to be related to a combination of (i) decreased iron uptake, (ii) impaired iron absorption, and (iii) chronic subliminal blood loss secondary to the hyperemic, friable gastric mucosa primarily involving the margins of the stoma where the stomach connects with the small intestine (2,29). Because iron absorption requires an acidic environment to maximally occur, any gastric procedure that would alter acidity can contribute to malabsorption. Examples would include vagotomy, antrectomy or a

medwedi.ru

620

Part Two: The Alimentary Tract—Other Conditions

subtotal gastrectomy in which the antrum and portions of the parietal cell mass would be removed. Generally, the addition of iron supplements to the patient’s diet corrects this type of anemia. A megaloblastic anemia can also occur following subtotal gastrectomy (50% or greater), but only rarely develops after partial gastric resection (e.g., antrectomy). This problem is caused by a deficiency of vitamin B12 secondary to poor absorption of this substance because of the lack of intrinsic factor secretion in the gastric juice (2,29). The more extensive the gastric resection, the more likely is this deficiency; it always occurs following total gastrectomy. If a patient develops a macrocytic anemia, a serum B12 level should be obtained. If this is abnormal, the patient should be treated by intramuscular injection of cyanocobalamin every three to four months indefinitely, because its administration orally is not a reliable route. The other cause of macrocytosis is a folate deficiency. This is a rare anemia following gastric resection, but it may coexist with an iron or vitamin B12 deficiency anemia. It is usually a consequence of inadequate oral intake and can generally be corrected by dietary supplementation. Impaired absorption of fat is relatively common following any type of gastric operation, but the magnitude of fecal fat loss is usually small and of little importance clinically. Occasionally, steatorrhea is seen after a Billroth II gastrectomy and probably occurs as a result of inadequate mixing of bile salts and pancreatic lipase with ingested fat because of bypass of the duodenum. When this results, deficiencies in the uptake of fat-soluble vitamins may also be observed. For mild degrees of fat malabsorption, no treatment is indicated. If steatorrhea develops, pancreatic replacement enzymes are often effective in decreasing fat loss. Feeding with medium-chain triglycerides is also of value, because these substances do not require bile and pancreatic lipase for absorption. Occasionally, gastric resection is associated with the development of bone disease. Both osteoporosis and osteomalacia have been observed and appear to be caused by deficiencies in calcium absorption. If fat malabsorption is also present, the calcium problem is further aggravated, because free fatty acids bind calcium; further, fat malabsorption also inhibits the absorption of vitamin D, an important component in normal calcium balance (2). The incidence of this problem clearly increases with the extent of gastric resection and is mainly an aberration associated with a Billroth II gastrectomy (29,30). Usually the bone disease develops insidiously, and symptoms are generally not seen until four or five years after surgery. Occasionally, spontaneous fractures or unexplained aches and pains in the back or bones may be the only indication that a calcium deficiency exists. Treatment of this disorder is usually straightforward and includes the administration of calcium supplements (1–2 g/day) and vitamin D (500–5000 U daily). In patients developing postgastrectomy bone disease, serial serum calcium determinations are indicated, and adjustments in calcium supplementation and vitamin D administration are altered accordingly. Weight loss is relatively common following surgical procedures on the stomach but is generally not a significant problem, except in those individuals who have had either all or substantial portions of their stomach removed, in which case considerable malnutrition may develop. The degree of weight loss correlates closely with such factors as the presence or absence of dumping, steatorrhea, diarrhea, abdominal discomfort during eating, and bilious vomiting (31,32).

Treatment of malnutrition is directed at improving nutritional balance by multiple small feedings, avoidance of factors that may precipitate the dumping syndrome, and dietary or pharmacologic management of diarrhea and/or steatorrhea. If such manipulations are not successful in treating this problem, some type of surgical procedure to delay gastric emptying and/or enhance the gastric reservoir effect, as outlined previously, may become necessary.

Derangements Related to Gastric Reconstruction A number of disorders may develop following gastric resection that are directly related to the approach used to establish gastrointestinal continuity. All these problems are more commonly encountered in patients who have had a Billroth II gastrectomy, and the afferent loop and retained antrum syndromes occur exclusively in patients with this type of gastrectomy.

Afferent Loop Syndrome The afferent loop syndrome is a mechanical problem produced by partial obstruction of the afferent loop resulting in its inability to empty its contents. Consequently, it can only occur following gastrectomy with a Billroth II type of reconstruction. A variety of causes can give rise to this obstruction, including angulation of the anastomosis with kinking, herniation of the afferent loop posterior to the efferent loop, stenosis of the gastrojejunostomy, volvulus, and adhesions (Fig. 3). This disorder is nearly always associated with the presence of a long ( > 30–40 cm) afferent limb that has been anastomosed to the gastric remnant in an antecolic fashion. Both acute and chronic forms of this disorder have been recognized, but chronic afferent loop obstruction is clearly more common (33,34). From a pathophysiologic standpoint, the syndrome occurs because of an accumulation of pancreatic and

Figure 3 Causes of the afferent loop syndrome.

Chapter 30: Derangements in Gastrointestinal Function Secondary to Previous Surgery

hepatobiliary secretions within the obstructed loop, resulting in its distention. The stimulus for such secretion is the presence of food in the gastric remnant and efferent loop, which elicits the various neurohumoral mechanisms involved in normal digestion. Such distention results in epigastric discomfort and cramping. If the loop is only partially obstructed, the increasing intraluminal pressure is usually capable of overcoming it, following which the afferent loop empties its contents into the stomach, resulting in forceful (and sometimes projectile) vomiting of bilious material with immediate relief of symptoms. The vomitus lacks food, because any ingested meal has already passed into the efferent limb. If the obstruction is complete, necrosis and perforation of the loop can occur. This is a consequence of the surgical closure of the proximal duodenum that is performed during a Billroth II gastrectomy, resulting in a closed-loop type of obstruction. In this circumstance, constant abdominal pain is noted that can involve the entire upper abdomen, often more pronounced in the right upper quadrant, with radiation into the interscapular area. Unless this distention is surgically relieved, a lethal outcome may ensue from perforation and subsequent peritonitis. In most patients suffering from the afferent loop syndrome, only partial obstruction of the afferent limb is present (33,34). Symptoms may exist for months or sometimes even years. These symptoms are directly related to eating, at which time the hepatobiliary and pancreatic secretions distend the loop. Bile-stained material devoid of food is vomited after the meal has passed into the efferent limb, relieving symptoms; and the patient is relatively comfortable until the next meal. Obviously the degree of afferent loop obstruction influences the extent to which the patient is incapacitated by the symptoms and the need to seek medical treatment. If partial afferent loop obstruction has been present for a long period, it may be aggravated by the development of the blind loop syndrome. In this condition, bacterial overgrowth of enteric organisms proliferates in the static loop and binds with vitamin B12 and deconjugated bile acids (2). This results in a systemic deficiency of vitamin B12 with the development of megaloblastic anemia and an inefficient micellization of fat that, if severe enough, can create steatorrhea. The acute form of afferent loop obstruction may occur early after operation (within a few days) or may develop quite unexpectedly months to years following the Billroth II gastrectomy. In both circumstances it is caused by acute blockage of the afferent limb, as may occur with volvulus or herniation of the afferent loop posterior to the efferent loop. Because of the resulting closed-loop type of obstruction, acute afferent loop obstruction must be corrected by immediate operation. Although physical findings are usually nonspecific with the exception of the occurrence of a palpable abdominal mass in about one-third of patients (2), the associated pain and the tenderness are usually severe enough to indicate the necessity of urgent operative intervention. Even if the diagnosis may not have been made before surgery, findings at surgery confirm the underlying cause. In contrast to the diagnosis of the acute form, that of chronic afferent loop obstruction may be more difficult. Although symptoms are often suggestive of this abnormality, confirmation of the diagnosis may be difficult. Usually the dilated afferent limb is not demonstrable on plain films of the abdomen, and only occasionally do contrast barium studies of the stomach delineate the presence of an obstructed loop. Failure to visualize the afferent limb on upper endoscopy is suggestive evidence for the diagnosis.

621

Hepatobiliary radionuclide imaging techniques have been used with some success in diagnosing the afferent loop syndrome (2). With this technique, the hepatic excretion of a previously administered radionuclide is followed after giving a patient a fatty meal or the hormone cholecystokinin. If the nuclide fails to pass into the stomach or distal bowel after being excreted into the afferent limb, the possibility of an afferent loop obstruction must be considered. Although this technique shows diagnostic promise, its clinical usefulness remains to be determined. Because the afferent loop syndrome, whether acute or chronic, is a mechanical problem, operation is the only effective treatment. With few exceptions, a long afferent limb is usually the underlying problem. Thus treatment involves the elimination of this loop. A variety of procedures have been advocated to accomplish this feat, including the conversion of a Billroth II construction into a Billroth I anastomosis, enteroenterostomy below the stoma, and the use of a Roux-en-Y anastomosis (Fig. 4) (1). If the latter procedure is used, a concomitant vagotomy should also be performed to prevent marginal ulceration from the diversion of duodenal contents from the gastroenteric stoma.

Efferent Loop Obstruction Compared to other derangements in gastric function following previous surgery, obstruction of the efferent limb of a gastrojejunostomy is relatively rare. Clearly the most common cause of such obstruction is herniation of the limb behind the anastomosis in a right-to-left direction (35). This problem occurs because of the space that exists posterior to the anastomosis after construction of a gastrojejunostomy and has been described with both antecolic and retrocolic gastrojejunostomies. The preference for herniation in the right-to-left direction most likely results from the fact that the gastrojejunostomy lies to the left of the main mass of small intestine, thus making it mechanically easier for herniation to occur from right to left (1). Although obstruction of the efferent loop is the usual circumstance with this type of herniation, it may also compress the mesentery of the afferent limb and thereby compromise its blood supply and/or obstruct the afferent limb as well.

Figure 4 Surgical management of the afferent loop syndrome.

medwedi.ru

622

Part Two: The Alimentary Tract—Other Conditions

Efferent limb obstruction following gastrojejunostomy from a retroanastomic hernia may occur at any time following surgery, but more than half of the patients who develop this disorder do so within the first postoperative month. Diagnosis is frequently difficult. Initial complaints include colicky left upper quadrant pain; copious, bilious vomiting; and abdominal distention. Usually the most helpful diagnostic maneuver is a contrast barium study of the stomach in which barium fails to enter the efferent limb. Operative therapy is virtually always required and consists in reducing the retroanastomotic hernia and ensuring that the retroanastomotic space is securely closed to prevent recurrence of this condition.

Alkaline Reflux Gastritis Reflux of bile into the stomach is relatively common following surgical procedures on this organ. In a small percentage of patients, this reflux is associated with severe, continuous, unrelenting epigastric pain and bilious vomiting, and weight loss (2,36–40). Occasionally, this pain is substernal in nature, but despite its location, it is characteristically not relieved by food or antacids. The bilious vomiting may occur at any time during the day or night and not uncommonly awakens a patient from sleep. The diagnosis is made by taking a careful history along with a complete examination of the gastrointestinal tract including scintigraphic assessment of gastric emptying, gastroscopy in combination with multiple biopsy specimens taken away from the stoma, gastric analysis, gastric bile acid concentration content, and Tc-99m-labeled sulfur colloid to demonstrate reflux of bile into the gastric remnant. On endoscopic examination of the stomach, the mucosa is noted to be beefy red and friable and frequently demonstrates superficial erosions that may extend into the distal esophagus. Microscopically, both parietal and chief cells are greatly diminished, and superficial mucosal ulcerations are common with evidence of hemorrhage, atrophy, and intestinalization of the epithelial surface. It is not uncommon for achlorhydria to be present in many patients affected with this condition; and little, if any, response is elicited, following stimulation with a secretagogue such as pentagastrin. Associated with these findings is the frequent demonstration of an iron deficiency anemia and weight loss. Because patients with this constellation of signs and symptoms are lacking in other explainable causes, the association of an alkaline gastric content, endoscopic gastritis in combination with bile reflux, and histologic confirmation of mucosal injury has been termed ‘‘alkaline reflux gastritis’’ (2,39,40). In most patients who develop alkaline reflux gastritis, gastric resection with restoration of gastrointestinal continuity with a Billroth II approach has been used (2). The syndrome has also been reported after gastroduodenostomy or gastroenterostomy and in a few patients who have undergone vagotomy and drainage procedures (37). Symptoms may develop any time following operation and have been observed as late as 20 years, following surgery. Although bile reflux appears to be the inciting event, a number of problems remain unanswered with respect to the role of bile in its pathogenesis (2,39,40). For example, both clinical and experimental reports indicate that enterogastric reflux is quite common, following gastric surgery, although gastric mucosal injury is not an invariable consequence of this circumstance. In addition, asymptomatic patients frequently demonstrate histologic and endoscopic changes in the gastric epithelium not unlike those with symptoms of alkaline reflux gastritis.

Finally, a clear correlation between the volume of bile and its composition (i.e., primary and secondary bile acid components) and the subsequent development of alkaline gastritis has never been proved. Thus although it appears that the syndrome does in fact exist, caution must be exercised to be sure that it is not over-diagnosed. Although a variety of approaches have been used to manage the symptoms of alkaline reflux gastritis, medical treatment has usually failed in this condition. Antacids, histamine (H2) receptor antagonists (e.g., cimetidine), anticholinergics, and cholestyramine have been tried to relieve symptoms without consistently demonstrating efficacious results. Consequently, patients who have intractable problems with this disorder should undergo surgery. The principle underlying surgery is to divert the bile and pancreatic secretions away from the stomach. Although a large number of approaches have been used to accomplish this feat, the operative procedure favored by most surgeons in terms of relieving symptoms, promoting weight gain, and reversing the findings seen in alkaline gastritis has been the use of a Roux-en-Y gastrojejunostomy in which the Roux limb has been 41 to 46 cm in length (2,40,41). Other operative approaches include the interposition of a 40 cm isoperistaltic jejunal loop between the gastric remnant and the duodenum (42) and revision of a Billroth II gastrojejunostomy, if previously performed, using an enteroenterostomy (anastomosis between the afferent and afferent limbs) (43).

Retained Antrum Syndrome Occasionally, inadequate resection of the gastric antrum may occur during partial gastrectomy, even though the resection was carried beyond the pyloric sphincter. This happens because the antral mucosa may extend past the pyloric muscle for a distance of 0.5 cm (44). The significance in remembering this is that a Billroth II anastomosis can result in the development of a retained antrum syndrome if residual antrum is included in the duodenal stump. This circumstance allows the retained antrum to be continually exposed to an alkaline pH from the duodenal, pancreatic, and biliary juices that may in turn stimulate the release of large amounts of gastrin with a corresponding continuous hypersecretion of hydrochloric acid in the gastric remnant. This highly ulcerogenic preparation is responsible for about 9% of recurrent ulcers following previous surgery for peptic ulcer disease and is associated with an incidence of recurrent ulceration as high as 80% (45,46). This potential problem can virtually be eliminated if biopsy confirmation of duodenal mucosa is obtained during resection of the proximal duodenum at the time of a Billroth II gastrectomy. If a patient develops a recurrent ulcer following previous gastrectomy for ulcer disease in which a Billroth II anastomosis was fashioned, the possibility of a retained antrum must be entertained. To exclude this possibility, a technetium scan may prove helpful (47). In patients having a retained antrum, this scan demonstrates a hot spot that is adjacent to the area where normal uptake of technetium by the gastric mucosa of the remaining stomach occurs. Antral cuffs as small as 1 cm have been detected experimentally with this technique (47). If a retained antrum is diagnosed, pharmacologic management with an H2 receptor blocker or pump inhibitor may prove helpful in controlling the acid hypersecretion. If this is not effective, either conversion of the Billroth II anastomosis to a Billroth I reconstruction or excision of the retained antral tissue in the duodenal stump with reclosure should obviate the problem.

Chapter 30: Derangements in Gastrointestinal Function Secondary to Previous Surgery

Jejunogastric Intussusception Jejunogastric intussusception is a rare entity that results when the afferent or efferent limb intussuscepts into the stomach or residual gastric pouch. It may occur in any patient whose stomach has been anastomosed to the jejunum, but has been most commonly seen following simple gastroenterostomy. Both acute and chronic variants have been described (48). Although surgical intervention is the treatment of choice for both types of the disease, it is a surgical emergency in the acute variety to prevent strangulation of the intussuscepted bowel. Foster (49) has summarized the important features of diagnosis and has emphasized that any patient who has had gastric surgery (i.e., gastric resection or gastroenterostomy) and who subsequently develops the following should be suspected of having jejunogastric intussusception until proven otherwise: 1. 2. 3. 4. 5.

Severe epigastric pain Persistent vomiting (either bile stained or bloody) A palpable epigastric mass Tenderness over the epigastrium Any combination of these signs or symptoms

The more chronic form of the disease is less dramatic clinically and usually presents as recurrent episodes of vague upper abdominal pain that is exacerbated by meals. The pain ceases after eating, because the intussuscepted limb reduces itself. Although jejunogastric intussusception may involve either the afferent or the efferent limbs, the efferent limb is the more common intussuscipiens and is responsible for more than 80% of the reported cases (48). Depending on findings at surgery, surgical approaches may include reduction of the intussuscepted intestine and/or its resection, takedown of the anastomosis, or its revision. Generally, the afferent and efferent limbs of jejunum are also fixed to adjacent tissue such as the mesocolon, colon, or stomach to prevent recurrence.

Roux Syndrome The Roux syndrome refers to the symptom complex characterized by gastric vomiting, epigastric pain, and weight loss in a patient with Roux-en-Y reconstruction following distal gastrectomy (50). On endoscopic evaluation, the gastric remnant is usually dilated as well as the Roux limb, but no evidence of mechanical obstruction is noted. The etiology of this condition appears to be dysfunction in the motility of the Roux limb such that its propulsive activity proceeds toward the stomach rather than away from it (51,52). Actually in studies of patients undergoing Roux-en-Y reconstruction, this disordered motility pattern is rather commonplace; why only a small subset of patients develop the Roux syndrome is uncertain. Management of this disorder is usually empiric. Fortunately, many patients will respond to promotility agents. In those who do not, some type of surgical procedure is usually required. Because no one surgeon has a large experience with this condition, various operative strategies have been employed (42,43). These include taking down the original Roux limb and (i) constructing a second Roux limb, (ii) anastomosing the gastric remnant in a Billroth II fashion with an enteroenterostomy between the afferent and efferent limbs, and (iii) creating an isoperistaltic jejunal interposition between the gastric remnant and the duodenum. If a concomitant problem with gastric motility appears to be a contributing factor, a 95% gastrectomy has been performed

623

in some patients (53). Data supporting one approach over another are unavailable.

Derangements Related to Vagal Transection Postvagotomy Diarrhea Diarrhea of varying degrees is relatively common following gastric surgery, and if carefully questioned, 30% or more of patients indicate some difficulty with this problem (54). Fortunately, it is not severe in the majority of individuals and often disappears within the first three or four months following surgery. In many patients with diarrhea, it is part of the dumping syndrome. As the patient develops more discriminating eating habits, the dumping improves along with the diarrhea. Distinct from the diarrhea associated with an inadequate gastric reservoir, vagotomy itself is associated with alterations in stool frequency. As many as 30% to 70% of patients report an increased frequency in daily bowel movements following truncal vagotomy (55–59). For a previously constipated patient, this is often viewed as beneficial. In some patients, actual diarrhea develops that may occur two to three times weekly or manifests itself once or twice a month, at which times it lasts three or four days. In others, it may be more explosive, resulting in the soiling of clothing. Between attacks, bowel movements may be entirely normal. Fortunately, most patients developing diarrhea following vagotomy find a diminution in this problem with time. The mechanisms responsible for postvagotomy diarrhea have remained elusive. That it indeed occurs is borne out by the Leeds/York trial, in which 7% of patients developed diarrhea following subtotal gastrectomy, compared to an impressive 23% who underwent resection of the same magnitude in combination with a truncal vagotomy (56– 59). Bacterial overgrowth in the upper gastrointestinal tract has been proposed as one possible mechanism on the basis of the observation that colonization of the jejunum with aerobic and anaerobic bacteria is relatively common following vagotomy. The problem with this hypothesis is that the degree of overgrowth does not appear to be different in patients developing postvagotomy diarrhea and those who are asymptomatic (60). Denervation of the intestine in dogs following truncal vagotomy was shown to enhance the movement of small intestinal contents into the colon through a loss of the sphincteric mechanism of the ileal cecal valve (61). Although a similar circumstance may occur in humans, data relative to that issue are unknown. However, other experimental observations have failed to uncover differences in small intestinal morphology, small intestinal fluxes of fluid and electrolytes, or the fecal output of fat in patients with and without vagotomy (1). Some studies have suggested a more rapid gastric emptying in patients developing postvagotomy diarrhea compared with those without this problem, but consensus on this issue is far from uniform (3). Although the incidence of postvagotomy diarrhea in patients who are subjected to selective vagotomy was initially reported as being less than a comparable group receiving truncal vagotomy, further follow-up with larger groups of patients has not borne out this contention (1,62). From a therapeutic standpoint, it is known that cholestyramine, an anionic exchange resin that absorbs bile salts and thereby renders them unabsorbable and inactive, can significantly decrease the severity of diarrhea in patients developing this problem following vagotomy (63). The possible explanation for this relates to the finding of Allan et al. (61) who noted that although the total bile acid content in the stools of patients was not significantly greater in the presence

medwedi.ru

624

Part Two: The Alimentary Tract—Other Conditions

or absence of diarrhea, those with postvagotomy diarrhea excreted more than twice the amount of chenodeoxycholic acid than vagotomy patients without diarrhea. Because postvagotomy diarrhea is usually a selflimited disease, treatment should be symptomatic. In the 5% of patients in whom symptoms are severe and interfere drastically with lifestyle, cholestyramine is the treatment of choice. Ayulo (63) noted improvement within one to four weeks of treatment with this agent in almost all patients receiving the drug. Significant decreases in urgency, frequency, and severity of diarrhea were noted. Treatment consists of the administration 4 g of cholestyramine with meals three times daily and adjusted to a maintenance dosage, allowing one to two formed bowel movements per day (63). In patients refractory to cholestyramine treatment, codeine of loperamide may prove helpful. Only in extremely rare instances is operative treatment justified for postvagotomy diarrhea. When diarrhea has remained incapacitating for at least one year following initial operation and fails to respond to cholestyramine, codeine or loperamide, remedial surgery is indicated. If patients are selected properly, this involves no more than 1% of all patients undergoing vagotomy. The operative procedure of choice is to interpose a 10 cm segment of reversed jejunum 70 to 100 cm from the ligament of Treitz (Fig. 5) (64). In patients subjected to this operation, sustained relief from diarrhea has resulted.

Postvagotomy Dysphagia Although it is rare, occasionally after vagotomy a patient complains of dysphagia, which is usually noted within the first two weeks following operation. It is probably related to edema or an intramural hematoma of the esophagus

Figure 5 Surgical management of postvagotomy diarrhea.

resulting from injury to the esophageal wall at the time of vagal section and is more commonly noted after the transthoracic approach of performing a vagotomy than following a transabdominal procedure (65,66). Radiologically the disorder resembles achalasia; but, unlike this disease, liquids pass easily, whereas solids usually evoke symptoms. Esophagoscopic and manometric findings are usually normal, indicating that both esophageal sphincter function and peristalsis are intact. Treatment is usually symptomatic because the condition generally disappears spontaneously within 2 to 12 weeks of vagotomy. If dysphagia is particularly troublesome, esophageal dilation may be indicated with the use of a mercury-weighted bougie such as a Maloney dilator.

Postvagotomy Gastric Atony Delayed gastric emptying is also a consequence of vagotomy, and it is for this reason that a drainage procedure must be performed when a truncal or selective vagotomy is performed. This relates to the normal function of the vagus nerve in adjusting gastric tone to the volume of the stomach so that peristalsis is initiated and coordinated properly. Because parietal cell vagotomy does not disrupt this function due to the maintenance of antral innervation, postvagotomy atony is not a problem with this procedure. Sometimes after vagotomy (i.e., truncal or selective) and an apparently adequately performed drainage procedure, a patient may have persistent and bothersome gastric stasis that causes food to be retained in the stomach for several hours. Usually this is accompanied by no more than a feeling of fullness in the mid-epigastrium. At times this is associated with marked abdominal pain and rarer still with a functional gastric outlet obstruction. The diagnosis of gastroparesis is confirmed on scintigraphic assessment of gastric emptying. However, to correctly establish the diagnosis of gastroparesis, other causes of delayed gastric emptying such as diabetes mellitus, electrolyte imbalance, drug toxicity, and neuromuscular diseases must be excluded. Further, mechanical causes of gastric hypomotility such as postoperative adhesions, afferent or efferent loop obstruction, and internal herniations must be ruled out. If endoscopic examination of the stomach reveals no evidence of a true anatomic obstruction and other causes of gastroparesis have been eliminated, watchful waiting is usually the treatment of choice. Occasionally, when observation fails, short-term treatment with various pharmacologic agents is indicated to improve gastric tone. Pharmacotherapy usually consists of using one of several gastrokinetic agents including metoclopramide (67), domperidone (68), and/or erythromycin (69). Metoclopramide exerts its gastrokinetic effects by acting as a dopamine antagonist and by cholinergic enhancing effects as a result of facilitation of acetylcholine release from enteric cholinergic neurons (67). In contrast domperidone works on both the stomach and the intestine by facilitation of acetylcholine release from the mesenteric plexus of the gut (68). Finally, erythromycin markedly accelerates gastric emptying by binding to motilin receptors on gastrointestinal smooth muscles, where it acts as a motilin agonist (69,70). One of these three agents usually suffices to enhance gastric tone and improve gastric emptying.

Incomplete Vagal Transection Because vagotomy is an important component of the surgical treatment of peptic ulcer disease, it is important that

Chapter 30: Derangements in Gastrointestinal Function Secondary to Previous Surgery

vagal transection of the acid-secreting portion of the stomach be complete. If this is not ensured, the patient is predisposed to the possibility of recurrent ulcer formation. The type of vagotomy influences the likelihood of this circumstance. In highly selective vagotomy (i.e., parietal cell) in which meticulous vagal denervation of the stomach is accomplished, an incomplete vagotomy is rarely a problem. In contrast, truncal vagotomy may be associated with a high incidence of incomplete transection because of the variability in size of the two vagal trunks and their anatomic position. Although inadequate transection of either vagus nerve may occur during truncal vagotomy, the right vagus nerve is inadequately transected three times more frequently than the left vagus (71,72). This relates to the fact that the right vagus nerve is frequently buried in the right periesophageal fibroareolar tissue—in contrast to the left vagus nerve, which usually hugs the anterior esophageal surface. The likelihood of incomplete vagotomy can be greatly lessened by confirming vagal transection histologically at the time of operation by frozen section examination of excised nerve tissue.

INTESTINAL DYSFUNCTION Short Bowel Syndrome The short bowel syndrome (SBS) is the designation used for a symptom complex that results when large portions of the small intestine have been resected, so that the remaining intestinal surface area is inadequate to perform normal absorption and digestion. The strict definition for this syndrome assumes that less than 200 cm of small bowel remains. In reality, patients with inflammatory bowel disease (e.g., Crohn’s disease) and other disorders may actually have many of the features of SBS due to malfunction of the affected bowel even though more than 200 cm of small bowel exist. Clinically, SBS is characterized by varying degrees of postprandial watery diarrhea, weight loss, and malabsorption of essential nutrients related to the functional surface area of the small intestine that remains. Diarrhea may result from malabsorption of bile acids and nutrients as well as an increase in gastric and intestinal secretory activity. Patients with SBS are frequently dependent on parenteral fluids and/or special nutritional formulae in order to avoid dehydration and cachexia.

625

site for absorption of vitamin B12 and bile salts, such that resection of the ileum may result in deficiency of these substances. In patients exhibiting SBS who previously had undergone massive small bowel resection, gastric hypersecretion may exist. This condition develops early and continues for at least six months to a year if not adequately suppressed with the administration of high-dose proton pump inhibitors. Its pathogenesis continues to be debated. Some evidence suggests that a mediator secreted by the resected bowel normally inhibits gastric acid secretion. Other findings are consistent with the notion that the acid hypersecretion is due to the loss of the ‘‘ileal brake’’ mechanism whereby intraluminal fat in the distal small bowel normally inhibits gastric secretion (73). In the normal individual, the duodenum is the primary site for iron and calcium absorption. The duodenum and jejunum normally absorb fats, carbohydrates, proteins, minerals, and all vitamins except for B12. The ileum is the primary site for absorption of bile salts, cholesterol, and vitamin B12. In cases of total jejunal resection, the normal ileum is able to compensate for its absence. However, the jejunum is not able to compensate for a comparable ileal resection with respect to vitamin B12 and bile salt absorption (Fig. 6). Due to the stimulatory effect of bile salts on colonic water secretion, replacement of fluid losses can be very problematic even in patients able to absorb adequate nutrients by an enteral route. Patients with an intact ileocecal valve and colon have improved outcome due to slowed transit time and colonic adaptation to absorb more fluid and carbohydrates. The colon has been shown to have the capacity to absorb up to 1200 kcal/day (75). Without the ileocecal valve and colon in continuity, fluid losses may exceed 5 to 10 L/ day, in addition to the excessive loss of electrolytes, fat, protein, vitamins, and carbohydrates (Fig. 7). The small intestine has an unusual capability to adapt following massive bowel resection. The mechanisms responsible for this are poorly understood. Studies have

Pathogenesis SBS most commonly occurs following massive ileal resection for conditions such as acute mesenteric ischemia with gangrene or repeated resections for complicated Crohn’s disease. In children, SBS may result from resections for necrotizing enterocolitis, gastroschisis, or midgut volvulus. The normal adult has a small intestinal length between 400 and 700 cm, of which about 25 to 30 cm is duodenum, 160 to 200 cm jejunum, and 200 to 500 cm ileum. The absorptive capacity of the small bowel is so massive that resections of up to half of the small bowel are relatively well tolerated. Of course, the critical piece of information is how much healthy bowel remains in the patient and whether it is in continuity. The site of resection and the presence of an ileocecal valve and colon in continuity are important prognostic factors. Patients with less than 60 cm of small bowel have a decreased survival rate, particularly if the terminal ileum is absent (73). Ileal metabolism is unique in that it is the only

Figure 6 Sites of nutrient absorption in the gastrointestinal tract. Source: From Ref. 74.

medwedi.ru

626

Part Two: The Alimentary Tract—Other Conditions

water content. This effect leads to voluminous watery diarrhea and excessive fluid and electrolyte losses (75). The loss of bile salt reabsorption, and thus recirculation of bile salts, results in an overall bile salt deficiency as the liver is not able to increase synthesis sufficiently to compensate for the loss. The deficiency further limits the patient’s ability to absorb fats and fat-soluble vitamins. Another effect of bile salt deficiency is that the composition of bile in the liver and gallbladder is altered, rendering it lithogenic. Studies have shown that the incidence of cholelithiasis is 30% to 70% within one year in patients with SBS. Because of this finding, some authors advocate cholecystectomy at the time of small bowel resection when feasible (79). Bile salt–binding resins, such as cholestyramine, have been used in the treatment of diarrhea due to excessive bile salts in the stool. Its use is empiric, however, as there are no definitive tests to confirm its effectiveness. While it will improve symptoms in patients with minimal to moderate bile salt losses, its use is contraindicated in patients with excessive losses. In such patients, the use of cholestyramine augments bile salt deficiency, worsens fat malabsorption, induces fatsoluble vitamin deficiencies, and causes steatorrhea (80).

Figure 7 Normal daily intestinal fluid balance. Source: From Ref. 76.

proposed a number of putative agents that not only enhance the absorptive capacity of the remaining small bowel mucosa but also induce villous hypertrophy. These include epidermal growth factor, enteroglucagon, glucagon-like peptide-II, insulin-like growth factor-1, cholecystokinin, gastrin, growth hormone, neurotensin, and glutamine (77). Although some lengthening of small bowel has been observed, the primary increase in absorptive capacity during the adaptive phase is due to mucosal hyperplasia and bowel dilatation. Although polymeric enteral nutrition augments and hastens adaptation, elemental enteral nutrition has been shown to have little effect or even a detrimental effect on gut mucosa. While most adaptive mechanisms develop within the first one to two years postoperatively, there are reports of patients requiring total parenteral nutrition (TPN) for five to seven years before being successfully weaned from this modality (78).

Special Nutritional Considerations in SBS Enterohepatic Circulation Bile Salt Metabolism. Bile salts are synthesized in the liver, stored in the gallbladder, and secreted into the duodenum upon the stimulus of intraluminal fat. While some fats are absorbed in the duodenum in the form of free fatty acids, and the remainder of fats and fat-soluble vitamins are normally absorbed in the jejunum, these processes are dependent on solubilization within bile salt micelles. Over 90% of synthesized bile acids are reabsorbed in the terminal ileum and returned to the hepatic circulation (73). In patients who have undergone resection of the terminal ileum, there is a loss of bile salt absorption. In patients with a colon in continuity with the remaining small intestine, bile salts are then emptied into the colon. These bile salts have a direct toxic effect on colonic mucosa and have been shown to stimulate the secretion of water by the colon. One study showed that for each additional millimole of bile salt emptied into the colon, there is an 11 mL increase in stool

B12 Absorption Vitamin B12 absorption also takes place in the terminal ileum, and depends on a complex mechanism involving Peptide YY in saliva, binding to intrinsic factor from the stomach, and a sodium-coupled active transport system in the ileum. Disruption of any of these factors will affect the absorption of vitamin B12. Patients who have undergone ileal resection will require monthly parenteral B12 administration, as do most patients with extensive gastric resection or long-limb gastric bypass. The absence of the ileocecal valve is also thought to impair absorption of vitamin B12 and other nutrients, as it predisposes to bacterial overgrowth that in turn competes for intraluminal nutrients (81–83). Vitamin B12 deficiency should be suspected in a patient with macrocytic anemia, although more progressive symptoms include neurologic deficits and ataxia. The Schilling test is performed to confirm the diagnosis. Calcium Metabolism Calcium is absorbed primarily in the duodenum. Patients with SBS are frequently deficient in total body calcium, and this requires either parenteral administration or oral supplementation of calcium and vitamin D. Magnesium deficiency is also problematic, as oral supplementation is poorly tolerated due to its cathartic effect. Deficient total body magnesium in turn affects calcium metabolism through its inhibition of parathyroid hormone secretion. Intestinal calcium normally binds to oxalate making it insoluble. However, in patients with SBS and a colon in continuity, calcium is presented to the colon bound to unabsorbed fatty acids, rather than to oxalate. As a result, there is increased absorption of dietary oxalate in the colon, leading to the development of calcium oxalate urolithiasis. Patients receiving nutritional support from an enteral diet should therefore have restriction of oxalate intake in order to prevent stone formation (75).

Medical Treatment Therapy of SBS is initially aimed at replacing fluid and electrolyte losses and essential nutrients, and in the long-term preventing nutritional deficiencies. In the immediate postoperative period, it is usually necessary to restrict oral intake

Chapter 30: Derangements in Gastrointestinal Function Secondary to Previous Surgery

entirely in order to minimize intestinal secretion. Administration of proton pump inhibitors will help control gastric hypersecretion. Intravenous fluid and electrolyte supplementation is necessary to prevent dehydration, and may be necessary even in patients who eventually tolerate adequate oral nutrition. Patients will usually require TPN once hemodynamically stable, with gradual advancement to an enteral diet as tolerated. Many patients will require longterm TPN, which may lead to other complications including cholestasis, cirrhosis, and catheter-related infections and thromboses (see Chapter 3 on Surgical Nutrition for details). Agents shown to be helpful in improving absorption and minimizing fluid losses include antidiarrheal agents, bulking agents, and high fiber diets. Certainly an effective method to increase absorption is to increase the intake of electrolytes and nutrients, encouraging patients to take frequent meals and oral rehydration solutions. It is important to aggressively treat any underlying disease of the remaining bowel (e.g., Crohn’s disease) in order to optimize its function and absorptive capacity. Another effect of SBS is that many drugs will be poorly absorbed and higher doses may be necessary. Various investigators have shown improved intestinal absorption with the administration of glutamine, growth hormone, and a high fiber diet (84–86). Studies evaluating the effectiveness of high-dose growth hormone and glutamine without dietary modifications, however, failed to show any sustainable benefit (87).

Surgical Treatment Perhaps the most significant surgical advance has been its role in preventing SBS. Crohn’s disease is now a rare cause of the disorder due to the reluctance to operate on patients merely for the presence of active disease, and the broad use of stricturoplasty for localized obstruction of the small bowel rather than resection of significant strictures. It is now standard procedure that a patient with ischemic bowel will have any questionable bowel reevaluated at a ‘‘second look’’ operation rather than having an extensive resection performed at the first operation, in an attempt to preserve as much useful bowel as possible. Further, once a patient has undergone a major bowel resection, reestablishing bowel continuity as soon as the patient can tolerate the procedure will allow the adaptive process to begin. Surgical attempts to treat SBS have included a variety of bowel lengthening procedures to increase absorptive surface area, or procedures to slow transit such as reversed segments or creation of artificial sphincters (88,89). Unfortunately, none of these approaches have been shown to be effective. Small bowel transplantation in patients with severely limited intestinal surface area is being performed more frequently and results are improving, with three-year survivals of 73% in those requiring sole intestinal transplants and 40% in those with a combination bowel/liver graft (90,91). Transplant surgeons argue that patients should be referred for intestinal transplant earlier, because the results with multivisceral transplantation are so much poorer. Of the 1000 grafts transplanted since 1985, most were performed in 1 of about 50 centers in the United States, and almost all patients were successfully weaned off TPN. Medicare now has established guidelines to define TPN failure as the indication for small bowel transplantation. These are overt or impending liver failure, thrombosis of two or more central veins, frequent or severe catheter-related sepsis, or frequent and severe dehydration. The procedure is still

627

challenging, however, due to the high immunogenicity of the small bowel. There is a high incidence of graft loss due to rejection and death due to sepsis from the required high doses of immunosuppressive agents. Over 60% of patients with intestinal transplants were children at the time of the transplant.

Pouchitis ‘‘Pouchitis’’ is the term originally used to describe the ileitis seen as a complication in patients who had undergone a continent ileostomy procedure, but is also seen in the now more frequently performed ileal pouch-anal anastomosis after total proctocolectomy for ulcerative colitis. In fact, pouchitis remains the most frequent complication seen in this latter group of patients, occurring in approximately 60% within two years. About 10% of these patients will develop chronic pouchitis, defined as continuous disease or more than six episodes per year (92). The clinical presentation includes increased watery stool output, urgency, leakage or incontinence, abdominal cramps, and malaise. Patients may also experience bleeding, fever, generalized weakness, and toxicity. Endoscopy reveals edematous friable folds, surface bleeding, and ulceration. Histologically, there is an increase in the number of inflammatory cells within the pouch wall. Although the etiology has not been clearly delineated, it is thought to result from bacterial overgrowth related to stool stasis within the pouch. It is interesting, however, that the incidence of pouchitis is very low (6%) in patients who undergo the identical procedure for familial polyposis when compared with those having ulcerative colitis (93). Because of this fact, some authors postulate that pouchitis may be related to ulcerative colitis. It is also more common in patients who had extraintestinal manifestations of ulcerative colitis preoperatively (93). Others have suggested that mucosal ischemia within the pouch is the culprit (94). Acute episodes usually respond well to a short course of oral metronidazole. While the symptoms of chronic pouchitis will be improved with antibiotic therapy, other modalities are commonly employed, including steroid enemas, salicylate enemas, or probiotics. Probiotics such as VSL#3, which contain lactobacilli and bifidobacteria—the so-called ‘‘good’’ bacteria, have been shown to prevent the occurrence of pouchitis when used postoperatively or after an antibiotic-induced remission (95). It is prudent to perform further investigative studies in patients with severe or refractory pouchitis, such as periodic endoscopic examination with biopsies, to rule out the presence of malignancy or unsuspected Crohn’s disease. Despite the frequency and chronicity of pouchitis in some patients, few actually require resection of the pouch with permanent ileostomy placement. Pouch loss is a rare phenomenon, reported at 1% to 4% (92). Risk of pouch failure has been shown to be slightly higher in those over 56 years of age at the time of the initial operation (96).

Blind Loop Syndrome The clinical syndrome of abdominal cramping, bloating, diarrhea, excessive weight loss, and varying degrees of malnutrition occurring in patients who have undergone some form of intestinal bypass is known as blind loop syndrome. Although this may occur with a variety of surgical procedures, the more common ones leading to this disorder include intestinal bypass procedures for obesity and gastrectomy with Billroth II anastomosis (see also section

medwedi.ru

628

Part Two: The Alimentary Tract—Other Conditions

on Afferent Limb Syndrome). Similar symptoms, however, are seen in patients with duodenal or jejunal diverticulosis. The etiology of blind loop syndrome is thought to be similar to that of pouchitis, that is, stasis leading to bacterial overgrowth. Stasis of intestinal contents in the bypassed segment may result from anastomotic stricture, poor motility in a limb connected in antiperistaltic fashion, or other mechanical outlet obstruction. The resulting bacterial overgrowth augments the malabsorptive state created by the original procedure as intraluminal bacteria compete for ingested nutrients and deconjugate bile acids. This contributes both to fat and to B12 malabsorption, and leads to the development of diarrhea, steatorrhea, fat-soluble vitamin deficiencies, and macrocytic anemia (78,97). Blind loop syndrome can be difficult to verify radiographically, although one may see preferential filling of a distended afferent limb (if this is the cause), which empties poorly on barium studies, or failure of the afferent limb to fill at all. In other situations, an abdominal computed tomography (CT) scan may reveal a markedly distended segment of small bowel corresponding with the postsurgical anatomy. Initial treatment is directed at correcting fluid, electrolyte, and vitamin deficiencies, as well as the administration of intermittent oral antibiotics. As symptoms and deficiencies are effectively managed, nutritional status will improve. Occasional patients are refractory to this approach, however, and may require surgical correction if feasible. Surgical options include takedown of an intestinal bypass or revision to Roux-en-Y anatomy after the patient has been medically and nutritionally optimized.

Enterocutaneous Fistula Classic teaching regarding the development of a fistula outlines the various predisposing factors of infection, inflammation, malignancy, foreign body, trauma, radiation, epithelialized tract, and distal obstruction. In reality, the majority of fistulae develop in the immediate postoperative period and are related to direct injury of bowel, compromise of its blood supply, anastomotic leak, or erosion by a foreign body or adjacent intraabdominal abscess. The typical patient will develop a fever and leukocytosis accompanied by an increase in abdominal pain and tenderness. Eventually drainage of succus or feculent material will be identified in the wound or drain site. Although initial management must consist of fluid and electrolyte replacement and protection of the surrounding skin, the patient should be studied to determine whether there are any indications for emergent surgical intervention, such as removal of a retained foreign body, abscess drainage, diversion of anastomotic leak, or correction of bowel obstruction. Plain abdominal X rays may reveal a retained foreign body. An abdominal CT scan with oral and IV contrast is sufficient to rule out an associated intraabdominal abscess. This study may also reveal the presence of free intraabdominal air, suggesting an anastomotic leak. Barium studies may be performed through the fistula itself and through the proximal and distal bowel. If an anastomotic leak is suspected, water-soluble contrast should be used initially. Such studies are useful in determining the anatomic origin of the fistula, the presence of any underlying bowel pathology, and whether the fistula is contained and well drained. As the contrast passes into distal bowel, a mechanical bowel obstruction may be excluded.

An intraabdominal abscess may be amenable to percutaneous drainage; however, if there is a free leak of bowel contents into the peritoneal cavity, surgical exploration is indicated. The involved bowel should be resected and diverted. Reanastomosis may be undertaken at a later date when there is no evidence of sepsis, hemodynamic instability, or severe nutritional compromise. If there is no indication for urgent exploration, the patient should be medically managed with close attention to control of sepsis, as many fistulas will close spontaneously. In one study, 90% of enterocutaneous fistulas closed within a month (98). During this time, adequate nutritional support and protection of surrounding skin are imperative. Patients with proximal or high output fistulas will require parenteral nutrition, while those with distal or low output fistulas may tolerate enteral nutrition without an increase in the fistula output or delay in healing. The fistula output should be measured and its electrolyte composition analyzed in order to render proper fluid replacement. Somatostatin analogs have been shown to decrease fistula output, and thus may be helpful in maintaining fluid volume and skin integrity in patients with very high output fistulas (>500 mL/day); however, its widespread use for all fistulas is not indicated. The drug is very expensive, and has not been shown to speed healing time for enterocutaneous fistulas. Before consideration of elective fistula closure, the fistula and postsurgical anatomy should be clearly delineated. In addition, surgical closure should not be undertaken if the patient has any ongoing signs of infection or malnutrition. The primary reason for delay in definitive fistula closure is to get the patient nutritionally and medically optimized. Under such conditions, the abdomen can be carefully reexplored, and the involved segment of bowel should be completely resected. Care should be taken to avoid injury to other segments of bowel. The proximal and distal ends of healthy bowel, in the absence of infection, may be safely anastomosed to establish intestinal continuity. Although these patients are at risk for development of incisional hernias, the placement of mesh in this setting is ill advised and may predispose to development of another fistula. The seriousness of developing an enterocutaneous fistula should not be minimized. The overall mortality of patients who sustain this problem is 10% to 20%, related to uncontrolled sepsis and malnutrition (98).

SUMMARY Derangements in gastric function are common following operations on the stomach. These aberrations in normal physiology can result from a loss of gastric reservoir function when a portion of the stomach has been removed, from motility disturbances secondary to transection of the vagus nerves, or from interruption of the normal pyloric sphincter mechanism secondary to pyloroplasty; or they can be directly related to the type of reconstructive procedure that has been undertaken to restore normal gastrointestinal continuity. Although most patients experience some type of postoperative symptomatology following a gastric operation, many of these problems are short lived and abate with time. In a small percentage of patients, however, significant untoward sequelae result that may require substantial dietary manipulation and occasionally pharmacologic management to alleviate distressing signs and symptoms and enable a patient to function adequately in society. Occasionally, reoperation becomes necessary to correct the underlying

Chapter 30: Derangements in Gastrointestinal Function Secondary to Previous Surgery

physiologic dysfunction. Fortunately, patients in this latter category are less commonly seen today than they were a decade or so ago because of the decreasing incidence of gastric cancer and the development of new strategies to manage acid-peptic diseases of the stomach, both of which have resulted in fewer operative procedures involving the stomach. Derangements in intestinal function are usually a consequent of decreased functional intestinal surface area, so that digestion and absorption cannot proceed normally. This situation commonly results from resections of various parts of the small bowel or disruption in normal epithelial function as occurs in inflammatory bowel disease (e.g., Crohn’s disease). The resultant dysfunction may be profound, as seen in the SBS, following massive intestinal resection or more localized to a specific region of the gut as seen in Crohn’s disease. Obviously, the greater the intestinal surface affected, the more challenging will be the treatment. Unfortunately, in patients with minimal functional small bowel, digestion is severely impaired necessitating lifelong parenteral nutrition or, in selective circumstances, small bowel transplantation. More focused abnormalities such as pouchitis, the blind loop syndrome, and enterocutaneous fistula commonly respond to conservative treatment measures; only in a small subset of patients is surgical intervention necessary to restore normal physiologic function.

REFERENCES 1. Fromm D. Complications of Gastric Surgery. New York: John Wiley, 1977. 2. Ritchie WP Jr, Perez AR. Postgastrectomy syndromes. In: Moody FG, et al., eds. Surgical Treatment of Digestive Disease. Chicago: Year Book, 1986. 3. Johnson LP, et al. Serotonin antagonists in experimental and clinical ‘‘dumping.’’ Ann Surg 1962; 156:537. 4. Reichle FA, et al. The effect of gastrectomy on serotonin metabolism in the human portal vein. Ann Surg 1970; 172:585. 5. Wang PY, et al. Kallikrein-kinin system in postgastrectomy dumping syndrome. Ann Intern Med 1974; 80:577. 6. Blackburn AM, et al. Elevation of plasma neurotensin in the dumping syndrome. Clin Sci 1980; 59:237. 7. Sagor GR, et al. Release of VIP in the dumping syndrome. Br Med J 1981; 282:507. 8. Bloom SR, Rorpton CMS, Thomson JPS. Enteroglucagon release in the dumping syndrome. Lancet 1972; 2:789. 9. Lawaetz O, Blackburn AM, Bloom SR, et al. Gut hormone profile and gastric emptying in the dumping syndrome: a hypothesis concerning the pathogenesis. Scand J Gastroenterol 1983; 18:73. 10. Tulassy Z, Tulassay T, Gupta R, Rascher W. Decreased activity of atrial natriuretic peptide in dumping syndrome after gastric surgery. Dig Dis Sci 1991; 36:1177. 11. Yamashita Y, Toge T, Adrian TE. Gastrointestinal hormones in dumping syndrome and reflux esophagitis after gastric surgery. J Smooth Muscle Res 1997; 33:37. 12. Eldkh J, et al. Long-term results of surgical treatment for dumping after partial gastrectomy. Br J Surg 1974; 61:90. 13. Donovan IA. The different components of gastric emptying after gastric surgery. Ann R Coll Surg Engl 1976; 58:368. 14. Lawson-Smith C, Thomson JPS. A dumping provocation test. Br J Surg 1975; 62:153. 15. Chaimoff CH, Dintsman M. The long-term fate of patients with dumping syndrome. Arch Surg 1972; 105:554. 16. Silver D, et al. The mechanism of the dumping syndrome. Surg Clin North Am 1966; 46:425. 17. Jenkins DJA, et al. Effect of dietary fiber on complications of gastric surgery: prevention of post-prandial hypoglycemia by pectin. Gastroenterology 1977; 72:215.

629

18. Geer RJ, et al. Postgastric surgery syndromes: octreotide in dumping syndrome—efficacy of octreotide-acetate in treatment of severe postgastrectomy dumping syndrome. Ann Surg 1990; 212:678. 19. Richards WO, et al. Octreotide acetate induces fasting small bowel motility in patients with dumping syndrome. J Surg Res 1990; 49:483. 20. Mackie CR, et al. The effect of isoperistaltic jejunal interposition upon gastric emptying. Surg Gynecol Obstet 1981; 153:813. 21. Remus NI, Williamson RCN, Johnston D. The use of jejunal in terposition for intractable symptoms complicating peptic ulcer surgery. Br J Surg 1982; 69:265. 22. Sawyers JL, Herrington JL. Superiority of anti-peristaltic jejunal segments in management of severe dumping syndrome. Ann Surg 1973; 178:311. 23. Hocking MP, et al. Delayed gastric emptying of liquids and solids following Roux-en-Y biliary diversion. Ann Surg 1981; 194:494. 24. Vogel SB, Hocking MP, Woodward ER. Clinical and radionuclide evaluation of Roux-Y diversion for postgastrectomy dumping. Am J Surg 1988; 155:57. 25. Speth PAJ, Jansen JBMJ, Lammers CBHW. Effect of acarbose, pectin, or a combination of acarbose with pectin, and placebo on postprandial reactive hypoglycemia after gastric surgery. Gut 1983; 24:798. 26. Fink WJ, et al. Treatment of postoperative reactive hypoglycemia by a reversed intestinal segment. Am J Surg 1976; 131:19. 27. Sawyers JL. Surgical management of post-gastrectomy syndrome. J Miss State Med Assoc 1974; 14:28. 28. Cuschieri A. Long-term evaluation of a reservoir jejunal interposition with an isoperistaltic conduit in the management of patients with small stomach syndrome. Br J Surg 1982; 69:386. 29. Alexander-Williams J, Donovan IA. Postgastrectomy and postvagotomy syndromes and their management. In: Glass GBJ, Sherlock P, eds. Progress in Gastroenterology. Vol. 4. New York: Grune & Stratton, 1983. 30. Morgan DB, et al. Search for osteomalacia in 1228 patients after gastrectomy and other operations on the stomach. Lancet 1965; 2:1085. 31. Pryor JP, et al. The long-term metabolic consequences of partial gastrectomy. Am J Med 1971; 51:5. 32. Wheldon EJ, Venables CW, Johnson IDA. Late metabolic sequelae of vagotomy and gastroenterostomy. Lancet 1970; 1:437. 33. Jordon GL Jr. The afferent loop syndrome. Surgery 1955; 38:1027. 34. Mitty WE Jr., Grossi C, Nealon TF Jr. Chronic afferent loop syndrome. Ann Surg 1970; 172:996. 35. Rutledge RH. Retroanastomotic hernias after gastrojejunal anastomoses. Ann Surg 1973; 177:547. 36. Boren CH, Way LH. Alkaline reflux gastritis: a revaluation. Am J Surg 1980; 140:40. 37. Bushkin FL, et al. Postoperative alkaline reflux gastritis. Surg Gynecol Obstet 1974; 138:933. 38. Davidson ED, Hersh T. The surgical treatment of bile reflux gastritis: a study of 59 patients. Ann Surg 1980; 192:175. 39. Ritchie WP Jr. Alkaline reflux gastritis: an objective assessment of its diagnosis and treatment. Ann Surg 1980; 192:288. 40. Ritchie WP Jr. Alkaline reflux gastritis: a diagnosis in search of a disease. J Clin Surg 1982; 1:414. 41. Fromm D. Ulceration of stomach and duodenum. In: Fromm D, ed. Gastrointestinal Surgery. New York: Churchill Livingstone, 1985. 42. Aronow JS, Mathews JB, Garcia-Aquilar J, et al. Isoperistaltic jejunal interposition for intractable postgastrectomy alkaline reflux gastritis. J Am Coll Surg 1995; 180:648. 43. Vogel SB, Drane WE, Woodward ER. Clinical and radionuclideevaluation of bile diversion by Braun enteroenterostomy: prevention and treatment of alkaline reflux gastritis: an alternative to Roux-en-Y diversion. Am Surg 1994; 219:458. 44. Ruding R, Hirdes WH. Extent of the gastric antrum and its significance. Surgery 1963; 53:743. 45. Allen WA, Welch CE. Gastric resection for duodenal ulcer. Ann Surg 1942; 115:530.

medwedi.ru

630

Part Two: The Alimentary Tract—Other Conditions

46. Stabile BE, Passaro E. Recurrent peptic ulcer. Gastroenterology 1976; 70:124. 47. Chaudhuri TK, et al. Radioisotopic scan—a possible aid in differentiating retained antrum from Zollinger-Ellison syndrome in patients with recurrent peptic ulcer. Gastroenterology 1973; 65:697. 48. Wait JO, Beart BW Jr., Charbaneau W. Jejunogastric intussusception. Arch Surg 1980; 115:1449. 49. Foster DG. Retrograde jejunogastric intussusception—rare cause of hematemesis. Arch Surg 1956; 73:1009. 50. Hollands MJ, Filipe I, Edwards S, et al. Clinical and histological sequelae of Roux-en-Y diversion. Br J Surg 1989; 76:481. 51. Van der Milje HCJ, Kleibeuker JH, Limber AJ, et al. Manometric and scintigraphic studies of the relation between motility disturbances in the Roux limb and the Roux-en-Y syndrome. Am J Surg 1993; 166:11. 52. Cullen JJ, Kelly KA. Gastric motor physiology and pathophysiology. Surg Clin North Am 1993; 73:1145. 53. Eckhauser F, Knol JA, Roper SA, Guice KS. Completion gastrectomy for post-surgical gastroparesis syndrome. Ann surg 1988; 208:345. 54. Goligher JC, et al. Several standard elective operations for duodenal ulcer. Ten to 16 year clinical results. Ann Surg 1978; 189:18. 55. Duthie HL, Kwong NK. Vagotomy or gastrectomy for gastric ulcer. Br Med J 1973; 4:79. 56. Goligher JC, et al. Five to eight year results of Leeds/York con trolled trial of elective surgery for duodenal ulcer. Br Med J 1968; 2:781. 57. Goligher JC, et al. Clinical comparison of vagotomy and pyloro-plasty with other forms of elective surgery for duodenal ulcer. Br Med J 1968; 2:787. 58. Goligher JC, et al. Five to eight year results of truncal vagotomy and pyloroplasty for duodenal ulcer. Br Med J 1972; 1:7. 59. Kronborg O. Clinical results 6 to 8 years after truncal vagotomy and drainage for duodenal ulcer in 500 patients. Acta Chir Scand 1975; 141:657. 60. Browning GC, Buchanan KA, MacKay C. Clinical and laboratory study of postvagotomy diarrhea. Gut 1974; 15:644. 61. Allan JC, Gerskovitch VP, Russell RI. The role of bile acids in the pathogenesis of postvagotomy diarrhea. Br J Surg 1974; 61:516. 62. Kennedy T. The vagus and the consequences of vagotomy. Med Clin North Am 1974; 58:1231. 63. Ayulo JA. Cholestyramine in postvagotomy syndrome. Am J Gastroenterol 1972; 57:207. 64. Herrington JL, et al. Treatment of severe postgastrectomy diarrhea by reversed jejunal segment. Ann Surg 1968; 168:522. 65. Edwards DA. Postvagotomy dysphagia. Lancet 1970; 2:90. 66. Suleiman SI, Maglad SA, Hobsley M. Dysphagia following selective vagotomy. Br J Surg 1979; 66:607. 67. McClelland RN, Horton JW. Relief of acute, persistent postvagotomy atony by metoclopramide. Ann Surg 1978; 188:439. 68. Davis RH, Clench MH, Mathias JR. Effects of domperidone in patients with chronic unexplained upper gastrointestinal symptoms. Dig Dis Sci 1988; 33:1505. 69. Tack J, et al. Gastric emptying problems: diabetic gastropathy—effect of erythromycin on gastric motility in controls and in diabetic gastroparesis. Gastroenterology 1992; 103:72. 70. Peeters TL, et al. Gastric emptying problems: motilin in diabetic gastroparesis—effect of motilin on gascric emptying in patients with diabetic gastroparesis. Gastroenterology 1992; 102:97. 71. Fawcett AN, Johnston D, Duthie HL. Revagotomy for recurrent ulcer after vagotomy and drainage for duodenal ulcer. Br J Surg 1969; 56:111. 72. Venables CW. The value of a combined pentagastrin/insulin test in studies of stomal ulceration. Br J Surg 1970; 57:757. 73. Hodin RA, Matthews JB. Small Intestine. In: Norton JA, Bollinger RR, et al, eds. Surgery-Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001:638. 74. Davis JH, ed. Clinical Surgery. St. Louis: Mosby, 1987.

75. Nordgaard I, Hansen BS, Mortensen PB. Colon as a digestive organ in patients with short bowel. Lancet 1994; 343: 373. 76. Chopra S, Trier JS. Diarrhea and malabsorption. In: Chopra S, May RJ, eds. Pathophysiology of Gastrointestinal Disease. Boston: Little Brown, 1989. 77. Nightingale J, Kamm MA, van der Sijp JRM. Gastrointestinal hormones in short bowel syndrome. Gut 1996; 39:237. 78. Buchman AL. The medical and surgical management of short bowel syndrome. Med Gen Med 2004; 6(2). 79. Thompson J. The role of prophylactic cholecystectomy in the short-bowel syndrome. Arch Surg 1996; 131:556. 80. Hofmann AF, Poley JR. Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection: response to cholestyramine or replacement of dietary long chain triglyceride by medium chain triglyceride. Gastroenterology 1972; 62(5):918. 81. Fedorak RN, Madsen KL. Probiotics and prebiotics in gastrointestinal disorders. Curr Opin Gastroenterol 2004; 20(2):146. 82. Penner RM, Fedorak RN. Probiotics in the management of inflammatory bowel disease. Med Gen Med 2005; 7(3). 83. Sartor RB. Targeting enteric bacteria in treatment of inflammatory bowel diseases: why, how, and when. Curr Opin Gastroenterol 2003; 19(4):358. 84. Byrne T, Persinger R, Young L, Ziegler T, Wilmore D. A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet. Ann Surg 1995; 222:254. 85. Ellegard L, Bosaeus I, Nordgren S, Bengtsson BA. Low-dose recombinant human growth hormone increases body weight and lean body mass in patients with short bowel syndrome. Ann Surg 1997; 225(1):88. 86. Scolapio J, Carnilleri M, Fleming C, et al. Effect of growth hormone, glutamine, and diet on adaptation in short-bowel syndrome: a randomized, controlled study. Gastroenterology 1997; 113:1074. 87. Szkudlarek J, Jeppesen PB, Mortensen PB. Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomized, double blind, crossover, placebo controlled study. Gut 2000; 47(2):199. 88. Panis Y, Messing B, Rivet P, et al. Segmental reversal of the small bowel as an alternative to intestinal transplantation in patients with short bowel syndrome. Ann Surg 1997; 255:401. 89. Thompson J, Langnas A, Pinch L, Kaufman S, Quigley E, Vanderhoff J. Surgical approach to short-bowel syndrome. Experience in a population of 160 patients. Ann Surg 1995; 222:600. 90. Fishbein TM, Kaufman SS, Florman SS, et al. Isolated intestinal transplantation: proof of clinical efficacy. Transplantation 2003; 76(4):636. 91. Fryer JP. Intestinal transplantation: an update. Curr Opin Gastroenterol 2005; 21(2):162. 92. Michelassi F, Lee J, Rubin M, et al. Long-term functional results after ileal pouch anal restorative proctocolectomy for ulcerative colitis. Ann Surg 2003; 238(3):433. 93. Lohmuller JL, Pemberton JH, Dozois RR, et al. Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch-anal anastomosis. Ann Surg 1990; 211:622. 94. Corman ML. Pouchitis. In: Corman ML, ed. Colon and Rectal Surgery. 4th ed. Philadelphia: Lippincott-Raven Publishers, 1998:1169. 95. Gionchetti P, Rizello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebocontrolled trial. Gastroenterology 2003; 124:1202. 96. Delaney CP, Fazio VW, Remzi FH, et al. Prospective, agerelated analysis of surgical results, functional outcome, and quality of life after ileal pouch-anal anastomosis. Ann Surg 2003; 238(2):221. 97. Krok KL, Lichtenstein GR. Nutrition in Crohn’s disease. Curr Opin Gastroenterol 2003; 19(2):148. 98. Hollington P, et al. An 11 year experience of enterocutaneous fistula. Br J Surg 2004; 91(12):1646.

PART THREE: The Cardiothoracic System LUNG

31 Pathobiology of Surgically Relevant Pulmonary Disease Daniel G. Tang, Jonathan Kiev, and Neri M. Cohen

INTRODUCTION The pulmonary system is the body’s gateway for exchange of gasses, principally oxygen and carbon dioxide. This critical function is essential to maintain the vital processes that enable the body to carry out its many functions. An understanding of the various derangements that may alter normal lung function is mandatory for the surgeon involved in the care of seriously ill patients. This chapter reviews the normal physiology of the pulmonary system and how aberrations from the norm present in surgically relevant lung disease.

ANATOMY AND PHYSIOLOGY The airway consists of the oropharynx, trachea, bronchi, and bronchioles. The trachea extends from the cricoid cartilage of the larynx to the carina, where it branches into the left and right main bronchi. Bronchial branching is more acute on the left than the right, creating a more direct path to the right, which is therefore more frequently involved in aspirations and inadvertent bronchial main stem intubations. From the carina, the bronchi undergo approximately 25 subdivisions to the alveoli. The bronchi sequentially divide into lobar bronchi, segmental bronchi, bronchioles, and then alveoli. Anatomically, the lungs are divided into lobes and then segments based on the bronchial branching. There are three lobes on the right (upper, middle, and lower) and two lobes on the left (upper and lower; the lingula corresponds to the middle lobe) (Fig. 1).

Airway The trachea is supported by 15 to 20 C-shaped cartilaginous rings anteriorly. The bronchi are also supported by

cartilaginous plates, whereas the bronchioles and alveoli lack such support and are therefore susceptible to collapse. The trachea and the first 16 divisions of the bronchi to the terminal bronchioles constitute the conducting zone of the airways. The conducting zone has a continuous mucosal lining, which is not involved in gas exchange, creating an anatomic dead space. The mucosa is lined with pseudostratified columnar epithelium predominantly made up of ciliated cells interspersed with mucus-secreting goblet cells. Ciliated cells are estimated to contain approximately 200 cilia each, which beat approximately 1000 times/min. Goblet cells secrete mucus as well as immunologic proteins such as immunoglobulin A. The mucus and beating cilia produce a mucociliary escalator that provides the first line of defense against inhaled particles, moving these particles up to the pharynx to be swallowed or expectorated. Smoking is associated with both abnormalities in ciliary motility and mucus production, thereby compromising this protective mechanism. Distal to the conducting zone, the next few divisions of the bronchioles leading to the most proximal alveoli consist of respiratory bronchioles or the transitional zone. The remaining subdivision lies within the lung parenchyma itself. These branches are lined with alveolar ducts and make up the respiratory zones of the airways. This efficient branching organization leads to approximately 300 million alveoli, which provide 7 m2 of surface area for gas exchange (2,3).

Alveoli The alveoli make up the functional respiratory unit. The alveolar wall provides an alveolar epithelial and capillary endothelial interface. The alveolar epithelium has two types of cells. These cells are joined by tight junctions, forming a monolayer barrier to the diffusion of solutes. Type I alveolar

Figure 1 Segmental anatomy of the lung. Source: From Ref. 1.

medwedi.ru 631

632

Part Three: The Cardiothoracic System—Lung

cells are thin and make up the vast majority of the epithelial layer ( > 95%). These cells contain few intracellular organelles and appear to be relatively metabolically inert, allowing for maximal oxygen delivery with minimal energetic demand. These cells also function to reabsorb pathologic accumulation of alveolar fluid (4). In contrast, type II alveolar cells are sparsely interspersed cuboidal cells with an abundance of intracellular organelles and are metabolically active. These cells produce surfactant and can regenerate the epithelium by differentiating into type I cells. Surfactant is a lipoprotein complex containing large amounts of saturated lecithins and other proteins and serves two main functions. Surfactant reduces surface tension at the air–tissue interface of the lung, reducing inhalational work. It also stabilizes the alveoli, thereby contributing to the general compliance of the lung. Surfactant also has an immunoprotective role. Two surfactant proteins, SP-A and SP-D, have been described to have a host of immune functions, including pathogen opsonization, regulation of inflammatory mediators, and even direct antimicrobial activity by increasing membrane permeability (5,6). The capillary endothelial cell makes up the other half of the blood–air interface. The endothelial cells are water permeable, but impermeable to macromolecules. They are metabolically active and secrete prostaglandins, and can deactivate bioactive compounds such as histamine and serotonin. The alveolar epithelium and capillary endothelium are supported by a thin interstitium, composed of a proteoglycan matrix embedded with elastin and collagen, which is produced by fibroblasts. Elastin can stretch to 130% of its length while retaining recoil properties and is the prime determinant of the mechanical properties of the lung. Its loss, as seen in patients with emphysema, leads to hyperexpansion and loss of elastic recoil. Stimulation of fibroblasts during disease processes can lead to severe pathology such as pulmonary fibrosis or acute respiratory distress syndrome (ARDS). Interspersed in the interstitium are alveolar macrophages, which provide a further layer of immunologic defense. They appear to be derived from a pluripotential cell—possibly circulating monocytes, which remain dormant until needed for differentiation. Alveolar macrophages actively engulf bacteria and inert particles and experimentally have been demonstrated to clear 95% of aerosolized bacteria within four hours of exposure (7).

The Chest Wall and Diaphragm Bony Thorax The chest wall is supported by the 12 thoracic vertebrae and the associated ribs. Movement of the ribs during forced respiration changes the dimension of the thorax facilitating inspiration and expiration. Movement of the upper six ribs during respiration has been likened to that of a waterpump handle, increasing the anterior–posterior dimension. Movement of the 7th through 10th ribs has been likened to that of a water bucket handle, increasing the lateral thoracic dimension.

Muscles of Respiration The diaphragm is the chief muscle of inspiration. Concentric contraction of its muscle fibers lowers the central tendon from the level of the nipples to the costal margin, greatly increasing the thoracic vertical dimension. Between the ribs are the external, internal, and innermost intercostal muscles.

Contraction of the interchondral intercostal muscles rotates the ribs upward, while contraction of the interosseous intercostal muscles rotates the ribs downward. Contraction of the neck muscles and other chest wall muscles (scalenes, sternocleidomastoid, pectoral muscles, etc.) can also contribute to movement of the ribs and changes in thoracic dimension during active respiration. Additionally, contraction of the abdominal wall muscles compresses the abdomen, pushing the diaphragm upward and augmenting active expiration.

Pleura The parietal pleura lines the inner chest wall, while the visceral pleura lines the lungs. The two pleurae are continuous with each other, joining at the lung hilum. The space between the parietal and visceral pleura is normally only a potential space containing a few milliliters of serous fluid. It can become abnormally enlarged in conditions such as pneumothorax, pleural effusion, hemothorax, and empyema.

Lung Volumes and Pulmonary Function Tests The inspiratory–expiratory cycle can be divided into four lung volumes (Fig. 2). The tidal volume (TV) is the volume of air inspired during a normal breath. The inspiratory reserve volume (IRV) is the volume of air, beyond the TV, that can be inspired with maximal inspiratory effort. The expiratory reserve volume (ERV) is the volume of air that can be expelled with maximal effort following a normal passive exhalation. The residual volume (RV) is the volume that still remains in the lung following maximal expiration. These volumes can also be grouped into four standard capacities. The total lung capacity is the total volume of air in the lung at maximum inhalation and is equal to the sum of all four volumes (TV þ IRV þ ERV þ RV). The vital capacity (VC) is the maximal amount of air that can be moved in one breath and is equal to the sum of TV þ IRV þ ERV. The functional residual capacity (FRC) is the volume that remains in the lung after normal passive exhalation and is equal to the sum of ERV þ RV. The inspiratory capacity is the maximal amount of air that can be inhaled after a normal passive exhalation and is equal to the sum of TV þ IRV. Although whole body plethysmography is considered the gold standard in the measurement of lung volumes and capacities, it is not clinically practical to use. Lung volumes and capacities that do not include RV are easily measured with a spirometer. Measurements with a spirometer are also performed over time. The simple and clinically useful measures of pulmonary function obtained with spirometry include the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). Normal values can vary based on sex, age, and height. A

Figure 2 Spirometry. Abbreviations: ERV, expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capacity; RV, residual volume; TLC, total lung capacity; TV, tidal volume; VC, vital capacity. Source: From Ref. 8.

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

633

Table 1 FEV1 and FVC in Normal and Diseased Lungs Normal lung

Obstructive lung disease

Restrictive lung disease

FVC ¼ normal FEV1 ¼ normal FEV1/FVC > 75% FVC ¼ normal or decreased FEV1 ¼ decreased FEV1/FVC < 75% FVC ¼ decreased FEV1 ¼ decreased FEV1/FVC > 75%

Figure 3 Themechanicalwork required to overcome the compliance of the respiratory system (triangular area) and the airway resistance (curved loop) during lung inspiration. The total work is the sum of the two. Source: From Ref. 11.

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

normal 70-kg adult male will have an FEV1 of about 4 L and an FVC of about 5 L. The ratio of FEV1 to FVC can be used to define normal, restrictive, and obstructive patterns of lung function. Normal healthy individuals have an FEV1/FVC of 80%. FEV1 is determined in part by airway resistance, which is increased with various diseases such as asthma and chronic bronchitis, and pulmonary irritants such as smoke. With increased airway obstruction, FEV1 will fall by a much greater level relative to the FVC and the ratio will drop. With restrictive patterns of lung disease, there will also be a reduction in FVC, but not as large a drop in FEV1, and the ratio may be normal or even elevated (Table 1). Genetics and environmental factors can also affect pulmonary function tests (PFTs). Spirometry and genomic scanning of individuals enrolled in the Original and Offspring Cohort Framingham studies demonstrated loci on chromosomes 4, 6, and 21 that strongly influence FEV1 and FVC (9). Diets high in vitamin C have also been associated with a lower age–related decrease in FEV1 (10).

Mechanics of Respiration Air movement into and out of the lungs is driven by changes in thoracic pressure. Thoracic pressure is created by a balance between the elastic nature of the lungs, the respiratory muscles, and the chest wall. During quiet respiration (near FRC), inspiration is active, while expiration is passive. At the end of a normal passive exhalation, the atmospheric and alveolar air pressures are equal, and there is no pressure gradient for gas movement. The respiratory muscles are relaxed and the inward elastic contractive force of the lungs equals the outward expansive force of the chest wall. Active contraction of expiratory muscles, as described above, can further enhance expiration by compressing the thoracic cavity. Active contraction of inspiratory muscles increases the thoracic volume, lowering intrathoracic pressure and causing inward movement of air. At end-inspiration, potential energy has been stored into the tissues and elastic recoil drives expiration. In the compression and expansion of gas, work (W) is defined by the product of pressure (P) and volume (V), where W ¼ PV Pressure volume loops (Fig. 3) during respiration can be constructed, and the total area represented by TV multiplied by dP (the change in intrapleural pressure) is proportional to the work of breathing. Normally, the work of breathing represents 2% to 3% of resting oxygen consumption. Lung compliance and airway resistance are the principal determinants of respiratory work. Compliance (C) is

defined by the change in volume (V) produced by a change in pressure (P) where, C ¼ dV=dP Using the same pressure volume loops, the compliance of the lung is equal to the slope of the line from the beginning to the end of inspiration. Total compliance is the sum of chest wall and lung compliance. Generally, chest wall compliance remains fairly constant, and clinically significant changes in compliance are due to changes in lung compliance.

Perfusion The lungs have a dual blood supply: the pulmonary vasculature and the bronchial vasculature. Systemic venous blood returning to the heart is mixed with cardiac venous blood (via the coronary sinus and thebesian veins) with an oxygen saturation of 68% to 76% normally. The entire output of the right ventricle is then ejected into the pulmonary artery. The pulmonary artery branches into lobar, then segmental branches corresponding to the bronchopulmonary segments (Fig. 4). The pulmonary arterial vessels are thinner and less muscular than systemic vessels, resulting in a distensible, low-pressure, low-resistance circuit. Normal pulmonary blood pressure is approximately one-fifth of systemic circulation (15–30/6–12 mmHg). After passage through the pulmonary capillaries, blood is then returned by right and left, superior and inferior pulmonary veins. In contrast, the bronchial arteries receive 1% to 2% of the cardiac output from the left ventricle, with an oxygen saturation of 100% because they arise from the aorta. Some bronchial arteries will bypass the capillary network and drain directly into the pulmonary venous system, contributing to physiologic shunting. Distribution of blood flow within the lung is not uniform. Gravity and alveolar pressure influence regional lung perfusion. West described three zones of perfusion in an upright individual from cranial to caudal relating PA, Pa, and PV (Fig. 5). When moving from the lung apices to the bases, hydrostatic pressure in the blood vessels increases while the alveolar pressure remains constant. Thus the vessels in the dependent portions of the lungs are at higher pressures and receive greater blood flow. In zone 1, near the lung apices, the alveolar pressure, PA, may exceed both Pa and PV, preventing blood flow, and thus creating dead space (areas of ventilation but no perfusion). This does not occur normally, but can occur if the Pa pressures are abnormally low (such as in hypovolemia) or if the PA is abnormally high

medwedi.ru

634

Part Three: The Cardiothoracic System—Lung

Figure 4 Pulmonary artery segmental anatomy. Source: From Ref. 12.

(such as in mechanical ventilation). In contrast, reduced blood flow can be seen at the base of the lung as well if pulmonary venous pressures (PV) are abnormally high, as in left heart failure (3). Blood flow is also affected by the local alveolar oxygen tension. Local hypoxia produces pulmonary vasoconstriction, which is further potentiated by hypercapnia and acidosis. Functionally, hypoxic pulmonary vasoconstriction helps match pulmonary blood flow to alveolar ventilation by shifting blood flow to alveoli with higher oxygen levels (which is locally related to the alveolar ventilation).

Carbon dioxide is about 25 times more soluble than oxygen. CO2 is then rapidly converted to bicarbonate and approximately 90% of carbon dioxide is transported as bicarbonate. The remaining fraction is transported as dissolved carbon dioxide and protein-bound carbamino compounds. Only a small gradient is required to facilitate carbon dioxide uptake from peripheral tissues and elimination at the alveolus [normal venous partial pressure of CO2 (PCO2 ) of 46 mmHg; and arterial PCO2 ¼ alveolar PCO2 of 40 mmHg—Fig. 6]. At steady state, CO2 production is directly proportional to the product of alveolar ventilation (VA) and the PCO2 , where

Ventilation Ventilation refers to the movement of gases between the lungs and the atmosphere. Not all of the gases taken in participate in gas exchange at the alveolar capillary membrane. As described above anatomic dead space ventilation occurs within the conducting airways that do not participate in gas exchange. Additional physiologic dead space ventilation occurs in alveoli that are underperfused and thus not able to fully participate in gas exchange. The volume of gas that reaches the alveoli and is able to participate in gas exchange is referred to as alveolar ventilation.

VCO2 ðCO2 productionÞ VA PCO2 Therefore, if CO2 production is relatively constant, VA is inversely proportional to PCO2 . Practically, this can be used to predict how changes in minute ventilation, VE (assuming a relatively small effect from dead space ventilation), will affect PCO2 . For example, changing a patient with a minute ventilation of 10 L/min and an arterial PCO2 of 40 mmHg to a VE 8 L/min would be expected to change the arterial PCO2 to 50 mmHg (10 40/8).

ZONE 1 PA > Pa > PV

ZONE 2 Pa > PA > PV

Alveolar PA Pa Arterial

PV Distance Venous

ZONE 3 Pa > PV > PA Blood flow

Figure 5 Differential pulmonary perfusion in an upright individual. Note: Three-zone model designed to account for the uneven topographic distribution of blood flow in the lung. Abbreviations: Pa, pulmonary arterial pressure; PA, pulmonary alveolar pressure; Pv, pulmonary venous pressure. Source: From Ref. 13.

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

635

Figure 6 Gas exchange across the alveolus. Relationship between driving pressures for oxygen and carbon dioxide exchange at alveolocapillary membranes. Abbreviations: CO2, carbon dioxide; O2, oxygen; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; PCO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen. Source: From Ref. 2.

Similar to pulmonary perfusion, there are also regional differences in lung ventilation. At FRC, dependent alveoli are less distended due to increased hydrostatic pressure from gravity. Thus, dependent alveoli expand more with inspiration and receive greater ventilation. Accordingly, in an upright healthy individual, during normal respiration the lung bases receive more ventilation than the apices. However, with lower lung volumes approaching RV, intrapleural pressure can exceed intraluminal pressure, resulting in peripheral airway collapse and atelectasis. This volume is called the closing volume (CV). In normal individuals, the CV is about 10% of the VC. As patients age, and especially in bedridden patients, the CV can approach and exceed FRC, resulting in peripheral airway collapse during a significant portion of the respiratory cycle.

hemoglobin for oxygen and facilitating oxygen unloading at the periphery. 2,3-DPG binds to the b chain of deoxyhemoglobin, decreasing the affinity for oxygen and also shifts the curve to the right. Chronic hypoxia stimulates increased synthesis of 2,3-DPG. Blood storage results in a marked decrease in 2,3-DPG.

Diffusion The diffusion of gases across capillary surfaces is affected by the tissue solubility of the gas, dimensions of the alveolar– capillary interface, the driving pressure gradient of the gas, and the rate of equilibration of gas exchange. Changes in the thickness and surface area dimensions of the alveolar–capillary interfaces affect diffusion. Reduction in the exchange surface area as with emphysema, or

Oxygenation The oxygen requirement for a normal healthy adult is about 200 mL/min. The normal oxygen gradient at room air is about 60 mmHg (alveolar PO2 of 100 mmHg, arterial PO2 of 90–95 mmHg; and venous PO2 of 40 mmHg). As oxygen diffuses across the alveolar wall, it dissolves in plasma and then diffuses into red blood cells, where it is bound by hemoglobin. The oxygen-carrying capacity (CO2 ) of blood is far more dependent on the concentration of hemoglobin and percent saturation than the partial pressure of dissolved oxygen. One gram of hemoglobin can bind 1.36 mL of oxygen, and oxygen has a solubility coefficient of 0.0031 mL O2/mmHg/dL blood. Thus, CO2 ¼ 1:36 ðHgbÞ ðSaO2 Þ þ 0:0031 ðPO2 Þ Each molecule of hemoglobin has four binding sites for oxygen. With each binding of an oxygen molecule, there is an increased affinity for the next. This produces a sigmoidal relationship between the oxygen saturation of hemoglobin and the partial pressure of oxygen (Fig. 7). Such an arrangement facilitates hemoglobin loading with oxygen in the lungs with higher oxygen tension and unloading of oxygen in the periphery at lower oxygen tension. The affinity of oxygen for hemoglobin is also affected by other factors, such as temperature, PCO2 , pH, and 2,3-diphosphoglyceric acid (2,3-DPG). Increased exertion and metabolic stress (as reflected by increased temperature, PCO2 , and decreased pH) shift the curve to the right, decreasing the affinity of

Figure 7 Oxygen–hemoglobin dissociation curve. Note: The percent saturation of hemoglobin with oxygen at different oxygen tensions is depicted by the middle sigmoidal curve. The P50 (i.e., oxygen tension at which the hemoglobin molecule is one-half saturated) is about 27 mmHg in normal erythrocytes (dotted lines). Heterotopic modifiers of hemoglobin function can shift the curve leftward by increasing or rightward by decreasing its oxygen affinity. Source: From Ref. 13.

medwedi.ru

636

Part Three: The Cardiothoracic System—Lung

increase in the thickness as with interstitial lung disease and pulmonary edema, decreases the diffusion of gases and limits gas exchange. The variable affinity of hemoglobin for oxygen as described above, as well as the rate at which hemoglobin is circulated through the capillary bed (i.e., the cardiac output), has an effect on measuring oxygen-diffusing capacity. On average, a red blood cell takes approximately 0.75 second to cross the pulmonary capillary. Oxygen has a higher driving pressure gradient, while CO2 has a higher solubility. Normally, it takes about 0.25 second for the pressure gradient across the alveolar–capillary interface to equilibrate. Thus, gas exchange is normally perfusion limited and the only way to increase gas exchange is to increase perfusion. However, as described above, many diseases can limit gas exchange such that there is no equilibration by the time blood crosses the capillary and gas exchange is diffusion limited. Clinically, the diffusing capacity of carbon monoxide (DLCO, normal about 30–35 mL/min/mmHg) is usually measured as a surrogate with a single breath of a low concentration of carbon monoxide. Carbon monoxide has a molecular weight similar to oxygen but binds with a higher affinity to hemoglobin, creating a low partial pressure and essentially a constant pressure gradient for its diffusion, which simplifies measurement of diffusing capacity.

Ventilation/Perfusion

Pco2 mm Hg

The relationship between ventilation and perfusion is important in the exchange of oxygen and carbon dioxide. Matching alveolar ventilation (V) to pulmonary blood flow (Q) is important for achieving ideal gas exchange and is measured by the V/Q ratio. Normally each liter of blood flow is matched with 0.8 L of ventilation. High V/Q ratios are produced by excessive ventilation or inadequate blood flow. At one extreme is dead space or ventilation that receives no perfusion for gas exchange, with a V/Q ratio of infinity. At the other extreme is shunt, or perfusion without ventilation, with a V/Q ratio of zero. Low V/Q ratios are generally caused by inadequate ventilation or excessive blood flow (Fig. 8). In the research setting, the V/Q ratio can be measured with the multiple inert gas elimination technique, although this is not practical clinically. Assessment of V/Q mismatch becomes clinically important when assessing the etiology of hypoxia.

50

v Decreasing . . VA/Q

A Normal

0

50

100

.

∝

/Q VA

g sin ea

Inc .r

150

Po2 mm Hg Figure 8 V/Q mismatch. Note: Oxygen–carbon dioxide diagram shows how the PO2 and PCO2 of a lung unit alter as the ventilation–perfusion ratio is changed. Abbreviations: I, inspired gas; ¯v, mixed venous blood. Source: From Ref. 15.

Hypoxia In general, hypoxia is caused by V/Q mismatch, shunt, alveolar hypoventilation, and increased diffusion gradient. V/Q mismatch is one of the most common causes of hypoxemia, but can be difficult to assess and is generally a diagnosis of exclusion. Shunt is the fraction of blood that enters arterial blood without gas exchange. Bronchial blood flow causes physiologic shunt. Normal shunt is about 5%. Pathologic intrapulmonary shunt occurs when portions of lung are perfused but not ventilated, as in lung consolidation from pneumonia or atelectasis. Extrapulmonary shunts also occur as in right-to-left cardiac shunts. Shunt can be measured by: QS =QT ¼ ðCiO2 CaO2 Þ=ðCiO2 CvO2 Þ As defined by the following abbreviations: QS/QT: (shunt flow/total flow) CiO2 : ideal O2 content or pulmonary capillary O2 content CaO2 : arterial O2 content CvO2 : mixed venous O2 content Alveolar hypoventilation can be caused by thoracic wall and neuromuscular disorders as well as by central respiratory depression. As described above, an increased diffusion gradient can be caused by changes in the dimensions of the alveolar–capillary interface, as in interstitial lung diseases and with pulmonary edema. Both alveolar hypoventilation and increased diffusion gradient can be treated with oxygen administration. True shunt will not be affected by additional oxygen administration. V/Q mismatch will respond partially to oxygen administration, depending on the amount of tendency toward shunt.

PERIOPERATIVE PULMONARY ASSESSMENT Preoperative Assessment Preoperative assessment of pulmonary risk begins with the history and physical examination. Obviously patients with a history of significant pulmonary disease, especially chronic obstructive pulmonary disease (COPD), are at increased risk, as are patients with significant heart disease and poor nutritional status. Preoperative counseling in patients with a smoking history has been demonstrated to have an impact as well. Physiologically, smoking cessation more than 48 hours has been demonstrated to decrease systemic carbon monoxide levels and improve mucosal ciliary function. Cessation of one to two weeks is associated with decreased sputum production. Cessation more than six weeks is associated with improved spirometry. Patients undergoing coronary artery bypass demonstrate a fourfold decrease in pulmonary complications with smoking cessation of two months. Smokers who stopped smoking for six months had a pulmonary complication rate equivalent to that of nonsmokers (16). Physical examination findings demonstrating use of accessory muscles, prolonged expiration, a barrel chest, cyanosis, heart failure, and pulmonary edema require further investigation. In general, patients without evidence of pulmonary disease on history and physical examination do not require further preoperative testing if they are being prepared for operations not involving the thoracic cavity. Patients with pulmonary disease and/or patients undergoing thoracic surgery should have further testing as indicated. Preoperative

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

arterial PO2 < 60 mmHg, and arterial PCO2 > 45 mmHg is associated with increased perioperative morbidity. In patients with known disease, a preoperative chest X ray can provide a useful baseline for comparison. PFTs can risk stratify high-risk patients and should be performed in all patients undergoing planned pulmonary resections. Pulmonary function testing indicators of high risk in nonthoracic surgery patients include an FVC < 2 L (or < 50% predicted), an FEV1/FVC < 50% predicted, and a diffusing capacity < 50% predicted (17). In patients undergoing pulmonary resection, PFTs are used to define the risk for postoperative respiratory insufficiency. In general, pulmonary resections with a predicted postoperative FEV1 of greater than 800 mL can be tolerated. Patients with an FEV1 > 2 L can tolerate most resections, including pneumonectomy. Patients with an FEV1 < 2 L may still be able to tolerate pulmonary resection, and ventilation perfusion studies can help predict how much the planned area of resection contributes to overall function. As experience with lung volume reduction surgery in patients with emphysema expands, it has been demonstrated that pulmonary resection of severely diseased tissue may even enhance postoperative pulmonary function (18). In patients with borderline PFTs, physiological exercise testing with measurement of VO2 max is predictive of outcomes. Patients who achieved VO2 max of more than 20 mL/ kg/min, even with poor PFTs, will generally tolerate pulmonary resection. Patients with an estimated postoperative VO2 max of less than 10 mL/kg/min have prohibitively high rates of complication and are not surgical candidates (19).

Postoperative Pulmonary Complications Postoperative pulmonary complications involving the lung are a leading cause of morbidity and mortality. In a review of 10,000 major operations, 10% of operative deaths occurred in patients who developed pneumonia (20). Stated another way, there was a 46% mortality in 1.3% of patients who got pneumonia. Postoperative complications involving the lung can be broadly defined and studies differ in their approach to recording and reporting complications. Complications include a spectrum of disorders from dyspnea, atelectasis, and increased sputum production, to pneumonia, respiratory failure, and death. The risk for complications also depends on the anesthetic technique used as well as the surgical procedure. Thoracic incisions, upper abdominal incisions, and procedures lasting more than three hours are at increased risk of resulting in pulmonary complications. Minimally invasive surgery, such as laparoscopic cholecystectomy and video-assisted thoracoscopic surgery have been demonstrated to have fewer pulmonary complications (21). Postoperative pain control techniques, such as patient-controlled analgesia and intercostal nerve blocks, have been demonstrated to decrease complications (22). Chest physiotherapy, incentive spirometry, and/or bronchodilators can prevent or reverse hypoxemia from atelectasis.

COMMON PULMONARY DISORDERS Acute Respiratory Failure In 1967, Ashbaugh et al. described a syndrome of dyspnea, hypoxemia, decreased pulmonary compliance, and diffuse alveolar infiltrates in 12 patients without a prior history of lung disease or congestive heart failure, which was termed adult respiratory distress syndrome or ARDS (23). In 1994,

637

the American–European Consensus Committee on ARDS redefined this acronym as Acute Respiratory Distress Syndrome to reflect its occurrence in children as well, and introduced the term Acute Lung Injury (ALI) to identify a similar but lower severity of respiratory failure. Both ALI and ARDS refer to a syndrome defined by inflammation and increased permeability associated with a constellation of clinical, radiologic, and physiologic abnormalities that cannot be explained by left atrial or pulmonary capillary hypertension (i.e., PCWP < 18 mmHg). ALI and ARDS are differentiated by the severity of hypoxemia as defined by the PaO2 /FiO2 (P/F) ratio. ALI is defined by a P/F ratio of 200 to 300, while ARDS is defined by a P/F ratio < 200 (24). The reported incidence of ARDS has varied in part due to previous variations in definitions. A recent 2002 study of every admission to 21 adult Australian intensive care units over a two-month period, using the consensus definition, found an incidence of ALI and ARDS of 34 and 28 per 100,000, respectively. The 30-day mortality was 32% and 34%, respectively, for these conditions (25). Previous studies report a mortality of approximately 50%. Multivariate analysis from multiple studies has demonstrated that the main risk factor for ARDS in patients is some type of systemic infection or sepsis. Blood transfusions, advanced age, and smoking have also been identified as independent risk factors. Recent epidemiologic studies have further found a genetic susceptibility associated with an angiotensin-converting enzyme (ACE) polymorphism. This polymorphism is associated with high circulating levels of ACE, which adversely affect pulmonary vascular tone, vascular permeability, epithelial survival, and fibroblast activation (26). Male sex and black race are also associated with a higher mortality in patients developing ARDS. Clinically, ALI and ARDS present with an acute onset. Fifty percent of patients develop ARDS within 24 hours of the inciting event; 85% develop this condition within 72 hours (27). The earliest signs of ALI include tachypnea and anxiety. This is then followed with a progressively worsening dyspnea, tachycardia, mental status changes, rales, rhonchi, and ultimately consolidation that often requires mechanical ventilation to prevent pulmonary failure. While the degree of hypoxemia distinguishes ALI from ARDS, the initial P/F ratios and ventilatory parameters have not been predictive of outcome. Chest X-rays may reflect the initial inciting event or be normal. As lung injury progresses, X-rays demonstrate edema with bilateral diffuse infiltrates, followed by diffuse alveolar/reticular opacification (i.e., ground-glass opacification). Computed tomography (CT) imaging demonstrates diffuse pulmonary consolidation with air bronchograms and later cystic changes within the pulmonary parenchyma. However, imaging may not parallel the clinical spectrum of disease and often lags well behind the clinical course. Histologically, three phases have been described. Initially there is an exudative phase. Damage to the alveolar epithelium and vascular endothelium allows leakage of fluid, protein, blood, and inflammatory cells into the interstitium and alveolar lumen. This is followed by a proliferative phase. Destruction of type I cells leads to accumulation of protein, fibrin, and other cellular debris forming hyaline membranes. Destruction of type II cells leads to alveolar collapse; type II cells then proliferate (fibroblastic reaction, remodeling, and differentiation to and regeneration of type I epithelium). Finally, there is a fibrotic phase. Fibroblastic remodeling can become irreversible with collagen deposition and development of microcysts (28).

medwedi.ru

638

Part Three: The Cardiothoracic System—Lung

Treatment of ALI/ARDS has been intensely studied (29). Treatment is focused on aggressive management of the initiating factors, appropriate control of underlying infection, aggressive nutritional support, and gentle mechanical ventilation management. With mechanical ventilation, it is important to avoid both barometric and volumetric trauma. The ARDS network study demonstrated a 22% decrease in mortality with low volume ventilation (TV < 6 mL/kg) and low plateau airway pressure strategy (30). Insisting on a normal pH and PCO2 by increasing minute ventilation may actually worsen lung injury, and strategies of gradual permissive hypercapnia allow lower volume ventilations. Arterial PCO2 of 50 to 77 mmHg with a pH of 7.2 to 7.3 appear to be well tolerated. High concentrations of oxygen (FiO2 > 60%) are also damaging and associated with increased edema, alveolar thickening, and fibrinous exudates. Adding positive end-expiratory pressure can help reduce FiO2 , although this may have the negative effect of impairing venous return and cardiac performance. Reverse inspiratory to expiratory (I:E) ratio ventilation has been proposed to decrease peak inspiratory and plateau pressures, but is associated with higher mean airway pressures that have not been shown to improve outcomes compared to conventional ventilation techniques (31). Prognosis in ARDS is multifactorial. Death in ARDS is usually due to multisystem organ failure (MOF) and not simply respiratory failure itself. Increased age, immunocompromise, and chronic liver disease have also been demonstrated to increased mortality in ARDS (27). In patients who recover, pulmonary dysfunction can persist and present with a mix of obstructive, restrictive, and diffusion pulmonary impairments. Pulmonary function studies demonstrate that most patients will show general improvement at three to six months, with a plateau in improvement at one year (32). Neuropsychiatric testing has also demonstrated significant deficits that may persist beyond two years, associated with prolonged hypoxemia (33). Because MOF is commonly encountered in critically ill surgical patients and is intimately linked with ARDS, further discussion of this linkage can be found in the chapter on MOF (Chapter 11).

Atelectasis Atelectasis is the term used to refer to a loss of lung volume. Depending on the cause, this volume loss may only involve a small portion of the lung that is not readily diagnosed on chest X-ray. In this circumstance, it is commonly called ‘‘micro’’ atelectasis. More substantial involvement can range from subsegmental, segmental, to involvement of an entire lobe. A wide variety of conditions may give rise to this disorder. For example, a space-occupying lesion within the lung parenchyma itself, such as a tumor, may compress adjacent lung tissue so that involved alveoli collapse. Similarly, a space-occupying abnormality in the pleural space, such as pneumothorax or hydrothorax, can also collapse adjacent lung. If a major bronchus or several secondary bronchi are occluded, an absorption-type atelectasis can occur due to resorption of air in the lung tissue distal to the obstruction. Examples of the obstructing agents include a foreign body, tumor, or mucus plug. Abnormalities in surfactant, which is a lipoprotein that is important in keeping alveoli open, may result in atelectasis in various inflammatory conditions such as pneumonia. In this setting, the surfactant may be inadequately synthesized, rapidly degraded, or become functionally suboptimal. The net result of any of these circumstances is alveolar collapse.

Atelectasis is a common postoperative problem that can be related to the effects of anesthesia, the underlying pulmonary status of the patient, and the type of incision used to carry out the operative procedure. Further, obesity, chronic bronchitis, pain, and advanced age are all predisposing factors. The pathophysiology of this condition in the postoperative period is related to various factors, all of which contribute to bronchial obstruction. These include a defective cough response so that retained secretions in the bronchus are not properly expectorated, and a reduction in the caliber of the bronchus, which may occur from direct airway trauma due to intubation, or result in edema and/or inflammation arising from this maneuver. Finally, the thickness of the bronchial secretions and the ability to clear them from the tracheal bronchial tree may prove difficult even when effective coughing seems adequate. Although the true incidence of atelectasis is unknown, most patients undergoing chest or abdominal procedures probably have some degree of microatelectasis. Involvement of segments or subsegments of the lung may occur in as many as 2% to 3% of all operations performed. Atelectasis may be clinically manifested by fever, tachypnea, and tachycardia. The cause of the fever has been debated, but is probably related to secondary bacterial proliferation in the atelectatic areas of the lung (34). By the time these various clinical parameters become apparent, the atelectasis has usually been present for a day or more. Because prevention is always easier than cure, all patients undergoing a general anesthetic, regardless of the operative procedure, should be considered to be at risk for the development of postoperative atelectasis. Accordingly, such patients should be mobilized and encouraged to ambulate as quickly as possible after operation. Further, deep breathing, coughing, and nasotracheal suction should be instituted as appropriate. A bedside spirometer in a patient who has been extubated can be especially helpful in getting patients to maximally aerate their lungs. Pain management through the use of epidural catheters and intercostal nerve blocks can greatly minimize the splinting caused by pain, with resultant lobar collapse that is commonly seen in patients who have undergone upper abdominal and thoracic incisions. Marked global respiratory muscle dysfunction and deterioration are not uncommon following operations in which these incisions have been used. Bronchial breathing or moist rales involving the lung bases are common clinical presentations of atelectasis. Aggressive pulmonary toilet, postural drainage, and nebulizer treatments are effective adjunctive therapies that may shorten the patient’s hospitalization once atelectasis becomes a factor in management. Atelectasis caused by airway obstruction (tumor or foreign body) presents with wheezing and occasionally progresses to pneumonia. In such a patient, clearing secretions distal to the obstruction is often difficult and commonly results in pooling of secretions and bacterial overgrowth. Prompt mobilization with aggressive nasotracheal suctioning is necessary to overcome the tenacious sputum impactions that commonly occur. Flexible bronchoscopy should be utilized liberally to insure a rapid return to normal pulmonary function.

Parenchymal Lung Disease Chronic Obstructive Pulmonary Disease (COPD) COPD is a major source of morbidity and mortality worldwide, and is currently the fourth leading cause of these problems in the United States. Previous definitions of COPD

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

have focused on chronic bronchitits and emphysema, reflecting a heterogeneous mix of airway disease and parenchymal destruction. In an effort to standardize terminology, an international consensus panel (Global Initiative for Chronic Obstructive Lung Disease) has produced a working definition of COPD as a disease state characterized by airflow limitation that is not fully reversible, usually progressive, and associated with an abnormal inflammatory response to noxious stimuli (35). With this broadened definition, emphysema, chronic bronchitis, and asthma are all variants of COPD, and all can evoke varying degrees of bronchospasm and increased airflow resistance. The common result of these abnormalities is an increased work of breathing and impaired gas exchange with enhanced difficulty in clearing the bronchial tree. This circumstance may express itself clinically as atelectasis, pneumonia, or even frank respiratory failure. Because smoking is so commonly linked with COPD, cessation of this habit (as mentioned above) can greatly lessen perioperative complications in patients with obstructive lung disease. Bronchodilation therapy has also proved effective in improving pulmonary mechanics and secretion removal (36). Albuterol (a b2-agonist) has been especially beneficial in this regard when administered as a wet nebulizer. As with other pulmonary conditions, deep breathing and coughing are effective adjunctive measures in the early postoperative period in patients with COPD, along with early ambulation to prevent complications such as atelectasis and pneumonia. Attention to such detail will result in a successful pulmonary outcome for most patients with COPD needing surgical intervention.

639

Sarcoidosis Sarcoidosis is a worldwide noncaseating granulomatous disease with multisystem involvement and a variable clinical course (37). This disease is more common in blacks and can affect any organ. While the lungs and mediastinal lymph nodes are most commonly involved, 25% of patients exhibit ocular and skin involvement as well. The diagnosis is established by clinical history and tissue confirmation. The differential diagnosis includes fungal diseases, tuberculosis, and malignancy. The cause of this disease is unknown. While infectious and environmental etiologies are suspected and the disease similarities to tuberculosis are remarkable, to date, no conclusive evidence supports any risk factors. The majority of patients are asymptomatic with hilar adenopathy. Symptomatic patients present with cough and dyspnea. Abnormal findings on chest X-rays are seen in 90% of patients, and the progression of sarcoidosis is easily seen as the hilar involvement advances to incorporate lung involvement. CT reveals the areas of mediastinal lymph node involvement; bronchoscopic biopsy is reliable (90%) in establishing the diagnosis. While 30% to 40% of patients undergo remission, many need corticosteroids to manage progressive involvement. Occasionally, cytotoxic and other alternative therapies are necessary, but responses to such therapy are inconsistent. Although the majority of patients with sarcoidosis who undergo an operation experience no untoward pulmonary problems, those with severe pulmonary fibrosis (approximately 10%) should be carefully screened as postoperative pulmonary sequelae are not infrequent.

Idiopathic Pulmonary Fibrosis

Infectious Lung Disease Pneumonia

Idiopathic pulmonary fibrosis (IPF) is the most commonly diagnosed diffuse lung disease seen in clinical practice (37). It is characterized by acute diffuse interstitial fibrosis of the lungs. Extrapulmonary involvement does not occur. It is heralded by progressive cough, dyspnea, and pulmonary infiltrates on chest X-ray. PFTs reveal a restrictive ventilatory pattern as the lung parenchymal destruction progresses. Peak onset occurs in the sixth decade and is more common in males who smoke. Possible etiologies of this disabling and frustrating disease are numerous and include exposure to various dusts and minerals, as well as being associated with other conditions, including collagen vascular disease, radiation therapy, and exposure to varied pharmacologic and cytotoxic agents. High-resolution CT scan reveals the ground-glass opacities with honeycombing that typifies IPF. From a physiologic standpoint, IPF patients demonstrate a restrictive defect on testing with impaired oxygenation and impaired gas exchange. Exercise is especially known to impair oxygenation and most patients experience hypoxemia at rest. Definitive diagnosis is made through surgical biopsy of the lung. Unfortunately, this disease does not respond to treatment and is rapidly progressive (37). Although high-dose corticosteroids given in combination with immunosuppressive medications are used to modify its progression, there is little improvement in survival or quality of life. Survival is measured in years, with only 15% of patients surviving 10 years from the time of diagnosis. Selected patients with IPF may benefit from lung transplantation (see below). Because of the marked compromise in ventilatory function that exists in IPF, great caution should be exercised in operating on patients with this disease for elective problems that can be adequately managed otherwise.

Pneumonia is a condition in which the respiratory tract is colonized with substantial numbers of microorganisms so that neutrophils migrate to the locus of colonization, and along with alveolar macrophages, induce the development of a cellular alveolar inflammatory exudate (38). As the inflammatory process evolves, it is ultimately seen on the chest X-ray as an infiltrate. The lower respiratory tract is more typically involved with pneumonia than other parts of the lung. The usual signs of pneumonia include a purulent productive cough, fever ( > 38 C), and rales overlying the site of infection on auscultation. In the intubated patient, purulent debris is commonly noted on suctioning. In both situations, leukocytosis is usually present. Pneumonia is a common problem in the postoperative surgical patient. The vast majority of pneumonias that occur in the surgical patient are nosocomial (i.e., hospital acquired). Most are related to endotracheal intubation or tracheostomy and mechanical ventilation. Ventilator-associated pneumonia is a serious issue in critically ill patients with an attributable mortality of 33% to 50% (39). Although the overall risk for nosocomial pneumonia varies between 5 to 10 cases per 1000 hospital admissions, it increases greatly in patients with chronic illness, prolonged malnutrition, advanced age, and conditions of immunodeficiency (e.g., HIV/AIDS). Other risk factors include patients receiving various drugs such as corticosteroids, cytotoxic agents, or inappropriate antibiotic agents, or possessing comorbid conditions such as coma, trauma, burns, and cirrhosis. Prolonged surgery can also be a risk factor. In patients requiring ventilatory support, pneumonia may occur in as many as 30% of those ventilated more than 48 hours (39). Aspiration is a major risk factor for pneumonia in the surgical patient. It can result from inhalation of oropharyngeal secretions, which typically contain high concentrations

medwedi.ru

640

Part Three: The Cardiothoracic System—Lung

of microorganisms, or inhalation of sterile gastric secretions that reflux up the esophagus from the stomach. Risk factors for aspiration include aberrations in the level of consciousness (e.g., head injury, stroke, or drug overdose), defective cough reflex (e.g., neuromuscular disorders), and problems with swallowing or esophageal function (e.g., tracheostomy, nasogastric intubation, or incompetent lower esophageal sphincter). Aspiration of oropharyngeal contents is particularly common in patients with altered or impaired consciousness, and is often seen in conditions of drug overdose or alcohol abuse. Aspiration of gastric contents is a frequent problem in patients with intestinal obstruction whether functional (e.g., postoperative ileus, dysmotility) or mechanical in nature. It is especially important to keep the head of the bed up and to monitor gastric residuals with some frequency to minimize the potential aspiration volume and protect those who are at highest risk for this complication (i.e., altered mental status). Although intubated patients and those with tracheostomy tubes are often thought to be protected from aspiration, in reality such patients are also at risk. Causative organisms for pneumonias resulting from orophyaryngeal aspiration include anaerobic and gramnegative bacteria. Although gastric fluids are usually sterile, bacterial colonization and secondary infection is not uncommon following aspiration of gastric contents. Diagnosis can be difficult. Critically ill patients have many reasons for fever and elevated white blood cell counts. Pulmonary infiltrates on chest X-ray can represent pneumonia, but can also represent ALI/ARDS, pulmonary edema, and/or pulmonary contusions. Chest X-ray findings often lag behind the clinical presentation. The sensitivity of chest X-ray for pneumonia is only 62% and the specificity is even less at 28% (39). Quantitative bronchoalveolar lavage with a threshold of 10,000 cfu/mL is emerging as the test of choice in diagnosing pneumonia in the intubated patient with a sensitivity and specificity of 91% and 78%, respectively (40). Several studies have looked at ways to reduce nosocomial pneumonia. Elevation of the head of the bed and avoidance of nasogastric tubes helps minimize the risk of aspiration. One randomized trial was stopped early when interim analysis demonstrated that semirecumbent positioning reduced the frequency of pneumonia from 23% to 5% compared to the supine position (41). Maintenance of gastric acidity may also reduce the incidence of pneumonia by preventing colonization of gastric contents, which can occur when acid-suppressing drugs are administered. Prophylactic systemic antibiotics have not been demonstrated to reduce nosocomial pneumonia. Multiple meta-analyses on selective decontamination of the digestive tract by oral antibiotics have shown that this can reduce infection rates and mortality. However, utility of such an approach is limited by development of antimicrobial resistance (42,43). Treatment of pneumonia includes pulmonary toilet (local drainage) and specific tailored antibiotic therapy. Because most pneumonias in the surgical patient are related to intubation, aggressive weaning from the ventilator and extubation are important. Patients not easily weaned should be converted to a tracheostomy. Patients who are suspected of aspiration present with cough, tachypnea, and tachycardia. Many immunocompetent patients mount a febrile response. Chest X-ray reveals atelectasis and infiltrates. Treatment of these patients requires early and repeated suctioning to clear the tracheobronchial tree. Prophylactic antibiotics are not usually indicated initially, but may be required if secondary infection develops. Steroids were previously used to treat aspiration,

but many investigators now believe that they have no place in the management of aspiration because of their deleterious effects on pulmonary host defenses.

Lung Abscess Lung abscesses are usually related to aspiration and typically occur in the superior segments of the right and left lower lobes as well as the posterior segment of the right upper lobe (44). The most common organisms are anaerobic bacteria from the oropharynx and gastrointestinal tract. The organisms stimulate fibroblastic proliferation, which can erode into adjacent bronchoalveolar spaces. Clinical findings include cough (especially hemoptysis, and/or productive of malodorous sputum), fever, and an air–fluid level on chest X-ray. Chest CT is the definitive study for diagnosing a lung abscess. Treatment for lung abscess is generally conservative and basically follows the principles of pneumonia treatment, with focus on pulmonary toilet and tailored antibiotic therapy. Surgical therapy, including drainage and resection, is indicated in patients who fail to respond to conservative measures. Relative indications for surgery include patients with severe hemoptysis, bronchopleural fistula, empyema, and/or an abscess cavity more than 6 cm in diameter.

Tuberculosis Pulmonary tuberculosis is the number one infectious disease resulting in death throughout the world. Despite advances in antibiotic treatment, tuberculosis has seen a recent resurgence due to HIV infections, and other increases in immunocompromised patients (cancer, transplant recipients, etc.). Treatment of pulmonary tuberculosis is primarily pharmacologic. The usual regimen is isoniazid, rifampin, pyrazinamide 2 months þ isoniazid and rifampin 4 months, or isoniazid and rifampin 9 months. Surgery is indicated for patients with positive sputum cultures and cavitary lesions greater than five months despite treatment; severe or recurrent hemoptysis; bronchopleural fistula not resolved by chest tube; mass-associated lesions; and disease due to drug resistant atypicals such as Mycobacterium avium-intracellulare.

Pulmonary Embolism Blood clots from the systemic venous circulation can obstruct the pulmonary artery, causing significant morbidity and mortality. The differential diagnosis of acute pulmonary embolism (PE) is complex because PE can present in a variety of ways depending on the size of the clot, its location, and the underlying comorbidities of the patient. Myocardial infarction, pneumonia, and congestive heart failure may mimic PE. While there are known hypercoagulable states and genetic factor deficiencies, which contribute to PE formation, hospitalized patients have their own acquired risk factors that must be taken into consideration. Surgery and trauma are the key areas for surgical patients that may be impacted for prevention. Low-molecular-weight heparins administered preoperatively in addition to pneumatic compression sleeves for the legs significantly lessen, but do not eliminate, the clot risk. The underlying pathophysiologic abnormality that occurs in PE is occlusion of the pulmonary arteries, so that alveoli subserved by this arterial system are ventilated but no longer perfused. This results in a ventilation–perfusion mismatch, the consequence of which is increased deadspace ventilation (45). Accompanying this event is a reflex airway constriction along with a vasoactive response that

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

initiates a generalized pulmonary vasoconstriction. A variety of mediators have been proposed as possible etiologic agents, but the exact cause of the actions is poorly understood. The net result of these perturbations is an elevation in the pulmonary vascular resistance and a redistribution of pulmonary blood flow that often aggravates the V/Q mismatch triggered by the PE, and local atelectatsis and edema may eventuate in congestive atelectasis or pulmonary edema. It is quite understandable why patients with PE often present with hyperventilation and hypoxia in addition to chest pain in the region of the PE. Clinical suspicion is the key to making the diagnosis of PE. Patients presenting with acute-onset dyspnea, tachypnea, and apprehension should be suspected of harboring a PE. Lab tests, EKG, and physical examination are unreliable and rarely are specific enough to document PE. Ventilation– perfusion scans, which historically were used to make the diagnosis, have generally been supplanted by CT angiography as the imaging modality of choice. Pulmonary angiography is the gold standard in the diagnosis of PE. In the patient suspected of having a PE, immediate anticoagulation with heparin should be administered. Supportive care with supplemental oxygen should also be rendered. These measures are quite efficacious in altering symptomatology and helping to reverse the aberrations induced by the PE.

Pleural Disease Pneumothorax Air in the potential space between the visceral and parietal pleurae is called pneumothorax. The loss of negative intrapleural pressure that occurs from this air collection allows the lung to collapse from elastic recoil. Pneumothorax usually occurs as a result of ruptured alveoli (from a congenital bleb, pneumatocele, or emphysematous bulla) or from small lacerations in the pulmonary parenchyma (rib fractures in blunt trauma, lacerations through the chest wall in penetrating trauma, or iatrogenic injuries such as needle injury during the placement of a central venous line). In most cases of pneumothorax, the damaged lung quickly seals so that the condition is not progressive. Thus, there is no shift in the mediastinal structures and the opposite lung is not adversely affected. A tension pneumothorax, on the other hand, occurs if the pressure of accumulated air in the pleural space exceeds the ambient pressure, resulting in net positive intrathoracic pressure. In this condition, the progressive accumulation of air within the thoracic cavity shifts the cardiomediastinal structures away from the affected lung. If the resultant tension pneumothorax is substantial, compression of the contralateral lung may occur. Tension pneumothorax can be conceived as a one-way valve in which air enters the pleural space during inspiration but cannot escape during expiration. It occurs from a ruptured bleb or lung laceration that has failed to seal. The resultant increase in pleural pressure can have profound effects on the venous return to the heart, usually by direct pressure on the low-pressure vena cava. If not recognized and rapidly treated, hypotension and complete circulatory collapse may promptly occur. Pneumothorax can generally be diagnosed by auscultating the lungs. On the affected side, air movement is compromised to the extent that the pleural space has been replaced by air and the affected lung volume has been compromised. Often percussion of the chest wall will demonstrate hyper-resonance. If a tension pneumothorax has occurred, shifting of the trachea away from the affected side may be seen. There is usually pain in the hemithorax

641

involved. Profound dyspnea and panic may accompany tension pneumothorax. Treatment of pneumothorax will depend on its clinical presentation. If diminished breath sounds and mild-tomoderate pain are major presenting clinical findings in the absence of severe dyspnea, pneumothorax probably is not progressive and the offending lung abnormality has sealed off. If marked dyspnea exists and little-to-no breath sounds can be heard on the affected side, irrespective of whether clear evidence of tracheal shift has occurred, a tension pneumothorax is probably responsible for the clinical situation. In this circumstance, immediate decompression of the affected hemithorax is required to obviate the respiratory and/or hemodynamic embarrassment. This is most readily achieved by needle thoracostomy to relieve the positive intrathoracic pressure. Tube thoracostomy after needle decompression constitutes definitive therapy. In the more common circumstance in which tension does not appear to be a component of the pneumothorax, the type of treatment will be dictated by the volume of lung parenchyma compromised. If less than a 30% pneumothorax appears to exist on chest X-ray, watchful waiting may be all that is needed. For a more substantial pneumothorax, tube thoracostomy is usually required. Once the affected lung injury seals (usually 2–3 days), the tube can be removed. In interpreting X-ray findings of pneumothorax, Richardson (2) has emphasized that it must be remembered that the lung is a sphere and that the volume loss is calculated by the equation V ¼ pR3. Thus, if the diameter has been determined to have decreased from 20 to 16 cm on a chest radiograph, which assesses things from a two-dimensional frame of reference, the actual radius changes from 10 to 8 cm. This translates into a 50% net volume loss, rather than the 20% calculated by simple measurement of diameter loss from the radiograph itself (2).

Hemothorax Hemothorax refers to a condition in which blood is present in the pleural space, usually resulting from trauma to the chest wall. Traumatic hemothorax represents a spectrum of clinical challenges. Most patients can be treated by tube thoracostomy and evacuation of the pleural space. However, a small subset of patients require operative intervention for hemorrhage control and adequate evacuation of the pleural space. Posttraumatic hemothorax of sufficient size to be apparent on chest X-ray is most commonly due to laceration of the pulmonary parenchyma or chest wall vessels (intercostals or internal mammary artery). Standard treatment is large caliber–tube thoracostomy, which allows evacuation of the blood, reduces risk of clotted hemothorax, and provides accurate determination of the extent of ongoing bleeding. In the vast majority of cases, bleeding is self-limited, and operative intervention is unnecessary. After tube thoracostomy, current guidelines recommend immediate surgery if 1500 mL of blood is evacuated initially or if drainage of 200 mL/hr for the ensuing two to four hours occurs (46). These guidelines coincide with the amount of blood loss expected to produce hemorrhagic shock in a previously healthy patient. Occasionally, despite early tube thoracostomy, the hemothorax is only partially evacuated. The residual blood then serves as a nidus for the development of empyema or fibrothorax, which ultimately may lead to thoracotomy and decortication to liberate the trapped lung. Advances in video-assisted thoracic surgery (VATS) have allowed the development of minimally

medwedi.ru

642

Part Three: The Cardiothoracic System—Lung

invasive methods for draining retained hemothorax, and thereby have decreased the likelihood of developing empyema or fibrothorax. Clinical experience suggests that chest X-ray is insufficient to distinguish between retained hemothorax and contusion, and atelectasis or intraparenchymal hemorrhage that are not amenable to VATS treatment. Chest CT is much more useful in this scenario. Progressive clot organization and adherence leaves a window of three to five days postinjury when the semisolid clot and serum can be evacuated via VATS with a high degree of success. It may however, require persistence and multiple procedures to completely clear the pleural space. Repeated episodes of one-lung ventilation may actually increase the alveolar– arterial gradient and exacerbate relative hypoxemia.

Chylothorax Chylothorax is the presence of lymph within the pleural space. It may be caused by congenital or primary lymphatic disease, but is usually due to intrathoracic malignancy with intrinsic or extrinsic obstruction, iatrogenic injury, or trauma. Postoperative chylothorax may complicate surgical procedures anywhere along the path of the thoracic duct between the diaphragm and the neck. Initial symptoms of dyspnea and exercise intolerance are the result of a large volume chylous effusion causing compressive atelectasis of the lung. Prolonged drainage leads to dehydration, malnutrition, and immunologic compromise due to loss of fluid, fat, protein, and lymphocytes, which make up the lymph fluid. Nonoperative management may be appropriate as an initial strategy, particularly in the first few days after surgery or trauma, or in cases of malignancy that may respond to treatment of the primary disease (principally lymphoma). The components of initial management are drainage of the pleural space, reduction of chyle flow, and maintenance of hydration and adequate nutrition. Evacuation of the pleural space is most commonly achieved by tube thoracostomy, which facilitates pulmonary re-expansion and provides continuous drainage and accurate measurements of chyle flow. Chemical sclerotherapy is used to accelerate pleural symphysis and achieve obliteration of the pleural space. Failed nonoperative management warrants surgical thoracic duct ligation. Lymphangiography provides useful information regarding the lymphatic anatomy and fistula site. Because it is quite challenging at times, it is usually only done in refractory chylothoraces that have failed initial surgical closure. Other methods to locate the leak include preoperative injection of Evans blue dye (1% subcutaneous in the thigh) or enteral administration of fat (cream or olive oil). Surgical options include direct ligation of the thoracic duct at the site of the leak, mass ligation of the thoracic duct and surrounding tissues, application of fibrin glue, or creation of a pleuroperitoneal shunt. If the chyle leak can be identified, direct ligation should be performed on either side of the leak. If the leak cannot be identified, mass ligation of all tissue between the aorta, spine, esophagus, and pericardium is best performed above the diaphragm in the right pleural space. This can be achieved either by thoracotomy or video-assisted thoracoscopy.

Traumatic Lung Injury Smoke Inhalation and Pulmonary Dysfunction Following Burns Burn injuries include smoke inhalation, direct thermal airway injuries, and pulmonary dysfunction caused by the

products of combustion. The specific nature of the chemical products determines the lethality of the burn injury. Certain materials and chemicals are direct toxins to the airways and must be addressed aggressively if the burn victim is to survive. Edema formation and bronchoconstriction are early responses to released leukotrienes. Direct alveolar injury leads to increased lung water and difficulty in ventilation. Through the complement cascade, neutrophils migrate to the injured mucosa. All patients with facial burns should be suspect for distal airway injuries. Upper airway edema and obstruction rapidly become life threatening and require bronchoscopy and intubation. This process progresses as high-volume fluid resuscitation and capillary leakage continues. While carbon monoxide levels are routinely obtained, many of the CNS manifestations are masked by intravenous narcotics needed for pain management. Ventilatory support with the judicious use of fluids is critical if the patient is to survive. Pneumonias are expected with the prolonged need for pulmonary toilet and repeated bronchoscopy.

Chest Trauma Chest trauma accounts for 10% to 12% of all trauma admissions to the hospital, but for nearly 25% of all deaths due to trauma (47). Chest wall injury is the most common thoracic injury, and rib fracture is associated with a 12% mortality. Chest trauma from penetrating sources is usually caused by knives or bullets, while blunt trauma injury usually comes from motor vehicle deceleration injuries. Fewer than 30% of all chest trauma patients require thoracotomy. In the immediate period, following a major motor vehicle collision, fatal injuries usually involve the thoracic aorta or heart and these patients typically die at the scene of the accident. Other life-threatening injuries can be managed effectively if they are recognized early. The initial assessment of the trauma patient is the first priority. A patent airway must be confirmed and established rapidly. In certain instances, a surgical airway must be established when passage of an endotracheal tube is not possible or when upper airway obstruction exists. Hemodynamic control is the next priority and a large-bore intravenous access is mandatory for all patients. Most importantly, physical examination will reveal life-threatening injuries, which many times must be treated before obtaining diagnostic X-rays. These include tension pneumothorax, ruptured bronchus and diaphragm, and airway obstruction. While complete management algorithms of each of these entities are beyond the scope of this chapter, a basic understanding of these physiologic derangements is necessary to treat these patients. In many instances, chest tube insertion is the only interventional measure necessary for the management of these patients. Tension pneumothorax must be recognized immediately during physical examination and treatment instituted with equal rapidity. The hallmarks of tension pneumothorax consist of complete lung collapse with concomitant tracheal deviation and mediastinal shift. Tachypnea, distended neck veins, and diaphoresis may be missed in a busy trauma bay. Because there is decreased venous return to the heart, hemodynamic instability in the form of hypotension and tachycardia occurs rapidly. Needle decompression followed by chest tube insertion is life saving and is warranted without X-ray examination. Tracheobronchial injuries may be life threatening as well. Usually occurring within 2 cm of the carina, most

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

injuries can be exposed and repaired through a right thoracotomy. Rarely is cardiopulmonary bypass necessary for the repair. These patients present with subcutaneous emphysema, pneumothorax, and massive air leak. Any patient with a pneumothorax that does not re-expand with chest tube insertion should be suspected of having a tracheobronchial injury. A definitive diagnosis requires careful bronchoscopy. Generally, repair consists of carefully placed interrupted absorbable sutures. Fractures involving the upper six ribs are associated with life-threatening intrathoracic injuries, while fractures involving the lower six ribs are associated with lifethreatening intra-abdominal injuries. Multiple rib fractures resulting in a flail segment have a significantly higher morbidity due to underlying pulmonary contusion. Elderly patients and/or patients with preexisting comorbidities and other underlying physiologic changes tend to have poorer outcomes. Flail chest is the most serious chest wall injury encountered. Mechanically, it is the complete disruption of a portion of the chest wall by segmental fractures of two or more adjacent ribs (Fig. 9). It also may result from disruption of the ribs from the sternum at the costochondral cartilage and a fracture of the rib. Aside from the deleterious effects on chest wall mechanics and respiration, the force required to cause a flail chest places the patient at significant risk for other intrathoracic injuries. Pain management is the most significant component to successful treatment of rib fractures and flail chest. The disruption of chest wall mechanics may decrease TV and impair the ability to generate an effective cough. This situation leads to the development of hypoventilation and subsequent atelectasis and pneumonia (48). Unless the affected segment is large, these alterations generally can be managed with incentive spirometry and aggressive pulmonary toilet, which require active patient participation. Oral narcotics rarely achieve effective pain control. Intravenous narcotics are able to provide adequate pain relief but at a degree of sedation that frequently will impair the patient’s ability to effectively participate in pulmonary toilet. The preferred option for pain management is thoracic epidural

643

anesthesia. A combination of narcotic and local anesthetic acts synergistically to provide excellent pain control without sedation. The patient can now breathe deeply and cough, and has increased mobility. This prevents hypoventilation, promotes clearance of secretions, and improves the chances of avoiding endotracheal intubation and mechanical ventilation. Operative stabilization may be necessary for selected patients in whom adequate pain control cannot be achieved or who fail to be weaned from mechanical ventilation. Methods using either permanent or absorbable plates, screws, Kirschner wires, or Judet staples have been described. Stabilizing every other fractured rib is usually adequate to provide normalization of chest wall movement, decrease pain, and improve respiratory mechanics. Pulmonary contusion is a diffuse hemorrhage into the lung parenchyma, resulting from either blunt or ‘‘blast injury’’ penetrating trauma (49). It commonly appears within several hours of the event as a patchy opacity on the chest X-ray, which then progresses over the next several days. Hemoptysis is a frequent manifestation of pulmonary contusion. Small peripheral contusions may produce only blood-tinged sputum, whereas injuries near the hilum may develop massive bleeding into the tracheobronchial tree that rarely may lead to life-threatening airway obstruction. In such circumstances, immediate resection of the damaged lung tissue and clearance of the airway is required. Nonoperative management with attention to pulmonary toilet, incentive spirometry, and pneumonia surveillance is usually sufficient to treat the contusion (50). Strict attention to volume status is critical because overresuscitation can contribute to pulmonary edema and hypoxia and volume depletion may result in hypotension and malperfusion syndromes. Monitoring central venous pressure and urine output is mandatory and some patients may require the use of pulmonary artery catheters. Effective drainage of effusions, hemothorax, or pneumothorax will greatly facilitate pulmonary expansion and maintain adequate oxygenation and ventilation.

NEOPLASTIC CONDITIONS Mediastinum and Mediastinal Masses

Figure 9 Fracture of chest wall in two locations is necessary for development of flair chest. Classic concept of altered mechanics causing ‘‘to-andfro’’ movement of air between major bronchi (double arrow) has largely been dispelled. Source: From Ref. 2.

The anatomy and the borders of the mediastinum predict the lesions that occur in this region. While surgical approaches were previously recommended for diagnosis of mediastinal masses, technological imaging advances have allowed greater noninvasive access to previously remote areas (Table 2). The anterior-superior mediastinum is the largest compartment and contains the greatest variety of pathology (50,51). Specific borders include the posterior sternum extending to the anterior pericardium. Typical components include the thymus gland, fat, and lymph nodes. The wellknown mnemonic, the ‘‘4Ts’’ of the anterior mediastinum, includes thymoma, teratoma, terrible lymphoma, and thyroid. Access to this area can be readily obtained through anterior mediastinotomy and video thoracoscopy. The middle mediastinum, also known as the visceral compartment, contains the heart, superior and inferior vena cava, ascending aorta and arch, main pulmonary arteries, phrenic and vagus nerves, trachea and main stem bronchi, and lymph nodes (50,51). Foregut duplication cysts originating from sequestrations of the ventral foregut are common. Bronchogenic cysts are the most common cysts followed by pericardial cysts. Mediastinoscopy is the most common

medwedi.ru

644

Part Three: The Cardiothoracic System—Lung

Table 2 Tumors of the Mediastinum Anterior-superior compartment Parathyroid adenomas Thyroid tumors and cysts Thymic tumors and cysts Teratomas Pericardial cysts Germ cell tumors Bronchogenic cysts Lymphomas Middle compartment Lymphatic tumors Lymphomas Foregut cysts Esophageal leiomyomas Pericardial cysts Bronchogenic cysts Posterior compartment Neurogenic tumors Ganglioneuromas Gastroenteric cysts

diagnosis, often utilizing flow cytometry, is all that is necessary. Once obtained, appropriate oncologic regimens are initiated. Substernal goiters cause compressive symptoms, including dyspnea and dysphagia and are more common in females. The majority (95%) can be removed through a cervical collar incision. Larger or deeper lesions may require partial sternal split for access and excision. Recurrent laryngeal nerve injury is rare despite the bulk of these lesions, due to the marked displacement of the normal anatomical structures. Descending necrotizing mediastinitis must be considered when discussing the mediastinum. This rare polymicrobial infection commonly originates from an oropharyngeal source and carries a 50% mortality. The key to understanding this process is the realization that all three deep spaces of the neck (pretracheal, retrovisceral, and prevertebral) communicate with the chest and the mediastinum. Early aggressive drainage and debridement is needed with prolonged critical support if the patient is to survive. Many patients require additional drainage procedures because of developing loculations and empyema collections.

Tumors of the Lung access approach to this area. The posterior mediastinum extends from the posterior pericardium to the posterior chest wall and includes the esophagus, descending aorta, and the thoracic duct (50,51). Neurogenic tumors are the most common lesions in the posterior mediastinum. Typically, these lesions are malignant in children. Clinically, the majority of mediastinal masses are asymptomatic and the physical examination is nondiagnostic. Lesions that are symptomatic have a higher likelihood of malignancy. While CT scan is the diagnostic test of choice, in certain circumstances, magnetic resonance imaging (MRI) is useful for delineating vascular and neuroanatomy relationships. Key tumor markers include LDH for lymphomas and seminoma differentiation. bHCG and alphafetoprotein levels should be obtained in all male patients and are complementary to a testicular examination and ultrasound. Thymoma is the most common tumor of the anterior mediastinum. Thirty to fifty percent of patients have the autoimmune disease myasthenia gravis (MG). While many MG patients have muscle weakness, including diplopia and dysarthria, others present with paraneoplastic syndromes including agammaglobulinemia. CT is the diagnostic test of choice. Staging of thymoma is done at the time of surgery as determined by gross evidence of invasion. Surgical management of thymoma includes transcervical, median sternotomy, or VATS removal. The key surgical principle is complete surgical removal of the gland without leaving rests of residual tissue, precipitating recurrence. Adjuvant radiation therapy is used for frank invasion or residual tumor. The anterior mediastinum is also the most common site of extragonadal germ cell tumors. Because they occur in young males (ages 20–35), all male patients should undergo testicular examination, including ultrasound and measurements of serum tumor markers. In general, cisplatin-based chemotherapy provides 50% five-year survival. Resection is reserved for teratomas and residual postchemotherapeutic tumor burden. Neurogenic tumors are the most common posterior mediastinal tumor, with most being exposed by thoracotomy or VATS. Dumbbell tumors extending into the spinal canal require MRI for delineation and neurosurgical assistance for removal. Lymphomas commonly affect the mediastinum. Resection is rarely indicated or achievable; usually tissue

Lung cancer is the second most common malignancy in the United States. It is second in incidence to only prostate cancer in men and breast cancer in women. It is the leading cause of cancer-related deaths in men and women. The average age at diagnosis is 60 years. Despite some improvements in short-term survival, overall five-year survival remains at only 14%. The major cause of lung cancer has been clearly linked to smoking, with 80% to 90% of lung cancers occurring as a direct result of tobacco use. Although both benign and malignant tumors occur in the lung, the vast majority (95–97%) of them are malignant. Malignant lung tumors are generally divided into non– small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) (52,53). NSCLC makes up about 80%, while SCLC makes up 10% to 15% of malignant lung tumors. Mixed tumor types are possible, and small cell carcinoma can be found with a non–small cell carcinoma in the same tumor, suggesting that both share a common precursor. With respect to benign neoplasia, hamartomas are the most common, followed by a variety of other tumors such as xanthomas, inflammatory pseudotumors, lipomas, myoblastomas, and fibrous mesotheliomas. The vast majority of patients with lung tumors will present with symptomatic disease. Five percent of tumors are found incidentally on chest X-rays. The most common presenting symptoms are cough, weight loss, dyspnea, and chest pain; 30% of patients will present with hemoptysis. Occasionally, an unexplained solitary pulmonary nodule (‘‘coin lesions’’) will be seen on chest X-ray in an asymptomatic patient. Most of these lesions are located in the lung periphery, are well circumscribed, are less than 5 cm in diameter, and occasionally exhibit calcifications. Half or more of these lesions will demonstrate malignancy on biopsy. Advanced tumors invading the mediastinum may present with a wide range of findings depending on the structure involved (52,53). Vocal cord paralysis may result from invasion of the recurrent laryngeal nerve. Superior vena cava (SVC) syndrome results from SVC obstruction and may present with facial, neck, and upper extremity swelling, edema, cyanosis, headache, conjunctival injections, and occasionally orthopnea with a feeling of impending doom. Radiation therapy may alleviate some of these symptoms, but survival is usually measured in weeks to months. Extension of tumors

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

into the thoracic inlet may result in shoulder and arm pain, Horner’s syndrome (ptosis, miosis, exopthalmosis, and decreased sweating on the involved side due to involvement of the sympathetic ganglia), and Pancoast’s syndrome (loss of upper-arm strength and ulnar paresthesisas due to involvement of the brachial plexus). Ten to twenty percent of patients will present with a paraneoplastic syndrome in which various humoral agents are secreted by the tumor. Small-cell carcinoma and squamous cell carcinoma are the histologic subtypes commonly associated with these syndromes. Examples include the secretion of adrenocorticotrophic hormone–like substance that mimics Cushing’s syndrome, a parathormone-like substance simulating hyperparathyroidism, and the manifestation of water retention and symptoms of hyponatremia due to secretion of an antidiuretic hormone–like substance. A particularly interesting extrapulmonary manifestation of lung cancer is hypertrophic pulmonary osteoarthropathy. This condition is characterized by clubbing of the fingers, diffuse bone (not joint) tenderness, and finger X-rays demonstrating linear calcium deposition along the periosteum. The precise mechanism responsible for this abnormality is unknown. Diagnosis and staging of lung cancer is focused on early identification of patients with potentially curable tumors. In addition to the history and physical, imaging can help define tumor extent. In general, patients with X-ray findings of a suspicious pulmonary nodule should have a CT scan of the chest and upper abdomen. Patients with nonspecific neurologic or bony symptoms should have a head CT and/or radionuclide bone scan to assess for metastatic disease. Histologic confirmation of lung cancer is not required prior to resection in an otherwise healthy patient with no evidence of advanced disease. If advanced disease is suspected and nonsurgical treatment is planned, histologic confirmation through bronchoscopy, transthoracic needle aspiration, and thoracoscopic and/or open biopsy should be obtained. Mediastinal lymph nodes larger than 1 cm seen on imaging should be biopsied by cervical mediastinoscopy or video-assisted thoracoscopic techniques.

645

The TNM staging of NSCLC is shown in Figure 10. In general, tumors invading the mediastinum, those associated with a malignant pleural effusion, those with nodal metastasis to the contralateral side (stage IIIB), and those with metastasis to distant organ sites (such as brain, bone, kidneys, adrenals, etc.) represent advanced disease that will not be helped with aggressive surgical therapy. Survival following surgical resection is shown below:

Stage I Stage II Stage IIIa

1-yr survival (%)

5-yr survival (%)

72–94 55–89

38–67 22–55 23–25

Recent studies have shown a survival benefit for patients receiving adjuvant platinum-based chemotherapy after complete surgical resection. In the International Adjuvant Lung Cancer Trial, there was a 4.1% survival advantage in the surgery plus chemotherapy group (over surgery alone) for patients in stage I to stage III (57). In the Cancer and Leukemia Group B Protocol 9633, for patients with stage IB disease, chemotherapy after surgical resection conferred a 12% survival advantage (58). In the NCIC-BR10 study, a similar 15% overall survival advantage was seen for stage IB and stage II patients who received adjuvant chemotherapy (59). Recent trials regarding preoperative induction chemotherapy or chemoradiation therapy suggests there may be a benefit in a patient with stage II to IIIa disease.

Small Cell Lung Cancer (SCLC) Approximately 15% of all lung cancers are SCLC. The vast majority present with advanced disease and surgery is generally not indicated (60). The overall five-year survival is 5% to 10%. One percent of patients with SCLC present with stage I or II disease. Five-year survival rates of approximately 50% have been reported in patients with SCLC with stage I or II disease, who underwent resection followed by chemoradiation.

LUNG TRANSPLANTATION

Non–Small Cell Lung Cancer (NSCLC) NSCLC can be divided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the most common type of lung cancer. Tumors are typically situated in the periphery and arise from subsegmental bronchioles. They can spread by both lymphatic and hematogenous routes. Squamous cell carcinoma is the next most common type of lung cancer. These tumors typically are centrally located. They can grow to a large size before metastasizing and can present with bronchus obstruction and central necrosis. They tend to metastasize to peribronchial or hilar lymph nodes. Large cell carcinoma is an undifferentiated aggressive tumor that can be difficult to distinguish from poorly differentiated adenocarcinoma or small cell carcinoma. Depending on the size of the tumor and its location, lobectomy or pneumonectomy is the usual surgical option. Multiple genetic derangements have been described (54,55). The most common activated proto-oncogene in NSCLC is k-ras. In more than 50% of NSCLC, the tumor suppressor gene p53 is overexpressed or mutated. Other genes implicated include erbB, Rb, and bcl-2. A genetic susceptibility to lung cancer has also been demonstrated, and the most common chromosomal abnormalities involve chromosomes 1, 3, 7, 9, and 17.

As of 2001, 12,000 lung transplants have been performed worldwide, with one-year survivals being in the 75% range for most patients requiring this form of treatment to manage their underlying pulmonary disease (61). Functional results are durable when the procedure is performed at experienced centers. Clinical indications for single- and doublelung transplantation are very specific and guidelines for both the donor and recipient must be adhered to because of the scarcity of available organs. Improvement in patient selection is the single most important factor responsible for the success of pulmonary transplantation. The majority of adult lung transplants are performed for emphysema due to COPD or alpha-1 antitrypsin deficiency. Other indications include cystic and pulmonary fibrosis. Operative mortality and long-term survival are directly associated with the patient’s underlying diagnosis; patients with pulmonary hypertension and pulmonary fibrosis are typically more difficult to manage. Expected improvements in FEV1 are well documented following successful surgery. Specific lung transplant complications include early allograft dysfunction, which may be caused by poor donor preservation or underlying lung pathology. Airway anastomotic complications have decreased as surgical anastomotic techniques

medwedi.ru

646

Part Three: The Cardiothoracic System—Lung

Figure 10 Staging of lung cancer. (A) Stage IA disease (T1 N0 M0) identifies a small ( < 3 cm) tumor surrounded by lung parenchyma. (B) Stage IB disease (T2 N0 M0) includes larger tumors that invade the visceral pleura or the main bronchi, or that have evidence of atelectasis/pneumonitis extending to the hilar regions. No metastatic disease is present with stage I tumors. (C) Stage IIA (T1 N1 M0) identifies small tumors with T1 characteristics ( < 3 cm) involving the peribronchial or hilar nodes by extension or metastasis. (D) Stage IIB disease includes larger tumors ( > 3 cm) involving the peribronchial or hilar lymph nodes (T2 N1 M0) or tumors with limited extrapulmonary extension such as involvement of the chest wall or the pericardium (T3 N0 M0) but no evidence of metastasis. (E) Stage IIIA describes tumors with localized extrapulmonary extension and involvement of peribronchial or hilar lymph nodes (T3 N1 M0) as well as any T1, T2, or T3 tumors with metastasis to the ipsilateral mediastinal and subcarinal lymph nodes (T1, T2, or T3 N2 M0). (F) Stage IIIB describes either extensive extrapulmonary tumor invasion (T4 any N M0) or metastasis to the contralateral mediastinal and hilar lymph nodes as well as ipsilateral and contralateral supraclavicular/scalene lymph nodes. Source: From Ref. 56.

and perioperative management have improved. Bronchiolitis obliterans with a decline in FEV1 has continued to plague long-term lung transplantation results and survival. This form of chronic allograft dysfunction is undergoing aggressive research and may be related to the high frequency of gastroesophageal reflux in lung transplant patients.

SUMMARY Oxygen delivery to meet tissue needs is critical to the survival of the human organism. The lungs make this possible

by optimally matching ventilation to pulmonary arterial perfusion, so that inhaled oxygen is effectively diffused across the alveolar-capillary membrane in exchange for carbon dioxide, which is then removed from the body during exhalation. Disturbances in ventilation, perfusion, or alveolar-capillary membrane diffusion can drastically perturb the adequacy of tissue oxygenation and thereby directly influence not only the risk of undergoing an operative procedure, but also the likelihood that postoperative complications will occur. Accordingly, it is essential that the surgeon fully understand the basic mechanisms responsible for normal pulmonary function, and the way to optimize this

Chapter 31: Pathobiology of Surgically Relevant Pulmonary Disease

function in patients with lung disease to insure a smooth perioperative course when surgical intervention is necessary. This chapter has summarized the basic mechanisms of lung function and how they are perturbed by a variety of insults, including intrinsic disease, infection, trauma, and neoplasia.

REFERENCES 1. Jackson CL, Huber JF. Correlated applied anatomy of the bronchial tree and lungs with a system of nomenclature. Dis Chest 1943; 9:319. [Adapted by Putnam JB Jr. Lung (including pulmonary embolism and thoracic outlet syndrome). In: Townsend CM Jr., et al., eds. Sabiston Textbook of Surgery. Philadelphia: Saunders WB and Co. 7th ed. 2001:1207]. 2. Richardson JD. Common pulmonary derangements, respiratory failure, and adult respiratory distress syndrome. In: Miller TA, ed. Modern Surgical Care: Physiologic Foundations & Clinical Applications. 2nd ed. St. Louis: Quality Medical Pub, 1998:738–764. 3. West J. Pulmonary pathophysiology. Baltimore: Williams & Wilkins, 1982. 4. Whitcomb ME. The Lung, Normal and Diseased. St. Louis: Mosby, 1982:viii, 360. 5. Wright JR. Pulmonary surfactant: a front line of lung host defense. J Clin Invest 2003; 111(10):1453. 6. Wu H, Kuzmenko A, Wan S, et al. Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J Clin Invest 2003; 111(10):1589. 7. Richardson JD, Woods D, Johanson WG Jr, et al. Lung bacterial clearance following pulmonary contusion. Surgery 1979; 86(5):730. 8. Peters RM, et al. The Scientific Management of Surgical Patients. Little, Brown & Co, Boston: 1983. 9. Joost O, Wilk JB, Cupples LA, et al. Genetic loci influencing lung function: a genome-wide scan in the Framingham Study. Am J Respir Crit Care Med 2002; 165(6):795. 10. McKeever TM, Scrivener S, Broadfield E, et al. Prospective study of diet and decline in lung function in a general population. Am J Respir Crit Care Med 2002; 165(9):1299. 11. Crim C. Physiology of respiration. In: Miller TA, ed. Modern Surgical Care: Physiologic Foundations & Clinical Applications. 2nd ed. St. Louis: Quality Medical Pub, 1998, pp 729–737. 12. Scott–Conner C. Operative Anatomy, Lippincott. 13. West JB, Dollery CT, Naimark A. Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. J Appl Physiol 1964; 19:713. 14. Benz EJ Jr. Synthesis, structure and function of hemoglobin. In: Kelly WN, Devita VT, eds. Textbook of Internal Medicine. Vol. 1. Philadelphia, JB Lippincott, 1989:236. 15. West JB. Respiratory Physiology–The Essentials. 7th ed: Baltimore: Lippincott Williams & Wilkins, 2005. 16. Warner MA, Offord KP, Warner ME, et al. Role of preoperative cessation of smoking and other factors in postoperative pulmonary complications: a blinded prospective study of coronary artery bypass patients. Mayo Clin Proc 1989; 64(6):609. 17. Dunn WF, Scanlon PD. Preoperative pulmonary function testing for patients with lung cancer. Mayo Clin Proc 1993; 68(4):371. 18. Fessler HE, Scharf SM, Permutt S. Improvement in spirometry following lung volume reduction surgery: application of a physiologic model. Am J Respir Crit Care Med 2002; 165(1):34. 19. Weisman IM. Cardiopulmonary exercise testing in the preoperative assessment for lung resection surgery. Semin Thorac Cardiovasc 2001; 13(2):116. 20. Daly JM, Barie PS, Fahey TJ III. Preparation of the patient. In: Baker RJ, Fischer JF, eds. Mastery of Surgery. 4th ed. Philadelphia: Lippincott William & Wilkins, 2003:23–53. 21. Schauer PR, Luna J, Ghiatas AA, et al. Pulmonary function after laparoscopic cholecystectomy. Surgery 1993; 114:389.

647

22. Bonnet F, Marret E. Influence of anaesthetic and analgesic techniques on outcome after surgery. Br J Anaesth 2005; 95(1):52. 23. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2(7511):319. 24. Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149(3 Pt 1):818. 25. Bersten AD, Edibam C, Hunt T, et al. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002; 165(4):443. 26. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002; 166(5):646. 27. Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med 1999; 159(6):1849. 28. Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990; 11(4):593. 29. Dellinger PR. Adult respiratory distress syndrome: current consideration and future directions. New Horizons 1993; 1. 30. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342(18):1301. 31. Hirvela ER. Advances in the management of acute respiratory distress syndrome: protective ventilation. Arch Surg 2000; 135(2):126. 32. Aggarwal AN, Gupta D, Behera D, et al. Analysis of static pulmonary mechanics helps to identify functional defects in survivors of acute respiratory distress syndrome. Crit Care Med 2000; 28(10):3480. 33. Hopkins RO, Weaver LK, Collingridge D, et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005; 171(4):340. 34. Shields RT. Pathogenesis of postoperative pulmonary atelectasis. Arch Surg 1949; 58:489. 35. Calverley PM. The GOLD classification has advanced understanding of COPD. Am J Respir Crit Care Med 2004; 170(3):211; discussion 4. 36. Nelson HS. Beta-adrenergic bronchodilators. N Engl J Med 1995; 333:499. 37. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: current relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:1301. 38. Bowton DL. Nosocomial pneumonia in the ICU—year 2000 and beyond. Chest 1999; 115:28S. 39. Heyland DK, Cook DJ, Griffith L, et al. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am J Respir Crit Care Med 1999; 159(4 Pt 1):1249. 40. Chastre J, Fagon JY, Bornet-Lecso M, et al. Evaluation of bronchoscopic techniques for the diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 1995; 152(1):231. 41. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet 1999; 354:1851. 42. Kollef MH. Selective digestive decontamination should not be routinely employed. Chest 2003; 123(suppl 5):464S. 43. Kollef MH. Prevention of hospital-associated pneumonia and ventilator-associated pneumonia. Crit Care Med 2004; 32(6):1396. 44. Pohlson EC, McNamara JJ, et al. Lung abscess: a changing pattern of the disease. Am J Surg 1985; 150:97. 45. Cina G, Marra R, Di Stasi C, Macis G. Epidemiology, pathophysiology and natural history of venous thromboembolism. Rays 1996; 21:315.

medwedi.ru

648

Part Three: The Cardiothoracic System—Lung

46. Peitzman AB, Puyana JC. Hemothorax. In: Cameron JL, ed. Current Surgical Therapy. 8th ed. Philadelphia: Elsevier Mosby, 679. 47. Mattox KL, Feliciano DV, Moore EE. Trauma. 4th ed. New York: McGraw-Hill, 1999. 48. Ahmed Z, Mohyuddin Z. Management of flail chest injury: internal fixation versus endotracheal intubation and ventilation. J Thoracic Cardiovasc Surg 1995; 110:1676–1680. 49. Trinkle JK, et al. Pulmonary contusion: pathogenesis and effect of various resuscitative measures. Ann Thorac Surg 1973; 16:569. 50. Davis RD, Oldham HN, Sabiston DC. Primary cysts and neoplasms of the mediastinum: recent changes in clinical presentation, methods of diagnosis, management and results. Ann Thorac Surg 1987; 44:229. 51. Cirino LM, Milanez de Campos JR, Fernandez A, et al. Diagnosis and treatment of mediastinal tumors by thoracoscopy. Chest 2000; 117:1787. 52. Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and III A nonsmall cell lung cancer. J Clin Oncol 2002; 20:247. 53. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997; 111:1718.

54. Slebos RJC, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Eng J Med 1990; 323:561. 55. Rusch VW, Dmitrovsky E. Molecular biologic features of non-small cell lung cancer: clinical implications. Chest Surg Clin N Am 1995; 5:39. 56. Mountain CF. International system for staging lung cancer. Semin Surg Oncol 2001; 18:106. 57. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350(4):351. 58. Kato H, Tsuboi M, Kato Y, et al. Postoperative adjuvant therapy for completely resected early-stage non-small cell lung cancer. Int J Clin Oncol 2005; 10(3):157. 59. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352(25):2589. 60. Lassen U, Hansen HH. Surgery in limited stage small cell lung cancer. Cancer Treat Rev 1999; 25:67. 61. Lau CL, Davis RD. Lung transplantation. In: Norton JA, et al., eds. Surgery: Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001:1509.

HEART

32 Normal Cardiac Function Andrew C. Fiore and Andrew S. Wechsler

INTRODUCTION As a component of the cardiovascular system, the heart is responsible for maintaining adequate blood flow to meet the metabolic needs of the body. This is accomplished by the integration of neural, metabolic, anatomic, and physiologic subsystems that combine to form the intact, functioning human heart. An understanding of cardiac function must consider each of these factors, because a knowledge of only one, or even several, without an appreciation of the others gives an incomplete picture of the physiologic mechanisms responsible for this function. In discussing cardiac physiology, it is appropriate to begin with the molecular events underlying contraction and relaxation, to provide the basis for understanding the performance of the intact organ.

MOLECULAR MECHANISMS IN CONTRACTION AND RELAXATION The basis of cardiac function is the relationship between the contractile proteins, actin and myosin. The nature of this relationship determines to a large extent the characteristics of activation and relaxation in individual muscle cells and in the intact heart. As in skeletal muscle, the functional unit of cardiac muscle is the sarcomere. The sarcomere is composed principally of four proteins (1). These are the previously mentioned contractile proteins, actin and myosin and the regulatory complex consisting of tropomyosin and troponin. In electron micrographs, the sarcomere appears as an arrangement of thick and thin filaments. This arrangement is shown schematically in Figure 1. The thick filament exists as an aggregate of myosin molecules. Myosin consists of a pair of heavy, coiled polypeptide chains, each of which is attached to a globular head region. These head regions project from the axial core of the myosin aggregate and form cross-bridges to the thin filament (Fig. 2). The thin filament is made up of actin in association with troponin and tropomyosin. Actin is a globular molecule that polymerizes to form a double-stranded a-helical filament. Actin filaments attach to the Z line of the sarcomere and project inward as the thin filament. Here, they interact to various degrees with the thick filament. This interaction is regulated by troponin and tropomyosin. Tropomyosin spans the length of the thin filament, and the troponin complex is normally located at every seventh actin site (4). Troponin consists of three subgroups that are responsible for binding calcium ions and for regulating the formation of attachments between actin and myosin by way of the cross-bridges (5). Troponin I hugs the myosin-binding site on actin and thereby prevents interaction with myosin, which is necessary to form the actin–myosin cross-bridge.

Troponin T anchors the three troponin subunits to tropomyosin, while troponin C is involved in the initiation of contraction through its calcium-binding site (6–8). In the resting state, tropomyosin blocks the binding sites on actin so that cross-bridge interaction is prevented. The presence of calcium bound to the troponin complex leads to a conformational change in tropomyosin, such that the actin–myosin association is no longer blocked. It is the specific binding of calcium to troponin C that removes the inhibitory effect of troponin I on the myosin-binding site of actin. Such removal allows formation of the actin–myosin cross-bridge (6–8). The head region of myosin is the enzymatically active portion of the molecule (1). Adenosine triphosphate (ATP) binds here and is hydrolyzed to adenosine diphosphate and phosphorus (P). In this form, the affinity of myosin for actin is enhanced, such that if calcium is present, an actin–myosin complex is formed. As the hydrolysis products are released from the complex, the myosin head undergoes a conformational change that displaces the actin filament relative to the myosin. In this manner, force generation and shortening are accomplished. The addition of ATP to the actin–myosin complex results in dissociation of the filaments. The ATP is once again hydrolyzed, and the process repeats (6–10). Force generation during activation depends to a large extent on the number of cross-bridge attachments that are formed (11). This number is a function of the degree of filament overlap and the level of calcium present. The rate of shortening is a measure of the ATPase activity of myosin (12). It has been established that myosin exists in several forms that are distinguished by the composition of their heavy chains (13). These various forms differ in their ATPase kinetics and thus in their rate of fiber shortening (14). The

Figure 1 Schematic diagram showing the pattern of thick and thin filaments of one sarcomere. Degree of filament overlap varies with the phase of contraction. Source: From Ref. 2.

medwedi.ru 649

650

Part Three: The Cardiothoracic System—Heart

Figure 2 Detailed representation of filament structure. Helical tails of the myosin molecules form a rigid rod-like structure. Globular heads project from this toward the actin filament. (A–B) Threedimensional relationships. Each myosin is seen to interact with six actin filaments (B). Note steric hindrance provided by troponin (TROP) and tropomyosin (TM). Abbreviations: HMM, heavy meromyosin; LMM, light meromyosin. Source: From Ref. 3.

composition of the myosin subunits is genetically determined; however, it has been shown to change in response to such hormones as thyroxin and to chronic elevations in the mechanical loading of the muscle (15,16).

The Cellular Basis of Cardiac Contraction Cardiomyocytes may be considered to consist of three systems: (i) a sarcolemmal excitation system that participates in the spread of the action potential (AP) and functions as a switch that initiates the intracellular events giving rise to contraction, (ii) an intracellular excitation–contraction coupling (ECC) system that amplifies and converts the electrical excitation signal to a chemical signal that, in turn, activates the contractile system (iii) contractile system, a molecular motor based on formation of chemical crossbridges between the two proteins, actin and myosin.

in invaginations of the sarcolemma called the transversetubule system, in close proximity to the sarcoplasmic reticulum (SR) membrane–associated ryanodine receptor Ca release channels. The AP results in a net movement of Ca ions into and Na ions out of the cytoplasm. Ionic balance is restored mainly by another sarcolemmal ion-transport mechanism, the Na–Ca exchanger. The exchanger is a shuttle that moves one Ca ion out of the cell against its concentration gradient while using energy from the Na gradient to move one Na ion into the cell. The exchanger also can function in the so-called reverse mode, moving a Ca ion into and a Na ion out of the cytoplasm. Normally, the reverse mode does not contribute significantly to inward movement of Ca ions.

Excitation-Contraction Coupling Excitation System The cellular AP consists of a transient, local trans-sarcolemmal depolarizing current that raises the transmembrane potential from its normal resting value of negative 80 to 90 mV to slightly positive values, followed by a depolarizing current that returns the potential to its resting value. The AP is initiated within the specialized conduction tissue and is propagated to individual myocytes. It results from a series of coordinated changes in the conductance of specific ionic species through variably gated sarcolemmal channels. The earliest and largest component of membrane depolarization is caused by a rapid, inward Na current. The resting potential is established and maintained by the trans-sarcolemmal Na-K-ATPase, which uses energy from ATP hydrolysis to pump Na ions out of the cytoplasm. With respect to initiation of contraction, the most important component of AP is a relatively slow, inward Ca current through voltage-sensitive, L-type (for long-lasting) Ca channels. These channels open, and the current begins to flow when transmembrane potential reaches 35 to 20 mV and, because of its slow kinetics, continues well after the Na current has ceased. The Ca current is mainly responsible for the AP plateau phase. It ceases when L-type channels become inactivated and regenerative currents (mainly K efflux) begin the repolarization process. L-type channels, also termed dihydropyridine receptors, are concentrated

Myocardial contraction is initiated following a rise in cytosolic calcium. During the plateau phase of the cardiac AP, a small number of calcium ions enter the muscle cell through slow channels. These ions do not significantly alter myoplasmic calcium (Ca2þ), but they do cause release of calcium stores from SR (17). This release significantly elevates myoplasmic Ca2þ. Calcium is now available to bind to troponin C, and muscle activation occurs. This process, in which calcium entry triggers intracellular calcium release and muscle activation, is called ECC (Fig. 3). It is interesting to note the amplification of the effects of calcium in this process. The small number of ions entering the cell through the slow channel cause the release of intracellular stores that raise the myoplasmic Ca2þ from a resting value of 107 to 105 M (6). In turn, each calcium ion that binds to troponin C activates seven actin-binding sites. This two-step amplification illustrates the exquisite sensitivity of the muscle cell to calcium (18). Muscle relaxation depends on the presence of adequate levels of ATP, which act to dissociate the actin–myosin complexes and provide energy for the restoration of myoplasmic Ca2þ to resting levels. The latter is accomplished primarily by a calcium-activated ATPase in the membrane of SR. In addition, smaller amounts of calcium are extruded from the cell through an Naþ/Ca2þ exchange mechanism that operates secondary to the Naþ, Kþ-ATPase of the sarcolemma and is not voltage dependent, as are the slow

Chapter 32:

Normal Cardiac Function

651

Figure 3 Representation of the transmembrane calcium movements during a contraction cycle. At rest, calcium concentration in the sarcoplasm is low when compared with that in the extracellular space and the interior of sarcoplasmic reticulum (SR). Slow channel is closed, and Ca2þ pumps are inactive. During excitation, the slow channel opens, allowing a small number of extracellular Ca2þ ions to enter the cell. This entry triggers a release of Ca2þ from SR, and the contraction proceeds. Relaxation is accomplished by the active restoration of resting gradients. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate. Source: From Ref. 11.

channels (11,19,20). As calcium levels return to normal, troponin I reestablishes its cloaking of the myosin-binding site so that actin–myosin cross-bridging is again prevented.

Energy Metabolism Myocytes are heavily dependent on oxidative metabolism and endowed with large numbers of mitochondria. Under basal conditions, myocytes preferentially take up and oxidize fatty acids to generate ATP. During stress, however, glucose uptake, glycogenolysis, and glycolysis become increasingly important. Certain ion pumps (e.g., SERCA2, see below) may be especially dependent on glycolytic ATP. Nitric oxide generated by vascular endothelium decreases myocardial oxygen consumption (VO2) due to a direct effect on mitochondrial respiration, and may have a significant role in normal control of energy production and utilization. The processes that account for the great majority of myocardial energy consumption are cross-bridge cycling (myosin ATPase), Ca reuptake by SR (SERCA2), and basal metabolism. Each cross-bridge cycle consumes one highenergy phosphate bond, although at very rapid cycling rates, it may be possible for one ATP to fuel more than one cycle. SERCA2 uses one high-energy phosphate bond for every two Ca ions pumped. As indicated earlier, the rate of energy consumption is heavily dependent on loading conditions, and resulting work and power generation. The thermodynamic efficiency of the heart muscle, its total mechanical energy output divided by its total chemical energy input, is uncertain, in large measure because of difficulties in quantifying total energy output. A more conventional approach is estimation of efficiency of external work production. External work efficiency is heavily dependent on loading conditions, ranging from a maximum under unloaded conditions to zero for an isometric contraction.

MECHANICS OF ISOLATED MUSCLE Much of what is known about the nature of cardiac function has been learned from studies of isolated muscle. Under these conditions, it is possible to finely control the loading of the muscle while making accurate measurements of force

development and shortening characteristics. From these studies, three factors have arisen that determine the behavior of isolated muscle. They are muscle preload, afterload, and contractile state (21,22). Preload is defined as the distending force, or load, that is placed on a muscle before contraction. The preload and the distensibility of the muscle are the determinants of the initial length of the muscle before contraction. The load encountered by the muscle after activation is defined as the afterload. The magnitude of the afterload determines the nature of the subsequent contraction. If the muscle is able to generate a force equivalent to the afterload, shortening occurs. Such a contraction is termed isotonic, because the force developed by the muscle is equal to the load and therefore remains constant during shortening. If the muscle is unable to generate force equal to the load, no external shortening occurs and the contraction is said to be isometric. Contractility refers to the intrinsic ability of the muscle to contract independently of loading conditions. This meaning will become clearer as the characteristics of muscle activation are explained. Isotonic contractions are useful for studying the shortening characteristics of isolated muscle. From these studies, several fundamental principles of cardiac-muscle mechanics have been developed. The first of these defines the relationship between afterload and shortening. As the afterload is increased, the extent of muscle shortening and the velocity of shortening decrease (21). This effect is shown in isolated cat papillary muscle in Figure 4. Cardiac muscle exhibits length-dependent properties: the length of the muscle before contraction affects the nature of the contraction. As initial muscle length is increased, there is an increase in both the extent and the velocity of shortening (Fig. 5). A third property of cardiac muscle involves the response of the muscle to inotropic agents. Positive inotropes enhance the contractility of the muscle, as defined by an increase in the rate and extent of shortening generated from a given preload. Figure 6 shows the effects of a positive inotrope on the velocity and extent of shortening. A unique feature of the force–velocity relationship is that it allows an estimation of the contractile state of the muscle. Theoretically, the velocity of muscle shortening at zero load should

medwedi.ru

652

Part Three: The Cardiothoracic System—Heart

Figure 4 Force–velocity relations of isolated cat papillary muscle. (A) Velocity of the isotonic contraction is seen to be a decreasing function of load. Extrapolation of the velocity at 0 load (dashed line) provides an estimate of maximum velocity (Vmax). (B) Extent of shortening (DL) also decreases with increasing load. (C–D) Concomitant effects of increasing load (P) on power and work (W). PV, load velocity of muscle shortening. Source: From Ref. 21.

be determined only by the kinetics of the actin–myosin association. Because any muscle contraction is necessarily loaded to some extent by the preload, the velocity of shortening at zero load (Vmax) can be obtained only by extrapolation of

Figure 5 Effects of varied preload on the force–velocity relations of cat papillary muscle. As the preload is increased, the velocity of shortening increases. However, the maximum velocity (Vmax) does not change. Source: From Ref. 21.

Figure 6 (A) Application of norepinephrine causes an increase in the shortening and maximum velocity. (B) Extent of muscle shortening is also increased at any shortening load. (C) and (D) show concomitant effects of load on power and work. Source: From Ref. 21.

the force–velocity curve to zero load. For the relationship shown in Figure 6, the addition of norepinephrine resulted in an increase in the extrapolated value of Vmax. In contrast, Figure 5 demonstrates the required load independence of contractility as suggested by the stable estimates of Vmax (21). Isometric contractions provide a convenient means to study force development in isolated muscle. When a muscle is stimulated to contract isometrically, the amount of force (tension) developed depends only on the length before contraction and the inotropic state of the muscle. Variations in afterload are not a factor, because by definition, the magnitude of the afterload always exceeds the force-generating capability of the muscle. Increasing the initial length of the muscle at a given contractile state results in an increase in the level of resting tension borne by the muscle (Fig. 7). As the length of the muscle increases, the peak force generated from any given length also increases (Fig. 7), as does the rate of force development (dF/dt). The addition of Ca2þ has the effect of a positive inotrope on the isometric preparation. Specifically, resting tension is unaffected, but the peak force, time to peak force, and dF/dt are enhanced. When a muscle fiber is distended, a point is reached at which force development is maximum. The length at this point is termed Lmax. Further increases in muscle length beyond Lmax result in a reduction in the amount of developed tension (6). This and other length-dependent properties of the muscle can be explained in part by relating the various muscle lengths to the degree of overlap in the thick and thin filaments of the sarcomere (Fig. 8). At rest, sarcomere length, defined as

Chapter 32:

Normal Cardiac Function

653

Figure 8 Representation of the relationship between active tension, resting tension, and filament overlap in the feline right ventricle. These relationships form the basis of the Frank–Starling principle as seen in the intact heart. Note that the degree of active tension that is developed depends on the extent of filament overlap. Maximum active tension (Tmax) is developed at a sarcomere length of 2.2 mm (Lmax), which also corresponds to the optimum length for filament interaction. Abbreviation: NE, norepinephrine. Source: From Ref. 3.

Figure 7 When a muscle contracts isometrically, the amount of tension that is developed depends on the length and inotropic state of the muscle. In this figure, the upward exponential curve (squares) represents the resting tension existing in the muscle as it is stretched to increasing lengths. Developed tension (open triangles) generated during isometric contraction from each length increases as the muscle is stretched. Addition of calcium does not affect the resting length–tension curve but does cause an upward displacement of developed tension. Source: From Ref. 23.

the distance between adjacent Z lines, averages 1.8 mm. As the muscle is lengthened, sarcomere length increases. More importantly, there is an increase in the degree of overlap between the chemically active portions of the thick and thin filaments. Because the potential for the formation of force-generating cross-bridges is increasing, there is a concomitant increase in the amount of force developed. The length of the sarcomere at Lmax averages 2.2 mm. At this distance, the thick and thin filaments are arranged such that all myosin heads lie adjacent to actin filaments. In this state, the probability of interaction between the filaments is greatest; hence, force generation is greatest. With the application of large forces, cardiac muscle can be distended beyond Lmax. Little change occurs in the amount of filament overlap, even though active tension declines sharply. This decline has been attributed to the damage of the myocytes as a result of the large deformations produced by the loading force (24). This relationship explains why overdistention of the heart (excessive filling) results in deterioration of cardiac function. Examination of the resting force–length relationship reveals a nonlinear relationship between applied force and

deformation (25). This behavior is illustrated in the resting length–tension curves of Figures 7 and 8. At the lower ranges of preload, a given increment in applied force results in a relatively large degree of fiber deformation. In the upper range, the same increment in applied force results in a smaller deformation. This behavior is a manifestation of the mechanical properties of the tissue. The significance of this property will become evident when filling of the intact heart is discussed.

FUNCTION OF THE INTACT HEART The heart is composed of a complex array of muscle fibers that are arranged to form the various cardiac chambers. Each of these fibers operates under the same basic principles as those that have been established for isolated muscle, namely a dependence on preload, afterload, and contractility. Heart rate is a fourth determinant of the heart’s performance per unit of time. Each of these factors finds its analog at the organ level, and together they determine the ability of the intact heart to establish and maintain the circulation of blood in the body.

Wall Forces The force relationships that govern the function of muscle fibers in the intact heart are determined by chamber pressures and geometries. At any point in the cardiac cycle, the pressure within a given chamber exerts a load on the wall of the chamber. This load (in dynes) is equivalent to the product of the pressure (dynes/cm2) and the area over which the pressure acts (cm2). In accordance with Newton’s law of motion, this load must be precisely balanced by opposing forces in the wall. These forces, normalized to the areas over which they act, are known as wall stresses (26). Figure 9 shows the chamber pressure acting on a

medwedi.ru

654

Part Three: The Cardiothoracic System—Heart

Figure 9 Section removed from the wall of the left ventricle is by a force (F) equal to the product of the chamber pressure (P) and the area over which it acts. For this element to be in equilibrium, opposing forces exist in the wall, which precisely balance this load. These forces are called wall stresses. This figure shows the loading pressure and the two principal resultant forces. Source: From Ref. 26.

section of the wall of the left ventricle and the two principal resultant forces. Assuming an ellipsoidal representation for the left ventricle, application of the Laplace relationship results in the following expression for the meridional (s1) and equatorial (s2) components of stress: s1 s2 P þ ¼ R1 R2 h where, R1 and R2 represent the principal radii of curvature for the ellipsoid; P is the ventricular pressure, and h is the wall thickness. A number of expressions are available for independent solutions of s1 and s2 based on ventricular dimensions and pressure. These expressions and their limitations have been reviewed (27). An alternative method of conceptualizing force considers only the net force existing in the wall rather than the normalized force (28). The net wall force at any level may be calculated by imagining that the ventricle has been transected by a plane (Fig. 10). The force necessary to hold the ventricle intact, then, is the net force acting on the wall at that level. This force is equal to the product of the ventricular pressure and the area of the chamber included in the plane. For a sphere, this force is constant at any level. For an ellipsoid, the net force depends on the plane of the section. If the section is made normal to the long axis of the ventricle, the pressure area product is equivalent to the net force in the meridional direction. The magnitude of this force decreases as the plane of section is moved toward the poles of the ellipse, because chamber area is decreasing (29). Wall thickness also decreases toward the poles (30); therefore, stresses and deformation tend to remain uniform. If the plane of section is considered in the long axis, the pressure area product approximates the equatorial component of wall force. Figure 11 shows pressure, equatorial wall stress, and net wall force for the left ventricle during one cardiac cycle.

Ventricular Geometry and the Cardiac Cycle Efforts to quantify ventricular function often begin with the adoption of simplified geometric models. The normal left

Figure 10 Net wall force concept considers that the ventricle is divided by an imaginary plane located at the level of interest. Net wall force is simply the force necessary to hold the ventricle together at the given level. It is equal to the ventricular pressure multiplied by the area of the chamber involved in the plane. Source: From Ref. 28.

ventricle has been represented as an ellipsoidal shell, a sphere, or a cylinder, with varying degrees of success. Even during the dynamic events of filling and ejection, accurate determinations of ventricular dimensions can be obtained with the appropriate use of these models. The elliptical model of left ventricular geometry is often used because it accurately represents the configuration of the left ventricle throughout the cardiac cycle (26,30). In this model, the left ventricle is considered as a general ellipse axisymmetric about its major axis, having a finite but varying wall thickness. The base-to-apex (major) axis is consistently greater than the transverse (minor) axis. The thickness of the ventricular wall is maximum in the equatorial minor axis plane and tapers to a minimum value at the poles of the ellipse (30). During the cardiac cycle, muscle shortening produces variations in ventricular dimensions, with the resultant generation of pressures and volume displacements. Figure 12 illustrates left ventricular chamber

Figure 11 Left ventricular pressure and wall forces for one cardiac cycle in the canine heart. Shown here are pressure (open circles), equatorial wall stress (open squares), and net wall force (closed circles). Note the fall in stress and wall force as the ventricle unloads itself during ejection.

Chapter 32:

Normal Cardiac Function

655

Figure 12 Left ventricular chamber dimensions and pressure in the conscious dog.

dimensions and pressure for several beats. The complex anatomy, configuration, and contraction pattern of the right ventricle have precluded efforts to model this chamber accurately with simple geometric reference figures. Accordingly, the remainder of this section describes the pattern of hemodynamic events in both chambers, with the inclusion of dimensional information for the left ventricle. The cardiac cycle can be thought of as beginning with atrial contraction, as indicated by the P wave of the electrocardiogram (Fig. 13). Atrial contraction provides a final, active increment in ventricular filling before systole (32). With the onset of the QRS complex, the period of isovolumic ventricular contraction begins. This marks the beginning of ventricular systole. As ventricular pressures rise above atrial pressures, the AV valves close. The vibrations generated by the abrupt closure of these valves are responsible for the first heart sound. In the left ventricle, the minor axis dimension shortens, the major axis lengthens, and the thickness of the ventricular wall increases (30), resulting in an ellipsization of the chamber. During this period, there is a rapid rise in the rate of pressure generation (dP/dt). This parameter reaches a maximum value at the onset of the ejection phase. Ejection begins when pressure within each of the ventricles rises above the pressures in their respective outflow tracts. The higher ventricular pressures result in an opening of the semilunar valves, and the phase of rapid ejection ensues. Rapid ejection is followed by reduced ejection as pressures in the ventricles and great arteries fall. In left ventricular ejection, the minor and major axes shorten, and the wall becomes thicker, resulting in a decrease in the internal chamber volume. In the canine heart, the major axis, minor axis, and wall thickness changes account, respectively, for 9%, 47%, and 44% of volume output during systolic ejection (30). In the right ventricle, contraction occurs in a peristaltic wave moving from the sinus region toward the conus (33). As ventricular and

Figure 13 Phases of the cardiac cycle. Shown are left ventricular pressure and volume and the correlation of these measurements to left atrial and aortic pressures, heart sounds, and the electrocardiogram. A, Atrial sound; I, first heart sound; II, second heart sound; III, third heart sound. Source: From Ref. 31.

arterial pressures fall, flows in the great vessels reverse. This point marks the end of systole and the beginning of the first phase of diastole, known as protodiastole. Protodiastole ends with the closure of the semilunar valves, which produces the second heart sound. Such closure is also marked by the incisura of the arterial pressure tracing. Protodiastole is followed by the period of isovolumic relaxation. During this period, the geometric patterns observed during isovolumic contraction generally are reversed, and the peak fall in dP/dt occurs. Ventricular pressures fall until they are less than pressures in the atria. The AV valves open, and diastolic filling begins. Diastolic filling is composed of several phases. The first of these is the rapid filling phase, during which rapid volume expansion occurs. This phase is sometimes associated with an audible third heart sound. As the ventricles become full, the rate of filling slows, and the period of diastasis is approached. During diastole, the left ventricle becomes more spherical as the minor axis dimension increases with respect to the major axis, and the wall becomes thinner (30). The end of diastole is marked by atrial systole and the generation of the fourth heart sound. At slow heart rates, the atrial contribution to ventricular filling is minimal. At more rapid heart rates or with stenosis of the AV valves, the contribution of atrial systole to ventricular filling becomes more important. In the failing heart, the contribution by atrial systole can result in a 20% to 30% increase in cardiac output.

medwedi.ru

656

Part Three: The Cardiothoracic System—Heart

Diastolic Behavior Relaxation Diastole represents the period of relaxation and filling in the cardiac cycle. During relaxation, the ion fluxes that occurred during the process of ECC are reversed, and the contractile proteins assume their resting configurations. In the filling phases of diastole, the relaxed sarcomeres lengthen as the ventricles distend with blood and the initial muscle length for the next beat is determined. Relaxation is often thought of as a passive event, because pressures and flows are rapidly falling; however, it is a period of considerable metabolic activity, requiring the presence of ATP initially to dissociate the actin–myosin complexes and later to provide the energy for the active transport, which restores the resting ion gradients. For relaxation to occur, sarcoplasmic Ca2þ must be reduced to a level such that Ca2þ dissociates from the troponin complex. This activity is accomplished by pumps in the membrane of SR and to a lesser extent by transport mechanisms in the sarcolemma (11). The common feature of these transport processes is the requirement for ATP. In light of this, abnormalities of relaxation have been explained in part on the basis of reduced ATP availability in the injured or diseased heart (34). An additional role has been suggested for ATP in the relaxation process. Adding ATP to a cell that has normal levels of ATP results in an enhancement of the uptake of Ca2þ by SR. Thus, ATP may act in a regulatory manner in controlling Ca2þ transport. Slight reductions in cellular levels as a result of moderate degrees of energy deprivation could result in impaired relaxation, even though sufficient levels are available to saturate the primary transport mechanisms (11).

Filling The importance of the filling events of diastole as determinants of cardiac function was first noted by Frank in the late 19th century. Frank observed a direct relationship between end-diastolic volume (EDV) and the force of contraction in the isolated frog heart (35). Later, Starling made similar observations in the mammalian heart. This work culminated in the concept of the Frank–Starling relationship, which was simply stated as ‘‘the energy of contraction, however measured, is a function of the length of the muscle fiber’’ (36). In the intact heart, diastolic filling determines the length of the muscle fibers before contraction and therefore influences the force of contraction. The nature and extent of this filling, in turn, are influenced by a number of factors; among these are the level of filling pressure, the material properties of the myocardium, the geometry of the chamber, and such external forces as pericardial and pleural pressures (34). Within any of the cardiac chambers, the filling pressure produces distending forces within the wall of the chamber. These forces are a function of the magnitude of the pressure and the size and shape of the chamber. The resulting distention produced by a given increment of force is governed by the material properties of the myocardium. Because these forces act to determine the length of the muscle fibers before contraction, they may be considered analogs to the preload previously described for isolated muscle. The ‘‘material properties’’ of the myocardium refer specifically to the elastic and viscous characteristics of the muscle. An elastic material deforms when acted on by an external force and recovers from the deformation when

the force is removed. For a substance with linear elastic properties, deformation (e) is related to the force ( f ) as: f ¼ EðeÞ where E, the slope of the relationship, is known as the coefficient of elasticity or Young’s modulus (37). An increase in E reflects an increase in the stiffness of the material. In a viscoelastic material, force is a function of both deformation and the rate of deformation. Heart muscle is known to possess both elastic and viscous properties (38). The analysis of these properties and their influence on diastolic filling is complicated by the fact that the elastic properties, and possibly the viscous properties, are nonlinear entities (38). When a force is applied along the long axis of an isolated papillary muscle, the deformation of the muscle obeys the following relationship, assuming that the rate of deformation is small so that viscous effects are not important (25).

F a½ebðxx Þ 1 where, x is the muscle length, x is the resting muscle length, and a and b are elastic constants analogous to the coefficient of elasticity of Eq. (2). F is the fiber stress. Stress is an expression of normalized force, here equal to the applied force divided by the cross-sectional area of the muscle specimen. This nonlinear elasticity of heart muscle is the principal factor affecting the relationship between diastolic pressure and volume in the intact left ventricle (39). Figure 14 shows the pressure–volume curve obtained by slowly filling a canine heart with saline. Several important points are apparent from this illustration. First, even though the ventricle is composed of muscles that display exponential elastic behavior, the relationship between pressure and volume is not truly exponential. It is approximately linear in the lower pressure ranges and approaches exponentiality in the upper pressure ranges. Second, the elastic nature of the myocardium resists deformation above a filling pressure of about 20 mmHg. The significance of the second factor is that the increasing stiffness of the cardiac muscle prevents overextension of the individual sarcomeres, permitting the heart to function on the ascending limb of the Frank–Starling relationship, where increased volume results in increased output.

Figure 14 Relationship between pressure (dP) and volume (dV) [expressed as time (dt) of infusion of volume at a constant rate] in the isolated, arrested canine heart. The relationship is approximately linear in the lower pressure ranges and becomes exponential in the upper ranges. The increasing instantaneous slope of the pressure–volume curve reflects the increase in chamber stiffness that occurs as the ventricle is filled. Source: From Ref. 40.

Chapter 32:

Normal Cardiac Function

657

Systolic Function Normal pumping of the ventricles requires that they deliver appropriate amounts of blood to the tissues at acceptably low filling pressures (FPs). Thus, the most physiologically relevant means of characterizing the pump is to construct a function curve relating FP to a measure of mechanical output [stroke volume (SV), minute volume, work, and power]. Ventricular function curves display a prominent Frank– Starling effect, manifest as a curvilinear relationship between FP and output (once again, there is no descending limb in the normal ventricle). As discussed earlier, at the myocytes level, the Frank–Starling effect is mainly caused by increased myofilament Ca sensitivity at longer sarcomere lengths. Thus, a function curve relating EDV (ventricular preload) to mechanical output is a more accurate representation of the ventricular Frank–Starling effect. However, in the clinical setting, FP (pulmonary capillary wedge or right atrial pressure) is usually more readily available than volume. Whether FP or volume is employed, changes in intrinsic contractile performance result in upward or downward shifts of the ventricular function curve. However, characterization of ventricular performance in terms of function curves relating FP to output is a ‘‘black box’’ approach; alterations in diastolic compliance (see below) produce effects that are indistinguishable from alterations in contractile performance. The normal heart can pump adequate amounts of blood to meet the needs of the body under the most stressful conditions. Indeed, maximal cardiac output (CO) normally is not limited by pumping capacity but by the ability of the systemic circulation, via venoconstriction and the systemic venous system of valves and muscular pumps, to return blood to the heart. Under pathologic conditions, pumping capacity may limit CO. The peak force that can be generated at a given contractile state and EDV is attained in the isovolumically contracting heart (41). As EDV is raised, the peak developed force increases in a linear fashion (Fig. 15). This behavior demonstrates the operation of the Frank–Starling relationship in the intact ventricle, where force generation is an increasing function of fiber length, expressed here as EDV. The line that results from relating peak force to initial volume defines the limit of force generation for the ventricle. When the ventricle is permitted to eject, this line also defines the limit of systolic shortening (41).

Figure 16 Schematic diagram of the pressure–volume loops for several beats under various loading conditions. Contraction 1 is considered control, contraction 3 shows the effects of increased preload, and contraction 2 shows the effects of increased afterload on SV and pressure generation. Points E and F represent the peak pressures that could be generated if the ventricle were to contract isovolumically from preloads at points 2 and 3, respectively. Note that points E and F define the limit for shortening in the ejecting heart. See text for further details. Abbreviations: SV, stroke volume; LV, left ventricular. Source: From Ref. 23.

Figure 16 depicts the pressure–volume relationships for an ejecting ventricle under changing conditions of preload and afterload. Contraction 1, originating from EDV A, contracts isovolumically to point B. At point B, the ventricular pressure just exceeds aortic pressure, and ejection begins. During ejection (points B to C), the force sustained by the muscle fibers in the wall of the ventricle represents the afterload. Ejection continues until a point is reached at which muscle force is maximum for a given volume (point C). This point contracts the isovolumic pressure–volume line and represents the end of systolic shortening. When preload is altered as in contraction 3, there is a change in SV, but the extent of fiber shortening does not change. Contraction 3 still proceeds to point C. Increasing the afterload by augmenting aortic pressure (contraction 2) results in both decreased SV and a change in the extent of fiber shortening. Thus the degree of fiber shortening in the ejecting heart is determined by the instantaneous load borne by the muscle, not by alterations in loading before contraction (41). The ability of the ventricle to generate force is influenced by the contractile state of the muscle. A change in contractility is represented by a change in the peak force.

Electrical Activity

Figure 15 Development of pressure in the isovolumically contracting canine left ventricle. As resting volume is increased, the peak generated pressure increases. Line connecting the peak pressures defines the limit of force generation for the contracting ventricle. Source: From Ref. 42.

Electrically excitable tissues communicate within themselves and with other structures through the generation of APs. Within the heart, there are certain cells that generate spontaneous APs, which propagate and serve as a stimulus to initiate contraction. This property is referred to as automaticity. A second property, intrinsic to the electrical activity of the heart, is conductivity. Conductivity describes the lowresistance intercellular connections that permit any depolarization to be spread throughout the mass of the heart. Under normal circumstances, contraction of the heart is initiated by APs generated in the sinoatrial (SA) node (43). This structure, located at the junction of the right atrium and the superior vena cava, has the highest rate of intrinsic

medwedi.ru

658

Part Three: The Cardiothoracic System—Heart

pacemaker activity found in the heart. APs generated here spread slowly over the right and left atria, with resultant atrial contractions. Excitation moves to the cardiac ventricles through the AV node. In contrast to the atria, impulse conduction through this structure is extremely slow. This delay permits the completion of atrial contraction before ventricular activation. Having passed through the AV node, the wave of excitation enters the bundle of His, a structure located in the subendocardium of the right surface of the interventricular septum. The bundle of His then divides into right- and left-sided branches, which ramify in the fibers of the Purkinje system. The Purkinje system extends over the subendocardial surfaces of both ventricles. Its electrical activity is characterized by a high conduction velocity, which permits near-simultaneous activation of the ventricles. Many factors affect the nature of pacemaker activity and excitation in the heart. These include neural, hormonal, physicochemical, and pathologic influences. These influences often exert their effects by alterations of events occurring at the cellular level, specifically by inducing changes in the transmembrane electric potential and ion movement (44). Transmembrane electric potential (Vm) in cardiac cells comes about as a result of an unequal distribution of ions across the cell membrane. In cardiac cells, as in most other cells of the body, the internal potassium concentration is high and the internal sodium concentration is low. The contribution of each of these ions to the net charge on the membrane can be estimated from the Nernst equation (45). For an unspecified ion X, E¼

58 ½Xout log Z ½Xin

Ion concentrations across the membrane actually change very little. The arrival of an AP causes a rise in the resting Vm toward threshold value for the particular cell. Once threshold is achieved, a complex pattern of conductance changes ensues. Cardiac muscle cells and cells of the Purkinje system have a high relative gK at rest. Membrane potential is 80 to 90 mV, and threshold is approximately 60 mV. When cardiac muscle cells are stimulated, gNa becomes markedly elevated in what is known as phase 0 of the AP (Figs. 17 and 18). Sodium ions are now better able to cross the membrane. Note that this movement is favored by both chemical and electrical gradients; so it occurs quite rapidly. The net inward movement of positive charge causes depolarization of the cell; Vm moves toward and then past 0 mV. As the cell depolarizes, gNa falls, completing phase 0. Phase 1 is characterized by a rapid fall in Vm, thought to be the result of transient increase in membrane permeability to chloride (Cl). Phase 2 is the plateau phase of AP. This is brought about by a slow inward Ca2þ and Naþ current balanced by an outward Kþ current. Repolarization occurs in phase 3 and is a result of a further increase in gK combined with an inactivation of the slow inward current of phase 2. There are striking differences between APs seen in the nodal structures and those just described (Fig. 17). Recordings from cells of the SA node reveal a less negative resting potential, a decreased rate of phase 0 depolarization, no plateau, and a reduced rate of phase 3 depolarization. Perhaps most significant is the behavior that nodal tissue displays in phase 4. During this phase, Vm is not constant but moves steadily toward threshold. The basis for this

where, E is the equilibrium potential resulting solely from ion X, and Z is the charge number of the ion. If the membrane is permeable only to X, Vm equals E. When more than one ion is involved, Vm becomes a weighted average of the equilibrium potential of each ion. The weighting factors depend on the relative conductance of each ion. Conductance (g) is the reciprocal of resistance and is an expression of the ease with which an ion can cross the cell membrane. Thus, in general terms, for a cell permeable to ions A, B, and C, Vm could be approximated from the equation: Vm ¼

gA gB EA þ EB gA þ gB þ gC gA þ gB þ gC gC þ EC gA þ gB þ gC

where, in the case of cardiac tissue, the major ions involved in transmembrane flux are Naþ, Kþ, and Ca2þ such that: Vm ¼

gNa gK ENa þ EK gNa þ gK þ gCa gNa þ gK þ gCa gCa þ ECa gNa þ gK þ gCa

In the quiescent cardiac cell, Kþ permeability greatly exceeds Naþ and Ca2þ permeability, or in terms of conductances, gK greatly exceeds gCa and gNa. Given this fact, Eq. (6) then reduces to the Nernst equation for Kþ, and the resting Vm equals or approaches EK. APs in cardiac tissue result from changes in the relative conductances of the principal ions Naþ, Kþ, and Ca2þ.

Figure 17 Action potential seen in various cardiac tissues. (A) Ventricular muscle cell, (B) sinoatrial node, (C) atrial muscle. Time base for (B) is half that of (A) and (C). Source: From Ref. 46.

Chapter 32:

Normal Cardiac Function

659

Figure 19 Altering the rate of pacemaker activity. (A) Altering the rate of firing by a decrease in the rate of phase 4 depolarization. Threshold potential (TP) is not changed. (B) Changing threshold at a given rate of phase 4 depolarization can alter heart rate by changing the time required to reach TP (tracings a–b and a–c). Hyperpolarization can also influence rate (tracings a–e). Source: From Ref. 46.

Figure 18 Conductance changes seen within a Purkinje fiber. Typical action potential is shown at the top, with the accompanying changes in conductance for potassium (gK), sodium (gNa), chloride (gCl), and calcium (gCa). Source: From Ref. 31.

behavior is believed to be a time-dependent decrease in the outward Kþ movement in the presence of a small, steady, inward movement of Ca2þ. The loss of the Kþ current disrupts the balance of charge and results in membrane depolarization. When the membrane potential reaches threshold, an AP is generated. In this manner, a nodal tissue serves as a pace generator for the heart. The rate of pacemaker activity depends on the minimum phase 4 Vm, the rate of depolarization, and the threshold potential (47). These factors are under neural and hormonal controls that act to vary the heart rate (Fig. 19) (15). For example, increased vagal activity results in the release of acetylcholine at the SA node. This has the effect of increasing gK, which hyperpolarizes the membrane and slows the heart rate. Conversely, catecholamines can increase the inward phase 4 Ca2þ current, which would increase both the rate of depolarization and the heart rate (see section on ‘‘Neural Control’’) (20,44,47,48).

Neural Control The sympathetic and parasympathetic divisions of the autonomic nervous system act in concert to regulate cardiac function. Sympathetic effects are excitatory and are mediated through nerve fibers distributed to the atria, ventricles, and nodal tissue. Parasympathetic influences are generally inhibitory and act predominantly on atrial and nodal tissues.

The terminal regions of the sympathetic fibers synthesize and store norepinephrine, which is released as a result of nerve stimulation. Norepinephrine acts on b1 adrenergic receptors imbedded in the membrane of the cardiac cell. b-receptors in the myocardium are of two types, b1 and b2. b1-receptors are distributed exclusively to the ventricles, and their activation results in an increase in the ventricular contractility (49,50). The mechanism of action is thought to involve increases in the level of cyclic adenosine monophosphate, which in turn promote the phosphorylation and activation of calcium channels in the membrane (51,52). The net effect of b1-stimulation is an increase in calcium influx, which causes an increase in the contractile state of the muscle (14). b2-receptors are found in the atria. The activation of these receptors results in an increased heart rate through their positive chronotropic effects (10). The stimulus for activation of b2-receptors differs from that of b1 types in that b2 receptors are sensitive to epinephrine and norepinephrine. Parasympathetic effects are mediated by fibers of the vagus nerve that are distributed to the atria, and, to a lesser extent, to the ventricles. Activation of these fibers results in a release of acetylcholine, which causes a depression of cardiac function characterized by a reduction in heart rate and atrial contractility. Ventricular contractility is affected to a lesser extent (53). The diminution in ventricular function seen during vagal stimulation can be explained in part by reduced ventricular filling, which occurs secondary to the fall in atrial contractility. Acetylcholine produces its negative chronotropic effects by hyperpolarizing the nodal tissue. Hyperpolarization is a consequence of the increase in potassium permeability caused by the application of acetylcholine. Acetylcholine also binds to muscarinic receptors on the sympathetic nerve fibers. Activation of muscarinic receptors results in reduced catecholamine release during sympathetic stimulation. Thus, the inhibitory influences of parasympathetic activity are more pronounced when sympathetic activity is high. In recent years, an increasing emphasis on neural control of heart function has been evolving. Trauma, anesthesia,

medwedi.ru

660

Part Three: The Cardiothoracic System—Heart

and anxiety evoke major alternations in cardiovascular function and may be the precipitants of arrhythmias or cardiac dysfunction.

Coronary Flow and Myocardial Oxygen Consumption The energy imparted by the heart to the blood during the process of ejection is linearly related to three factors: heat rate, SV, and developed aortic pressure. A rise in any of these three variables leads to an increase in the myocardial oxygen consumption. Minute work of the heart is defined as the product of these three parameters. Changes in SV are associated with the greatest efficiency and the lowest energy cost to the heart, whereas increases in the heart rate and blood pressure are costly and require the greatest increase in myocardial oxygen delivery. Because heart rate and blood pressure figure so much more prominently in the determination of myocardial oxygen consumption than SV, two clinical indexes based on heart rate and aortic pressure have been developed for estimation of myocardial oxygen consumption. These are the ‘‘double product’’ (the heart rate multiplied by the blood pressure) and the ‘‘tension time’’ index (the average ejection pressure of the left ventricle multiplied by the duration of ejection). Both of these indexes correlate well with cardiac oxygen consumption, but neither takes into account the effect of ventricular dilation or altered contractility. It is obvious from this discussion that myocardial oxygen consumption can be decreased and the efficiency of the heart improved by a reduction in heart rate and a decrease in mean arterial blood pressure (vasodilation). The flow of oxygenated blood into the myocardium is controlled by the coronary circulation. Blood flow is regulated to ensure an environment of aerobic metabolism to support cardiac work. To accomplish this goal, the coronary circulation possesses two unique features: &

&

Under basal conditions, there is a high degree of oxygen extraction (coronary sinus oxygen saturation is 20–30%) so that the heart can adjust to changing oxygen needs by only a small increment in oxygen extraction. Accordingly, increasing oxygen requirements must be met by proportionate increases in coronary flow.

HEART FAILURE Contraction 3 in Figure 20 represents a decreased contractile state, as might be seen in conditions of heart failure (32,54,55). Failure occurs when the heart can no longer pump blood commensurate with the needs of the body. This condition can occur as a result of depression in the intrinsic contractility of the muscle or as a result of the imposition of increased loading conditions on ventricular ejection (23). The heart can compensate in several ways. Contractile state can increase with endogenous catecholamine release. Also, muscle preload can be augmented by the increased filling pressure that often accompanies the reduced pumping ability of the failing ventricle. Hypertrophy and/or chamber dilation also can occur. Associated with these compensatory mechanisms are certain detrimental factors that may contribute to the eventual failure of the heart. Increased preload results in an increased level of wall stress throughout diastole. Wall stress has been shown to be related to myocardial oxygen consumption (56); therefore, incorporation of this mechanism necessarily increases the flow requirements of the myocardium. As chamber

Figure 20 Conceptual pressure–volume loops for hearts at contractile states. Note the effect of the contractile state on the stroke volume (SV) generated from similar preloads at points 1, 2, and 3. During heart failure, SV may be decreased despite a slightly larger end-diastolic volume (EDV) at a comparable level of aortic pressure (see contraction 3). If EDV is further increased, SV may be restored (see contraction 4). Abbreviation: LV, left ventricular. Source: From Ref. 23.

enlargement occurs, several aspects of active force relations are affected. From the net wall force concept developed earlier, it is simple to see how an increase in the chamber size results in a decrease in the efficiency of the ventricular contraction. Recall that wall force (F) is equal to the product of chamber pressure (P) and area (A). Rearranged, this gives P ¼ F/A. The generation of a given pressure within the large ventricle (larger A) then requires the existence of a greater wall force. A second aspect of chamber enlargement concerns the unloading of the ventricle during systole. In a normal heart, the muscle load (stress) peaks soon after the onset of ejection and then declines through the remainder of systole (Fig. 11). This occurs because the decrease in chamber size is more than the increase in pressure , resulting in a partial unloading of the ventricle. To generate a given SV, the enlarged heart undergoes a smaller degree of systolic shortening. It therefore unloads itself less than would a smaller heart ejecting the same volume. Worsened ejection resulting from prolonged high wall tension creates an afterload mismatch in the coupling of the heart to the periphery. Vasodilator therapy normalizes this loading of the heart and thereby facilitates ejection. At the same time, smaller volumes and wall tension decrease myocardial oxygen consumption. A practical clinical index of global cardiac function is the ejection fraction (EF). EF is the percent of EDV that is ejected as the SV and is derived from the following equation: EF ¼

ðEDV ESVÞ EDV

where ESV is the end-systolic volume. A normal functioning heart has an EF of 55% to 75%. In patients with severe compromise in myocardial reserve due to chronic heart failure and/or scarring from previous myocardial infarction,

Chapter 32:

EF may be as low as 15% to 20%. Although EF is not a perfect measure of cardiac function in that it is sensitive to preload, afterload, heart rate, and ventricular compliance, it is sufficiently reliable overall as to give an accurate index of the contractile capabilities of the heart. It can be measured in a variety of ways including echocardiography, cineangiography, and ventriculography.

SUMMARY For many years, the complexity of the cardiovascular system prevented the systematic study of its properties. Although that complexity remains, several basic principles by which the heart functions have been determined. These principles include the dependence of myocardial performance on preload, afterload, and contractility. Preload is defined as the distending force, or load, that is placed on cardiac muscle before contraction. The preload and the distensibility of the muscle are the determinants of the initial length of the muscle before contraction. The load encountered by the cardiac muscle after activation is defined as the afterload. The magnitude of the afterload determines the nature of the subsequent contraction. Contractility refers to the intrinsic ability of the cardiac muscle to contract, independent of loading conditions. Heart failure occurs when the heart can no longer pump blood commensurate with the needs of the body. This condition can occur as a result of depression in the intrinsic contractility of the cardiac muscle or as a result of the imposition of increased loading conditions on ventricular ejection. Understanding the interplay among these various parameters and how their imbalance can be corrected or lessened, both medically and surgically, underlies the rationale for treatment in patients with cardiac dysfunction.

REFERENCES 1. Morkin E. Contractile proteins of the heart. Hosp Pract 1983; 18(6):97. 2. Murray J, Weber A. The cooperative action of muscle proteins. Sci Am 1974; 230(2):58. 3. Mason DT, et al. Mechanisms of cardiac contraction. In: Sodeman WA Jr, Sodeman TM, eds. Sodeman’s Pathologic Physiology. 6th ed. Philadelphia: WB Saunders, 1979. 4. Bremel RD, Weber AM. Cooperation with actin filament in vertebrate skeletal muscle. Nature (New Biol) 1972; 238:97. 5. Weber A, Murray JM. Molecular control mechanisms in muscle contraction. Physiol Rev 1973; 53:612. 6. Opie LH. Mechanism of cardiac contraction and relaxation. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. 7th ed. Philadelphia: Elsevier Saunders, 2005:457–489. 7. Spudich JA. How molecular motors work. Nature 1994; 372:515. 8. Ebashi S. Excitation–contraction coupling and the mechanism of muscle contraction. Annu Rev Physiol 1991; 53:1. 9. Elliott GF, Worthington CR. How muscle may contract. Biochim Biophys Acta 1994; 1200:109. 10. Honerjager P. Pharmacology of bipyridine phosphodiesterase III inhibitors. Am Heart J 1991; 121:1939. 11. Katz AM, Smith VE. Relaxation abnormalities. I. Mechanisms. Hosp Pract 1984; 19(1):69. 12. Schwartz K, et al. Myosin isoenzymic distribution correlates with speed of myocardial contraction. J Mol Cell Cardiol 1981; 13:1071. 13. Samuel JL, et al. Distribution of myosin isozymes with single cardiac cells: An immunohistochemical study. Circ Res 1983; 52:200.

Normal Cardiac Function

661

14. Van Breeman C, Aaronson P, Loutzenhiser R. Na–Ca interactions in mammalian smooth muscle. Pharmacol Rev 1979; 30:167. 15. Hoh JFY, McGrath PA, Hale PT. Electrophoretic analysis of multiple forms of rat cardiac myosin: effects of hypophysectomy and thyroid replacement. J Mol Cell Cardiol 1978; 10:1053. 16. Rupp H. The adaptive changes in the isoenzyme pattern of myosin from hypertrophied rat myocardium as a result of pressure overload and physical training. Basic Res Cardiol 1981; 76:79. 17. Fabiato A, Fabiato F. Calcium and cardiac excitation–contraction coupling. Annu Rev Physiol 1979; 41:473. 18. Barry WH, Bridge JHB. Intracellular calcium homeostasis. Circulation 1993; 87:1806. 19. Katz AM. Physiology of the Heart. New York: Raven Press, 1992. 20. Colucci WS, Braunwald E. Pathophysiology of Heart Failure. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. 7th ed. Philiadelphia: Elsevier Saunders, 2005:509–538. 21. Sonnenblick EH. Implications of muscle mechanics in the heart. Fed Proc 1962; 21(Suppl 12):975. 22. Katz AM. Regulation of cardiac contraction and relaxation. In: Willerson JT, Conn JN, eds. Cardiovascular Medicine. New York: Churchill-Livingstone, 1995:790. 23. Braunwald E. Pathophysiology of heart failure. In: Braumwald E, ed. Heart Disease. Philadelphia: WB Saunders, 1984. 24. Sonnenblick EH, et al. Redefinition of the ultrastructural basis of the cardiac length–tension relations. Circulation 1973; 48(suppl 4):65. 25. Glanz SA, Kernoff RS. Muscle stiffness determined from canine left ventricular pressure–volume curves. Circ Res 1975; 37:787. 26. Sandler H, Ghista DN. Mechanical and dynamic implications of dimensional measurements of the left ventricle. Fed Proc 1969; 28(4):1344. 27. Yin FCP. Ventricular wall stress. Circ Res 1981; 49(4):829. 28. Hefner LL, et al. Relation between mural force and pressure in the left ventricle of the dog. Circ Res 1962; 11:654. 29. Weber KT, et al. Contractile mechanics and the interaction of the right and left ventricles. Am J Cardiol 1981; 47:686. 30. Rankin JS, et al. The three-dimensional dynamic geometry of the left ventricle in the conscious dog. Circ Res 1976; 39(3):304. 31. Katz AM. Physiology of the Heart. New York: Raven Press, 1977. 32. Foex P, Leone BJ. Pressure–volume loops: a dynamic approach to the assessment of ventricular function. J Cardiothorac Vase Anesth 1994; 8:84. 33. Meier GD, et al. Contractile function in canine right ventricle. Am J Physiol 1980; 239(8):H794. 34. Grossman W, Barry WH. Diastolic pressure–volume relations in the diseased heart. Fed Proc 1980; 38:148. 35. Frank O. On the dynamics of cardiac muscle. Am Heart J 1959; 58(2):282. 36. Starling EH. The Linacre lecture on the law of the heart. London: Longmans Green, 1918. 37. Mirsky I, Pasipoularides A. Elastic properties of normal and hypertrophied cardiac muscle. Fed Proc 1980; 39:156. 38. Pouleur H, et al. Diastolic viscous properties of the intact canine left ventricle. Circ Res 1979; 45:410. 39. Glantz SA. Computing indices of diastolic stiffness has been counterproductive. Fed Proc 1980; 39:162. 40. Diamond G, et al. Diastolic pressure–volume relationship in the canine left ventricle. Circ Res 1971; 29:267. 41. Weber KT, Janicki JS. The heart as a muscle-pump system and the concept of heart failure. Am Heart J 1979; 98(3):371. 42. Strauer BE, ed. The Heart in Hypertension. Heidelberg: Springer-Verlag, 1981. 43. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993; 55:455. 44. Naccarelli GV, Willerson JT, Blomqvist CG. Recognition and physiologic treatment of cardiac arrhythmias and conduction disturbances. In: Willerson JT, Cohn JN, eds. Cardiovascular Medicine. New York: Churchill-Livingstone, 1995:1282.

medwedi.ru

662

Part Three: The Cardiothoracic System—Heart

45. DeVoe RD, Maloney PC. Principles of cell homeostasis. In: Mount-castle VB, ed. Medical Physiology. 14th ed. St Louis: Mosby, 1980. 46. Berne RM, Levy MN, eds. Physiology. St. Louis: Mosby, 1983. 47. Campbell DL, Rasmusson RL, Strauss HC. Ionic current mechanisms generating vertebrate primary cardiac pacemaker activity at the single cell level: an integrative view. Annu Rev Physiol 1992; 54:279. 48. Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 3rd ed. Philadelphia: WB Saunders, 2000. 49. Hedberg A, Minneman KP, Molinoff PB. Differential distribution of beta-1 and beta-2 adrenergic receptors in cat and guinea-pig heart. J Pharmacol Exp Ther 1980; 213:503. 50. Homcy CJ, Vatner ST, Vatner DE. Beta-adrenergic receptor regulation in the heart in pathophysiologic states: abnormal adrenergic responsiveness in cardiac disease. Annu Rev Physiol 1991; 53:137.

51. Feldman AM. Classification of positive inotropic agents. J Am Coll Cardiol 1993; 22:1223. 52. Leier CV. Current status of non-digitalis positive inotropic drugs. Am J Cardiol 1992; 69:120G. 53. Levy MN, Martin PJ. Neural control of the heart. In: Berne RM, ed. Handbook of Physiology. Section 2. The Cardiovascular System. Vol. 1. The Heart. Bethesda, Mary Land: American Physiological Society, 1979. 54. Folkow B, Svanborg B. Physiology of cardiovascular aging. Physiol Rev 1993; 73:725. 55. Klug D, Robert V, Swynghedauw B. Role of mechanical and hormonal factors in cardiac remodeling and the biologic limits of myocardial adaptation. Am J Cardiol 1993; 71:46A. 56. Braunwald E. 50th Anniversary Historical Article. Myocardial oxygen consumption: the quest for its determinants and some clinical fall out. J Am Coll Cardiol 2000; 35:45B.

33 Heart Failure and Resuscitation Heinrich Taegtmeyer

When the patient thinks there is something amiss with his heart, he fears it may fail. It is therefore necessary that the doctor should understand what heart failure is and the signs by which it is made manifest. Sir John Mackenzie, 1916 (1)

INTRODUCTION Heart failure is a systemic disease caused by an impairment of efficient energy transfer in heart muscle. Clinically, heart failure exists when the heart fails in one or both of its primary functions: during diastole to receive blood into the ventricles under low pressure, during systole to propel blood into the systemic circulation under high pressure (Grossman W. Personal communication, 1995). Because the heart is both a consumer and provider of energy, a restriction in energy consumption (e.g., as it occurs in ischemic heart disease) results in impaired energy delivery to the rest of the body (2). Impaired energy delivery, in turn, causes adaptive and ultimately maladaptive responses of the organism as a whole. This chapter focuses on aspects of heart failure most commonly encountered in the practice of surgery. The first part of the chapter reviews the etiology, pathophysiology, clinical manifestations, therapy, and prognosis of acute and chronic heart failure. A discussion of chronic heart failure is important, because it is often a comorbid condition in surgical patients and may significantly alter the care and prognosis of the patient. The second part of the chapter discusses the principles of cardiopulmonary resuscitation (CPR), because cardiopulmonary arrest (also termed ‘‘sudden death’’) is the extreme form of acute heart failure. The discussion includes the pathophysiology and etiology of cardiopulmonary arrest and techniques of resuscitation.

myocardial infarction, volume overload, or arrhythmias. Chronic heart failure develops over months or years, and may be due to a slow loss of functional myocardium (e.g., as in hypertensive cardiomyopathy). In addition, a patient with chronic heart failure may achieve a well-compensated state, only to experience a superimposed acute exacerbation of heart failure, for example, caused by arrhythmias, volume overload, systemic infection, or noncompliance with medications. In the hospitalized patient with symptoms and signs of pulmonary edema, it is often difficult to distinguish an acute exacerbation of chronic heart failure (i.e., acute on top of chronic heart failure) from a new presentation of acute heart failure. This is especially difficult in patients in the perioperative period, in patients with renal failure, and in those receiving blood products or intravenous fluids. Thus it is important to understand the etiology and pathophysiology of the various forms of acute and chronic heart failure so that effective diagnostic and therapeutic decisions may be made.

Etiology and Natural History of Heart Failure Heart failure can occur as the result of three general derangements. First, mechanical or anatomic abnormalities may be present within the heart, in the coronary circulation, or in the pulmonary or systemic vascular bed and may result in inefficient pump function. Second, functional myocardial abnormalities may occur as a result of long-standing pressure or volume overload, primary myocardial disease, or myocarditis. Third, rhythm disturbances may bring the rhythmic function of the heart out of order and lead to inefficient pump action. In each situation, the development of heart failure may be acute or chronic. In addition, certain causes of cardiac dysfunction may lead to reversible disease, whereas others, especially those that are chronic and cause intrinsic myocardial changes, may lead to progressive, irreversible derangements. A list of the different causes of heart failure is shown in Table 1.

HEART FAILURE Features of Heart Failure

Mechanical or Anatomic Abnormalities Causing Heart Failure

Irrespective of the causes of heart failure, it is useful to distinguish its clinical features, which can occur either alone or in combination with one another. These features include acute and chronic, high-output and low-output, right ventricular and left ventricular, backward and forward, and systolic and diastolic heart failure (3). The rapidity with which symptoms of heart failure develop depends on the underlying pathophysiology and on the time allowed for compensatory mechanisms to develop. Acute heart failure occurs within minutes or hours and may be caused by loss of cardiac muscle from acute

A hallmark of chronic heart failure is an initial phase of adaptation to environmental changes, which is followed by deadaptation of the heart muscle (4). Adaptation is characterized by hypertrophy, which is brought about either by pressure overload or by volume overload of the heart. When presented with a patient whose main problem is heart failure, an important early step for the physician is to establish the cause of the compensatory hypertrophy. An increased pressure load on one or both of the ventricles may be due to systemic or pulmonary hypertension, aortic or pulmonary valve stenosis, pulmonary embolus, or coarctation of

medwedi.ru 663

664

Part Three: The Cardiothoracic System—Heart

Table 1 Cardiac and Systemic Abnormalities Resulting in Heart Failure Structural myocardial abnormalities Cardiomyopathies (hypertrophic, dilated, restrictive) Inadequate myocardial mass (myocardial infarction, hypoplasia) Presbycardia (senile cardiomyopathy) Dysdynamic (ventricular aneurysm) Metabolic Endocrine (thyroid dysfunction, acromegaly, pheochromocytoma, hypoparathyroidism, diabetes mellitus) Thiamine deficiency (beriberi) Ischemia Acidosis Infections Viral, bacterial, rickettsial, parasitic, fungal Inflammatory Connective tissue disease Rheumatic fever Toxic Drugs [doxorubicin (Adriamycin), disopyramide, antituberculosis therapy, sulfonamides, heroin, cocaine, amphetamines, alcohol] Cobalt, iron, lead Radiation Infiltrative Amyloidosis Glycogen storage disease Mucopolysaccharidosis Leukemia Wegener’s granulomatosis Uremia Cor pulmonale Acute (pulmonary embolus) Chronic (emphysema) Arrhythmias

the aorta. An increased volume load may be caused by a valvular regurgitant lesion, an increased filling pressure, or a shunt between the systemic and pulmonary circulation such as an arteriovenous fistula, an atrial septal defect, or a patent ductus arteriosus. Obstruction to ventricular filling leads to a volume overload upstream from the stenotic lesion. Examples are mitral or tricuspid valve stenosis or rare congenital abnormalities such as cor triatriatum. Pericardial constriction and tamponade cause an extrinsic mechanical force that may lead to a restrictive pattern of heart failure. Other mechanical causes of heart failure include endocardial or myocardial restrictive disease, ventricular aneurysm, and ventricular asynergy.

Intrinsic Myocardial Abnormalities Causing Heart Failure Intrinsic myocardial abnormalities may cause heart failure either because of primary myocardial diseases, such as hypertrophic cardiomyopathy, or because of secondary influences such as viral infection. Although there are many primary and secondary causes of heart failure, the clinical presentation and treatment are very similar. Identification of the cause is crucial because treatment of the underlying disease may afford partial or complete reversal of the heart failure.

Rhythm and Conduction Disturbances Causing Heart Failure Rhythm and conduction system abnormalities may lead to symptoms and signs of heart failure. Extreme tachycardia such as seen in sinus tachycardia greater than 150 beats/min,

C=11%

D=30%

D=37% A=40%

A=40% C=15%

B=19%

B=7%

Men

Women

Figure 1 The prevalence of coronary artery disease and hypertension among 9405 male and female Framingham study subjects with congestive heart failure. A ¼ Coronary artery disease plus hypertension; B ¼ coronary artery disease alone; C ¼ neither hypertension nor coronary artery disease; D ¼ hypertension alone. Source: From Ref. 5.

ventricular tachycardia, atrial fibrillation or flutter, paroxysmal supraventricular tachycardia (atrioventricular nodal reentrant tachycardia), or multifocal atrial tachycardia may cause symptoms and signs of cardiac failure, often with a normal blood pressure. Electric asynchrony and conduction disturbances, as in atrial dysrhythmias and bundle branch blocks, cause a decrease in cardiac output and can lead to heart failure, especially in patients with underlying impaired ventricular function. The most common underlying abnormalities that result in heart failure include systemic hypertension and coronary artery disease. When the different causes of heart failure were evaluated in a long-term follow-up of 9405 subjects in the Framingham study, it was found that nearly 90% of patients with heart failure have a history of hypertension, coronary artery disease, or both (5). Other causes, including the different forms of cardiomyopathies, make up the remaining 10%. These findings are shown in Figure 1.

Pathophysiology of Heart Failure As stated earlier, heart failure is a systemic disease that begins and ends with the heart. Just as the causes of heart failure may be varied, there are different pathophysiologic mechanisms leading to the clinical entity of heart failure. Cellular biochemical mechanisms may be at work either as the precipitators of acute heart failure or as mediators of chronic heart failure. Pressure overload, volume overload, or both may be initiating factors. Heart failure may be due to loss of contractility from loss of heart muscle, abnormal muscle proteins, or impaired energy metabolism. Lastly, heart failure may also arise from extrinsic influences such as increased pericardial or pleural pressures.

Biochemical Derangements The heart consumes energy locked in the chemical bonds of fuel molecules through their controlled combustion and converts chemical energy into physical energy (predominantly mechanical pump work) (2). When this ability is impaired, it results in functional and metabolic abnormalities in the rest of the body, commonly referred to as ‘‘heart failure.’’ This may occur, for example, because of lack of supply of oxygen, as in coronary artery disease, or in inappropriate use of fuels, as in a cardiomyopathy. Ultimately, the increased energy demands and impaired energy production

Chapter 33:

Heart Failure and Resuscitation

665

lead to a state of energy starvation, with subsequent further cardiac deterioration (decreased capillary density, decreased number of mitochondria, and increased connective tissue). Other organs deteriorate because the heart no longer effectively provides energy in the form of substrates and oxygen to the rest of the body.

Left ventricular function is dependent on the filling pressure of the ventricle (preload) and contractility (Fig. 2), as well as the resistance of blood flow out of the ventricle (afterload) (Fig. 3). The impedance is the sum of resistance in small arteries and arterioles (resistance vessels) and compliance in larger arteries (conductance vessels). The normal left ventricle is able to adjust to changes in resistance through an increase in contractility. This increase is caused by an increase in ventricular filling pressure (Frank–Starling mechanism). After the ventricle has faced increased loading conditions for some time, the Frank–Starling curve becomes depressed, such that a higher loading condition no longer elicits a comparable increase in contractility. Thus the now dysfunctional ventricle does not respond as well to changes in loading conditions or increases in resistance (6).

Abnormal Cardiac Contractility The mechanism by which cardiac contractility becomes impaired is incompletely understood and may vary significantly depending on the cause. Loss of cardiac muscle may occur because of loss of myofibrillar protein, as seen in acute myocardial infarction. In chronic heart failure, muscular contraction may be compromised because of decreased activity of myofibrillar actinomyosin, or myosin adenosinetriphosphatase (ATPase) proteins (7,8). Additional abnormalities may occur because of decreased release or reuptake of calcium by the sarcoplasmic reticulum (9), decreased sodium/potassium exchange, or decreased cyclic adenosine monophosphate caused by decreased b-receptor activity

Normal

Stroke Volume

Mechanical Derangements

Mild Heart Failure Moderate Heart Failure Severe Heart Failure

Afterload

Figure 3 The relationship between ventricular function and afterload in the normal heart and in heart failure. Small increases in afterload may lead to a significant decline in ventricular function. Conversely, decreasing afterload improves the systolic performance of the failing heart.

(10) or decreased coupling with adenylate cyclase across the sarcolemma (6). We have observed that heart failure can also be caused by impaired substrate flux through metabolic pathways. An example is the acute decrease in contractile function of the working rat heart perfused with ketone bodies as the only substrate, which is completely reversible on addition of glucose. This substrate-induced contractile dysfunction occurs because of inhibition of the Krebs citric acid cycle at the level of the enzyme a-ketoglutarate dehydrogenase and is reversed through replenishment of citric acid cycle intermediates by pyruvate carboxylation (2).

Extrinsic Mechanisms

Stroke Volume

Normal

decreased preload and afterload

decreased afterload increased inotropy

Failing decreased preload

In addition to abnormal loading conditions, other extracardiac factors influence cardiac performance. For example, pericardial disease may produce an extrinsic mechanical stress that may impair myocardial relaxation, leading to a restrictive pattern of heart failure. In a similar way, increased pleural pressures may affect contractility, as seen in tension pneumothorax or mechanically ventilated patients with positive end-expiratory pressure. All these factors may decrease cardiac output, leading to high filling pressures and poor forward flow, thus causing the clinical syndrome of heart failure.

Compensatory Mechanisms

Preload Figure 2 Frank–Starling curves in the normal heart and in heart failure. An improvement in inotropy or reduction in afterload improves the ventricular performance. Reducing the preload alone does not improve performance, because there is no physiologically relevant ‘‘descending limb’’ of the curve. Combining preload reduction with either a reduction in afterload or a direct inotropic stimulus provides better systolic function and a reduction in ventricular filling pressure.

In both the heart and the body, the responses to altered pathophysiology are initially adaptive and later maladaptive. As we discuss the adaptive compensatory mechanisms in both systems, we recognize that the maladaptive responses in the body lead to the clinical presentation of heart failure. Myocardial Compensatory Mechanisms It is well recognized that in heart failure there are alterations of myocardial structure, changes in the contractile function of myocytes, and changes in blood flow to the heart. The myocardial response to volume as well as to pressure overload, results in an increase of contractile units (hypertrophy) and

medwedi.ru

666

Part Three: The Cardiothoracic System—Heart

thus a change in myocardial composition. This change leads to accelerated cell death with increased loading of the remaining normal cells (11). The mediators of ventricular remodeling and hypertrophy are local (autocrine) and systemic (neuroendocrine). The autocrine mediators are angiotensin, endothelin, endothelinderived relaxing factor, prostaglandin I2, and prostaglandin E2. The systemic mediators include the renin–angiotensin system (8), sympathetic stimulation (12), vasopressin, and atrial natriuretic peptide (ANP). Some of these mediators are vasoconstrictors, others are dilators, and it is the imbalance between these mediators that leads to decompensation and clinical manifestations in heart failure. Overload on the ventricles causes changes in gene expression, altered synthesis of myocardial proteins, and abnormal membrane assembly, resulting in preferential synthesis of fetal isoforms of several proteins, which have a shortened life span. In addition, there is evidence of overexpression of cellular proto-oncogenes c-fos, c-myc, and c-jun in response to myocardial overload, leading to altered protein synthesis and thus an abnormal myocardial structure (11). Pressure or volume overload on the ventricles results in an increase in the length of the sarcomeres and an increase in the total muscle mass. This mechanism allows maintenance of an elevated ventricular systolic pressure (in the case of volume overload) without depressed contractility. As heart failure advances, the alterations in contractility make this compensatory mechanism less and less efficient, ultimately resulting in depressed ventricular function (7). Following the sustained increase in stroke volume, there is cardiac dilation and an increased rate of relaxation. The combination of the above leads to an adequate cardiac performance until a phase of ‘‘exhaustion’’ is reached, which is characterized by lysis of myofibrils, interstitial fibrosis, a decreased capillary density in relation to myocytes, impaired coronary flow reserve, and ultimately deterioration of cardiac performance. Ventricular relaxation during diastole is also altered in the failing, hypertrophied heart (13). In this ‘‘diastolic dysfunction,’’ the delay in relaxation with pressure overload interferes with diastolic filling and leads to elevated left ventricular filling pressures (Fig. 4). Sometimes this mechanism

Normal

Systemic Compensatory Mechanisms Depressed systolic function of the heart leads to an inadequate effective arterial volume, which in turn triggers a series of humoral responses. Adrenergic stimulation, renin release, aldosterone secretion, and excessive release of vasopressin act to ensure adequate perfusion to vital organs. The adrenergic system in heart failure is characterized by increased levels of circulating norepinephrine (12). These levels correlate inversely with the severity of ventricular dysfunction and with prognosis. For example, in acute heart failure following myocardial infarction, the compensatory increase in norepinephrine in the early stages later becomes deleterious because of increased afterload and arrhythmogenicity. In chronic heart failure, the prolonged increase of circulating norepinephrine leads to a downregulation of cardiac b-adrenergic receptors, with a decrease in their density and subsequent reduction in contractility. Reversal of this downregulation may be achieved with b1-antagonists, which have been shown in some studies to be beneficial in low doses in the treatment of heart failure, possibly by restoring the responsiveness to adrenergic inotropic stimulation (14). Aldosterone secretion is stimulated by decreased renal blood flow and increased sympathetic activity (12). The release of renin leads to increased production of angiotensin II, which causes increased afterload and stimulates myocardial hypertrophy. The increased production of aldosterone increases retention of sodium and water with a further increase in preload. This chain of events leads to the so-called ‘‘vicious cycle of heart failure’’ (Fig. 5). Reversal of these effects by angiotensin-converting enzyme (ACE) inhibitors has been shown to decrease mortality in heart failure of different etiologies (15–17). Other systemic changes that occur in heart failure include changes in the levels of vasopressin, ANP, and peripheral oxygen delivery. The circulating levels of vasopressin are elevated in heart failure because of an abnormal response to serum osmolality. This causes systemic vasoconstriction and perhaps contributes to hyponatremia in the later stages of the disease. ANP is a counter-regulatory

Diastolic Dysfunction

Left Ventricular Pressure

Systolic Dysfunction

alone can be severe enough to cause clinically advanced heart failure.

Left Ventricular Volume

Figure 4 Pressure–volume loops comparing normal left ventricular function with impaired systolic and diastolic function. In systolic dysfunction, contractility is depressed and there is diminished capacity to eject blood into a high-pressure aorta. In diastolic dysfunction, there is diminished capacity to fill at low diastolic pressure. The left ventricular ejection fraction is low in systolic dysfunction and normal in diastolic dysfunction.

Chapter 33:

Right vs. Left Ventricular Failure Decreased Renal Perfusion

Increased Renin and Aldosterone

Figure 5 This ‘‘vicious cycle of heart failure’’ begins with an impaired cardiac function, leading to a low cardiac output and thus decreased renal perfusion. The subsequent release of renin and aldosterone causes an increased intravascular volume, increased afterload, and stimulation of left ventricular hypertrophy, all of which exacerbate cardiac dysfunction.

hormone opposing vasoconstriction and sodium and water retention, thus protecting the heart from volume overload. In acute heart failure, ANP inhibits the synthesis of renin, opposes the effects of angiotensin II, and stimulates renal excretion of sodium and water, thus, decreasing preload. Finally, there is a change in peripheral oxygen delivery in heart failure caused by the redistribution of cardiac output toward vital organs, an altered oxyhemoglobin dissociation curve, and an increased oxygen extraction by tissues. The compensatory mechanisms in heart failure are a ‘‘double-edged sword,’’ because they support myocardial performance in the early stages of heart failure but later cause undesirable effects leading to accelerated deterioration of the failing heart. Thus the goal in the treatment of heart failure is to modify these compensatory mechanisms using pharmacologic agents to break the cycle of maladaptive changes.

Clinical Manifestations of Heart Failure: A Series of Opposing Adjectives Heart failure is characterized by a number of factors: sodium and water retention, dyspnea or fatigue (limitation of exercise tolerance), neurohormonal activation, decreased peripheral blood flow with subsequent lowering of endorgan metabolism, impaired systolic function, ventricular arrhythmias, and ultimately decreased survival (6). In describing the clinical features of heart failure it is useful to consider a series of opposing adjectives (Table 2). These descriptions are useful particularly early in the course Table 2 Clinical Adjectives Used in Describing Heart Failure Acute vs. chronic Right vs. left sided High vs. low output Forward vs. backward Systolic vs. diastolic Primary vs. secondary Latent vs. overt Reversible vs. irreversible Compensated vs. refractory (intractable) Stable vs. unstable

667

of the disease, but they do not necessarily signify fundamentally different disease states. Late in the course of the disease, the differences between these forms often become less distinct (4).

Decreased Cardiac Function

Increased Intravascular Volume, Increased Afterload, Stimulation of Hypertrophy

Heart Failure and Resuscitation

The distinction between right and left ventricular failure was first proposed by Harrison et al. (18) in 1932. Pure right ventricular failure is most commonly caused by cor pulmonale from chronic lung disease and increased pulmonary vascular resistance. The symptoms include edema, congestive hepatomegaly, systemic venous distention, weakness, fatigue, and central nervous system symptoms. The signs include an elevated central venous pressure, hepatojugular reflux, ascites, pleural/pericardial effusion, bowel edema (causing anorexia, nausea, vomiting, and malabsorption), and cachexia. Left heart failure is characterized by poor cardiac output, an increased left ventricular filling pressure, and pulmonary congestion. The symptoms include dyspnea, orthopnea, paroxysmal nocturnal dyspnea, cough, nocturia, and hemoptysis. The signs are tachycardia, auscultatory gallop, inspiratory rales, expiratory wheezes, and pulsus alternans. Many patients with advanced left ventricular failure develop right ventricular failure, and a combination of both left and right ventricular failure is a common clinical presentation. This is especially true for patients with mitral stenosis and patients with a dilated cardiomyopathy.

High-Output vs. Low-Output Heart Failure The description, high output/low output, relates the cause to the typical clinical features. High-output heart failure is characterized by decreased peripheral resistance often in the absence of sodium and water retention. Etiologies known to cause high-output heart failure include hyperthyroidism, anemia, arteriovenous fistula, beriberi, Paget’s disease of the bone, Albright’s syndrome, multiple myeloma, hypernephroma with bone metastases, cirrhosis, and acute glomerulonephritis. Low-output heart failure is characterized by retention of sodium and water and often an elevated peripheral vascular resistance and is caused by anything that decreases the cardiac output, including left ventricular dysfunction, and restrictive influences on the heart.

Forward vs. Backward Heart Failure The concepts of forward and backward heart failure date back to 1913 and 1832, respectively (19,20); although they are old concepts, they retain clinical utility today. Forward heart failure involves inadequate discharge of blood into the arterial system, which leads to decreased renal perfusion, activating the renin–aldosterone axis and causing sodium and water retention, mental obtundation, and hypotension. In backward heart failure, the ventricle fails to discharge its contents normally, and the end-diastolic volume and the pressure in the atria and ventricles are elevated, leading to pulmonary and venous congestion and sodium and water retention. The manifestations are hepatomegaly, ascites, and peripheral edema.

Systolic vs. Diastolic Dysfunction Systolic dysfunction leads to increased filling pressures and pulmonary congestion, decreased cardiac output, redistribution of flow toward vital organs, decreased stroke volume, and increased left ventricular end-diastolic volume with dilation of the ventricle (21). There is a growing recognition of diastolic dysfunction (heart failure with normal heart size

medwedi.ru

668

Part Three: The Cardiothoracic System—Heart

and ejection fraction) as a cause for impaired pump function of the heart (22). As seen in Figure 3, this diastolic dysfunction or ‘‘input failure’’ is characterized by the inability of the ventricle to relax and fill normally, leading to an increased filling pressure, increased ventricular end-diastolic pressure, and a decreased stroke volume because of decreased myofibrillar stretch and impaired diastolic filling. It is important to recognize that traditional therapy aimed at stimulation of systolic ejection may be ineffective or even deleterious in pure diastolic dysfunction (13,22).

Other Adjectives Used to Describe Heart Failure There are other adjectives of value in describing heart failure, which may relate to cause, treatment, and prognosis. In ‘‘reversible heart failure,’’ the manifestations disappear if the underlying cause is removed early in the course of the disease. Examples include ischemia, valvular lesions, constrictive pericarditis, infectious endocarditis, hypertension, and most of the causes of high-output heart failure. ‘‘Irreversible heart failure’’ occurs when the manifestations do not disappear after precipitating factors are eliminated; in fact, they are often progressive. The classic example is myocardial infarction with extensive myocardial necrosis. Other factors leading to irreversibility include isolated myocardial cell loss and interstitial fibrosis with plastic transformation of the adjacent myocardium. The commonly used term ‘‘congestive heart failure’’ refers to abnormal circulatory congestion caused not only by impaired heart function but also by peripheral circulatory and sympathetic renal compensatory mechanisms. A ‘‘congested state’’ is an expanded intravascular volume with preserved ventricular function, for example, caused by vigorous volume infusions, anemia, beriberi, etc. It is often difficult to distinguish congestive heart failure from a congested state, especially in the postoperative patient and in patients with renal failure. It often becomes necessary to use invasive monitoring with determination of cardiac output and pulmonary capillary wedge pressure to make the distinction. If the precipitating factors persist, the congested state may become congestive heart failure (ventricular function becomes impaired). ‘‘Primary heart failure’’ refers to diseases arising from the myocardium, such as congenital heart diseases, neuromuscular diseases, myocarditis, and presbycardia (senile heart). ‘‘Secondary heart failure’’ occurs because of other factors such as ischemic disease, systemic disorders, and metabolic and inflammatory diseases. ‘‘Unstable heart failure’’ means a severe circulatory derangement, which is life threatening if not aggressively treated, and includes acute pulmonary edema and cardiogenic shock. ‘‘Transient heart failure’’ (flash pulmonary edema) is often seen in patients with diastolic dysfunction resulting from hypertension and following cardiopulmonary bypass.

Special Considerations Often a patient with chronic, well-compensated heart failure is hospitalized for a surgical procedure or other reasons and experiences an exacerbation of heart failure, leading to worsening of symptoms or signs of heart failure. There are many factors that may underlie the exacerbation, and most often it can be corrected by simply removing the offending cause (23); however, sometimes the cause leads to a direct worsening of ventricular function, which is irreversible and leads to unstable heart failure or a new level of compensation at a worsened functional class (Table 3).

Table 3 Events Precipitating or Exacerbating Heart Failure in Patients with Compensated Disease Changes in environment or diet Noncompliance with medical therapy Arrhythmias Myocardial ischemia Anemia Drugs: nonsteroidal anti-inflammatory drugs, corticosteroids, calcium channel blockers, b-blockers, etc. Thyroid dysfunction Metabolic deficiencies Infections Worsening renal function Pulmonary embolism Pregnancy Emotional factors Myocarditis Endocarditis Systemic hypertension Myocardial infarction

The New York Heart Association classification of heart failure (Table 4) has gained broad acceptance as the standard clinicians use to communicate with one another regarding the severity of heart failure. It is based on subjective and objective findings, with the objective assessment being based not only on physical examination but also on noninvasive and invasive tests to evaluate cardiac status. It is accepted that the severity of symptoms may not necessarily be matched by equivalent degrees of impaired structure and function of the heart (24).

Therapy Broad Objective: Correct the Deranged Physiology The goal in the treatment of heart failure is to correct the deranged physiology while establishing and treating the underlying cause. Despite this, prevention of heart failure exerts far more salutary effect on public health than treatment. Prevention of the most common causes involves

Table 4 The New York Heart Association Classification of Heart Failure Functional capacity Class I: Patients with cardiac disease, but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain Class II: Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain Class III: Patients with marked limitation of physical activity. They are comfortable at rest. Less-than-ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased Objective assessmenta A. No objective evidence of cardiovascular disease B. Objective evidence of minimal cardiovascular disease C. Objective evidence of moderately severe cardiovascular disease D. Objective evidence of severe cardiovascular disease a

For example, physical examination, electrocardiogram, chest X-ray examination, cardiac catheterization, echocardiography, radiologic imaging, and stress testing.

Chapter 33:

early and vigorous treatment of hypertension, hyperlipidemia, diabetes, and the promotion of lifestyle changes to lower the risk of coronary artery disease. In addition, the early use of thrombolytic therapy in acute myocardial infarction decreases the risk of development of heart failure. Finally, the identification and management of the specific causes and precipitating factors in heart failure are important (Tables 1 and 3). Once the diagnosis of heart failure is made, the therapeutic challenge is to alleviate symptoms and prolong life by correcting the abnormal physiology. The abnormal cardiac physiology involves both metabolic and mechanical derangements (25). The correction of mechanical derangements involves the increase in supply of energy substrates and blood flow to meet the increased energy demands. For example, coronary revascularization may improve ventricular performance in patients with coronary artery disease and depressed ventricular function. The treatment of the abnormal mechanical properties of the heart may include the reversal of maladaptive hypertrophy with ACE inhibitors or an increase in contractility with digoxin. The correction of systemic derangements involves lowering preload with salt restriction, diuretics, and venous vasodilators and lowering afterload with arterial vasodilators. The control of heart rate and rhythm is also important, and this can be achieved with b-blockers, antiarrhythmics, and pacemakers if needed. Lastly, in suitable patients with refractory heart failure, the treatment of choice may be cardiac transplantation; however, this option is limited by a supply of donor organs, which is only a fraction of the demand.

Treatment of Acute Heart Failure General Principles The therapy of acute heart failure and cardiogenic shock involves treatment modalities that are both similar and dissimilar to those used in chronic heart failure. The most prominent features include a clinical assessment of the intravascular volume status, invasive hemodynamic monitoring, inotropic pharmacologic therapy, and mechanical assist devices. The goal in treating hemodynamically unstable patients is to optimize oxygen delivery to vital organs by increasing cardiac output and decreasing pulmonary venous congestion. In the critical care setting, this therapy is assisted by a peripheral arterial catheter (for assessment of arterial pressure) and a balloon-tipped, flow-directed pulmonary artery catheter (for assessment of left ventricular filling pressure and cardiac output) (26,27). Before considering invasive or complicated techniques to treat acute heart failure, it is important to remember that there are frequently simple derangements contributing to pump failure that may be easily corrected. For example, acid–base imbalances, electrolyte abnormalities, and hypoxia may directly contribute to myocardial depression and should be aggressively corrected. In addition, arrhythmias, such as sinus bradycardia or atrioventricular block or dissociation, may contribute to a low cardiac output. Finally, mechanical complications of acute myocardial infarction, such as mitral regurgitation caused by papillary muscle infarction, ventricular septal rupture, and ventricular free wall rupture may be the culprit in acute heart failure and require immediate surgical intervention. Specific Measures In the patient with acute heart failure, the inadequate cardiac output may be increased by the following means. First,

Heart Failure and Resuscitation

669

by increasing the end-diastolic volume or preload through volume expansion, one augments cardiac output by utilizing the Frank–Starling mechanism. Inotropic agents such as dopamine, dobutamine, norepinephrine, and digitalis increase cardiac output by directly increasing contractility. Lowering afterload with agents such as nitroprusside and ACE inhibitors improves cardiac output by decreasing resistance to ventricular ejection. Decreasing the degree of ischemia in patients with coronary artery disease may influence cardiac output by improving ventricular wall motion. When the stroke volume is fixed, cardiac output can be augmented by increasing the heart rate with a pacemaker or a positive chronotropic agent. When these measures are undertaken, it is important to weigh the possible negative effects on the myocardium, caused by an increase in oxygen demand with the need to improve the cardiac output (28). An increase in pulmonary venous pressure is corrected by decreasing total circulating blood or fluid volume with diuretics or phlebotomy or by facilitating peripheral venous pooling with vasodilators or rotating tourniquets. In addition to decreasing the intravascular volume, diuretics also facilitate venous pooling (29). Mechanical Assist Devices In the setting of acute myocardial infarction, mechanical circulatory assistance devices such as the ‘‘intra-aortic balloon pump’’ (IABP) increase arterial pressure during diastole (diastolic augmentation) to maintain or enhance coronary arterial perfusion pressure and lower preejection and ejection pressures (systolic unloading) to reduce myocardial work and oxygen demand (28,30). In addition, the IABP improves the hemodynamic status and has been shown to reverse the shock syndrome. Despite these acute hemodynamic effects, the ultimate prognosis in patients using the IABP is not significantly improved. Indications for circulatory assistance using the IABP are cardiogenic shock secondary to myocardial infarction or myocardial depression following cardiac surgery, acute heart failure refractory to medical therapy, and recurrent life-threatening ventricular arrhythmias unresponsive to medication and/or pacing. In addition to these indications, the IABP is commonly used in the stabilization of patients who are hemodynamically compromised immediately after myocardial infarction while waiting for catheterization or cardiac surgery. Placement of an IABP is contraindicated in patients with irreversible brain damage, chronic end-stage heart disease, severe associated disease, or an incompetent aortic valve (26). The ‘‘left ventricular assist device’’ (LVAD) is an extracorporeal or intracorporeal pump that provides the power to shunt oxygenated blood from the left ventricle to the ascending aorta, while reducing the workload of the ventricle. It is used most commonly in patients with end-stage heart failure as a bridge to cardiac transplantation and in patients with stunned myocardium, when cardiac function is slow to recover. Further discussion of the LVAD and IABP can be found in the chapter on Mechanical Support of the Failing Heart. Metabolic Support The concept of providing metabolic support for the ischemic myocardium with glucose, insulin, and potassium has stimulated new interest in the treatment of acute heart failure refractory to conventional therapy (31). The administration of a solution of high doses of glucose, insulin, and potassium (the latter to prevent hypokalemia) has demonstrated utility in improving ventricular function in patients with

medwedi.ru

670

Part Three: The Cardiothoracic System—Heart

acute heart failure, especially after elective hypothermic ischemic arrest (31,32). Although it has been thought that the accumulation of glycolytic products worsens the functional effects of ischemia, the provision of glucose and insulin improves contractile function in myocardial infarction in the acutely ischemic, reperfused myocardium (33). It is thought that the glucose, insulin, and potassium solution preserves cell integrity (e.g., through preserving glycogen stores, activating ATP-sensitive potassium channels, and maintaining sodium and potassium ATPase activity).

Treatment of Chronic Heart Failure The basic principles in the treatment of chronic heart failure are first to eliminate precipitating factors, second to determine if systolic dysfunction or diastolic dysfunction prevails and treat accordingly, and finally to identify and correct any other underlying cause. Patients may have purely systolic or diastolic dysfunction, but frequently they have some combination of the two (4,34). As stated earlier, the ultimate goal in treatment of chronic heart failure is the reduction of morbidity and mortality. Approach to Asymptomatic Heart Failure Irrespective of its cause, systolic dysfunction has an asymptomatic, a symptomatic, and a refractory stage. In the asymptomatic patient, the treatment consists of modification of risk factors for coronary artery disease, such as smoking, hypertension, hyperlipidemia, and obesity. Whereas strenuous physical activity may overtax the circulation of the patient with compensated heart failure, regular aerobic exercise can enhance the efficiency of the cardiovascular system, with a resultant increase in exercise tolerance (35). ACE inhibitors inhibit the maladaptive myocardial hypertrophy and may prevent progression to the symptomatic stage; thus, they are very important in the treatment of the asymptomatic patient (36). There is mounting evidence that ACE inhibitors influence intracellular signaling cascades, which have effects on growth and thus may inhibit growth of overloaded myocardial cells (36,37). Approach to Symptomatic Heart Failure: Importance of Triple Therapy In the symptomatic patient, the goals of therapy are to relieve symptoms and to prolong life. Specifically, the hallmarks of treatment involve lowering the workload of the heart, increasing contractility, controlling sodium and water retention, and controlling associated arrhythmias. The workload may be lowered by physical and emotional rest, treatment of obesity, and the use of preload- and afterload-reducing agents. ACE inhibitors have been shown to be of the greatest benefit; however, the combination of nitrates and hydralazine has also shown benefit (15,38,39). In addition, ACE inhibitors have been shown to affect favorably long-term outcome in patients who have heart failure as a result of myocardial infarction by decreasing adverse left ventricular remodeling (16). Digoxin continues to be the only positive inotropic agent available for oral administration. Long-term administration of digoxin has been shown to reduce morbidity and mortality when combined with afterload reduction and diuretics (15). Sodium and water retention can be modulated by the use of a low-sodium diet and diuretics. Precautions must be taken when using diuretics to avoid electrolyte imbalances. The combination of afterload reduction, digitalis, and diuretics forms the cornerstone of the management of chronic symptomatic heart failure. Finally, it is important to preserve or restore normal sinus rhythm (40).

Special Considerations There are a number of special considerations in the treatment of heart failure, some of which have already been mentioned but are summarized once more here in context. First, the identification of diastolic dysfunction and pure right ventricular failure is important, because the treatment of these unique physiologic derangements is different from that of systolic left ventricular dysfunction (41). Second, in severe heart failure, the prevention of and treatment of thrombotic complications and arrhythmias is important. Lastly, the pharmacokinetics of many drugs may be altered in heart failure, even in the absence of renal impairment. Diastolic Dysfunction In contrast to the fundamental defect in systolic dysfunction, patients with isolated diastolic dysfunction have normal or often enhanced contractile function of the left ventricle (as measured by the ejection fraction). However, these patients also have dyspnea and fatigue and develop pulmonary edema in the same way as patients with systolic dysfunction. The key problem in this syndrome is that increased ventricular stiffness (or reduced compliance) leads to limitations on the use of preload reserve because of rapid increases in cardiac filling pressures at normal or slightly increased cardiac volume (13). Because the left ventricle contracts normally, there is no need to attempt to conserve or improve left ventricular function with inotropic agents. Similarly, there is no benefit from preload reduction, which may even worsen the situation. Treatment is instead directed at improving relaxation characteristics, mitigating the effects of an abnormal compliance, and prolonging diastole to allow for improved ventricular filling. Calcium channel–blocking agents and b-blocking agents have offered the best utility in this effort. ACE inhibitors cause regression of left ventricular hypertrophy and may have direct myocardial effects that improve diastolic function. Lowering of blood pressure into the normal range is of paramount importance and should be done with one of these three agents. Arrhythmias As ventricular performance deteriorates in chronic heart failure and the cardiac muscle is remodeling in response to overload, electrophysiologic abnormalities develop. The majority of patients with severe chronic heart failure have ventricular arrhythmias often manifested by ventricular tachycardia and ventricular fibrillation. It would be expected that patients with the most frequent or serious arrhythmias would be at the greatest risk for sudden death, but this does not seem to be the case. Complex ventricular arrhythmias are more a reflection of the severity of the patient’s hemodynamic and functional status rather than a specific pathophysiologic event. Nonsustained ventricular tachycardia occurs in 40% to 60% of patients with the New York Heart Association class III and IV heart failure, and sudden death may occur in 40% of patients in class III and IV (Table 4). Antiarrhythmic therapy may suppress ventricular arrhythmias but does not prolong life in these patients (6). Furthermore, antiarrhythmic drugs appear to be most proarrhythmic in these myopathic ventricles. Some of these drugs were actually shown to increase mortality in certain circumstances (such as class IC agents following myocardial infarction) (42,43). Thus the jury is still out on the utility of antiarrhythmic therapy in patients with advanced heart failure. Anticoagulation Dilated atria and/or ventricular chambers can be the site of thrombi; however, because of its inherent morbidity, routine

Chapter 33:

anticoagulation for prevention of thromboembolic events is not uniformly recommended. Patients with echocardiographic evidence for mural thrombi, presenting with a history of systemic or pulmonary embolism, or patients with a history of atrial fibrillation should be anticoagulated. Otherwise, the risks of complications from chronic anticoagulation, including intracranial or gastrointestinal hemorrhage, do not warrant the expected benefits (44). Altered Pharmacokinetics In heart failure, decreased gastric emptying delays absorption and decreases the peak plasma concentration of digoxin, furosemide, and bumetanide. Decreased first-pass metabolism in the liver increases the concentration of nitrates, morphine, and hydralazine. Decreased biotransformation to active forms causes diminished activity of ACE inhibitors. Thus the use of various medications necessitates frequent monitoring of blood levels, electrolytes, and clinical effects of the medication. Right Ventricular Infarction Right ventricular infarction, which occurs in less than 7% of patients with acute myocardial infarction, may lead to right ventricular failure. The hemodynamic picture in these patients is characterized by markedly elevated right atrial and right ventricular end-diastolic pressures with a normal or reduced right ventricular systolic pressure, normal or reduced pulmonary artery systolic pressure, and a normal or slightly elevated pulmonary capillary wedge pressure. Because of a markedly reduced right ventricular output, the left ventricle filling pressure becomes inadequate, and left ventricular output therefore decreases. Volume expansion to maintain right ventricular filling pressure and output has been the mainstay of treatment in the acute phase. Vasodilators may improve right ventricular output and, therefore, left ventricular filling pressure and output in the long term (26,27,43).

Therapy of Refractory Heart Failure: Cardiac Transplantation Refractory heart failure does not respond to conventional therapy, and thus more aggressive therapies must be used, usually in an inpatient setting. Inotropic support with parenteral inotropes such as dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone has been used widely to alleviate the symptoms and signs of heart failure temporarily. Removal of excess fluid by paracentesis, thoracentesis, or dialysis may be necessary. Mechanically assisted circulation with the IABP or the left or right ventricular assist device may become the last resort, but usually only as a bridge to transplantation. Cardiac transplantation has a greater than 60% five-year survival; however, the greatest hurdle is the timely procurement of donor organs, which limits this option to relatively few patients (45).

Future of Treatment Strategies for Chronic Heart Failure

Heart Failure and Resuscitation

671

agents may come into use (20,46,47). Both modalities merit a brief mention. Total Artificial Heart A new emphasis on the concept of the total artificial heart (TAH) has emerged, and prototypes are being developed at institutions in the United States and Japan. The new generation of TAH will be totally implantable with no transcutaneous implements. Power will be supplied by transmission of energy through intact skin to a subcutaneous receiver from battery packs worn by the patient. The development teams believe that new technology in microminiaturization and computer-aided design will enable the new TAH to overcome the pitfalls of the existing Jarvic TAH, such as thrombosis and infection. It is hoped that this technology will supplant cardiac transplantation and become a therapeutic option for both chronic and acute heart failure (48). Effective devices have already been tested in humans, with limited short-term success (see chapter on Mechanical Support of the Failing Heart). Gene Therapy Gene therapy is aimed at correction of abnormal cardiac gene expression, and it is believed that the gene response to overload may lead to cell death. The target gene(s) has (have) not been identified; however, the genes responsible for some specific cardiac disease states have been found, and research is under way to develop treatments based on them (49,50). For example, it has been shown that a mutation on a specific site on chromosome 14 encoding the myosin heavy chain is associated with familial hypertrophic cardiomyopathy, and thus, theoretically, the reversal of this mutation could prevent the development of this disease (51).

RESUSCITATION Cardiopulmonary arrest is the extreme form of acute heart failure. During cardiopulmonary arrest there is the cessation of systemic blood circulation and effective ventilation. Basic life support, or CPR, provides artificial ventilation and circulation until advanced cardiac life support (ACLS) can be initiated. Modern CPR has revolutionized the treatment of sudden death and began with the observation of Kouwenhoven et al. (52), in 1960, that rhythmic depression of the sternum in animals produced pulsations in arterial pressure and permitted successful closed-chest electric defibrillation after prolonged ventricular fibrillation. Since the introduction of this technique, many modifications have been proposed, but none have consistently been proven superior to the basic idea that to be successful the pump function of the heart must be maintained and/or restored. Because of the poor long-term survival rates of patients receiving CPR, it has been difficult to quantitate the survival benefit of traditional CPR or any newer techniques (53). The clinical scenarios in patients most likely to be successfully resuscitated using traditional CPR are outlined in Table 5.

Pathophysiology of Cardiopulmonary Resuscitation

The future of treatment of chronic heart failure will involve the development of new high-technology devices to augment or supplant the pumping function of the heart and also the elucidation of the genetic basis of heart failure and attempts to alter this genetic destiny. In addition, as more knowledge about the complex neurohormonal interactions involved in heart failure becomes available, new therapies such as the use of low-dose b-adrenergic blocking

Blood flow during CPR is maintained by a generalized increase in intrathoracic pressure, causing blood to move from the vascular structures of the thorax to the peripheral circulation. When the chest compression is released, blood flows back from the peripheral structures to the thorax. The flow is maintained in the antegrade direction by the valves in the heart and the veins and can reach 1.7 L/min (54). Some investigators have proposed that the increase in

medwedi.ru

672

Part Three: The Cardiothoracic System—Heart

Table 5 Clinical Scenarios of Patients Most Likely to Be Successfully Resuscitated with Traditional Cardiopulmonary Resuscitation Witnessed sudden arrest caused by ventricular fibrillation outside the hospital, when electric countershock can be performed within 7–8 min Hospitalized patients with primary ventricular fibrillation and ischemic heart disease Cardiac arrest in the absence of life-threatening coexisting conditions Primary respiratory arrest Arrest caused by hypothermia, drug overdose, or airway obstruction

pleural pressures rather than compression of the heart results in blood flow to the periphery (55). It has been shown that mechanical ventilation alone increases intrathoracic pressures. Translocation of blood from the pulmonary bed into the systemic bed with forward flow can be achieved with the left heart chamber as a conduit (56). Forceful, rhythmic cough can also generate systolic pressures equivalent to normal cardiac activity and sustain cardiac output during asystole, maintaining cerebral blood flow and peripheral flow (57). Paradoxically, the compression of the heart and the increase in intrathoracic pressure with CPR can lead to pulmonary edema in one-third to one-half of patients, representing a major cause of hypoxemia during resuscitation. Some investigators have found that pulmonary artery mean pressure and pulmonary capillary wedge pressures increase within 5 to 10 minutes of CPR and return to baseline within five minutes of effective spontaneous circulation (58). The experimental strategies to increase the effectiveness of CPR are aimed at making pleural pressures more positive during cardiac emptying and more negative during filling. The former can be achieved by inflation of the lungs during chest compressions and the use of a pneumatic vest. The latter is accomplished with chest cuirass, stimulation of the inspiratory muscles, negative airway pressure during the filling phase, and increasing the abdominal pressure during filling (59).

Cerebral Blood Flow During Cardiopulmonary Resuscitation Irreversible brain damage occurs within four to six minutes of anoxia. Although isolated neurons show complete recovery after 20 to 60 minutes of anoxia, the postischemic damage is due to hypoperfusion secondary to vasospasm and the release of oxygen-derived free radicals from injured tissues and neuronal calcium overload. Experimental techniques used to preserve cerebral function during CPR include calcium channel blockers, free radical–scavenging agents, transient postresuscitation hypertension, retrograde arterial perfusion with low-viscosity solutions, anticoagulation, hypothermia, barbiturate coma, and hyperosmotic solutions (60). None of these have been shown to be consistently effective in clinical trials. Excessive volume loading is actually detrimental to cerebral perfusion because of cerebral edema or shunting of blood through extracerebral vessels (61).

Coronary Blood Flow During Cardiopulmonary Resuscitation The basal myocardial oxygen consumption is 30% to 40% of normal during ventricular fibrillation; thus if coronary perfusion cannot meet this demand, the likelihood of successful defibrillation is low. Coronary blood flow decreases from

30% to 5% of normal within the first 20 minutes of CPR. This decrease in flow may be due to epinephrine, direct heart compression, abdominal compression, or negative pleural pressure during the filling phase. Other methods employed to increase the effectiveness of CPR include vigorous volume infusion and the use of glucose-containing fluids. These methods are controversial because they may increase cerebral damage during ischemia or after reperfusion or may cause pulmonary edema (56). High doses of epinephrine may increase aortic pressure and coronary flow, and the a-receptor stimulation may restore a spontaneous heartbeat; however, the b-receptor activity increases oxygen consumption and may be detrimental (62,63). Calcium channel blockers theoretically would decrease intracellular damage and postischemic cerebral and coronary vasospasm, but their negative inotropic and chronotropic action precludes their use. Sodium bicarbonate corrects systemic acidosis, which may compromise cardiac function, suppresses spontaneous cardiac activity, decreases the threshold for ventricular fibrillation, and impairs cardiac and peripheral response to catecholamines. Despite these beneficial effects, bicarbonate may also exacerbate central nervous system acidosis, produce a paradoxic intracellular acidosis, change the oxygen dissociation curve so as to decrease oxygen delivery, increase osmolality, and cause hypernatremia. Studies have failed to show an improved outcome with its use in CPR. Ventilation during CPR should be achieved with endotracheal intubation if at all possible. This method is the best at achieving oxygenation during arrest. Other lesseffective methods are mouth-to-mouth ventilation, mouthto-mask ventilation, esophageal obturator, or multiluminal airway device (64–66).

Advanced Cardiac Life Support The initial objective of ACLS has been the treatment of lifethreatening arrhythmias. The prototypical arrhythmias causing cardiopulmonary arrest are ventricular tachycardia and ventricular fibrillation, which are treated with a series of electric countershocks to achieve defibrillation to normal rhythm. This has been shown to be very successful, especially in patients in the intensive care unit setting when defibrillation can be accomplished early. If another rhythm is the cause of the arrest or if ventricular tachycardia or fibrillation persists after countershock, endotracheal intubation, chest compressions, intravenous access, and delivery of medications should take precedence over other measures (64,66). When ventricular fibrillation is successfully electrically cardioverted, 70% to 80% of patients convert to a rhythm that is capable of supporting adequate perfusion if cardioversion is done within three minutes of onset (64). If ventricular fibrillation persists after the initial countershocks, epinephrine should be given prior to further attempts. Although the use of antiarrhythmic agents is encouraged, whether there are true benefits is controversial. Asystole is frequently the initial rhythm identified in patients with cardiac arrest found outside the hospital and in critically ill inpatients. This rhythm carries the worst prognosis, with less than 2% of patients surviving hospitalization. In addition to epinephrine and atropine, the use of transcutaneous and transvenous pacing should be encouraged if they can be instituted in a short period of time. Pulseless electric activity, formerly also termed ‘‘electromechanical dissociation,’’ can be due to metabolic and mechanical derangements. This is a disturbance frequently encountered in the traumatized or burned patient where

Chapter 33:

hypovolemia, cardiac tamponade, tension pneumothorax, acidosis, and hypoxia are prevalent. Other causes may include pulmonary embolus and a large myocardial infarction. After ACLS has been initiated, each of the possible causes should be investigated and treated immediately.

Cardiopulmonary Arrest Following Trauma The approach to the patient with cardiopulmonary arrest as a result of trauma is different than that to the patient with arrest as a result of a primary cardiac or pulmonary event. The causes of arrest associated with trauma may include exsanguination with hypovolemia and diminished oxygen delivery, diminished cardiac output resulting from tension pneumothorax or pericardial tamponade from penetrating trauma, or direct trauma to the heart or great vessels. In addition, there may be causes that may not be as readily apparent as the purely mechanical causes, such as cardiovascular collapse or primary respiratory arrest resulting from a neurogenic response to severe central neurologic injury and trauma associated with a primary arrest, such as in the patient who suffers ventricular arrhythmias while driving a car. The management of patients who suffer arrest associated with trauma begins with immediate evaluation of the airway and electrocardiographic rhythm. Ventilation should be accomplished as first priority because the tolerance of pulselessness may be extended in patients who have achieved adequate oxygenation. While establishing an adequate airway, in-line stabilization of the neck should be performed, and lateral neck supports, strapping, and backboards should be used to prevent worsening of a possible neck injury. If after airway control and defibrillation of dysrhythmias there is no pulse or blood pressure, chest compressions may have to be initiated. In penetrating injury to the chest, the thorax should be vented if there is asymmetry of breath sounds or an increase in airway resistance. A thorough survey of the body should be made for penetrating injury that may cause pneumothorax or tension pneumothorax. Once identified, a penetrating injury should be sealed, and immediate monitoring for (and relief of) tension pneumothorax should be performed. Emergency thoracotomy permits direct massage of the heart and allows relief of tamponade, control of thoracic and extrathoracic hemorrhage, and aortic cross-clamping (64). Open cardiac massage increases cardiac output and aortic pressures more than standard CPR; however, it has been shown that there is no benefit of this procedure if initiated after 30 minutes of standard CPR (56,64,66). When a patient becomes pulseless as a result of intravascular volume loss, functional long-term survival is unlikely unless single-organ hemorrhage can be rapidly terminated, along with aggressive volume resuscitation, blood transfusions, and circulatory support. Patients with prehospital arrest caused by multiple-organ hemorrhage, as is commonly seen with blunt trauma, rarely survive neurologically intact, despite rapid prehospital and trauma-center response. Those who survive prehospital arrest associated with trauma are generally young, have penetrating injuries, have received early endotracheal intubation, and undergo rapid transport by highly skilled paramedics to a definitive care facility (64).

Monitoring the Effectiveness of Cardiopulmonary Resuscitation CPR is most effective when the mean and diastolic aortic pressures are maintained continually at an adequate level.

Heart Failure and Resuscitation

673

These are the critical pressures that define perfusion of oxygenated blood to the coronary arteries and systemic circulation. In addition, adequate aortic pressures are needed to promote effective circulation of emergency medications such as catecholamines and antiarrhythmics. However, if the left atrial pressure is as high as the aortic pressures, there may not be forward flow even with adequate aortic pressures, and the result may be reverse flow and pulmonary edema. This situation may be encountered, for example, in patients with mitral or aortic valvular dysfunction. Arterial pH and PO2 do not correlate well with outcome in CPR except in the extreme. With a very high pH, for example, there may be failure of defibrillation. A very low pH portends a poor outcome. Arterial lactate levels are an indicator of perfusion with oxygenated blood and have an inverse correlation with outcome. Mixed venous or coronary venous pH and PCO2 do not correlate with outcome; however, failure to eliminate carbon dioxide as measured by an increased mixed venous carbon dioxide and a low end-tidal carbon dioxide tension is associated with the onset of ventricular fibrillation (64,66,67).

Morbidity, Mortality, and Prognosis With in-hospital cardiopulmonary arrest, there is a 55% rate of successful resuscitation; however, only 15% of the patients survive the hospitalization (64,66,68). The extent of prearrest morbidity plays an important role in the outcome of CPR. Approximately one out of five survivors suffers serious permanent brain damage, and this complication is most correlated to the amount of time in cardiopulmonary arrest prior to beginning CPR and ACLS. The most important prognostic factors are a prolonged delay in the onset of CPR, a prolonged duration of CPR, age less than 40 or greater than 70, the presence of hypotension and lactic acidosis after arrest, severe hypoxia before arrest, azotemia, hyperglycemia, and comorbid conditions such as sepsis, renal failure, and malignancy (64).

SUMMARY As the general population ages, acute and chronic heart failure is an increasingly important cause of morbidity and mortality in the adult surgical patient. While there are a large number of causes and exacerbating factors for heart failure, management issues may be similar. With this in mind, it is important to understand the pathophysiology of heart failure, because the treatment is aimed directly at influencing and hopefully reversing the maladaptive physiologic mechanisms both within the heart and systemically. Although there is great promise in the future for metabolic, molecular biologic, and sophisticated mechanical treatments for acute and chronic heart failure, early diagnosis and aggressive treatment while excluding reversible causes is and will remain the hallmark of treatment of heart failure. After more than 40 years of use, CPR remains a desperate effort to treat cardiopulmonary arrest, and, unfortunately, the benefits are limited to only a small number of patients. It is interesting that despite many efforts at change, the original technique of CPR has changed little throughout the years. Perhaps the greatest impact in the future will be the development of improved measures at prediction and prevention of arrest and improvement in postresuscitation measures.

medwedi.ru

674

Part Three: The Cardiothoracic System—Heart

REFERENCES 1. Mackenzie J. Principles of Diagnosis and Treatment in Heart Affections. London: Oxford University Press, 1916:38. 2. Taegtmeyer H. Energy metabolism of the heart, from basic concepts to clinical applications. Curr Probl Cardiol 1994; 11:64. 3. Isselbacher K, ed. Harrison’s Principles of Internal Medicine. New York: McGraw Hill, 1994:989. 4. Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia: WB Saunders, 1992:393. 5. Ho KK, et al. The epidemiology of heart failure, the Framingham study. J Am Coll Cardiol 1993; 22(suppl A):6A. 6. Willerson JT, ed. Treatment of Heart Diseases. London: Gower Medical Publishing, 1992:2.3. 7. Gerdes AM, et al. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation 1992; 86:426. 8. Weber KT, Brilla CC. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-aldosterone system. Circulation 1991; 86:426. 9. Langer GA. Calcium and the heart: exchange at the tissue, cell and organelle levels. FASEB J 1992; 6:893. 10. Ungerer M, et al. Altered expression of beta-1 adrenergic receptors in the failing human heart. Circulation 1993; 87:454. 11. Schwartz K, et al. Switches in cardiac muscle gene expression as a result of pressure and volume overload. Am J Physiol 1992; 262:364. 12. Goldsmith SR, Hasking GJ, Miller E. Angiotensin II and sympathetic activity in patients with CHF. J Am Coll Cardiol 1993; 21:1107. 13. Goldsmith SR, Dick C. Differentiating systolic from diastolic heart failure: pathophysiologic and therapeutic considerations. Am J Med 1993; 95:645. 14. Bristow MR. Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with beta blocking agents. Am J Cardiol 1993; 71:12C. 15. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987; 316:1429. 16. Pfeffer MA, et al. The effect of captopril on mortality and morbidity in patients with left ventricular dysfunction following myocardial infarction: Results of the survival and ventricular enlargement (SAVE) trial. N Engl J Med 1992; 327:669. 17. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced LV ejection fraction. N Engl J Med 1992; 327:685. 18. Harrison TR, et al. Congestive heart failure. The mechanism of dyspnea on exertion. Arch Int Med 1932; 50:690. 19. Hope JA. Treatise on the Diseases of the Heart and Great Vessels. London: Williams-Kid, 1832. 20. Mackenzie J. Diseases of the Heart. 3rd ed. London: Oxford University Press, 1913. 21. Carabello B. Clinical assessment of systolic dysfunction. ACC Curr J Rev 1994; 23:25. 22. Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of congestive heart failure: mechanisms and management. Ann Intern Med 1992; 117:502. 23. Fleisher LA, Eagle KA. Lowering cardiac risk in noncardiac surgery. N Engl J Med 2001; 345:1677. 24. Dolgin M, ed. Nomenclature and Criteria for Diagnosis of Disease of the Heart and Great Vessels. 9th ed. New York: Little Brown, 1994:253. 25. Scheuer J. Metabolic factors in myocardial failure. Circulation 1993; 87(suppl 7):VII54. 26. Chatterjee K. Acute Heart Failure, Critical Care Management. Boston: Little Brown, 1975:203. 27. Passmore J Jr., et al. Hemodynamic Support of the Critically 111 Patient in Cardiopulmonary Critical Care. Orlando, Florida: Grune & Stratton, 1986:359. 28. Braunwald E, et al. Effects of drugs and of counterpulsation on myocardial oxygen consumption. Circulation 1969; 40 (suppl 4):220.

29. Dikshit K, et al. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N Engl J Med 1973; 288:1087. 30. Kantrowitz A, et al. Initial clinical experience with intra aorta balloon pumping in cardiogenic shock. JAMA 1968; 203:135. 31. Taegtmeyer H. The use of hypertonic glucose, insulin and potassium (GIK) in myocardial preservation. J Appl Cardiol 1991; 6:255. 32. Grandinak S, et al. Improved cardiac function with glucoseinsulin-potassium after coronary bypass surgery. Ann Thorac Surg 1981; 48:484. 33. McElroy DD, Walker WE, Taegtmeyer H. Effects of glycogen on function and energy metabolism of the isolated rabbit heart after hypothermic ischemic arrest. J Appl Cardiol 1989; 4:455. 34. Hurst JW, ed. Current Therapy in Cardiovascular Diseases. Chicago: Mosby-Year Book, 1993. 35. Uren NG, Lipkin DP. Exercise training as therapy for chronic heart failure. Br Heart J 1992; 67:430. 36. Smith WHT, Ball SG. ACE inhibitors in heart failure: an update. Basic Res Cardiol 2000; 95(suppl 1):I8. 37. Katz AM. Treating heart failure: yesterday, today and tomorrow. Adv Cardiovasc 1994; Med 1:1. 38. Cohn JN, et al. Effects of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study (V-HeFT). N Engl J Med 1986; 314:1547. 39. Goldman S, et al. Mechanisms of death in heart failure: the vasodilator-HF trials. Circulation 1993; 3(87 suppl 6):VI-24. 40. Hochleitner M, et al. Usefulness of physiologic dual-chamber pacing in drug resistant idiopathic dilated cardiomyopathy. Am J Cardiol 1990; 66:198. 41. Gaash WH. Diagnosis and treatment of heart failure based on LV systolic or diastolic dysfunction. JAMA 1994; 271:1276. 42. Armstrong PW, Moe GW. Medical advances in the treatment of congestive heart failure. Circulation 1993; 88:2941. 43. Parrillo JE. Current Therapy in Critical Care Medicine. 2d ed. Philadelphia: BC Decker, 1991. 44. Clinical Practice Guideline #11. Rockville, Maryland: Agency for HealthCare Policy and Research, 1994:11. 45. DEFIBRILAT Study Group. Actuarial risk of sudden death while awaiting cardiac transplantation in patients with atherosclerotic heartdisease. Am J Cardiol 1991; 68:545. 46. Sonnenblick EH, LeJemtel TH. Heart failure: its progression and its therapy. Hosp Pract Sept 1993; 75. 47. Reiken S, Gaburjakova M, Gaburjakova J. Beta-adrenergic receptor blockers restore cardiac calcium release channel (iyanodine receptor) structure and function in heart failure. Circulation 2001; 104:2843. 48. Lenfant C. Report of the task force on research in heart failure. Circulation 1994; 90:1118. 49. Watkins H, et al. Characteristics and prognostic implications of myosin missense mutation in familial hypertrophic cardiomyopathy. N Engl J Med 1992; 326:1108. 50. del Monte F, Hajjar RJ, Harding SE. Overwhelming evidence of the beneficial effects of SERCA gene transfer in heart failure. Circ Res 2001; 88:E66. 51. Hejtmancik JF, et al. Localization of the gene for familial hypertrophic cardiomyopathy to chromosome 14ql in a diverse US population. Circulation 1991; 83:1592. 52. Kouwenhoven WB, Jude JR, Knickerbocker GG. Closed-chest cardiac massage. JAMA 1960; 173:1064. 53. Tucker KJ, et al. Cardiopulmonary resuscitation: historical perspectives, physiology, and future directions. Arch Intern Med 1994; 154:2141. 54. Rudikoff MT, et al. Mechanisms of blood flow during cardiopulmonary arrest. Circulation 1980; 61:345. 55. Chandra N, et al. Contrasts between intrathoracic pressures during external clot compression and cardiac massage. Crit Care Med 1981; 9:789. 56. Schleien CL, et al. Controversial issues in cardiopulmonary resuscitation. Anesthesiol 1989; 71:133. 57. Criley YM, et al. Modification of cardiopulmonary resuscitation based on cough. Circulation 1986; 74(suppl 4):42.

Chapter 33: 58. Ornato JP, et al. Rapid changes in pulmonary vascular hemodynamics with pulmonary edema during CPR. Am J Emerg Med 1985; 3:237. 59. Einagle V, et al. Interposed abdominal compress and carotid blood flow during CPR. Chest 1988; 93:1206. 60. Safar P, Bricher NG. Cardiopulmonary Cerebral Recirculation. 3rd ed. Philadelphia: WB Saunders, 1988:229. 61. Lumpkin JR, Safar P. Brain resuscitation after cardiac arrest. In: Harwood AL, ed. CPR. Baltimore: Williams & Wilkins, 1982:55. 62. Stiell IG, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med 1992; 327:1045. 63. Behringer W, Kittler H, Sterz F, et al. Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med 1998; 129:450.

Heart Failure and Resuscitation

675

64. Kern KB, Halperin HR, Field J. New guidelines for cardiopulmonary resuscitation and emergency cardiac care: changes in the management of cardiac arrest. JAMA 2001; 285:1267. 65. Hallstrom A, Cobb L, Johnson E, et al. Cardiopulmonary resuscitation by chest compression alone or with month-to-month ventilation. N Engl J Med 2000; 342:1546. 66. International guidelines 2000 conference on cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2000; 102(suppl I):II36. 67. Gudipati CV, et al. Expired carbon dioxide: a noninvasive monitor of CPR. Circulation 1988; 77:234. 68. Burns R, et al. Prediction of in-hospital cardiopulmonary arrest outcome. Arch Intern Med 1989; 149:1318.

medwedi.ru

34 Mechanical Support for the Failing Heart: Current Physiologic Concepts of Management Sina L. Moainie and Bartley P. Griffith

INTRODUCTION The development of the extracorporeal heart–lung machine, or cardiopulmonary bypass (CPB) circuit as it is sometimes called, made possible heart surgery as we know it today. Even with this technology, however, not all patients with cardiac disorders are suitable candidates for coronary bypass operations or valve replacement surgery due to the magnitude of the underlying disease. Fortunately, other technological advances have occurred so that devices are now available to support even the most profound circulatory failure. These include the intra-aortic balloon pump (IABP) for acute management of cardiac failure and the left ventricular assist device (LVAD) for chronic end-stage LV failure. While such devices are generally employed to salvage whatever cardiac function exists in anticipation for future cardiac transplantation, more recent technological approaches have aimed at the management of the failing heart from the standpoint of maintaining additional years of meaningful life even when transplantation is not a suitable alternative. This chapter reviews the technological strategies currently available to support the failing circulation and which patients are likely to benefit most from these approaches.

CARDIAC SUPPORT IN END-STAGE HEART FAILURE Pathophysiology of Heart Failure Heart failure is defined as the pathologic state in which the heart is unable to pump blood at a rate adequate to meet the physiologic requirements of the tissues despite normal cardiac filling pressures (1). This disease affects an estimated five million Americans, with approximately 550,000 new cases diagnosed each year (2). Coronary artery disease is the most common etiology of heart failure with only approximately 30% of cases of heart failure resulting from other causes including congenital malformations, valvular disease, or viral or idiopathic cardiomyopathy (3). Following an initial event resulting in diminished cardiac function, a number of compensatory mechanisms are initiated to maintain normal organ perfusion. In response to the decrease in cardiac function, the sympathetic nervous system and the renin–angiotensin system are activated. Release of the neurotransmitter norepinephrine from cardiac adrenergic nerves results in increased vascular tone, leading to improved preload and increased myocardial contractility. Activation of the renin–angiotensin system not only increases preload via an increased renal fluid retention, but also results in vasoconstriction mediated by angiotensin II. The combined effect of the sympathetic and renin–angiotensin response is an increase in preload and myocardial contractility with an ensuing increase in stroke volume via the Starling mechanism.

While the activation of the sympathetic nervous system and rennin–angiotensin system are initially compensatory in response to diminished cardiac function, these responses ultimately become maladaptive. The progressive decompensation in ventricular function following an index cardiac event is a consequence of adverse ventricular remodeling. The chronic increase in preload and vascular tone increases myocardial wall stress, which sets in motion a biochemical cascade resulting in regional and global myocardial dysfunction (4). Additionally, angiotensin II and aldosterone stimulate collagen synthesis and inhibit collagen degradation leading to interstitial fibrosis (5–7). Pathologic increases in myocardial interstitial collagen content reduce ventricular filling by increasing diastolic stiffness (8). The physiologic consequences of altered ventricular stiffness are manifest by increased central venous and pulmonary artery pressures as well as decreased cardiac output. Another maladaptive consequence of ventricular remodeling is an increase in ventricular volume and sphericity (9,10). Increased ventricular sphericity, volume, and stiffness have all been demonstrated to result in increased ventricular wall stress with an ensuing increase in myocardial metabolic requirements (8). The mismatch between increasing myocardial metabolic requirements and decreasing cardiac output results in progressive myocardial ischemia. Because intramyocardial pressure has its most profound effects on the subendocardium, it is this region that is most affected by the decrease in blood flow. Several investigators have hypothesized that it is this mismatch between increasing myocardial oxygen demand and decreasing coronary perfusion that leads to the progressive decline in function in advanced heart failure (11,12). Myocyte loss occurs in the failing heart not only due to necrosis from subendocardial ischemia, but also from myocardial apoptosis. Apoptosis, or programmed cell death via an energy-requiring enzymatic destruction of myocyte DNA, has been demonstrated in failing hearts (13,14). The exact mechanism by which myocardial apoptosis is initiated is as yet unclear, but factors that initiate cellular apoptosis such as upregulation of the gene p53, and increase of the cytokine tumor necrosis factor–alpha have been observed in failing hearts. Additionally, oxygen free-radical generation in response to increased ventricular wall stress has also been implicated in the induction of myocyte apoptosis (15). The end result of the combined effects of increased myocardial metabolic need, diminishing cardiac function, and progressive myocyte loss lead to a heart that is unable to meet the metabolic needs of the body. Ongoing tachycardia and increasing sympathetic tone secondary to decreased cardiac output further exacerbate the vicious downward spiral resulting in advancing cardiac dysfunction ultimately

medwedi.ru 677

678

Part Three: The Cardiothoracic System—Heart

leading to a heart that is unable to meet the resting metabolic requirements of the tissues. The disparity between the continually increasing population of patients with advanced heart failure and the fixed supply of donor organs for cardiac transplantation has fueled the interest in mechanical support for the failing heart.

Mechanical Circulatory Support Currently, approximately 6000 patients per year in the United States receive some form of cardiac support following cardiac surgery. The hospital survival for these patients ranges between 20% and 40%. An additional 400 patients per year receive a cardiac support device as a bridge to transplantation, with a survival rate through transplantation ranging between 50% and 70% (16). With the approval of ventricular assist devices for permanent use or ‘‘destination’’ therapy of heart failure, the number of assist devices implanted is expected to increase significantly in the future. Cardiac support devices may be divided into two broad categories; those designed for acute use of days to two weeks and those for longer bridge-to-transplant (BTT) or permanent support.

Acute Support Devices Intra-Aortic Balloon Pump The easiest device to apply and the most commonly used remains intra-aortic balloon counterpulsation, which was introduced clinically in 1967 to support patients with acute cardiac decompensation (17). The IABP (Fig. 1) consists of a catheter-mounted inflation/deflation balloon that is positioned in the descending thoracic aorta just distal to the takeoff of the left subclavian artery. It is usually placed using percutaneous introduction into a femoral artery. Generally, the device is inserted in an intensive care unit, in a cardiac catheterization laboratory, or in a cardiac surgical suite. A patient supported by IABP must remain prone with the hip fully extended. This limits its use to less than a week. The indications for IABP support include (i) cardiogenic shock secondary to an ischemic event, (ii) acute treatment of intractable angina prior to planned coronary intervention, (iii) temporary cardiac support of a patient with perioperative cardiogenic shock, or (iv) periprocedural support during complex angioplasty (18,19). Chief in the decision to proceed with IABP placement is the assumption that the source of the cardiogenic shock and/or ischemia necessitating support is thought to be temporary (planned revascularization of ischemic myocardium or anticipated rapid ventricle recovery from post-CPB myopathy). Contraindications to placement of an IABP include aortic valvular insufficiency, aortic dissection, distal aortic occlusion, large aortic aneurysm, or severe peripheral vascular disease. The IABP augments cardiac function by increasing diastolic blood pressure and reducing afterload. Using ECG, aortic pressure, or set pacing as a trigger, the balloon is set to inflate just after the aortic valve closes and to deflate just after the aortic valve opens. The effectiveness of the device is limited at heart rates above 120 bpm and when ventricular arrhythmia is common. Inflation begins just after the aortic valve closes (the start of diastole), and the increased pressure within the proximal aorta raises the diastolic pressure and thus the coronary perfusion. The augmentation of coronary perfusion pressure reduces myocardial ischemia, which then leads to an improvement in myocardial contractility. Given that the balloon functions in part by augmenting diastolic flow, aortic insufficiency is a

Figure 1 Illustration demonstrating correct positioning of intra-aortic balloon pump with proximal aspect just distal to branching of the left subclavian artery. Source: Courtesy of Arrow International, Reading, Pennsylvania, U.S.A.

contraindication to IABP placement because the increase in diastolic pressure would exacerbate aortic regurgitation and lead to increased LV distention. Deflation of the balloon immediately after the aortic valve opens (the start of systole) causes a decrease in the aortic volume (volume occupied by the inflated balloon). Because pressure is directly proportional to volume, deflation of the balloon leads to a resultant decrease in the systolic aortic pressure (afterload). Decreased afterload and increase in coronary perfusion combine to result in an increase in cardiac output of approximately 10% to 25%. The IABP is most commonly introduced via the femoral artery using a percutaneous Seldinger technique. When extensive occlusive peripheral vascular disease prevents femoral arterial access, the IABP may be introduced directly into the thoracic aorta; this approach is rarely used because this mode of insertion would necessitate a thoracotomy. This approach has been used after cardiac surgery, but most surgeons opt for placement of a temporary ventricular assist device in lieu of an IABP in this circumstance (20). Fluoroscopy is generally not necessary for IABP placement but a chest radiograph should be obtained following placement to confirm correct positioning. The radiopaque tip of the balloon should be positioned just distal to the takeoff of the left subclavian artery, which can be identified radiographically using the second rib as a landmark. The complications of IABP use include visceral or limb ischemia,

Chapter 34: Mechanical Support for the Failing Heart

arterial perforation, retroperitoneal hemorrhage, aortic dissection, and thrombocytopenia resulting from platelet aggregation secondary to a foreign body reaction (21,22). Visceral ischemia may be the result of balloon malposition and may be treated with repositioning of the device. Daily chemistry profiles may alert the clinician to visceral malperfusion as evidenced by rising tests of liver function, serum creatinine or decreasing serum bicarbonate. Limb ischemia is the most common complication of IABP use occurring in 5% to 19% of patients (23). Often limb ischemia resolves with the removal of the IABP, but surgical intervention in the form of angiography, thrombectomy, or angioplasty is required in some cases. Any patient with a femorally placed IABP should have hourly assessment of distal perfusion by physical examination and bedside Doppler. Most physicians opt to anticoagulate patients with heparin to reduce the risk of arterial thrombosis and emboli. Daily complete blood count measurements can alert the clinician to the possibility of hemorrhage or the development of thrombocytopenia. When the patient demonstrates recovery of ventricular function as evidenced by a cardiac index greater than 2.0 L/min/m2, a systolic blood pressure greater that 90, and an absence of metabolic acidosis while on minimal inotropic support, IABP support may be withdrawn. Weaning of the IABP is accomplished by decreasing the frequency of augmentation from 1:1 (in which the IABP augments every heart beat) to 1:2 and then 1:3 (IABP augments every third heart beat) in stepwise increments decreasing support every two to three hours. If the patient has continued stable hemodynamics with no increasing inotrope requirement with the IABP on 1:3 augmentation, the device may be removed (24). Ventricular Assist Devices While the IABP is relatively easy to use and can be applied within minutes, often the degree of cardiac dysfunction is more than can be supported with counterpulsation. Several devices have been approved to address this profound loss of cardiac function. These fully supporting blood pumps are identified commonly as ventricular assist devices. Several have been targeted for very short-term use of approximately one week, while others are designed with more durable components and have supported patients for up to several years (Table 1). Short-Term Ventricular Assist Devices. Both the devices currently in use for short-term ventricular support are extracorporeal pulsatile systems. The Thoratec ventricular assist system (VAS) (Fig. 2) is a pneumatically powered device that may be used for univentricular or biventricular support. This pump is composed of a polyurethane compressible

679

Figure 2 Illustration demonstrating biventricular support with Thoratec device. Right ventricular support utilizes right atrial inflow and pulmonary artery outflow. Left ventricular (LV) support is achieved using LV apical inflow and aortic outflow.

sac-like chamber that draws blood from and through inlet and outlet valves. It has been used as short-term postcardiotomy support for 7 to 10 days but also is durable for longer BTT type support, lasting months or even years. The device is approved for out-of-hospital use, and the pneumatic power source has a rechargeable battery and is packaged in a roll-on type suitcase. When used for LV support, the inflow (fill) cannula is placed either into the LV apex or via the right side interatrial groove into the left atrium. The outflow graft is sewn to the ascending aorta. The right atrium provides inflow and the main pulmonary artery is used for outflow in cases of right ventricular support. Bjork-Shiley mechanical tilting-disk valves are incorporated within the device housing to ensure unidirectional flow. The inlet and outlet cannulae are externalized subcostally and connected to the pump that is powered using pressurized air controlled by the external drive console. The Thoratec VAS has a maximum stroke volume of 65 cc and can provide 6.5 L/min of flow (25). When used for biventricular support, the right ventricular assist device (RVAD) is

Table 1 Mechanical Circulatory Assist Available in the United States Device ABIOMED BVS5000 AB50001 Ventricle IAPB Thoratec VAD HeartMate VAD WorldHeart VAD CardioWest TAH MicroMed Axial VAD Jarvik Axial VAD

Power

Type

Target indication

Duration of use

FDA approval

Pneumatic Pneumatic Pneumatic Pneumatic Electric Electric Pneumatic Electric Electric

Pulsatile extracorporeal Pulsatile extracorporeal Pulsatile extracorporeal Pulsatile extracorporeal Pulsatile intracorporeal Pulsatile intracorporeal Pulsatile intracorporeal Continuous flow intracorporeal Continuous flow intracorporeal

Postcardiotomy shock Postcardiotomy shock and BTT Acute cardiac decompensation/ischemia Postcardiotomy shock and BTT BTT permanent use BTT Permanent use BTT BTT BTT

24 hr to 10 days 1–6 mo 1–7 wk 1 wk to 1 yr 1 mo to 1.5 yr 1 mo to 1 yr 1 mo to 1 yr 1 mo to 1 yr 1 mo to 3 yr

þ þ þ þ (BTT) BTT, destination þ (BTT) BTT – –

Abbreviations: BTT, bridge-to-transplant; FDA, Food and Drug Administration; VAD, ventricular assist device; TAH, total artificial heart.

medwedi.ru

680

Part Three: The Cardiothoracic System—Heart

set at an output that is less than that of the LVAD to prevent pulmonary congestion. The Thoratec VAS may be programmed to operate in a fixed rate, volume, or synchronous mode. In the volume mode, the pump is triggered to contract when the sac is fully filled. The volume mode is most commonly utilized and provides maximum output. The synchronous mode uses the r-wave of the patient’s electrocardiogram for triggering and is most effective for weaning from support. As with the IABP, assist device can be set from a range of 1:1 to 1:3, and weaning is accomplished in a similar manner as with the IABP by gradually reducing the number of assisted heartbeats (26–28). The Thoratec is useful for acute cardiac decompensation usually associated with failed cardiac surgery. It is unique in that it is also durable enough to provide long-term BTT support as well. Because it is positioned paracorporeally, it can be used in patients of small body size (body mass index 1.25 m2) and is the choice of most surgeons when severe biventricular failure indicates the need for combined left and right ventricular support. Because the patient’s blood is in contact with the prosthetic material of the cannula, valves and pump sac that activate clotting, and anticoagulation are required. Generally, the circumstance requiring univentricular support is one in which the left ventricle has suffered an acute (ischemic) or chronic power failure. In this circumstance, the ability of the native right ventricle to deliver blood flow across the left heart is critical in determining the adequacy of univentricular versus biventricular support. As with the Thoratec VAS, the Abiomed BVS5000 (Fig. 3) is a paracorporeal pulsatile ventricular assist device that may be used for left, right, or biventricular support. It is economical and thus is available in most cardiac surgical suites. It is easy to insert and operate, but it lacks durability and has a relatively high incidence of emboli within 10 days of use. Unlike the Thoratec device, the Abiomed BVS5000 requires the patient to remain recumbent. Cannulation for right and left ventricular support is identical to that for the Thoratec device. Like the heart itself, the Abiomed device contains a reservoir that receives blood from the inflow chamber. This chamber in turn loads the pumping chamber. The chambers are connected by a unique trileaflet polyurethane valve that assures unidirectional flow (29). Blood flows into the pump by gravity, and a drive console is used to pneumatically compress the pumping chamber. The device is designed for complete support of the left and/or right heart, and the system microprocessor manages the duration of pump systole and diastole to optimize pump function and maintain a targeted stroke volume of 83 mL after cardiac surgery. The Abiomed BVS5000 also requires the use of systemic anticoagulation as soon as mediastinal hemorrhage abates to prevent formation of device-related thrombus. Recently, the Abiomed company has introduced a pneumatic, sac-like ventricular assist devices (VAD) with polyurethane inlet and outlet valves that connect to the same cannulae for easy exchange. This device, like the Thoratec, is more durable and expensive than the ABVS5000, and permits patients to ambulate in the hospital. Long-Term Ventricular Assist Devices. A number of devices have been developed to target the need for long-term LV support. Most of the systems use a similar cannulation schema with an LV apical conduit used for device inflow and the ascending aorta used for device outflow. Because the aim of all of the long-term assist devices is to provide outpatient support, these devices tend to use small electric

Figure 3 (A) Illustration of Abiomed BVS5000 paracorporeal pulsatile ventricular assist device demonstrating position of chambers in pump diastole and systole. (B) In vivo positioning of Abiomed BVS5000.

AC battery power and controller modules. The newer flexible and small bore percutaneous power cords have been well tolerated and generally have not been a source of inevitable driveline infection that ascends along the subcutaneous track or seeds the intimal components of the device via homologous spread. WorldHeart Novacor LVAS. The WorldHeart Novacor LVAS (Fig. 4) is placed via an extended median sternotomy with

Chapter 34: Mechanical Support for the Failing Heart

681

Figure 5 Illustration demonstrating left ventricular (LV) support with the Thoratec XVE. Inflow is via LV apex and outflow is via proximal aorta. Abbreviations: LVAD, left ventricular assist device. Figure 4 Illustration demonstrating left ventricular (LV) support with the Novacor LVAD. Inflow is via LV apex and outflow is via proximal aorta.

the LV apex inflow and aortic outflow conduits connected to the pump that is positioned in the anterior abdominal wall. The pump utilizes two electrically powered opposing pusher plates to eject blood and bioprosthetic valves within the conduits to ensure unidirectional flow. A percutaneous cable connects the pump to the external controller and battery pack, both of which may be worn on a belt to provide for excellent patient mobility. The cable also contains the vent line for the pump. In addition to the fixed-rate mode, the device may also be operated in a synchronized mode that uses an electrocardiographic signal to time pump diastole to cardiac systole and vice versa. The synchronized mode thus provides the most effective means of cardiac unloading because the heart is ejecting into the low resistance pump hence limiting strain on the heart. Although the Novacor LVAS employs smooth, seamless blood-contacting surfaces and bioprosthetic valves to limit thrombogenicity, systemic anticoagulation is still required during the period of support. Thoratec HeartMate VE LVAS. The Thoratec HeartMate VE LVAS (Fig. 5) is electrically powered. The motor drives a cam mechanism up and down to power the pusher-plate mechanism. An external vent is utilized to equalize air pressure and provide a means for emergency pneumatic device actuation. Should the electrical motor fail, the device may be pneumatically powered by a hand-held portable pump. The electrical motor is normally powered by two rechargeable batteries, delivering four to six hours of power per charge. The batteries may be worn on a vest or belt, thus allowing for high degree of mobility (30,31). A unique feature of the HeartMate device is that the blood-contacting surfaces of the device are designed to promote deposition of circulating cells creating a ‘‘pseudoneointimal’’ layer that discourages platelet adhesion and thrombosis. Additionally,

the device uses a pusher-plate blood pump that creates a central vortex of blood preventing stagnant flow. The combination of these features reduces the likelihood of thrombus formation and so lesser degrees of anticoagulation are required for use of the device, and in fact, the device may be used safely with no anticoagulation when used for longterm support (32). Lionheart LVD2000 LVAS. The Lionheart System (Fig. 6) is similar in design to other long-term displacement pumps in that it includes an LV apex inflow conduit and aortic outflow conduit that are connected to a subdiaphragmatically placed VAD. The device uses an electrically powered roller screw mechanism to power a pusher plate that compresses the blood sac. Tilting-disk valves provide unidirectional flow. Uniquely, the Lionheart system utilizes a transcutaneous energy transmission system that transfers power from the external battery pack across intact skin using electromagnetic induction. By utilizing a transcutaneous power transfer mechanism, the Lionheart device eliminates the need for a transcutaneous driveline or cables, theoretically reducing the risk of infection (33). Because there is no percutaneous driveline to vent the displacement of the sac, the Lionheart includes an intrathoracically placed compliance chamber that allows air to be vented to the chamber during diastole and toward the pump during systole. The compliance chamber is placed in the left thorax. To counteract passive diffusion of gas out of the chamber and into the surrounding tissue, the chamber is recharged with atmospheric air every few weeks through a subcutaneous port. Long-Term Nonpulsatile Ventricular Assist Devices. All of the implantable pulsatile LVADs share several disadvantages that include relatively large size, the need for valves to prevent reversal of flow, and the need for either a large bore percutaneous vent/driveline or a compliance chamber. Several continuous axial flow pumps currently under clinical

medwedi.ru

682

Part Three: The Cardiothoracic System—Heart

Figure 6 Illustration demonstrating left ventricular (LV) support with the Lionheart Left Ventricular Assist Device (LVAD). Inflow is via LV apex and outflow is via proximal aorta. The compliance is placed within the right chest. Source: Courtesy of Arrow International, Reading, Pennsylvania, U.S.A.

trial potentially overcome these limitations. Given the extremely small ‘‘D-cell battery’’ size of the axial flow pumps, the devices may be thought of essentially as ‘‘powered apicoaortic conduits’’ that can provide up to 5 to 6 L/min of nonpulsatile flow using the LV apex for inflow and the aorta for outflow. The devices currently undergoing investigation in the United States are the HeartMate II, Jarvik 2000 (Fig. 7),

Figure 8 Illustration demonstrating replacement of native heart with the CardioWest Total Artificial Heart.

and DeBakey/NASA LVAD (34–36). These devices provide continuous flow and induce a reduced pulse pressure. Generally, most of these pumps have been used to assist the left ventricle as opposed to completely replacing its function. Most investigators tend to run their pumps at a speed that enables LV ejection and thus pulsatile flow. Total Artificial Heart The CardioWest C-70 Total Artificial Heart (Fig. 8) (formerly called the Symbion or Jarvik Total Artificial Heart) allows for total, biventricular cardiac support using a pulsatile pneumatically powered pump. The device is placed orthotopically and requires native cardiectomy for placement. Mechanical valves housed in the inflow and outflow orifices ensure unidirectional flow. The device is powered and controlled by an external console that is connected to the pump via a percutaneous driveline (37). The device does require anticoagulation to prevent thrombus formation.

Clinical Use of Mechanical Circulatory Support Devices Figure 7 Illustration of the original concept for the Jarvik 2000 fully implanted system with the use of lithium polymer batteries and electronics implanted within the prosthetic ribs. Inflow is via left ventricular apex and outflow is via the descending thoracic aorta. Source: Courtesy of Rob Jarvik, M.D., Jarvik World Heart, New York, New York, U.S.A.

Currently, mechanical cardiac support is used both as a BTT and more recently as destination therapy. A recent study demonstrated significantly improved survival in transplant recipients who were supported with an LVAD versus those in a control group (71% vs. 36%, respectively, 90 days posttransplant) (38). The improved survival is most likely secondary to the superiority of mechanical support over

Chapter 34: Mechanical Support for the Failing Heart

medical therapy in providing tissue perfusion thus enabling improved peritransplant organ function leading to improved survival. The benefits of mechanical circulatory support are balanced to some degree by the complications associated with device use. Bleeding and infection are the most prevalent complications associated with mechanical support devices. Bleeding rates are described as high as 60% and are more likely in patients requiring biventricular support as compared to those requiring univentricular support. The high rate of bleeding is related to coagulopathy due to heart failure–induced hepatic dysfunction, and the combined effects of CPB and device-related rheology resulting in platelet dysfunction (39). Infection rates range from 30% to 40% and this results in significant morbidity. The newer totally implantable devices eliminate percutaneous cables, which should theoretically reduce infection rates by eliminating the significant factor of a percutaneous portal of entry of infectious agents.

11.

12.

13. 14. 15. 16.

17.

SUMMARY This chapter has summarized the enormous advances that have been made in recent years to support the failing circulation due to underlying heart disease. Not only can survival from acute cardiac failure be anticipated in many patients using IABP, but chronic end-stage LV failure can also be now supported for months to years, if necessary, in anticipation of cardiac transplantation. Even when the latter approach is not a suitable option, the LVAD has been shown to afford meaningful life in patients who a decade ago would have been subjected to sudden death. While the total artificial heart is still in its infancy, models currently available have been shown to support the entire circulation satisfactorily for many months. It is only a matter of time until an artificial heart is developed, which can add years to the life of a cardiac cripple who without such technology would die.

REFERENCES

18.

19.

20.

21.

22.

23.

24.

1. Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia: WB Saunders, 2001. 2. American Heart Association. Heart Disease and Stroke Statistics— 2004 Update. Dallas, TX: American Heart Association, 2003. 3. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 1998; 97:282–289. 4. Jackson BM, Gorman JH, Moainie SL, et al. Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. JACC 2002; 40:1160–1167. 5. Tan LB, Jalil HE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991; 69: 1185–1191. 6. Brilla CG, Maische B. Regulation of the structural remodeling of the myocardium: from hypertrophy to heart failure. Eur Heart J 1994; 15(suppl D):45–52. 7. Brilla CG, Matsubara L, Wber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary aldosteronism. J Mol Cell Cardiol 1993; 25:563–575. 8. Beltrami CA, Finato N, Rocco M, et al. Structural basis of endstage failure in ischemic cardiomyopathy in humans. Circulation 1994; 89:151–163. 9. Borow KM, Neumann A, Wynne J. Sensitivity of end-systolic pressure-dimension and pressure-volume relations to the inotropic state in humans. Circulation 1982; 65:988–997. 10. Lamas GA, Vaughan DE, Parisi AF, Pfeffer MA. Effects of left ventricular shape and captopril therapy on exercise capacity

25. 26.

27.

28.

29.

30.

31.

32.

683

after anterior wall acute myocardial infarction. Am J Cardiol 1989; 63:1167–1173. Unverferth D, Magorien R, Lewis R, Leier C. The role of subendocardial ischemia in perpetuating myocardial failure in patients with non-ischaemic congestive cardiomyopathy. Am Heart J 1983; 105:176–179. Parodi O, De MR, Oltrona L, et al. Myocardial blood flow distribution in patients with ischemic heart disease or dilated cardiomyopathy undergoing heart transplantation. Circulation 1993; 88:509–522. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996; 335:1182–1189. Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med 1997; 336:1131–1141. Mak S, Newton GE. Oxidative stress hypothesis of congestive heart failure: radical thoughts. Chest 2001; 120(6):2035–2046. Stevenson LW, Kormos RL. Mechanical cardiac support 2000: current applications and future trial design. JACC 2001; 35(1):340–370. Kantrowitz A, Tjonneland S, Freed PS, Phillips SJ, Butner AN, Sherman JL Jr. Initial clinical experience with the intraaortic balloon pumping in cardiogenic shock. JAMA 1968; 203: 113–118. McEnany MT, Kay HR, Buckley MJ, et al. Clinical experience with intraaortic balloon pump support in 728 patients. Circulation 1978; 58:I124–I132. Kern MJ, Ahuirre F, Bach R, Donahue T, Siegel R, Segal J. Augmentation of coronary flow by intra-aortic balloon pumping in patients after coronary angioplasty. Circulation 1993; 87:500. Gueldner GL, Lawrence Gh. Intra-aortic balloon assist through cannulation of the ascending aorta. Ann Thorac Surg 1975; 19:88–91. Creswell LL, Rosenbloom M, Cox JL, Ferguson TB Sr, Kouchoukos NT, Spray TL. Intraaortic balloon counterpulsation: patterns of usage and outcome in cardiac surgery patients. Ann Thorac Surg 1992; 54:11–20. Macoviak J, Stephenson LW, Edmunds LH Jr, Harken AH, Macvaugh H. The intraaortic balloon pump: an analysis of five years experience. Ann Thorac Surg 1980; 29:451–480. Lefemine AA, Kosowsky B, Madoff I, Black H, Lewis M. Results and complications of intra-aortic balloon pumping in medical and surgical patients. Am J Cardiol 1977; 40:416–420. Baumgartner WA, Owens SG, Cameron DE, Reitz BA. The Johns Hopkins Manual of Cardiac Surgical Care. St. Louis: Mosby-Year Book, 1994. Hunt SA, Frazier OH. Mechanical circulatory support and cardiac transplantation. Circulation 1998; 97:2079–2090. Ko¨rfer R, El-Banayosy A, Posival H, et al. Mechanical circulatory support with the Thoratec assist device in patients with post-cardiotomy shock. Ann Thorac Surg 1996; 61:314–316. McBride LR, Naumheim KS, Fiore AC, et al. Clinical experience with 111 Thoratec ventricular assist devices. Ann Thorac Surg 1999; 67(5):1233–1238; discussion 1238–1239. Ko¨rfer R, El-Banayosy A, Arusoglu L, et al. Temporary pulsatile ventricular assist devices and biventricular assist devices. Ann Thorac Surg 1999; 68(2):678–683. Gray LA, Champsaur CG. The BVS 5000 biventricular assist device: the worldwide registry experience. ASAIOJ 1994; 40:M460–M464. Oz MC, Argenziano M, Catanese KA, et al. Bridge experience with long-term implantable left ventricular assist device. Circulation 1997; 95:1844–1852. McCarthy PM, Smedira NO, Vargo RL, et al. One hundred patients with the Heartmate left ventricular assist device: evolving concepts and technology. J Thorac Cardiovasc Surg 1998; 115:904–912. Rose EA, Levin HR, Oz MC, et al. Artificial circulatory support with textured interior surfaces: a counterintuitive approach to minimizing thromboembolism. Circulation 1994; 90:II-87–II-91.

medwedi.ru

684

Part Three: The Cardiothoracic System—Heart

33. Pagani FD, Aaronson KD. Mechanical circulatory support. In: Greenfield LJ, Mulholland MW, Oldham KT, Zelenock GB, Lillemoe KD, eds. Surgery: Scientific Principles and Practice. 3rd ed. Philadelphia: Lippincott, 2001:1505–1528. 34. Westaby S, Katsumata T, Houel R, et al. The Jarvik 2000 Oxford System: increasing the scope of mechanical circulatory support. J Thorac Cardiovasc Surg 1997; 114:467–474. 35. Westaby S, Katsumata T, Houel R, et al. Jarvik 200 Heart: potential for bridge to myocyte recovery. Circulation 1998; 98:1568–1574. 36. DeBakey ME. A miniature implantable axial flow ventricular assist device. Ann Thorac Surg 1999; 68:637–640.

37. Copeland JG, Pavie A, Duveau D, et al. Bridge to transplantation with the CardioWest total artificial heart: an international experience 1993 to 1995. J Heart Lung Transplant 1996; 15(pt 1): 94–99. 38. Frazier OH, Rose EA, McCarthy P, et al. Improved mortality and rehabilitation of transplant candidates treated with longterm implantable left ventricular assist system. Ann Surg 1995; 222:327–336. 39. Goldstein DJ, Beauford RB. Left ventricular assist devices and bleeding: adding insult to injury. Ann Thorac Surg 2003; 75:S42–S47.

35 Congenital Heart Lesions Ralph S. Mosca and Edward L. Bove

INTRODUCTION The surgical treatment of congenital heart defects has progressed at a rapid rate since its beginning more than half a century ago. Numerous technical achievements have been made possible by advances in many fields. Precise knowledge of anatomy and physiology, detailed noninvasive diagnostic capabilities, better perfusion and myocardial preservation techniques, and improved neonatal intensive care have all played major roles in allowing the management of congenital heart disease to progress to this extent. Nearly all congenital heart defects are now amenable to surgical repair. This chapter discusses the pathophysiology underlying some of the cardiac defects more commonly encountered by the pediatric cardiac surgeon and covers the physiologic rationales behind their treatment.

ADJUSTMENTS IN THE CIRCULATION AFTER BIRTH Although it is beyond the scope of this chapter to discuss in detail the physiology of the intrauterine circulation and its adaptation to extrauterine life, a brief description is included to aid in the understanding of the topics to follow. Oxygen-enriched placental blood returns to the fetus through the umbilical vein and then passes through the liver. There it joins the inferior vena caval return and enters the right atrium. Much of this blood passes across the patent foramen ovale (PFO) by preferential streaming into the left atrium, left ventricle, and ascending aorta, from where it is distributed to the brain and coronary circulations (Fig. 1). Superior vena caval return is directed across the right atrium, tricuspid valve, and right ventricle to be ejected into the pulmonary artery. Nearly all this blood passes across the patent ductus arteriosus (PDA) into the descending aorta. Because the ductus is nonrestrictive, both ventricles essentially function as a unit and eject blood against the same overall resistance. However, systemic vascular resistance is low because of the placental circulation, and pulmonary vascular resistance (PVR) is high in the nonaerated fetal lung, resulting in less than 10% of the fetal cardiac output going to the lungs. At birth, the placenta is eliminated from the circulation, resulting in an abrupt rise in the systemic vascular resistance. Expansion of the lungs leads to a fall in PVR. As arterial and alveolar partial pressure of oxygen (PO2) increase, PVR falls further and pulmonary blood flow rises, resulting in an increase in the left arterial pressure and functional closure of the flap valve of the foramen ovale. The increase in arterial PO2 also causes constriction of the smooth muscle in the wall of the ductus arteriosus, closing the duct and completing the separation of the two

circulations. PVR falls to adult normal levels within two to four weeks in the term infant.

CONGESTIVE HEART FAILURE Simply defined, congestive heart failure is the failure of myocardial oxygen supply to meet oxygen demand. The classic findings of congestive heart failure in infants include tachypnea, tachycardia, diaphoresis, and hepatomegaly. Peripheral edema and rales are not typically noted in infants. The neonatal myocardium is already functioning at maximal stroke volume and can only increase cardiac output by increasing heart rate. Further, the neonatal myocardium has a reduced density of contractile elements. For these reasons, the already stressed neonate with limited cardiac reserve is easily susceptible to congestive heart failure. Congenital heart disease typically results in congestive heart failure in either of two ways, volume overload or pressure overload. Volume overload occurs with either a large communication between the systemic and pulmonary circulations or valvular regurgitant lesions (Fig. 2). When a left-to-right shunt occurs, the volume of shunted blood depends on

Figure 1 Course of the intracardiac circulation before birth. Most inferior vena caval blood passes across the PFO to the left atrium. The superior vena caval return is directed predominantly across the PDA. Abbreviations: PFO, patent foramen ovale; PDA, patent ductus arteriosus.

medwedi.ru 685

686

Part Three: The Cardiothoracic System—Heart

and the branch pulmonary arteries (tetralogy of Fallot). Resistance to flow through the obstruction is at least that through the communication, allowing desaturated blood to enter the systemic circulation directly. Cyanosis may also occur as a result of inadequate mixing of the blood between the systemic and pulmonary circulations. This situation is classically seen in transpositiontype physiology. Although total systemic and pulmonary blood flow may be normal or increased, the effective flow is reduced. That is, the amount of desaturated blood actually reaching the lungs and the amount of fully saturated blood reaching the body are decreased. This condition is discussed in detail later in this chapter. Finally, common mixing occurs when desaturated and saturated bloods freely mix, allowing some desaturated blood to reach the body. This can occur at atrial (common atrium), ventricular (common or single ventricle), or great vessel level (truncus arteriosus).

OBSTRUCTIVE LESIONS Coarctation of the Aorta

Figure 2 Chest radiograph of a patient with atrial septal defect. There is cardiomegaly and an increase in pulmonary vascular markings as a result of the large left-to-right shunt.

the relative resistances of the two vascular beds. As the PVR falls during the first few weeks of life, pulmonary blood flow may increase dramatically, producing a large volume overload of the left ventricle. Because this shunt depends on a falling PVR, congestive failure from volume overload is not usually seen until two or three weeks of age. Pressure overload results from an obstruction to ventricular emptying. This obstruction is usually located at the level of the semilunar (pulmonary or aortic) valve, but it may be seen with subvalvular or supravalvular blockage. When the ventricle can no longer eject an adequate blood volume through the obstruction, pulmonary and systemic venous congestions with congestive heart failure result.

Cyanosis Cyanosis is a blue discoloration of the skin and mucous membranes caused by the presence of at least 5 g/dL unsaturated circulating hemoglobin. When it is noted in infancy, the administration of 100% oxygen is a reliable test to establish the presence of intracardiac shunting related to congenital heart disease. If the PO2 in the right radial artery rises above 250 mmHg, cyanotic heart disease is virtually eliminated. Although values less than 250 mmHg are not certain indicators of cardiac disease, a PO2 less than 100 mmHg generally indicates a cardiac problem. Cyanosis resulting from congenital heart disease may be caused by decreased pulmonary blood flow with intracardiac right-to-left shunting or by abnormalities of intracardiac mixing. When cyanosis is caused by decreased pulmonary blood flow, two conditions are necessary— obstruction to flow into the lungs and an intracardiac communication between the two circulations proximal to the obstruction. The obstruction may be located anywhere between the systemic venous atrium (tricuspid atresia)

Coarctation is a narrowing in the thoracic aorta most commonly located just distal to the left subclavian artery, opposite the insertion of the ductus arteriosus or ligamentum arteriosum (Fig. 3A). Obstruction to left ventricular emptying results in a pressure overload of the ventricle, which may lead to congestive heart failure. In infancy, associated defects often dictate the hemodynamic condition. When the ductus arteriosus is patent, blood may flow from the pulmonary artery across the duct into the descending aorta (Fig. 3B). In this situation, differential cyanosis is present, with desaturated blood perfusing the lower extremities and saturated blood perfusing the upper body. Approximately 20% of patients have an associated ventricular septal defect (VSD). The impedance to left ventricular emptying imposed by the coarctation increases the left-to-right shunt and results in severe congestive heart failure from combined pressure and volume overload. Other obstructive lesions in the left side of the heart may also be seen with coarctation; most common is aortic stenosis related to a bicuspid aortic valve. When coarctation results in congestive heart failure in infancy, nonoperative treatment carries a high mortality rate. Most patients with coarctation, however, do not have symptoms, and the defect is not found until after infancy. The discovery of upper-extremity hypertension with diminished or absent femoral pulses typically leads to the diagnosis. Flow murmurs over the back and palpable pulsations in the subscapular area from prominent collaterals may be present. All extremity pulses must be carefully palpated. A decrease in the left-arm pulse may indicate the involvement of the origin of the left subclavian artery in the coarctation. Plain chest radiographs may show dilation of the aorta proximally and distally to the narrowed segment (3 sign) and notching of the ribs related to enlarged intercostal arteries. In the past, aortography was generally recommended to accurately define the anatomy of the coarctation before surgical repair. Today, noninvasive techniques, including Doppler echocardiography and magnetic resonance imaging, are generally adequate to delineate the anatomy. In rare cases, the coarctation may be in an unusual location. The exact cause of hypertension in coarctation remains obscure. The etiology in older patients is apparently more than obstruction alone, because relief of coarctation in adulthood does not result in the restoration of normal blood

Chapter 35: Congenital Heart Lesions

687

Figure 4 Repair of coarctation with the subclavian angioplasty technique. (A) Left subclavian artery is mobilized and divided distally. (B) Longitudinal incision through the artery and adjacent aorta is made. This incision must extend distally beyond the coarctation until normal aorta is reached. (C) Completed repair.

Figure 3 Hemodynamic abnormalities in coarctation (C) of the aorta. (A) Pathophysiology in the older child or adult. (B) In infancy, PDA allows blood flow to the descending aorta from the right ventricle. Abbreviations: LA, ligamentum arteriosum; LSCA, left subclavian artery; VSD, ventricular septal defect; PDA, patent ductus arteriosus.

pressure in every case. It seems certain that in these cases, a renal mechanism is in part responsible. In a classic experiment performed by Scott et al. (1), coarctation was surgically created in dogs. The resultant hypertension was relieved by removal of one kidney and transplantation of the other above the level of the coarctation. When abnormal plasma renin activity is unmasked by volume depletion, abnormally high renin–angiotensin activity has been found in patients with coarctation (2). Virtually all patients with hemodynamically significant coarctation of the aorta should undergo operative repair. The ideal age for repair in the child without symptoms is not well defined, but it has been moved earlier and earlier in recent years. Repair is probably best accomplished between the ages of one and three years. Earlier operation may increase the risk of recoarctation with growth of the aorta, whereas delaying repair beyond childhood increases the chance of persistent hypertension (3). The presence of congestive heart failure in infancy dictates operative intervention, regardless of age or size. The classic surgical technique remains resection of the narrowed segment with end-to-end anastomosis. The

benefits of this technique include removal of all the ductal tissue, thus decreasing the risk of recoarctation. The potential disadvantages include the need for greater dissection, increased technical difficulty, and the possibility of tension at the repair site. Concerns about growth of the aorta in the face of a circumferential suture line have been minimized by the use of absorbable suture material and further alleviated by good results with other similar neonatal repairs, such as the arterial switch procedure. We prefer the resection and end-to-end anastomosis in virtually all cases. However, the subclavian angioplasty procedure, first reported by Waldhausen in 1966 (Fig. 4) (4), is preferred by some groups. Although this technique does not remove all the ductal tissue and is not suitable for augmentation of more proximal aortic narrowing, it is technically easier and avoids suture line tension. Division of the subclavian artery can, on occasion, lead to disparate upper-extremity growth. Synthetic patch aortoplasty retains abnormal ductal tissue and may lead to aneurysm formation on the aortic wall opposite the patch (also reported with subclavian flap technique). This technique should be used only in cases of discrete recoarctations in which mobilization for end-toend repair is not feasible. Balloon angioplasty is being performed in several centers for both native and recurrent coarctation (5). Controversy continues regarding the safety and efficacy of angioplasty of native coarctation (6); however, new balloon-expandable and covered stents may be useful in older adolescents and adults (7). Results appear quite good for catheter-based treatment of recurrent stenosis (8). Coarctation associated with a large VSD is best treated by a single-stage complete repair through a median sternotomy. During a period of circulatory arrest, the coarctation is resected and repaired with the mobilized distal aortic segment used to augment the transverse aortic arch if necessary. The VSD is then closed from a transatrial approach.

medwedi.ru

688

Part Three: The Cardiothoracic System—Heart

Aortic Stenosis The most common cause of obstruction to left ventricular ejection is aortic stenosis. The obstruction is typically located at the level of the valve, but it may be subvalvular or supravalvular (Fig. 5). Valvular aortic stenosis is usually caused by a bicuspid aortic valve with varying degrees of fusion of the commissures, although fused tricuspid valves may also be found. A dome-shaped unicusp valve may result in significant obstruction in infancy. Subvalvular aortic stenosis may be discrete or diffuse. In the discrete form, a fibrous membrane is found just below the aortic valve leaflets. The diffuse form is seen in obstructive cardiomyopathies, such as idiopathic hypertrophic subaortic stenosis or muscular tunnel-type subvalvular hypoplasia. In supravalvular stenosis, the obstruction is most commonly caused by an hourglass deformity of the ascending aorta just above the valve. Valvular aortic stenosis may be seen at any age. In infancy, severe stenosis may cause congestive heart failure (9). In most children, however, an asymptomatic heart murmur is detected on physical examination beyond the neonatal period. When symptoms are present in childhood, exertional dyspnea, syncope, and angina pectoris are the usual manifestations. Syncope is caused by the inability of the left ventricle to maintain adequate cerebral blood flow through a narrow, fixed orifice valve during exercise. Angina pectoris, although rare in childhood, may be seen when pressure overload results in significant left ventricular hypertrophy and myocardial blood flow does not adequately perfuse the thickened, hypertensive ventricular muscle.

Figure 5 Anatomic types of left ventricular outflow tract obstruction. (A) Valvular stenosis related to a bicuspid aortic valve. Note the poststenotic dilation of the ascending aorta. (B) Hourglass narrowing of the ascending aorta, resulting in supravalvular stenosis. (C) Subvalvular stenosis resulting from diffuse hypertrophy of the ventricular septum. (D) Subvalvular stenosis resulting from a discrete subaortic membrane.

Indications for operation in patients with valvular aortic stenosis include syncope, congestive heart failure, or angina with a significant left ventricular outflow tract gradient. A significant gradient is usually considered to be at least 50 mmHg, unless cardiac output is greatly diminished. The timing of operative intervention in the child without symptoms who has moderate or severe obstruction is less well defined. Electrocardiographic changes indicating left ventricular strain or ischemia, either at rest or induced during exercise, are considered definite indications. Severe gradients, greater than 70 mmHg, are best treated promptly, even in the absence of symptoms or electrocardiographic changes. Options for relief of critical aortic stenosis in the neonate include open valvotomy, transventricular dilatation, and transcatheter therapy. The standard approach has been open valvotomy with cardiopulmonary bypass. Relief of valvular aortic stenosis is accomplished by direct incision of fused commissures. The incision is stopped 1 to 2 mm from the annulus to avoid detaching all leaflet support and creating significant aortic regurgitation. In a true bicuspid valve, rudimentary commissures must not be incised, or a flail leaflet will result. Although satisfactory reduction of the gradient can usually be accomplished, it may be difficult to provide complete relief of obstruction in all cases (10). Certain bicuspid valves may not lend themselves to valvotomy and may remain obstructive despite lack of commissural fusion. Although a few studies have reported good results with open aortic valvotomy (11,12), the mortality rates have remained high in most series. This may be in part because congenital aortic stenosis is a heterogeneous, complex disorder in which the aortic valvular and annular substrates may not be conducive to direct operative intervention. Transventricular dilatation, first described by Trinkle et al. (13) in 1975, provides a simple and effective technique of closed aortic valvotomy in infants. Through an apical left ventricular approach, progressive dilatation of the valve is accomplished with or without cardiopulmonary bypass. Transventricular dilatation provides effective relief of the obstruction without creating significant aortic insufficiency, and it avoids the myocardial ischemia inherent in open techniques (14). Transcatheter therapy through the femoral, umbilical, or carotid arteries is also quite effective in the neonatal population. The risks of balloon aortic valvotomy continue to include inadvertent aortic cusp perforation, with resultant severe aortic insufficiency as well as arterial injury. Most centers believe that surgical and balloon valvotomy for critical aortic stenosis in the neonate have similar outcomes and therapy is program specific (15–17). The goal of treatment of neonates’ and infants’ critical aortic stenosis is to establish an effective aortic orifice, thereby relieving the left ventricular pressure overload without inducing hemodynamically significant aortic insufficiency. Few of these patients are cured by their initial procedure. Because of the complexity of the disease (valvular stenosis, annular hypoplasia, varying degrees of subaortic stenosis, and the turbulent flow as a result of these), most patients require further operative intervention. Replacement of the aortic valve with a pulmonary autograft (Ross procedure) can be performed at any age, even in the neonate, and is the optimal procedure when more conservative treatment fails. Operation for subvalvular stenosis is recommended for the same indications as in valvular obstruction. The required gradient may be somewhat less for discrete subvalvular stenosis, however, because resection of the

Chapter 35: Congenital Heart Lesions

membrane is more often curative (18). Many patients with untreated discrete subvalvular stenosis later have progressive aortic regurgitation related to turbulence beneath the valve. Early resection of the membrane, often combined with a septal myectomy, may prevent this complication. Diffuse, muscular left ventricular outflow tract obstruction is more difficult to relieve. Transaortic resection of hypertrophied septal muscle, an aortoventriculoplasty, or bypass of the obstruction by insertion of a valved conduit from the left ventricular apex to the aorta is often needed (19,20). Supravalvular aortic stenosis is the least common site of left ventricular outflow tract obstruction. Isolated supravalvular aortic stenosis is rare in infants and may occur as part of the Williams syndrome in older children. This lesion is also highly variable, ranging from a membranous ringlike constriction, the classic hourglass deformity, to a diffuse form involving much of the aorta and brachio-cephalic vessels. The coronary arteries are exposed to high pressure, and degenerative changes may be seen early in life. Indications for operation include a gradient greater than 50 mmHg and evidence of coronary obstruction. Repair involves a longitudinal incision in the ascending aorta, extended proximally into both the noncoronary and right coronary cusps in an inverted Y configuration. The patch is then extended as far distally as necessary to relieve the obstruction.

LEFT-TO-RIGHT SHUNTS Atrial Septal Defect Atrial septal defect (ASD) accounts for approximately 10% of all congenital cardiac lesions. The defect in the septum allows blood to flow from the left to the right atrium, producing a volume overload of the right ventricle and pulmonary circulation. The shunt is directed from left to right because of the greater diastolic compliance and lower diastolic pressure in the right-sided chambers. Moderatesized defects result in pulmonary blood flow from one and one half to three times the systemic flow, whereas in large defects, the pulmonary to systemic flow ratio exceeds three to one. In most cases, pulmonary artery pressure and systemic blood flow remain normal. ASDs often occur as isolated lesions and tend to remain asymptomatic until early adult life (21). When present, symptoms are often nonspecific and consist of fatigue or mild dyspnea on exertion. In the presence of a large left-to-right shunt, overt congestive heart failure can occur at any age. Most commonly, however, nearly normal activity is maintained until the third or fourth decade of life, when symptoms of congestive heart failure become manifest. Any chronic left-to-right shunt may eventually produce changes of pulmonary vascular occlusive disease. Although these changes occur more frequently and earlier in life with defects that cause an increase in both pulmonary blood flow and pressure, uncomplicated ASDs may result in irreversible pulmonary occlusive changes. This problem is discussed in detail in the following section concerning VSDs. Most ASDs occur in the center of the atrial septum and are referred to as ostium secundum ASDs (Fig. 6). In approximately 5% to 10% of patients, the defect is located high in the atrial wall, where the superior vena cava joins the right atrium. These defects, known as sinus venosus ASDs, are almost always associated with drainage of the right upper lobe pulmonary veins into the right atrium or

689

Figure 6 Locations of the three common types of atrial septal defect. The sinus venous defect is shown with anomalous drainage of the right upper lobe pulmonary vein (I). The ostium secundum defect is in the mid-portion of the septum (II). The ostium primum defect is located in the base of the septum, with its inferior edge formed by the continuity of the tricuspid and mitral valves (III). Note the cleft-like anomaly in the anterior leaflet of the mitral valve visible through the defect.

superior vena cava. About 5% of patients have another variety of defect, called ostium primum ASDs. These defects, which are located low in the septum, are part of a more complex anomaly referred to as endocardial cushion defect. In its simplest form, the ostium primum ASD is associated with a cleft in the anterior leaflet of the mitral valve. Mitral regurgitation may be present and can be severe. Any ASD in which the ratio of pulmonary to systemic blood flow (Qp/Qs) is at least 1.5:1 should be closed. Operative correction prevents the long-term complications of congestive heart failure and pulmonary vascular occlusive disease. Studies on patients who did not undergo surgery indicated that life expectancy is significantly reduced, to the fourth or fifth decade of life. To prevent these complications, elective repair before school age is advised. The technique of repair involves suture closure during cardiopulmonary bypass in most patients. Through an incision in the right atrium, the anatomy is easily exposed. In large defects, a patch of pericardium or polytetrafluoroethylene (Gore-Tex) may be necessary to avoid tension on the edges of the repair. In sinus venosus defects with partial anomalous pulmonary venous return, closure is achieved by modifying the patch to redirect the pulmonary veins to the left atrium. Ostium primum ASDs must also be repaired with a patch, because no lower rim of atrial septum is present. The lower edge of this defect is the junction of mitral and tricuspid valves on the crest of the ventricular septum. If significant mitral regurgitation is present before the operation, the valve should be studied carefully at operation and a valvuloplasty should be performed (22). Secundum ASDs of the appropriate size and location are now being closed routinely with transcatheter techniques. Results are good and continue to evolve (23).

Ventricular Septal Defect Excluding bicuspid aortic valve, VSD is the most common congenital structural cardiac anomaly. It accounts for 20%

medwedi.ru

690

Part Three: The Cardiothoracic System—Heart

to 25% of all cardiac lesions and is estimated to occur in 2 of 1000 live-born infants. The hemodynamics, symptoms, and treatment depend on the size of the VSD and on the magnitude of the shunt. With a small VSD, right ventricular pressure remains normal, Qp/Qs is less than 1.5:1, and symptoms are usually absent. Moderate-sized defects have right ventricular pressure as great as half of systemic levels and a Qp/Qs as great as 2.5:1 or 3:1. Some degree of congestive heart failure is often present, but growth is usually normal. A large VSD is present when the Qp/Qs exceeds 3:1. Right ventricular pressure usually exceeds half that of the left ventricle, but it may be normal when PVR is low. Severe congestive heart failure and poor growth are often found. Approximately 50% of VSDs discovered in infancy undergo spontaneous reduction in size or complete closure. Thus, all defects are initially managed medically, with early surgical intervention reserved for those with refractory congestive heart failure. Small VSDs usually do not require treatment, and nearly all eventually close. Spontaneous closure is less likely with larger defects but may still occur. In response to the increasing pulmonary blood flow seen with moderate and large VSDs, pulmonary arteriolar resistance rises, and pulmonary artery pressure may also become elevated. Sustained increases in pulmonary artery flow and pressure can lead to early development of pulmonary vascular occlusive disease. Irreversible changes in resistance may become apparent by two years with an isolated large VSD or by six months in patients with associated trisomy 21. These changes have been classified by Heath and Edwards (24) on a histologic level. The early changes in the small pulmonary arteries and arterioles of medial hypertrophy (grade I) and intimal proliferation (grade II) are considered reversible. More advanced changes, consisting of intimal fibrosis (grade III) and progressive dilation lesions with eventual arterial necrosis (grades IV–VI), are irreversible. Cardiac catheterization documents the magnitude of the shunt, right ventricular and pulmonary artery pressures, and PVR. Left ventricular cineangiography and two-dimensional echocardiography delineate the locations and number of VSDs. Associated defects, including coarctation, aortic stenosis, PDA, and pulmonary stenosis, are common and must be identified. VSDs may be single or multiple. Most VSDs are single and located high in the membranous portion of the ventricular septum, just beneath the aortic valve. These defects are classified by their relationship to structures in the right ventricle (25,26). The typical high VSD, referred to as infundibular VSD, can be found beneath the anteroseptal commissure of the tricuspid valve (Fig. 7). Inlet VSDs are located more inferiorly, beneath the septal leaflet of the tricuspid valve, and subarterial VSDs occur high in the septum immediately below the pulmonary valve. When a VSD extends to the annulus of the tricuspid valve, it is referred to as perimembranous; otherwise, it is a muscular defect. Muscular defects occurring in the heavily trabeculated portion of the septum are more likely to be multiple. The indications for surgery depend on the hemodynamic situation and presence of symptoms. With moderate and large VSDs, persistent, severe congestive heart failure (often with failure to thrive) despite medical management is an operative indication. When heart failure is well controlled medically, the primary factors influencing the decision to operate are the pulmonary arterial pressure and PVR. These should be assessed by 12 months of age. If the pulmonary arterial pressure is greater than half of systemic levels by this age, surgical intervention should be carried

Figure 7 Locations of the common types of ventricular septal defect. Subarterial defects (I) are located in the infundibular portion of the septum, beneath the pulmonary valve. In the most common type, perimembranous infundibular (II), part of the defect edge is formed by the tricuspid valve. Inlet defects (III) are found more inferiorly, beneath the septal leaflet of the tricuspid valve. Muscular defects (IV) are remote from the valve annulus.

out to prevent progressive changes in PVR. Moderate defects with minimal symptoms and normal pulmonary artery pressure and PVR may continue to be observed, because late spontaneous closure could still occur. If VSDs do not close by three to five years of age, operative therapy is indicated. If the PVR is severely elevated, above two-thirds of systemic resistance, VSD closure may be contraindicated. When PVR reaches this level, it will often progress further and eventually exceed that of the systemic circulation. Reversal of flow through the defect then occurs (Eisenmenger’s syndrome), and cyanosis results. Closure of the VSD in this situation would result in right-sided heart failure and shortened life expectancy. The optimal surgical treatment of VSDs consists of patch closure. In infants, deep hypothermia with reduced flow on cardiopulmonary bypass is used to facilitate exposure and reduce operative risk. The operative approach for most defects is through the right atrium and tricuspid valve. A patch of polytetrafluoroethylene (Gore-Tex) is sutured to the right ventricular side of the defect edge; care is taken not to injure the conduction tissue, which must be precisely located for each VSD (27). In complex lesions, the atrioventricular node and bundle of His may be identified with endocardial mapping. Subpulmonary defects are best closed through the right atrium or pulmonary artery. Anterior muscular VSDs can often be quite difficult to close because they are obscured by the heavy trabeculations of the right ventricle. Apical muscular defects may require a small apical left ventriculotomy for proper exposure. In each case, initial exposure and evaluation through the tricuspid valve allow the surgeon to plan the best approach. Complete repair in infancy may not be advisable in all cases. When multiple defects are found, for example, palliation with pulmonary artery banding may be indicated. With constriction of the main pulmonary artery, the resistance to flow into the lungs is markedly increased, reducing the magnitude of the left-to-right shunt and controlling

Chapter 35: Congenital Heart Lesions

691

congestive heart failure. Further, the pulmonary vascular bed is protected against the development of pulmonary vascular occlusive disease, allowing complete repair to be done at less risk when the patient is older. Because of the good results of complete repair of most congenital heart defects in infants, multiple, complicated VSDs may be one of the few remaining indications for pulmonary artery banding in infants.

Patent Ductus Arteriosus PDA is the most common cause of left-to-right shunting at the great artery level. Because aortic pressure is greater than pulmonary artery pressure throughout all phases of the cardiac cycle, shunting occurs in both systole and diastole. This gives rise to the typical continuous or machinery-like murmur. Additionally, the diastolic runoff into the lowresistance pulmonary circulation results in a wide pulse pressure and bounding arterial pulses. A large PDA may allow substantial left-to-right shunting and significant heart failure. Pulmonary artery pressure and PVR may be elevated as described in the previous section, resulting in eventual pulmonary vascular occlusive disease. The anatomy of the duct is quite constant. Its aortic end originates just distal to the left subclavian artery, and it enters the pulmonary artery bifurcation or proximal left pulmonary artery. Any duct that remains patent beyond infancy should be closed. Elective closure is usually recommended in early childhood. A large PDA in a patient with heart failure and pulmonary hypertension should be closed immediately. Small PDAs may be complicated by bacterial endarteritis, aneurysm formation, or calcification. Closure prevents these complications. The operative approach is through a left thoracotomy. Exposure of the duct is easily accomplished after opening the mediastinal pleura. Care must be taken to avoid injury to the recurrent laryngeal nerve. Closure of the duct may be done by simple ligation, usually over a length of the duct, by division and suture, or by hemoclip occlusion in premature infants. Recently, new forms of therapy have been introduced, including transluminal placement of coils, umbrellas, or clamshell devices (28–30) and clipping of the PDA by means of video-assisted thoracoscopy (31).

Figure 8 (A) Tricuspid atresia with normally related great vessels and without a ventricular septal defect. Pulmonary blood flow is duct dependent. (B) When a septal defect is present, forward flow across the pulmonary valve can occur.

and the pulmonary artery receives the direct output of the left ventricle, resulting in an increase in pulmonary blood flow and pressure. The initial surgical treatment of tricuspid atresia with decreased pulmonary blood flow is aimed at increasing this flow by a systemic artery–to–pulmonary artery shunt (33,34). The modified Blalock–Taussig procedure, in which an interposition graft of polytetrafluoroethylene (Gore-Tex) is placed between the sides of the subclavian and pulmonary arteries, is the most commonly used operation (Fig. 9) (35). This procedure provides a source of pulmonary blood flow with minimum risk of increasing PVR or causing congestive heart failure. A relatively large graft (4 or 5 mm) is used, even in infants, because flow is limited by the smaller-sized native vessels. With growth of the subclavian and pulmonary arteries, flow can potentially increase and maintain effective palliation. Other shunt procedures are used much less commonly today. These include the Waterston (ascending aorta–to–right pulmonary artery), Potts (descending aorta– to–left pulmonary artery), and Glenn (superior vena cava– to–right pulmonary artery) anastomoses.

RIGHT-TO-LEFT SHUNTS Tricuspid Atresia Tricuspid atresia is an uncommon defect in which the tricuspid valve is completely absent. The ASD that is invariably present shunts all vena caval blood directly to the left atrium. The degree of cyanosis depends on the amount of pulmonary blood flow. When no communication between left and right ventricles is present, the ductus arteriosus is the sole source of flow to the lungs (Fig. 8A). These patients are deeply cyanotic in early infancy, and emergency prostaglandin infusion may be necessary (32). Prostaglandins of the E type relax the smooth muscle in the wall of the duct and are used to maintain ductal patency before palliative surgery. In some cases, a VSD allows blood to flow from the left ventricle directly to the hypoplastic right ventricle and then to the pulmonary circuit (Fig. 8B). Depending on the size of this communication, cyanosis may be mild. However, these VSDs often undergo spontaneous reduction in size, thus decreasing pulmonary blood flow as the child grows. Less commonly, the aorta and pulmonary artery are transposed,

Figure 9 (A) Standard Blalock—Taussig anastomosis between the right subclavian and pulmonary arteries. (B) Modification of the procedure with an interposition polytetrafluoroethylene graft.

medwedi.ru

692

Part Three: The Cardiothoracic System—Heart

The shunt procedure is then followed in many circumstances by a bidirectional Glenn or hemi-Fontan procedure. This second stage removes the volume load imposed by the aortopulmonary shunt, improves the effective pulmonary blood flow, and may allow ventricular remodeling prior to the Fontan procedure. The third stage, and the most satisfactory form of treatment for tricuspid atresia, was first reported in 1971 by Fontan and Baudet (36). Originally done by direct connection of the right atrium to the pulmonary artery or hypoplastic right ventricle, this procedure is now most commonly performed with the lateral tunnel technique (37). A tube of appropriately sized polytetrafluoroethylene (Gore-Tex) is opened longitudinally and sewn within the atrium to incorporate the orifices of the superior and inferior venae cavae without obstructing the pulmonary venous return (Fig. 10). Many centers now routinely incorporate a fenestration of the lateral baffle to allow a small degree of mixing of saturated and desaturated blood. This serves as a ‘‘pop-off’’ mechanism, limiting systemic venous pressures to an extent and preserving cardiac output, albeit with desaturated blood. Later, the fenestration is closed by means of a snare device or by transcutaneous umbrella occlusion, restoring normal systemic oxygenation and eliminating left ventricular volume overload. Although the early results with this procedure have been most gratifying, long-term follow-up is lacking and a late rise in the hazard function for survival has been noted (38–40). Specifically, the late

Figure 10 Fontan procedure (lateral tunnel technique). Following a hemiFontan reconstruction, the inferior vena caval blood is tunneled within the atrium to the confluent pulmonary arteries.

effects of chronic venous hypertension and lack of pulsatile pulmonary blood flow are unknown.

Tetralogy of Fallot The most common congenital heart defect resulting in cyanosis is tetralogy of Fallot. In this abnormality, obstruction to pulmonary blood flow occurs at the level of the right ventricular outflow tract, usually as the result of a combination of infundibular and pulmonary valvular stenoses (Fig. 11). The basic anatomic defect is anterior and superior displacement of the infundibular (outlet) portion of the ventricular septum. This obstructs right ventricular outflow and results in a large malalignment VSD (Fig. 12). Overriding of the aorta above the VSD and right ventricular hypertrophy (related to obstruction) complete the tetrad. The clinical status of patients with tetralogy of Fallot depends on the severity of the right ventricular outflow tract obstruction. In its severest form, pulmonary atresia may be present with duct-dependent pulmonary blood flow. More commonly, infundibular obstruction coexists with varying degrees of pulmonary valve hypoplasia, resulting in moderate cyanosis. Patients with tetralogy of Fallot may have hypercyanotic ‘‘tet’’ spells. These occur when the dynamic portion of the obstruction is transiently worsened as a result of increased contractility of the muscle in the right ventricular outflow tract, often in combination with a decrease in systemic vascular resistance. Pulmonary blood flow is dramatically reduced, with an increase in the right-to-left shunt across the VSD. Complete repair is now possible with good results in the infant and neonate (41). It is believed that by early repair, the consequences of severe right ventricular hypertrophy (ventricular systolic and diastolic dysfunction) can be reduced or eliminated. In addition, early reestablishment of normal pulsatile pulmonary arterial blood flow may

Figure 11 Typical anatomy in tetralogy of Fallot. The large ventricular septal defect (VSD) with overriding of the aorta is shown. The right ventricular outflow tract obstruction results in desaturated blood crossing the VSD directly into the aorta.

Chapter 35: Congenital Heart Lesions

Figure 12 Cineangiogram from a patient with tetralogy of Fallot. Abbreviations: AV, aortic valve; IS, infundibular stenosis; LV, left ventricle; PV, pulmonary valve; RV, right ventricle; VSD, ventricular septal defect.

improve the development of alveoli and intraparenchymal pulmonary arteries (42). Contraindications to repair in infancy may include significant hypoplasia of the pulmonary arteries and the origin of the anterior descending coronary artery from the right coronary artery. Because relief of the obstruction in the latter situation may require the insertion of a valve-bearing conduit or allograft, repair may best be postponed until the patient reaches an age at which a larger conduit may be inserted. Complete repair includes relief of right ventricular outflow tract obstruction and closure of the VSD. Relief of the obstruction is governed by the individual anatomy. Whenever possible, pulmonary valve function should be preserved and resection of right ventricular muscle should be minimized (43). In the past, the standard repair involved a right ventriculotomy to close the VSD and divide or resect the obstructing muscle bundles. Obstruction at the level of the pulmonary valve or annulus was dealt with by a commissurotomy or transannular patch as necessary. In the vast majority of patients, this can be performed through a transatrial approach across the tricuspid valve. In neonates and infants, obstructing muscle bundles need only be divided, not resected. If pulmonary valvular stenosis is present, a commissurotomy is performed. Pulmonary valvular hypoplasia is treated with a limited (< 10 mm) transannular patch. Only in cases of true infundibular hypoplasia are a formal ventriculotomy and large outflow tract patch needed. The operative mortality rate for repair of tetralogy of Fallot is 5% or less. Transatrial repair in the neonatal and infant period may improve the development of the pulmonary vascular bed and help to avoid the late sequelae of a right ventriculotomy (right ventricular dysfunction and ventricular dysrhythmias).

INADEQUATE MIXING Transposition of the Great Arteries In transposition of the great arteries (TGA), two separate and parallel circulations—systemic and pulmonary—are present. In the simplest form of TGA, the aorta arises from

693

the right ventricle and receives the desaturated systemic venous return and the pulmonary artery arises from the left ventricle and receives oxygenated pulmonary venous blood (Fig. 13). Some exchange of blood between the two circulations (mixing) must be present to sustain life. This most commonly occurs by means of an interatrial communication allowing saturated blood to pass from the left to the right atrium and then to the right ventricle and aorta. An equal amount of desaturated blood must pass from right to left atrium to reach the pulmonary circulation. The adequacy of this mixing determines the amount of saturated venous blood reaching the aorta (effective systemic blood flow) and desaturated venous blood reaching the pulmonary artery (effective pulmonary blood flow), and thus the clinical status of the infant. Even with adequate intracardiac mixing, the neonate with TGA has noticeable cyanosis. Quite often, the interatrial defect is restrictive, and profound cyanosis is detected within hours of birth. Arterial PO2 may be less than 25 to 30 mmHg, and progressive acidosis during the first days of life can occur. The clinical presentation is also influenced by the presence of associated lesions. In approximately 10% of cases, a large VSD or hemodynamically significant pulmonary stenosis is present. When only a VSD is present, cyanosis is lessened because mixing occurs at both the atrial and ventricular levels. Because total pulmonary blood flow is elevated further, however, severe congestive heart failure usually results. If pulmonary stenosis is also present, volume overload is reduced, tending to lessen the effect of the VSD. When pulmonary stenosis is particularly severe, with or without a VSD, total pulmonary blood flow may be reduced to a level below normal, and cyanosis may be worsened. Finally, communication between the two circulations may also occur from a PDA. Similar to the situation with a large VSD, both effective and total pulmonary blood flows are increased, improving oxygenation but resulting in congestive heart failure.

Figure 13 Anatomy of transposition of the great arteries. The aorta arises from the right ventricle, and the pulmonary artery arises from the left ventricle.

medwedi.ru

694

Part Three: The Cardiothoracic System—Heart

The initial treatment of an infant with TGA is aimed at improving the intracardiac mixing by enlarging the ASD. This is performed in the cardiac catheterization laboratory after the diagnosis has been established. The procedure, known as balloon atrial septostomy and originated by William Rashkind in 1966, involves passage of a balloon-tipped catheter from the right to the left atrium across the foramen ovale. The procedure can be performed in the catheterization laboratory or in the intensive care unit, with echocardiographic guidance used for accurate catheter placement. Once the catheter tip has been positioned in the left atrium, the balloon is inflated and the catheter is forcibly withdrawn to tear a portion of the atrial septum. This procedure is repeated two or three times to ensure a wide patency in the septum. Improvement in arterial oxygenation is usually noted immediately after the septostomy. A few neonates may continue to have unsatisfactory oxygenation even with a large ASD (44). The poor mixing in these cases may be caused by the failure of the PVR to fall to its normally low level after birth. The diastolic compliances of the two ventricles remain about equal, and no mixing of blood between the two sides occurs. When this is coupled with closure of the ductus arteriosus, effective pulmonary blood flow may be poor. This situation may be treated temporarily by the administration of a prostaglandin infusion, maintaining ductal patency and allowing mixing at the great vessel level (45,46). This restores satisfactory oxygenation for a few days until PVR falls. When TGA is associated with a large VSD, significant congestive heart failure and pulmonary hypertension may be apparent very early in life. Prior to the arterial switch repair, banding of the main pulmonary artery to reduce pulmonary blood flow and pressure was indicated. This procedure, however, invariably results in a drop in arterial PO2 because pulmonary blood flow is reduced by the band. An adequate interatrial communication is mandatory. If severe pulmonary stenosis is present and pulmonary blood flow and pressure are below normal, a systemic artery–to– pulmonary artery (Blalock–Taussig) shunt may be performed. Correction of TGA may be performed at the atrial, ventricular, or great vessel level, depending on the exact anatomy and associated defects. Prior to the 1980s, physiologic correction was achieved at the atrial level by redirecting venous inflow. This technique was first successfully performed by Senning in 1959 and revised by Mustard in 1964. Mustard’s procedure involves the complete removal of the atrial septum, followed by the placement of a ‘‘baffle’’ (usually pericardium) to repartition the atria (Fig. 14). Vena caval blood drains behind the baffle into the mitral valve, left ventricle, and pulmonary artery, and the pulmonary veins drain into the tricuspid valve and then into the systemic circulation through the right ventricle. In the Senning procedure, little prosthetic material is used because redirection of venous inflow is done with the patient’s own atrial tissue. Although more difficult to perform, Senning’s operation may allow better growth and function of the atrial chambers. The operative mortality rates for both procedures are low (< 5%), even in infancy, and long-term results are good. Significant technical complications, such as obstruction to caval (usually superior vena caval) or pulmonary venous flow and troublesome atrial arrhythmias, continue to be a problem. The major long-term difficulty with both the Mustard and the Senning procedures is the possible failure of the right ventricle to perform at systemic workloads for long periods (47). Late congestive heart failure, often with tricuspid insufficiency, has been recognized in a small percentage

Figure 14 Appearance of the atrial baffle in the Mustard procedure. Superior and inferior vena caval blood passes behind the patch to the mitral valve. The pulmonary venous blood passes over the patch to the tricuspid valve.

of children. Careful studies of right ventricular function late after repairs have shown impaired performance even in patients without symptoms. The exact cause remains unclear. Most children, however, have excellent long-term results after Mustard or Senning operations. During the last decade, the arterial switch has emerged as the procedure of choice in patients with TGA (Fig. 15). The arterial repair of TGA has the benefit of restoring the left ventricle as the systemic pump (48). Although early operative mortality rates were quite high, current techniques have reduced the risk to acceptable levels. These technical improvements include the refinement of coronary transfer, repair of the pulmonary artery with a pantaloon pericardial patch, and superior myocardial protection. Successful performance of this procedure seems to require that the left ventricle be prepared to pump against systemic resistance. Patients with TGA and a large VSD retain high pressure in the left ventricle and are ideal candidates for arterial repair. Banding of the pulmonary artery to raise

Figure 15 Steps in the performance of the arterial switch procedure. (A) The pulmonary artery is transected just proximal to its bifurcation. The aorta is transected at the same level. The coronary arteries are removed with wide buttons of adjacent aorta. (B) The distal aorta is brought behind the pulmonary artery confluence and anastomosed to the proximal pulmonary artery. The coronary arteries are then relocated to the new aorta. (C) The right ventricular outflow tract is reconstructed by anastomosing the distal pulmonary artery confluence to the proximal aorta.

Chapter 35: Congenital Heart Lesions

Figure 16 Repair of transposition of the great arteries with ventricular septal defect and pulmonary stenosis. The defect is patched to place both great vessels in continuity with the left ventricle. The pulmonary artery is ligated proximally. The right ventricle is then connected to the distal pulmonary artery with a valved conduit.

left ventricular pressure in some patients with TGA and intact ventricular septum has been advocated to prepare the left ventricle for an arterial switch procedure (49). When arterial repair is done within the first month of life, however, preliminary banding is unnecessary. In patients with TGA, large VSD, and left ventricular outflow tract obstruction (pulmonary stenosis), repair can be carried out at both the ventricular and great vessel levels. The VSD is closed in a way that diverts left ventricular blood through the defect into the aorta (Fig. 16). The main pulmonary artery is ligated, and the right ventricle is connected to the pulmonary artery bifurcation with a valved extracardiac conduit. The left ventricle is restored as the systemic pump, and the coronary arteries do not require relocation (50). Recently, surgeons have been performing a modified Rastelli procedure utilizing a sleeve of autograft aorta to avoid the use of a prosthetic right ventricle to PA conduit. This approach allows for primary correction in the young patient and perhaps reduces the need for further operative intervention (51).

HYPOPLASTIC LEFT HEART SYNDROME Hypoplastic left heart syndrome (HLHS) is a collective term referring to a spectrum of congenital heart defects with varying degrees of hypoplasia of left-sided cardiac structures. The vast majority of patients with HLHS (84%) have aortic and mitral atresia, hypoplasia, or stenosis (classic HLHS), whereas 16% have a malaligned atrioventricular canal defect (52). A coarctation is present in more than 80% of patients. Patients with HLHS have complex cardiopulmonary physiology. The pulmonary arteries, ductus arteriosus, and descending aorta are arranged in parallel circulations. Qp/ Qs depends on the balance between PVR and systemic vascular resistance. Because of its hypoplasia and obstructed outflow, the left ventricle is essentially a nonfunctional structure.

695

Pulmonary venous return is directed across an ASD and mixes with the systemic venous return. The right ventricle provides both the pulmonary and systemic output. Coronary and systemic perfusion is maintained through the ductus arteriosus. In most cases, the PVR declines after birth, leading to excessive pulmonary blood flow. Although this produces good arterial oxygen saturations, the systemic perfusion may be poor, resulting in metabolic acidosis. Without intervention, HLHS is almost uniformally fatal in the first weeks of life. Initial therapy is directed at maintaining an adequate PDA with prostaglandin E. This allows the child’s overall condition to stabilize. Surgical options for the treatment of HLHS consist of neonatal cardiac transplantation or staged reconstruction. In the best of situations, neonatal cardiac transplantation is associated with a one-year survival of 80% to 90% (53). However, because of the limited availability of organ donors, approximately 15% to 25% of patients die while awaiting organ transplantation. In addition, the patient faces the need for lifelong immunosuppression, with its attendant risks. For these reasons, many centers have opted to pursue palliative repair in this group of patients. The repair of HLHS involves three separate procedures: the Norwood, bidirectional Glenn, and Fontan procedures. The Norwood operation connects the right ventricle and pulmonary valve to the augmented ascending, transverse, and descending aorta and provides a limited amount of pulmonary blood flow through a modified Blalock–Taussig shunt. In the last two years, a modification of the Norwood procedure utilizing an RV-to-PA conduit for pulmonary blood flow has been revisited (54). The absence of a systemic artery–to– pulmonary artery shunt helps avoid the diastolic runoff inherent in this circulation and may prove beneficial in some patients early after the Norwood procedure (55). Performed at six months, the bidirectional Glenn procedure consists of division of the aortopulmonary shunt and connection of the superior vena cava to the cephalad portion of the right pulmonary artery. This decreases the volume load on the right ventricle and improves the effective pulmonary blood flow. A fenestrated Fontan procedure is then planned at 18 months to channel the desaturated inferior vena caval blood to the undersurface of the right pulmonary artery. Firststage reconstruction is now associated with an 85% to 90% in-hospital survival, and the actuarial survival for the three stages together is approximately 75% at two years (56). Overall, the outlook for patients born with HLHS has improved dramatically during the past few years. Cardiac transplantation offers good intermediate results but is plagued by donor shortages and the need for immunosuppression. Results of palliative procedures have improved greatly, but three operative procedures are required, and the right ventricle is retained as the systemic ventricle. Further study is needed to better categorize which patients benefit most from these treatment modalities.

SUMMARY Successful surgical treatment of most forms of congenital heart disease is now possible. However, the surgeon must be knowledgeable about more than just cardiac anatomy to achieve this success. In particular, a thorough understanding of cardiac physiology in infants and children is essential so that a well-conceived treatment plan can be devised for even the most complex of anomalies. In some cases, one or more palliative procedures may be necessary,

medwedi.ru

696

Part Three: The Cardiothoracic System—Heart

either because no definitive repair is ultimately possible or because it is best postponed until the patient is older. These procedures must provide satisfactory immediate palliation and, in addition, must ensure that ultimate repair can be performed with the lowest possible risk to the patient. Early corrective surgery, now routinely performed for many defects, is expected to significantly reduce the associated complications of congenital heart disease. The elimination of pulmonary vascular disease, chronic cyanosis, and long-standing congestive heart failure are only a few examples of the advantages of early correction. However, examining the benefits of surgical repair in light of the late results is increasingly important. The development of ventricular dysfunction and electrophysiologic abnormalities are examples of potentially serious consequences that may detract from an apparent early success. In some cases, a number of late studies have led to alterations in surgical technique designed to maintain excellent long-term functional results. These evaluations serve as a stimulus for cardiac surgeons to continue to strive for improvement in the treatment of congenital heart disease.

REFERENCES 1. Scott HW Jr, et al. Study of the renal pressure system in experimental coarctation of the abdominal aorta. Am Surg 1977; 43:771. 2. Parker FB, et al. Preoperative and postoperative renin levels in coarctation of the aorta. Circulation 1982; 66:513. 3. Simsolo R, et al. Long-term systemic hypertension in children after successful repair of coarctation of the aorta. Am Heart J 1988; 115:1268. 4. Waldhausen J. Repair of coarctation of the aorta with a subclavian flap. J Thorac Cardiovasc Surg 1966; 51:532. 5. Tynan M, Finley JP, Fontes V, et al. Balloon angioplasty for the treatment of native coarctation: results of Valvuloplasty and Angioplasty of Congenital Anomalies Registry. Am J Cardiol 1990; 65:790. 6. Hijazi ZM, Geggel RL, Marx GR, Rhodes J, Fulton DR. Balloon angioplasty for native coarctation of the aorta: acute and mid-term results. J Invasive Cardiol 1997; 9(5):344–348. 7. Macdonald S, Thomas SM, Cleveland TJ, Gaines PA. Angioplasty or stenting in adult coarctation of the aorta? A retrospective single center analysis over a decade. Cardiovasc Interventional Radiol 2003; 26(4):357–364. 8. Hijazi ZM, Fahey JT, Kleinman CS, et al. Balloon angioplasty for recurrent coarctation of the aorta. Immediate and long-term results. Circulation 1991; 84:1150. 9. Sandor CGS, et al. Long-term follow-up of patients after valvotomy for congenital valvular aortic stenosis in children. J Thorac Cardiovasc Surg 1980; 80:171. 10. Ankeney JL, Tzeng TS, Liebman J. Surgical therapy for congenital aortic valvular stenosis. J Thorac Cardiovasc Surg 1983; 85:41. 11. Buich M, et al. Open valvotomy for critical aortic stenosis in infancy. Br Heart, J 1990; 63:37. 12. Messina LM, et al. Successful aortic valvotomy for severe congenital valvular aortic stenosis in the newborn infant. J Thorac Cardiovasc Surg 1984; 88:92. 13. Trinkle JK, et al. Closed aortic valvotomy and simultaneous correction of associated anomalies in infants. J Thorac Cardiovasc Surg 1975; 69:758. 14. Mosca RS, Jannettoni MD, Schwartz SM, et al. Critical aortic stenosis in the neonate: a comparison of balloon valvuloplasty and transventricular dilation. J Thorac Cardiovasc Surg 1995; 109(1):147–154. 15. McCrindle BW, Blackstone BH, William WG, et al. Are outcomes of surgical versus transcatheter balloon valvotomy equivalent in neonatal critical aortic stenosis? Circulation 2001; 104(12, suppl 1):1-152–1-158.

16. Marasini M, Zannini L, Ussia GP, et al. Discrete subaortic stenosis: incidence, morphology and surgical impact of associated anomalies. Ann Thorac Surg 2003; 75(6):763–768. 17. McElhinney DB, Retrossian B, Tworetzkyw, et al. Issues and outcomes in the management of supravalvular aortic stenosis. Ann Thorac Surg 2000; 69(2):562–567. 18. Shem-Tov A, et al. Clinical presentation and natural history of mild discrete subaortic stenosis. Circulation 1982; 66:509. 19. Bjornstad PG, et al. Aortoventriculoplarty for tunnel subaortic stenosis and other obstructions of the left ventricular outflow tract. Circulation 1979; 60:59. 20. Sweeney MS, et al. Apioaortic conduits for complex left ventricular outflow obstruction: 10-year experience. Ann Thorac Surg 1986; 42:609. 21. Craig RJ, Selzer A. Natural history and prognosis of atrial septa defect. Circulation 1968; 37:805. 22. Losay J, et al. Repair of atrial septal defect primum. J Thorac Cardiovasc Surg 1978; 75:248. 23. Koenig P, Cao QL, Heitschmidt M, et al. Role of intra cardiac echocardiographic guidance in transcatheter closure of atrial septal defects and patent foramen ovule using the Amplatzer device. J Interventional Cardiol 2003; 16(1):51–62. 24. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 1958; 18:533. 25. Becker AE, Anderson RH. Classification of ventricular septal defects—a matter of precision. Heart Vessels 1985; 1:120. 26. Lincoln C, et al. Transatrial repair of ventricular septa defects with reference to their anatomic classification. J Thorac Cardiovasc Surg 1977; 74:183. 27. Milo S, et al. Surgical anatomy and atrioventricular conduction tissues of hearts with isolated ventricular septal defects. J Thorac Cardiovasc Surg 1980; 79:244. 28. Rashkind WJ, Cuaso CC. Transcatheter closure at patent ductus arteriosus. Pediatr Cardiol 1979; 1:3. 29. Sato K, et al. Transfemoral plug closure of patent ductus arteriosus: experience in 61 consecutive cases treated without thoracotomy. Circulation 1975; 51:337. 30. Rothenberg SS. Transcatheter versus surgical closure of patent ductus arteriosus. N Engl J Med 1994; 330:1014. 31. Laborde F, et al. A new video-assisted thoracoscopic surgical technique for interruption of patent ductus arteriosus in infants and children. J Thorac Cardiovasc Surg 1993; 105:278. 32. Freed MD, et al. Prostaglandin E1 in infants with ductus arteriosusdependent congenital heart disease. Circulation 1981; 64:899. 33. de Brux JL, et al. Tricuspid atresia. J Thorac Cardiovasc Surg 1978; 48:378. 34. Dick M, Fyler DC, Nadas AS. Tricuspid atresia: clinical course in 101 patients. Am J Cardiol 1975; 36:327. 35. Blalock A, Taussig HB. The surgical treatment of malformations of the heart. JAMA 1945; 128:189. 36. Fontan F, Baudet S. Surgical repair of tricuspid atresia. Thorax 1971; 26:240. 37. Jonas RA, Castaneda AR. Modified Fontan procedure: atrial baffle and systemic venous to pulmonary artery anatomic techniques. J Cardiac Surg 1988; 3:91. 38. Fontan F, et al. Repair of tricuspid atresia in 100 patients. J Thorac Cardiovasc Surg 1983; 85:647. 39. Fontan F, et al. Outcome after a ‘‘perfect’’ Fontan operation. Circulation 1990; 81:1520. 40. Sanders SP, et al. Clinical and hemodynamic results of the Fontan operation for tricuspid atresia. Am J Cardiol 1982; 49:1733. 41. Touati G, et al. Primary repair of tetralogy of Fallot in infancy. J Thorac Cardiovasc Surg 1990; 99:396. 42. Rabinovitch M, et al. Growth and development of pulmonary vascular bed in patients with tetralogy of Fallot with or without pulmonary atresia. Circulation 1981; 64:1234. 43. Bove EL, et al. The influence of pulmonary insufficiency on ventricular function following repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1983; 85:691.

Chapter 35: Congenital Heart Lesions 44. Mair DD, Ritter DF. Factors influencing systemic arterial oxygen saturation in complete transposition of the great arteries. Am J Cardiol 1973; 31:742. 45. Benson LN, et al. Role of prostaglandin E1 infusion in the management of transposition of the great arteries. Am J Cardiol 1979; 44:691. 46. Lang P, et al. Use of prostaglandin E1 in infants with D-transposition of the great arteries and intact ventricular septum. Am J Cardiol 1979; 44:76. 47. Benson LN, et al. Assessment of right ventricular function during supine bicycle exercise after Mustard’s operation. Circulation 1981; 65:1052. 48. Jatene AD, et al. Anatomic correction of transposition of the great vessels. J Thorac Cardiovasc Surg 1976; 72:364. 49. Yacoub M, et al. Clinical and hemodynamic results of the twostage anatomic correction of simple transposition of the great arteries. Circulation 1980; 62(suppl 1):1190. 50. Marcelletti C, et al. The Rastelli operation for transposition of the great arteries. J Thorac Cardiovasc Surg 1976; 72:427. 51. Metras D, Kreitmann B. Modified Rastelli using an autograft: a new concept for correction of transposition of the great arteries with ventricular septal defect and left ventricular outflow tract obstruction. Pediatr Cardiac Surg Annu Semin Thorac Cardiovasc Surg 2000; (3):117–124. 52. Bharati S, Lev M. The surgical anatomy of hypoplasia of aortic tract complex. J Thorac Cardiovasc Surg 1984; 88:97.

697

53. Bailey L, et al. Pediatric heart transplantation: issues relating to outcome and results. The Loma Linda Pediatric Heart Transplant Group. J Heart Lung Transplant 1992; 11:5267. 54. Sano S, Ishino K, Kawada M, et al. Right ventricle-pulmonary artery shunt in first-stage palliation of hypoplastic left syndrome. J Thorac Cardiovasc Surg 2003; 126(2):504–509. 55. Mair R, Tulzen G, Sames E, et al. Right ventricular to pulmonary artery conduit instead of modified Blalock-Taussig shunt improves postoperative hemodynamics in newborns after the Norwood operation. J Thorac Cardiovasc Surg 2003; 126(5): 1378–1384. 56. Iannettoni MD, Bove EL, Mosca RS. Improving results with first-stage palliation for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 1994; 107:934.

FURTHER READING Baue AE, et al., eds. Glenn’s Thoracic and Cardiovascular Surgery. 6th ed. Norwalk: Conn. Appleton & Lange, 1996. Castaneda AR, et al. Cardiac Surgery of the Neonate and Infant. Philadelphia: WB Saunders, 1994. Garson A Jr, Bricker JT, McNonara DG, eds. The Science and Practice of Pediatric Cardiology. Philadelphia: Lea & Febiger, 1990.

medwedi.ru

36 Acquired Cardiac Disorders Dipin Gupta, Andrew C. Fiore, and Glenn J. R. Whitman

INTRODUCTION In contrast to congenital heart disease, in which surgical intervention is usually required to restore the underlying pathophysiology to normalcy, acquired cardiac disorders are often amenable to medical management. Notwithstanding this circumstance, several diseases are still best treated surgically and will probably remain so for many years to come. Acquired heart disease in which surgical management plays a prominent role forms the basis for this chapter. The first sections focus on ischemic heart disease and abnormalities of the cardiac valvular system, and on the role that surgery plays in correcting disordered physiology in these conditions. Heart failure—and the novel surgical therapies that are currently being developed—forms the basis of the next section. The final sections concentrate on diseases that require surgical attention less commonly, but in which the cardiac surgeon still renders important help in the delivery of optimal care. These disorders include cardiac dysrhythmias, pericardial disease, and cardiac tumors.

The RCA runs in the right atrioventricular groove, where in 80% to 85% of cases it gives off the PDA, continuing with terminal branches to the posterior left ventricular wall. The RCA feeds the anterior surface of the right ventricle with acute marginal branches.

Coronary Veins Three venous systems drain the coronary circulation. (i) The coronary sinus located in the posterior atrioventricular groove receives blood from the great, middle, and small cardiac veins. The great cardiac vein ascends along the LAD and then follows the circumflex artery to empty into the coronary sinus. The middle cardiac vein follows the PDA, again emptying into the coronary sinus. The small cardiac vein follows the RCA in the atrioventricular groove before it, too, joins the coronary sinus. (ii) The thebesian veins are tiny venous orifices that drain directly into any of the four chambers of the heart. (iii) The anterior cardiac veins drain the right ventricular coronary system, traversing the right ventricular free wall and crossing the atrioventricular groove to empty directly into the right atrium.

Coronary Blood Flow

ISCHEMIC HEART DISEASE The Coronary Circulation Coronary Arteries The right coronary artery (RCA) and left coronary artery originate from the aorta just above the aortic valve cusps (Fig. 1). In fact, the positions of these two arteries within the sinuses of Valsalva designate the right and left coronary cusps. The third cusp is referred to as the noncoronary cusp, because it does not have an associated coronary ostium. The left main coronary artery, which travels posterolaterally to the left behind the pulmonary artery, divides into two main branches, the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. The LAD emerges from behind the pulmonary artery to course anteriorly within the interventricular groove. The initial tributary of the LAD is usually the first diagonal, which runs over the anterolateral surface of the left ventricle, followed by the first septal perforator, which emerges at a right angle from the LAD and penetrates into the interventricular septum. The LAD may then give off more diagonal and septal branches. The left circumflex coronary artery descends posteriorly from the left main coronary artery. In 80% to 85% of cases, it terminates with branches to the posterolateral wall of the left ventricle. In the remainder, it extends to the crux of the heart and then gives off the posterior descending coronary artery (PDA), which runs in the posterior interventricular groove. The branches of the circumflex artery are referred to as obtuse marginals and cover the lateral and posterolateral portion of the left ventricle.

The heart extracts a greater percentage of delivered oxygen than any other organ in the body. In fact, the heart uses 60% to 70% of the oxygen supplied, as opposed to only 25% for the body as a whole. Coronary sinus oxygen content is only 4 to 6 mL oxygen/dL blood, which corresponds to an oxygen tension of approximately 24 mmHg and a hemoglobin oxygen saturation of only 20% to 30%. Therefore, even at rest, the heart is extracting oxygen maximally, and, unlike in other organs, increased oxygen demand can only be met by increased delivery, rather than increased oxygen extraction. The most important factor that regulates coronary blood flow is perfusion pressure. Myocardial blood flow occurs almost entirely during diastole, because during systole, cavitary left ventricular pressure equal to that of aortic pressure prevents coronary flow. Coronary flow also depends on coronary luminal diameter. In general, obstruction is considered clinically significant when luminal diameter decreases to two-thirds of baseline. Myocardial blood flow thus depends on diastolic pressure as well as coronary arterial patency. Tachycardia can therefore lead to ischemia not only by increasing oxygen demand, but also by limiting diastolic perfusion time. A variety of metabolic factors regulate coronary circulation as well. In fact, these autoregulatory capabilities increase blood supply to the heart in response to increased myocardial oxygen requirements. The most important metabolic regulator of this phenomenon is the potent vasodilator adenosine (2). Increased oxygen demand increases

medwedi.ru 699

700

Part Three: The Cardiothoracic System—Heart

Figure 1 (A) Diagram of the right coronary artery circulation in the right anterior oblique and left anterior oblique projections. (B) Diagram of the left coronary arterial circulation in the right anterior oblique and left anterior oblique projections. Abbreviations: SA, sinoatrial; AV, atrioventricular. Source: From Ref. 1.

adenosine triphosphatase (ATP) use, with a resultant increase in adenosine concentration, because it is a direct breakdown product of ATP. This results in coronary vasodilation and increased oxygen delivery. Conversely, thromboxane A2 is thought to play a crucial role in coronary vasoconstriction. Interestingly, it is released by platelets, particularly in the setting of platelet clumping, a situation that occurs almost universally in the setting of angina with myocardial infarction (MI) (3).

Coronary Atherosclerosis The Lesion Atherosclerotic lesions all have in common a mixture of proliferating smooth muscle with a tissue matrix consisting of collagen, elastin, and proteoglycans formed by these cells, as well as the accumulation of intracellular and extracellular lipid (Fig. 2). The lesions characteristically occur within the intima and progress from benign, fatty streaks to complicated, occlusive plaques. It is known that fatty streaks may occur as early as the first decade of life. With time, particularly in populations at risk, the fatty streaks develop into a fibrous plaque, a protruding lesion that may become obstructive. The subintimal smooth muscle cell proliferation that goes along with this fibrous plaque is the factor most responsible for this protrusion. With time, the fibrous plaque may enlarge, become calcified, and degenerate on its intimal surface, resulting in ulcerations that are thrombogenic. Organization of clot with platelet clumping on this surface not only causes increased obstruction to flow, but also, as stated previously, may release thromboxane A2, further exacerbating the compromised delivery of blood and, therefore, oxygen to the myocardium. Risk Factors A number of established risk factors predispose patients toward atherosclerosis (5). These include a genetic predisposition, hypertension, diabetes mellitus, hyperlipidemia, and

cigarette smoking. Genetic factors appear to have a direct effect on endothelial cell biology and predisposition toward the development of atherosclerosis. The risk of coronary artery disease increases with increasing blood pressure; among patients with blood pressure greater than 160/ 95 mmHg, the incidence of coronary disease is five times greater than among those who are normotensive. Of most importance is the fact that control of hypertension decreases this risk. Diabetes mellitus is clearly associated with coronary artery disease. The risk of coronary disease is increased at least twofold in patients with diabetes, with the risk even higher among those with juvenile-onset diabetes. Unfortunately, it is not certain that rigorous control of hyperglycemia decreases coronary mortality rate in this population. The Lipid Research Clinics Trial (6) demonstrated an unequivocal association between cholesterol level and morbidity and mortality from coronary artery disease. As with hypertension, decreasing the level of hyperlipidemia decreases the risk of coronary disease. Interestingly, high-density lipoproteins (HDLs), which contain approximately 20% of total plasma cholesterol, protect one from coronary disease. HDL level is known to be raised by exercise and estrogens and decreased by cigarette smoking. Cigarette smoking is one of the most important risk factors for the development of coronary artery disease, not simply because it is so clearly related to its development but because its cessation so clearly decreases the risk. In patients who smoke only one pack of cigarettes per day, the death rate from coronary artery disease is 70% higher than in nonsmokers. Furthermore, cigarette smoking appears to potentiate other risk factors. Other factors postulated to contribute to the progression of coronary artery atherogenesis include increasing age, male gender, supranormal serum levels of homocysteine and lipoprotein A (7), and low-estrogen states such as menopause (8). Age has a complex association with the development of atherosclerosis, because many other risk factors are associated with aging. It is well documented that

Chapter 36: Acquired Cardiac Disorders

Figure 2 Developmental stages of the lesions of atherosclerosis. (A) The normal muscular artery consists of an internal intima with endothelium and internal elastic lamina. The smooth muscle of the vessel wall is in the media, and the thin adventitial layer contains connective tissue and vasovasorum. With age, the thin, sparsely muscled intima increases in thickness and smooth muscle cell content. (B) In the first phase of an atheroslerotic lesion, there is a focal thickening of the intima with smooth muscle cells and extracellular matrix. There is also initial accumulation of intercellular lipid deposits. (C) Extracellular lipid may also develop. (D) When both intracellular and extracellular lipids are present in the earliest phase, this is referred to as a fatty streak. (E) Fibrous plaque results from continued accumulation of fibroblasts covering proliferating smooth muscle cells laden with lipids and cell debris. The lesion becomes more complex as continuing cell degeneration leads to ingress of blood constituents and calcification. Source: From Ref. 4.

men are three times more likely than women to acquire coronary disease, and, in fact, the development of ischemic syndromes occurs, on the average, 10 years earlier in affected men than in affected women. Because of the recognition that atherosclerosis may begin as early as the first or second decade of life, primary prevention of this disease must begin early. The importance of understanding the risk factors for coronary disease and eliminating or modifying those over which we have control cannot be overemphasized.

Clinical Presentation of Ischemic Heart Disease The clinical presentation of ischemic heart disease can take many forms. As many as 25% of patients with positive stress test results due to coronary occlusive disease may have no symptoms. Similarly, some acute MIs may occur silently. In fact, in some patients sudden cardiac death is the first and only manifestation of this disease process. Another subset of patients without typical symptoms may have

701

progressive heart failure. This in general is caused by a slow, diffuse loss of ventricular function associated with increasing coronary obstructions. This entity is often referred to as ischemic cardiomyopathy. Most commonly, however, when significant coronary obstructive disease is present, angina pectoris results. The typical description of angina is as a pressure or heaviness felt in the middle of the chest, radiating to the left shoulder and down the left arm. Abdominal pain, nausea, belching, jaw pain, and hand heaviness or numbness are less typical manifestations of cardiac ischemia. In almost all cases, however, stable angina pectoris is brought on by reproducible increases in myocardial demand for a pathologically limited oxygen supply. Emotional excitement or stress, exposure to cold, eating, and exercise are typical historical events that trigger demand-induced angina. In unstable angina, however, the symptom of chest pain may occur at rest, or even when the patient is sleeping. These patients are exhibiting a phenomenon of myocardial ischemia without demonstrable changes in myocardial oxygen demand. This reflects a situation in which the supply of blood to the myocardium is so marginal that spontaneous coronary vasoreactivity alone may lead to symptoms. Prinzmetal’s or variant angina is a less typical form of angina that also may occur spontaneously without increasing myocardial oxygen demand. It is thought to result from spontaneous coronary arterial spasm, but it is almost always associated with underlying fixed atherosclerotic lesions. Patients may have ST-segment elevation, as opposed to the more typical ST-segment depressions associated with classical angina. Angina may be graded according to the Canadian Heart Classification scheme. Class I patients have no symptoms, class II patients have angina on significant exertion, class III patients have angina on mild exertion, and class IV patients have symptoms at rest. On physical examination, there is usually no detectable sign of coronary artery disease. There may be evidence of associated peripheral vascular disease, however, with loss of pulses or presence of bruits in the carotid arteries, abdominal aorta, or femoral arteries. Xanthomas or hypertensive retinal changes provide evidence of the presence of risk factors for coronary disease. Multiple studies are used to identify factors that may stress the heart. Anemia, of course, can exacerbate underlying coronary insufficiency. Results of electrocardiographic (ECG) examination are frequently normal, but some patients have evidence of old MIs, clearly indicating the presence of coronary disease. Stress testing is an ideal physiologic examination for assessing the functional significance of coronary disease. In this study, the patient undergoes graded exercise on a treadmill with continuous ECG monitoring. If the patient shows signs or symptoms of angina pectoris associated with typical ischemic ECG changes, this is considered a positive test result. Specificity of the test is improved dramatically if it is combined with the administration of thallium. Thallium is a radioactive isotope that is distributed in the intracellular space, like potassium. When thallium is injected during exercise, if a patient has coronary ischemia, the involved area of myocardium fails to pick up thallium and a defect is present on the scan. As the patient recovers from exercise and ischemia resolves, the myocardial defects fills in, suggesting the reversible nature of the problem. A defect on a thallium scan that never fills in is a sign of irreversibly scarred, nonviable myocardium. Despite the specific and sensitive nature of thallium stress testing, coronary arteriography, although invasive, is

medwedi.ru

702

Part Three: The Cardiothoracic System—Heart

the main modality used to make a definitive anatomic diagnosis of coronary artery disease. It is indicated in patients with atypical presentations in whom it is important to rule out a definitive diagnosis of coronary disease. Otherwise, patients with classic anginal symptoms and ECG changes in whom the diagnosis is not in question should undergo coronary arteriography; if the condition is refractory to medical therapy, they are candidates for revascularization, or both. If patients have suspected severe coronary disease, such as left main or severe proximal three-vessel disease, regardless of symptoms, coronary arteriography should be performed to document this condition in preparation for revascularization. Well-known survival benefits accrue to patients who undergo surgery after such documentation. Diagnostic coronary arteriography should also be performed in patients with other cardiac diseases such as valvular heart disease in whom valve surgery is planned but in whom there is a risk of concomitant coronary disease. Less invasive means of detecting coronary artery disease are being developed, and will likely obviate the need for coronary angiography in some patients in the future. To date, multislice spiral computed tomography has been found to have a sensitivity and specificity of 95% and 86%, respectively, when compared to angiography (9). Similarly, magnetic resonance coronary angiography has been found to have a sensitivity of 76% and specificity of 91% compared to angiography (10). With evolution of this technology, these tests are likely to gain further accuracy. The medical management of coronary disease includes the identification and reduction of controllable risk factors. Once the disease presents itself in the form of clinically significant ischemia, however, the focus for the clinician is on decreasing myocardial oxygen uptake and increasing myocardial oxygen supply. It therefore follows that patients with hyperthyroidism or anemia, one of which affects oxygen demand and the other supply, should have these underlying conditions corrected. In general, though, there are five classes of drugs, in the armamentarium of the physician, which are useful for treating ischemic heart disease. Aspirin plays a critical role in prevention of platelet aggregation. Nitrates are the most commonly used agents. They primarily dilate venous capacitance blood vessels, with resultant decreases in preload, wall tension, and oxygen uptake. Although nitrates do not appear to increase coronary blood flow in the normal heart, improvement in coronary collateral blood flow does occur in patients with ischemic heart disease. b-adrenergic blocking agents reduce myocardial oxygen demand by decreasing both cardiac contractility and heart rate. These agents may also reduce blood pressure and systemic vascular resistance, further reducing the work of the heart. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors—also known as ‘‘statins’’—have been shown to be effective in primary and secondary prevention of coronary artery disease by lowering serum concentration of low-density lipoprotein (11). Finally, calcium-channel–blocking agents such as nifedipine and diltiazem decrease myocardial oxygen uptake by decreasing ventricular contractility. By causing arterial dilation, they diminish systemic vascular resistance as well, and they are particularly effective in patients with a component of coronary vasospastic disease.

Acute Myocardial Infarction MI is one of the most common diagnoses of hospitalized patients in the United States. Approximately 1.5 million MIs occur each year, with an early mortality rate of approximately

25%. More than half of these deaths occur before the patient ever reaches the hospital. Acute MI is the direct result of interruption of blood supply to the myocardium. It almost always occurs as the result of coronary arterial thrombosis at the site of a significant stenosis over a complicated plaque. Although the acute event associated with acute MI is thrombosis, cardiac catheterization studies show that within days 20% to 30% of culprit coronary arteries are patent. This is more common in nontransmural MI than in transmural MI. A major determinant of prognosis after an acute MI is the amount of ventricular myocardium that undergoes necrosis. In patients who have ejection fractions greater than 50% after MI, three-year survival is close to 90%, but when ejection fraction after MI falls to less than 37%, three-year survival is only 50%. Loss of 25% of ventricular myocardium leads to symptomatic cardiac dysfunction, whereas the loss of more than 40% is frequently associated with cardiogenic shock and death. Therefore, efforts to treat patients who are having an acute MI should be focused on decreasing myocardial loss by improving flow to the area at risk, as soon as possible. Interestingly, although well-developed collaterals may not prevent demand-induced angina, they may significantly diminish the loss of myocardium after an acute MI.

Presentation Pain is the most common presenting complaint in patients with MI. It is by no means universally present, however, with 20% to 25% of patients having no symptoms. Interestingly, acute MIs associated with the LAD distribution frequently result in sympathetic hyperactivity, with tachycardia and hypertension, whereas inferior MIs involving the RCA frequently have parasympathetic activity with bradycardia and hypotension. The classic ECG picture of an acute MI is the development of Q waves and elevated coved ST segments in leads reflecting the affected areas (Fig. 3). In fact, the type of MI can frequently be characterized by the associated ECG changes. Transmural infarctions usually cause Q waves, whereas subendocardial or nontransmural MIs are usually characterized by transient ST-segment changes with inverted T waves, without the development of Q waves.

Figure 3 Acute inferior wall myocardial infarction (MI). The electrocardiogram of 11/29 shows minor nonspecific ST-segment and T-wave changes. On 12/5, an acute MI occurred. There are pathologic Q waves (1), ST-segment elevation (2), and terminal T-wave inversion (3) in leads II, III, and aVF, indicating the location of the infarct on the inferior walls. Reciprocal changes are seen in aVL (small arrow). Increasing R-wave voltage with ST depression and increased voltage of the T wave in V3 is characteristic of true posterior wall extension of the inferior infarction. Source: From Ref. 12.

Chapter 36: Acquired Cardiac Disorders

The most common modality used for diagnosing MI lies in the evaluation of specific cardiac isoenzymes released by necrotic myocytes in large enough quantities to be detected in the blood. In particular, serum levels of creatine kinase (CK), a cardiac enzyme involved with high-energy phosphate metabolism, are increased after MI, rising within 8 to 24 hours and returning to normal within one to two days. CK is found in brain (CK-BB) and skeletal muscle (CK-MM), and it can rise significantly after a variety of clinical scenarios such as stroke, surgery, cardiac catheterization, or simple intramuscular injection. It is therefore crucial to measure the cardiac-specific isoenzyme, CK-MB, when ruling out an MI. More recently, subunits of the troponin complex that regulates the calcium-mediated contractile process of striated muscle have been used in diagnosis of MI. Troponin T and troponin I have been observed to rise above the reference range within three hours of the onset of chest pain. These markers may persist in the serum for 10 to 14 days.

Medical Treatment During the early phase of MI, principles of management are to maximize oxygen delivery to myocardium and to minimize oxygen consumption. In this regard, oxygen should be administered, heart rhythm and rate should be monitored, and pain should be controlled usually with intravenous morphine. Decreasing pain has a significant therapeutic benefit because it decreases myocardial oxygen demand, helping to limit infarct size. Intravenous nitroglycerin should be initiated, because it may diminish infarct size, decrease the risk of sudden cardiac death, and lower the incidence of congestive heart failure (CHF) (13). b-Blockers have also been shown to limit infarct size and decrease early mortality rates (14). Angiotensinconverting enzyme (ACE) inhibitors have been shown to reduce morbidity and reduce the incidence of chronic CHF following acute MI, and are now regarded as essential therapy (15). In the mid-1970s, it was hypothesized that the administration of thrombolytic agents could lead to the dissolution of coronary thromboses, reversing the process precipitating the MI. A consequent European trial of streptokinase (SK) revealed a significant benefit when the drug was given within 12 hours of acute MI (16). Since then, thrombolytic trials have established without doubt the benefits of this approach, showing that thrombolysis reopens acutely occluded coronary arteries in most cases, restoring flow and reducing mortality rate (17). Four intravenous thrombolytic agents are currently approved by the Food and Drug Administration (FDA) for use in acute MI: SK, Anistreplase (APSAC), Alteplase (rTPA), and Reteplase. The most widely used is SK, which has been effective in several very large trials and is inexpensive. APSAC was developed to enable treating physicians to give one intravenous bolus dose in a few minutes, with maintenance of the effect for several hours because of its long half-life. However, APSAC has not been significantly better than SK, and its prolonged half-life has become a drawback rather than a benefit. rTPA produced by recombinant DNA techniques is more effective than SK. It also yields higher patency rates and generates less of a systemic fibrinolytic effect. However, rTPA is several times more expensive than SK, and it thus may not be cost-effective. What is clear is that the earlier the thrombolytic treatment, the greater the impact on post-MI morbidity and mortality, with the greatest benefit accruing to those patients treated within one to two hours of the onset of symptoms. Heparin and antiplatelet drugs should be added to

703

thrombolytic therapy, particularly to rTPA, which has a short half-life and exerts little antithrombin effect, because it does not generate excessive fibrin-degradation products. Hemorrhage is the major problem with all thrombolytic agents, occurring commonly at the site of vascular access. Strokes occur in fewer than 1% of patients but may be catastrophic because of their hemorrhagic nature (18). Platelet membrane glycoprotein IIb/IIIa inhibitors are a new class of potent antiplatelet agents that block the final common pathway in platelet aggregation. FDA approval has been obtained for the following intravenous agents: Abciximab (ReoPro, a monoclonal antibody), Eptifibatide (Integrilin, a synthetic peptide), and Tirofiban (Aggrastat, a nonpeptide mimetic). These agents have been tested with and without percutaneous coronary interventions. In addition, clinical trials are underway involving a new group of oral glycoprotein IIb/IIIa inhibitors. Ticlopidine (Ticlid) and Clopidogrel (Plavix) are a new class of antiplatelet agents, which act by irreversibly inhibiting the adenosine diphosphate receptor involved in platelet aggregation. Both have been shown to improve outcome in patients suffering acute coronary syndromes, though patients who received Clopidogrel plus aspirin suffered more bleeding complications than patients receiving aspirin alone (19).

Mechanical Intervention in Acute Myocardial Infarction After thrombolytic therapy with early recanalization, the issue remains whether anything more needs to be done in the acute setting. Despite early reperfusion, significant residual stenoses remain in the culprit coronary arteries. The Thrombolysis in Myocardial Ischemia (TIMI)-II trial (20) compared immediate cardiac catheterization with percutaneous transluminal coronary angioplasty (PTCA) with elective cardiac catheterization and PTCA, only if ischemia developed during the hospital course. The more invasive approach failed to provide any increased benefit with respect to early or late mortality rates. As a result of this and other studies, cardiac catheterization and mechanical intervention should be withheld in most patients after acute MI unless patients exhibit ischemia during their hospital stay or have poor results of a predischarge low-level exercise stress test.

Indications for Surgery After Acute Myocardial Infarction Postinfarction Angina Recurrent chest pain occurs in 10% to 15% of patients after acute MI, an incidence that increases to 30% to 35% among patients who receive thrombolytic therapy. It is well recognized that after MI, the mortality rate may increase several fold if infarct extension occurs (21). Infarct extension is a powerful predictor of post-MI mortality risk, as seen by an increase in the average one-year mortality rate from approximately 18% to 65%, if infarct extension occurs. Thus, postinfarction angina is an indicator of continued myocardial ischemia and a harbinger of infarct extension. It should be regarded as an indication for cardiac catheterization with mechanical intervention, either PTCA or coronary bypass surgery. Cardiogenic Shock Cardiogenic shock after MI is uncommon, only occurring in approximately 7% of patients with acute MI. Shock after acute

medwedi.ru

704

Part Three: The Cardiothoracic System—Heart

MI is associated with a 65% mortality rate, compared with a mortality rate of only 4% if shock is not present. The risk factors for development of cardiogenic shock after acute MI are age greater than 65 years, ejection fraction less than 35% on admission, a large MI as evaluated by peak CK-MB serum concentration, a history of diabetes mellitus, and a history of previous MI. Because shock develops after hospitalization in more than 50% of patients, identifying patients with these risk factors is important because it might possibly allow early intervention to prevent development of shock. Animal studies have shown that in cases of prolonged regional MI, intervention with emergency revascularization may decrease the amount of damage sustained by the myocardium. By focusing on ways to decrease myocardial energy expenditure during early reperfusion, as well as decreasing cell swelling and oxidant injury and improving intermediary cellular metabolism, a significant decrease in myocardial injury can be achieved. This has led to a prospective study evaluating the effect of coronary bypass surgery on patients in cardiogenic shock after MI (22). If surgery occurred within 18 hours of the onset of shock, mortality rate was reduced from 65% to 7%, whereas if surgery occurred after 18 hours, mortality rate was 31%, still a definite improvement from medical therapy. At centers capable of performing surgery of this kind, this may be an ideal approach to patients in shock after MI. However, these results have not been duplicated by other institutions. Until they are, they must be viewed as preliminary. Ventricular Septal Defect A ventricular septal defect (VSD) occurs in approximately 2% of patients after MI. This complication, which occurs when the myocardium is at its weakest, approximately three to five days after an MI, has an associated medical mortality rate of more than 90%. It is seen most frequently in elderly hypertensive female patients with anterior transmural infarcts. An increase in the right ventricular oxygen saturation is often observed. The initial medical therapy involves decreasing afterload as much as possible, invariably with the use of the intra-aortic balloon pump as well as vasodilator therapy. Preload is optimized and surgery is performed immediately. Early operation, before the complications of shock occur, appears to carry a much better survival rate (23). Acute Mitral Regurgitation As with VSD, acute papillary muscle rupture with mitral regurgitation occurs in only 2% of patients after acute MI. Posteroinferior MIs lead to this complication more frequently than do anterior MIs, almost certainly because the circumflex artery and PDA distributions are the most crucial blood supplies to the papillary muscles. This complication presents similarly to a VSD. As opposed to the pattern in patients with an acute VSD, however, the pulmonary capillary wedge pressure shows prominent V waves, and there is no right ventricular hemoglobin oxygen saturation step-up. Medical therapy involves maximizing afterload reduction through the use of an intra-aortic balloon pump. Early surgery, although it carries a high risk, decreases mortality rate from 90% to less than 50%. If the mitral valve apparatus can be preserved, mortality risk can be decreased even further. Free Wall Rupture Like the previous two complications, ventricular free wall rupture occurs at a time when the myocardium is at its

weakest, three to five days after acute MI. The medical mortality rate is exceedingly high (>90%), because the patients die acutely in tamponade. Surgical case reports cite dramatic rescues of these patients, but in general, for successful treatment, free wall rupture must be small and contained, allowing time for diagnosis and operative intervention. Most commonly, free wall rupture leads to pericardial tamponade, cardiogenic shock, and death.

Revascularization Angioplasty In the mid-1970s, Gruentzig and Hoff designed a balloon dilatation catheter for use in the coronary arteries and initiated the important treatment option for patients with ischemic heart disease currently known as PTCA. Under fluoroscopic guidance, a catheter is directed into the coronary artery. A guide wire is then placed across the obstructing lesion, and a balloon catheter is then passed over the guide wire and positioned in the mid-portion of the lesion. Under fluoroscopic control, the balloon is inflated to 4 to 10 atm pressure for 20 to 60 seconds in an effort to reduce the degree of coronary obstruction. The indications for PTCA are the same as those for coronary artery bypass surgery, which is the main alternative revascularization technique. Patients with intractable symptoms and those with proximal coronary stenoses that place a large amount of myocardium at risk are potential candidates for angioplasty. The ideal lesion is a symmetric, focal stenosis in a proximal epicardial vessel. PTCA is contraindicated if there is significant disease in the left main coronary artery, if the target coronary artery is less than 2 mm in diameter, if there are multiple significant obstructive lesions in the same artery, or if there are complex obstructive lesions involving arterial bifurcations. The primary risk of angioplasty is the dissection of the coronary artery with acute closure, which occurs in approximately 3% of cases and usually requires emergency coronary bypass surgery. Otherwise, the risks are similar to those of coronary arteriography and include cerebral vascular accidents and local arterial trauma. Under development are atherectomy catheters that incorporate tiny rotating blades for lysis of atheromatous plaque, as well as laser-tipped catheters that vaporize intraluminal obstructions. Coronary stents are small, implantable cylindric devices designed to maintain patency of diseased arteries when more conventional balloon angioplasty is ineffective. Successful dilation of favorable coronary arterial obstructive lesions occurs in more than 90% of PTCA attempts, with an immediate complication rate of only 3%. The most significant long-term problem with PTCA is the high incidence of restenosis, which occurs in between 20% and 40% of patients within the first four to six months after the initial PTCA (24). Although redilatation of recurrent stenotic lesions may be carried out successfully, many of these patients ultimately require coronary bypass surgery. The persistent problem of in-stent restenosis has yielded the development of coronary brachytherapy and drug-eluting stents. Radiation treatment using b-radiation or g-radiation has been observed to effectively reduce the degree of in-stent restenosis and to prevent recurrent restenosis (25). Local delivery of specific agents via the stent is also possible. In this manner, sirolimus (rapamycin, an inhibitor of smooth muscle cell and lymphocyte proliferation) and paclitaxel (an inhibitor of cell division) have been seen to dramatically lower the incidence of adverse cardiac events after stenting. For example, at follow-up of one year,

Chapter 36: Acquired Cardiac Disorders

major cardiac events were seen in approximately 6% of patients receiving a sirolimus-coated stent versus approximately 30% of patients receiving a standard stent (26). Given these encouraging results, FDA approval was obtained for use of sirolimus-coated coronary stents in 2002. Furthermore, Clopidogrel (Plavix) has been shown to be effective in reducing in-stent stenosis, as an adjunct therapy to aspirin (27), and thus most patients are placed on both drugs after percutaneous interventions.

Coronary Artery Bypass Surgery Coronary bypass surgery is among the most commonly performed operations in the United States today, with more than 250,000 procedures performed yearly. The goal, as with PTCA, is to treat ischemic heart disease by relieving the imbalance between myocardial oxygen supply and demand. Indications In general, data from clinical trials and retrospective studies show that as the number of diseased major coronary arterial segments increases, the greater the survival benefit from coronary bypass surgery. Three major prospective, randomized coronary bypass surgery studies—the Coronary Artery Surgery Study (CASS) (28), the Veterans Affairs Cooperative Study (29), and the European Cooperative Study (30)— are in large part responsible for how we treat patients with ischemic heart disease. Patients with intractable symptoms were not involved in these studies; those patients, in general, should undergo bypass surgery because it is the most successful way to relieve angina. These three studies have provided us with the anatomic indications for bypass surgery, which include left main stenosis and double- and triple-vessel disease involving the proximal LAD (Table 1). As stated previously, the most common indication for bypass surgery continues to be angina refractory to medical therapy. Bypass surgery can be expected to eliminate angina in more than 90% of patients at one year, with benefit continuing for 60% of patients at five years. Patients being medically treated for unstable angina require aggressive therapy, including nitrates, platelet inhibitors, b-blockers, and ACE inhibitors. Often, heparin anticoagulation is necessary. If the patient continues to have angina while receiving maximal medical therapy, urgent revascularization is indicated. Finally, as noted before, emergency coronary bypass surgery is necessary in approximately 3% of patients who have coronary occlusive complications after PTCA. Most of these occlusions result from coronary dissections proximal or distal to the site of dilatation. Most patients in the midst of an evolving MI have some attenuation of the ischemic injury by the placement of Table 1 Indications for Coronary Bypass Surgery Anatomy 1. Left main disease 2. Triple-vessel disease involving the proximal LAD, with normal or diminished ejection fraction 3. Double-vessel disease involving the proximal LAD, with normal or diminished ejection fraction Symptoms 1. Unstable (crescendo) angina 2. Post-MI angina 3. Acute coronary occlusion after PTCA 4. Symptoms unsuccessfully controlled with medical therapy 5. Controlled symptoms, but with unacceptable lifestyle Abbreviations: LAD, left anterior descending coronary artery; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty.

705

an intra-aortic balloon counter-pulsation device before transport to the operating room. If hemodynamic instability continues despite balloon pump support, portable cardiopulmonary bypass perfusion with femoral arterial and femoral venous cannulation may allow sufficient time to stabilize the patient’s condition for an operation. Surgical Technique In coronary artery bypass surgery, the diseased portion of the coronary artery is bypassed by the creation of an alternative conduit for delivery of blood beyond the stenosis. Grafts are constructed by making an end-to-side anastomosis to the coronary artery distal to the obstruction. The proximal end of the vein graft is usually sutured end-to-side to the ascending aorta. Use of arterial grafts has increased in recent years. The most commonly used arterial graft is the left internal thoracic artery (LITA), which is used as a pedicle retaining its origin at the subclavian artery with a distal end-to-side anastomosis to the diseased coronary artery. Most commonly, this is the LAD. The right internal thoracic artery (RITA) may be used as either a pedicle graft or a free graft as well when more than one arterial graft is desired. In a much more limited fashion, the gastroepiploic artery, the radial artery, and the inferior epigastric artery have been used as conduits. The main benefit of these grafts is improved long-term patency; the 10-year patency of the internal thoracic artery is between 90% and 95%, whereas saphenous vein grafts have only a 50% 10-year patency. Use of the LITA has been shown to improve survival and reduce the incidence of late MI, recurrent angina, and the need for further cardiac interventions (31). Simultaneous use of both LITA and RITA is becoming more common, and has been reported to have beneficial effects in large single-center studies (32). Traditionally, to maintain a quiet, bloodless field, cardiopulmonary bypass is employed for coronary bypass surgery (Fig. 4). With the patient on bypass and the heart empty, the distal ascending aorta is cross-clamped and potassium cardioplegic solution injected into the aortic root, causing nearly instantaneous cardiac arrest. The cardioplegic solution is usually between 4 C and 10 C, to induce rapid myocardial cooling. In addition, topical iced saline solution may be employed to provide surface cooling of the heart. The most important protective effects of cardioplegia are hypothermia and potassium, which causes arrest of the heart in diastole. Decreasing myocardial temperature to 10 C to 15 C, decreases the metabolic rate by as much as 80%, with mechanical arrest lowering the metabolic rate to as little as 5% of the normothermic, working heart. A great deal of investigative effort has gone into determining the best type of cardioplegic solution. Again, though, the most important aspects of arresting the ischemic heart are maintaining hypothermia as well as mechanical arrest. Newer techniques employ initial warm induction of arrest followed by cold cardioplegia. Furthermore, on completion of the operation, administration of a warm dose of cardioplegic solution before removal of the cross-clamp has also been advocated. Both the techniques are used in an attempt to allow the metabolic machinery to perform reparative processes before asking the heart to perform any mechanical work. In fact, some surgeons prefer to do the entire operation with the patient and the heart warm, while cardioplegic solution is being administered continuously (34). During the past several years, retrograde cardioplegic administration has come into vogue. Delivery of cardioplegic solution through the coronary sinus and the coronary veins may

medwedi.ru

706

Part Three: The Cardiothoracic System—Heart

there is no alternative. Because patients with such diffuse disease are already likely to have poor outcomes, it has been difficult to demonstrate a beneficial effect from coronary endarterectomy.

Figure 4 Schematic diagram of a typical cardiopulmonary bypass circuit. Blood is drained by gravity from the venae cavae (1) through venous cannula (2) into a venous reservoir (3). Blood from surgical field suction and from a ventricular vent (if used during operation) is pumped (B, C) into a cardiotomy reservoir (not shown) and then drained into a venous reservoir (3). Venous blood is oxygenated (4), temperature adjusted (5), raised to arterial pressure (6), filtered (7,8), and returned to the patient by way of a cannula in either the aorta (10B) or femoral artery (10A). Arterial line pressure is monitored (9). Source: From Ref. 33.

yield enhanced myocardial protection, because significant coronary stenoses can prevent the homogeneous antegrade delivery of cardioplegic solution. Retrograde cardioplegia is also useful in the presence of significant aortic insufficiency, because effective delivery of cardioplegic solution in an antegrade fashion is severely hindered by an incompetent aortic valve. The distal anastomoses are generally performed with the aid of optical magnification. In addition to individual vein or thoracic artery graft anastomoses, two or more distal anastomoses can be constructed from a single vein or thoracic artery. These sequential grafts are favored when multiple distal sites are planned for anastomoses, or when there is a shortage of suitable conduit material. Sequential grafting is achieved by performing side-to-side anastomoses between the conduit and recipient artery and ending the graft with an end-to-side anastomosis to the most distal coronary artery. After completion of the distal anastomoses and initiation of reperfusion, a partially occluding side-biting clamp is placed on the ascending aorta, and the proximal anastomoses are constructed. Rarely, if the recipient coronary artery is diffusely diseased with no available site for the distal anastomoses, the surgeon may be required to perform an endarterectomy to allow a reliable graft-to-artery anastomosis. Coronary endarterectomy sites are more vulnerable to early thrombosis and reocclusion, and this should be performed only if

New Developments In the last few years, increasing attention has been paid to coronary artery bypass grafting without use of the cardiopulmonary bypass circuit and its inherent need for systemic heparinization, its propensity for inducing a systemic inflammatory reaction, and its known generation of microemboli to the brain. After widespread retrospective reports of improved perioperative morbidity and mortality (35) after ‘‘off-pump’’ coronary artery bypass grafting (OPCABG), a prospective, randomized trial was recently completed. Patients undergoing OPCABG received a similar number of bypass grafts, had equivalent 30-day mortality and stroke rate, required fewer blood transfusions, and had a shorter postoperative hospital length of stay when compared to patients undergoing conventional CABG using cardiopulmonary bypass (36). This technique has been greatly enhanced by the use of cardiac stabilization devices. Current generation devices employ two instruments that contact the epicardium: an apical suction device to retract the heart in various angles, and stabilization plate to isolate a single area of epicardium for suturing (Fig. 5). Minimally invasive direct coronary artery bypass is a new technique that aims to avoid complications associated with a full sternotomy. Using a thoracic approach, all epicardial vessels can potentially be accessed. In addition, femoral artery and vein can be used for cardiopulmonary bypass cannulation sites, and the heart can be arrested and opened through this approach. Upon unclamping of the aortic cross-clamp during the weaning of cardiopulmonary bypass, atheromatous debris is released from the intimal surface, and is often of a significant enough quantity to cause cerebral ischemic or stroke. New intra-aortic filters are being tested, which slide through an additional lumen in the aortic cannula, and open after being placed inside the aortic lumen. These filters have been shown in preliminary trials to reduce the incidence of postCABG neurologic complications. Aortocoronary anastomotic devices are being developed and tested, which will allow complete anastomoses to be constructed without the need for aortic cross-clamping. This device expands once the tip has been introduced into the aortic lumen, and deploys a radially shaped metallic structure, which contains hooks and attaches to the intimal surface of the aorta. Trials are underway to assess orifice patency, operative times, ease of deployment, and potential effect on operative mortality. Postoperative Management After the operation, cardiac surgical patients are monitored in an intensive care unit, with careful hemodynamic evaluation. Arterial blood pressure, central venous pressure, pulmonary artery pressures, cardiac output (CO), mixed venous oxygen saturation, and urinary output all provide valuable information regarding the adequacy of tissue perfusion and organ function. Mediastinal and chest tube drainage should be monitored hourly and, in fact, can be transfused to minimize the use of banked blood products. All patients have a capillary leakage syndrome and fluid accumulation after cardiopulmonary bypass, with a marked increase in total body sodium, such that patients typically gain between 5 and 10 kg. Most patients are able to be extubated within 4 to 12 hours of surgery,

Chapter 36: Acquired Cardiac Disorders

707

management and optimization of CO. In the early postoperative period, hypovolemia, increased systemic vascular resistance, hypothermia, and arrhythmias (both bradycardic and tachycardic) may all contribute to low CO. Management of these patients is both challenging and rewarding, because the cause of low CO is almost always reversible. Low CO. When the calculated cardiac index (CI and CO divided by body surface area) is less than 2 L/min/m2, despite optimization of heart rhythm, preload, and afterload, use of an inotropic agent is invariably indicated (Table 2). If a patient remains in cardiogenic shock, despite significant inotropic support, consideration should be given to placement of an intra-aortic balloon pump. The balloon, which may be inserted percutaneously through the femoral artery, is positioned just beyond the subclavian artery takeoff of the aorta. Balloon inflation and deflation are timed so that intra-aortic balloon counter pulsation increases coronary artery perfusion pressure during ventricular diastole and, as a result of active deflation, maximally decreases afterload during ventricular systole. Rarely, if shock persists, a left ventricular-assist device (VAD) should be considered. However, the cause of persistent low CO in the early postoperative period should be pursued aggressively, with any reversible cause identified. Left VAD support is extremely labor intensive and costly, and it should only be considered if myocardial failure is considered to be reversible, or if the patient needs a bridge to transplantation.

Figure 5 (A) Cardiac stabilization device used during off-pump coronary bypass surgery. Newer devices use suction cups on the stabilization platform (1) as well as the apical cup (2) to pull the epicardium into the instrument. Use of suction avoids the need for pressure to accomplish coronary stabilization, thereby minimizing hemodynamic instability during the anastamosis. (B) Diagram of stabilization platform use during bypass of left anterior descending artery. Source: From Ref. 37.

and thereafter can be transferred to a step-down unit, where continuous monitoring for arrhythmias, gentle diuresis to attain preoperative weight, and early ambulation are achieved. Compared with other populations, the patient after cardiac surgery provides an opportunity for sophisticated

Postoperative Complications. The major complications after open-heart surgery include bleeding, tamponade, infection, and stroke. Platelet function and blood clotting factors are severely altered after bypass and may not return to normal for as long as 36 hours. Average postoperative blood loss is between 400 and 800 mL and, as stated previously, may be reinfused to decrease the need for homologous blood transfusions. When bleeding exceeds a rate of 200 mL/hr for four hours or longer, return to the operating room for correction of any surgical cause of the bleeding should be considered. Before then, all medical causes of coagulopathy should be corrected aggressively. It is simple and safe to give additional protamine to reverse the residual heparin used during bypass, but transfusions of platelets, fresh-frozen plasma, or cryoprecipitate should be considered only if indicated by coagulation studies. Cardiac tamponade is a potentially lethal cause of low CO early after operation. Clinically, one sees decreased CO increasing filling pressures and a narrowed pulse pressure. Pulsus paradoxus and a widened mediastinal silhouette on chest radiographs are frequently seen. Transesophageal echocardiography has made this diagnosis more easily established and should be used without hesitation when faced with this possible diagnosis. Table 2 Causes of Low Cardiac Output After Coronary Bypass 1. Inadequate preload 2. Excessive afterload 3. Poor ventricular contractility a. Perioperative ischemia b. Poor myocardial preservation 4. Arrhythmia 5. Severe acidosis 6. Tension pneumothorax 7. Tamponade

medwedi.ru

708

Part Three: The Cardiothoracic System—Heart

The major wound complication facing surgeons after coronary bypass is sternal infection with mediastinitis, dehiscence, or both. This complication occurs in as many as 2% to 4% of patients, with the incidence increased when bilateral thoracic arteries are used, particularly in elderly patients and those with diabetes. Staphylococci are the most common organisms, and because of the devastating nature of this complication, most patients receive antistaphylococcal prophylaxis in the perioperative period. Mortality after development of this complication is between 20% and 30% (38). Cerebral vascular accidents may be the most tragic of postoperative complications. Stroke is usually caused by atherosclerotic emboli that probably originate from the aorta, loosened by cannulation, cross-clamping, or the construction of the proximal anastomoses. Underlying cerebral vascular disease combined with hypotension during bypass contributes to this problem. Strokes occur in 1% to 2% of patients at low risk, but may occur in as many as 10% of octogenarians. No data suggest that the investigation of asymptomatic carotid bruits, prior to open-heart surgery with subsequent combined coronary bypass and carotid endarterectomy, would reduce the incidence of stroke after surgery. In patients who have both symptomatic carotid and coronary disease with significant stenosis of the carotid, however, a combined procedure is usually carried out. Risk Factors for Operative Death The assessment of the patient’s mortality risk after bypass surgery is an important component of the preoperative evaluation in coronary artery disease. Furthermore, as issues regarding quality assurance and the delivery of efficient, cost-effective health care loom ever larger in our society, scrutiny of the benefits and risks associated with this most expensive of medical procedures has come increasingly in vogue (Table 3). Clearly, patients with concurrent medical problems such as cerebral vascular disease, pulmonary or renal insufficiency, diabetes, and morbid obesity are at higher risk for development of postoperative complications. Poor ventricular function is among the most important factors increasing the mortality rate after bypass surgery (39). Operative risk is also increased when patients require additional operative intervention such as valve repair or replacement. It is well documented that increasing age itself increases mortality rate. In the CASS study (28), the mortality rate among patients older than 70 years was nearly 8%, compared with an overall mortality rate of 3%. It has also been stated that women have a higher mortality rate after bypass surgery than do men. The explanation for this is not exactly clear, but may be related to the fact that women undergoing coronary bypass surgery are on average 10

Table 3 Prediction of the Risk for Operative Death

Age (yr) Sex Diabetes Unstable angina Ejection fraction (%) Three-vessel disease Operative incidence Predicted mortality rate (%)

Low

Medium

High

60 Male No Yes 65 Yes First 0.8

75 Female Yes No 35 Yes First 3.4

75 Female Yes Yes 25 Yes Redo 12

Source: Based on The Society of Thoracic Surgery National Cardiac Database Risk Stratification Algorithm. Summit Medical Systems, Minneapolis, Minnesota, U.S.A.

years older than men and have a higher incidence of unstable angina, preoperative CHF, hypertension, and diabetes. It is more than conceivable that the higher risk for women is related to the higher incidence of these risk factors (40). Long-Term Results Most series show elimination of angina in 90% of patients at one year, with approximately 70% of patients remaining free of any cardiac event at three years. Although relief from symptoms is unquestioned, controversy exists regarding the long-term functional benefit of bypass surgery. However, functional improvement in left ventricular ejection fraction has been documented after bypass surgery and can be attributed to improved contractility in the myocardial regions in which there had been demonstrable ischemia prior to surgery. Clinical improvement obviously depends at least in part on short- and long-term graft patency. The overall occlusion rate for saphenous vein bypass grafts is 5% to 20% during the first operative year and 2% to 4% annually thereafter, for an occlusion rate of approximately 30% at 5 years and 50% at 10 years. Use of the internal thoracic graft has become increasingly favored because of its 95% one-year and 90% 10-year patency rates. Excellent late internal thoracic artery graft patency clearly correlates with increased patient survival, reduced symptoms, and fewer reoperations. In a study at the Cleveland Clinic, where internal thoracic artery grafts have been used extensively, the 10-year survival rate among patients with saphenous vein grafts for triple-vessel disease was 71%, compared with 83% in a comparable group of patients who had an internal thoracic artery graft to the LAD. Approximately 80% of all patients undergoing primary coronary bypass surgery survive for 10 years, and use of the internal thoracic artery graft improves 10-year survival to close to 90%. Furthermore, about one in seven patients who have had only vein grafts require reoperation at 15 years, twice the reoperation rate for those patients who received at least one thoracic artery bypass. Patients who undergo reoperation have approximately twice the primary operative mortality rate, because the operation is technically more difficult and because the patients are older, with more severe atherosclerotic disease (41). In addition, total revascularization is more difficult for technical reasons, and symptomatic relief is therefore usually of shorter duration as well.

Transplantation vs. High-Risk Coronary Surgery In deciding whether to recommend transplantation or bypass surgery to a patient at high risk as a result of severely depressed left ventricular function, it is important to assess whether the myocardium is viable. In patients with ischemic but viable myocardium, ventricular function may improve after bypass surgery once adequate blood flow is restored. The term ‘‘hibernating myocardium’’ has been used to describe ventricular dysfunction caused by inadequate coronary flow (42). This condition should be distinguished from an ischemic cardiomyopathy, which implies irreversible myocardial dysfunction. Anginal symptoms suggestive of reversible ischemia are often a useful measure of myocardial viability. Patients whose only symptom is heart failure should be approached with caution. Currently, myocardial viability may best be assessed by thallium scanning, either with exercise or at rest. Myocardium that takes up thallium either early or late is presumed to be viable. In this way, one may be able to estimate the possibly dramatic potential

Chapter 36: Acquired Cardiac Disorders

for improved ventricular function with revascularization in the patient who has severely depressed ventricular function but viable myocardium. In a patient with these findings, especially if angina is present, surgery rather than transplantation is indicated if there is operable coronary disease. In patients with CHF and no evidence of viable myocardium, however, bypass surgery clearly carries high risk and little benefit, and transplantation should be considered.

Transmyocardial Revascularization For those patients burdened with angina but whose coronaries are not anatomically approachable, transmyocardial revascularization is a new technique with promising initial results. This procedure employs a CO2 laser, a needle, or high frequency ultrasound to create transmural channels in the myocardium and allow oxygenated blood to reach previously ischemic regions of the heart. Nearly four years after this procedure, patients have been found to have fewer anginal symptoms, require fewer hospitalizations, and have equivalent ventricular ejection fraction and mortality compared to patients receiving medical therapy alone (43).

VALVULAR HEART DISEASE Aortic Valve Disease Aortic Valvular Stenosis The normal aortic valve consists of three equal-size leaflets attached to the aortic wall, forming the three aortic sinuses. As mentioned in the section on coronary artery disease, the coronary arteries arise from two of these sinuses, thereby defining the left, right, and noncoronary cusps. Pathologic Anatomy The most common cause of left ventricular outflow tract obstruction is aortic valvular stenosis. Supravalvular and subvalvular obstructions occur much less commonly. Aortic stenosis is the most common isolated valvular abnormality found in humans. Although congenital valvular stenosis may cause symptoms immediately, a congenital bicuspid valve is usually asymptomatic at birth and becomes symptomatic in the sixth to eighth decade of life. The turbulent flow across the bileaflet valve leads to fibrosis and calcification, so that stenosis develops with time. Rheumatic aortic stenosis, initially an inflammatory lesion, leads to fusion of the leaflet commissures, with thickening and calcification of the cusps themselves. Retraction of the leaflet borders, which occurs commonly, leads to regurgitation as well. In rheumatic aortic valvular disease, mitral involvement is invariably also present. In degenerative or senile aortic stenosis, normal leaflet stress leads to calcification and cusp immobility. This calcification can extend either interiorly onto the anterior mitral leaflet or upward along the aorta, occasionally causing coronary osteal stenosis (Fig. 1). Pathophysiology Narrowing of the left ventricular outflow tract becomes important when it obstructs flow, causing a transvalvular pressure gradient. In the presence of a normal CO, a transvalvular gradient of 60 mmHg or a calculated valve area of less than 0.7 cm2 is considered severe aortic stenosis. The normal response to aortic stenosis, a process that in itself can take years, is the development of left ventricular hypertrophy. This hypertrophy initially leads to a decrease in compliance, with an elevation in the left ventricular end-diastolic pressure. With progressive hypertrophy and loss of ventricular compliance, atrial contraction plays an

709

increasingly important role in left ventricular filling, so loss of a normal sinus mechanism [such as atrial fibrillation (AF)] can cause acute decompensation in these patients. Furthermore, with severe aortic stenosis, prolongation of the systolic ejection time and a concomitant elevation in left ventricular end-diastolic pressure act to decrease diastolic coronary blood flow, with a resultant oxygen debt. The subendocardium may become chronically ischemic, with cell death and fibrosis. In this situation, the left ventricle begins to fail as stroke volume decreases and CO falls. Paradoxically, follow-up of a patient with aortic stenosis may reveal a low or a decreasing aortic gradient during a period of years, which should not be confused with resolving or stable aortic valvular disease but rather indicates a failing left ventricle with a decreased stroke volume and therefore a decreased transvalvular gradient. The clinical course of aortic stenosis may be divided into two phases. The initial phase involves hypertrophy of the left ventricle because it compensates for increasing afterload. Angina, the hallmark of this stage of aortic stenosis, results from the imbalance of myocardial oxygen demand and myocardial oxygen delivery. The second stage involves the onset of left ventricular dysfunction, which is the result of a progressively stiffening ventricle that requires increasing preload for adequate filling, with resultant pulmonary hypertension, shortness of breath, and dyspnea on exertion. Diagnosis Although auscultation of the patient with aortic stenosis reveals a systolic murmur best heard at the base of the heart at the left sternal border radiating up into the neck, this murmur can also be associated simply with normal systolic ejection. However, a slow, prolonged rise in the arterial pulse, as opposed to a sharp upbeat, is a palpable indicator that significant ventricular outflow tract obstruction is present. Doppler echocardiography has become an invaluable tool in the noninvasive detection of aortic stenosis. The peak aortic valvular gradient can be calculated by the following formula (44): D ¼ 4V 2 where D is the peak gradient and V is the maximal measured blood velocity (in meters per second) across the valve. The most accurate measure of left ventricular outflow tract obstruction is determined invasively by cardiac catheterization, where a simultaneous aortic and ventricular pressure measurement can determine the exact aortic gradient (in the case of AF, this is the only acceptable means of determining this number). The aortic valve area (AVA, in square centimeters) may then be determined by the Gorlin formula (45): AVA ¼ AVF=44:5 ðgradientÞ1=2 where AVF is aortic valve flow, which equals CO in milliliters per minute divided by the systolic ejection period (in seconds per minute), and 44.5 is the empiric orifice constant (obtained by comparing calculated with measured AVA at operation or postmortem). For quick calculations, this simplifies to AVA ¼ CO=ðgradientÞ1=2 Patients frequently have symptoms when the AVA is less than 1 cm2, whereas they invariably have symptoms when the area is less than 0.7 cm2 (46). Angina is usually

medwedi.ru

710

Part Three: The Cardiothoracic System—Heart

in a retrograde fashion through the aortic orifice and inflated in an effort to crack the calcium that is retarding valvular motion. The immediate results show an increase in the AVA of 50%, with a 3% to 10% mortality rate and a similar stroke rate (55). Long-term results are abysmal, with a oneyear mortality rate of 25% and a 30% to 35% symptomatic recurrence rate during that period. With recurrence of symptoms, death, hemodynamic evidence of restenosis, or a combination of these occuring in more than 50% of patients at six months after percutaneous aortic ballon valvuloplasty, surgical valve replacement will remain the mainstay of therapy. If valvuloplasty has a role at all, it should be limited to the aged and frail patient whose long-term prognosis is also abysmal. Figure 6 Average course of medically treated valvular aortic stenosis in adults (postmortem data). Although one can understand the difficulty in operating on the patient without symptoms, the severe slope of the curve mandates that patients be seriously considered for surgery at the onset of symptoms. Source: From Ref. 47.

the earliest symptom in patients with aortic stenosis. The mean survival after its onset is 4.7 years. However, when a patient has syncope, survival is typically decreased to less than three years, whereas when a patient has dyspnea and CHF, survival is on the order of one to two years (Fig. 6) (48). Treatment The only effective therapy for symptomatic aortic stenosis is operative. Symptoms alone are an indication for aortic valve replacement. Occasionally, a patient with aortic stenosis may have no symptoms. The appropriate timing of surgery in such patients is not clear. Timely surgery provides the opportunity for resolution of left ventricular hypertrophy, whereas allowing the condition to persist may lead to irreversible myocardial fibrosis with dysfunction. In general, patients without symptoms with progressive left ventricular hypertrophy should be offered surgical therapy because survival is superior to that with medical therapy (49). An unwritten dictum is that all patients with aortic stenosis should be given the opportunity for surgical therapy because it is so effective in leading to reversal of symptoms. With progressive fibrosis and irreversible myocardial dysfunction, however, an occasional patient may have a decrease in ejection fraction out of proportion to the increase in wall stress caused by the aortic stenosis. With this ‘‘endstage aortic stenosis’’ (in which contractility has decreased out of proportion to the increase in wall stress), patients derive little benefit from surgical therapy (50,51). In patients with good ventricular function, aortic valve replacement has an associated mortality rate of 2% to 8%. Perioperative risk factors include age, left ventricular function, preoperative New York Heart Association functional classification, and pulmonary function. The projected fiveyear survival for patients after aortic valve replacement is 80% to 85%. Although symptoms are generally relieved in all patients, improvement in ejection fraction with resolution of left ventricular hypertrophy may require months to occur (52,53). In patients with aortic stenosis as well as coronary artery disease, valve replacement and myocardial revascularization should be performed concurrently (54). Percutaneous aortic balloon valvuloplasty is a ‘‘noninvasive’’ alternative to surgical therapy for aortic stenosis. In this procedure, either one or two balloon catheters are placed

Aortic Insufficiency Pathologic Anatomy Incompetence of the aortic valve may be the result of either primary valvular or aortic root disease (56). Rheumatic fever is a major cause of aortic insufficiency. As discussed with aortic stenosis, it causes retraction of the cusps, which prevents adequate apposition and leads to a central leak. Congenital bicuspid valves with time become calcified and generally lead to aortic stenosis. Ocasionally, however, bicuspid valves have a redundant leaflet that leads to regurgitation. Myxoid degeneration of the aortic valve, as seen in Marfan syndrome, Ehlers–Danlos syndrome, and cystic medial necrosis, may lead to redundancy, prolapse, and regurgitation. Infective endocarditis with bacterial destruction of the leaflets may also lead to valvular insufficiency. Ascending aortic dissection as a result of either trauma or hypertensive atherosclerotic disease often leads to loss of commissural suspension, with resultant leaflet prolapse. Furthermore, severe aortic dilation causes annular stretching (as seen in annuloaortic ectasia, syphilis, and ankylosing spondylitis), which leads to annular dilatation and central valvular incompetence. Pathophysiology With aortic regurgitation, there is a significant increase in preload, where end-diastolic volume is the result of both normal left ventricular filling through the mitral valve as well as left ventricular filling through the incompetent aortic valve. At the expense of an increase in left ventricular wall stress, ejection fraction remains normal as stroke volume and end-diastolic volume increase. Left ventricular dilatation increases wall tension, which increases myocardial oxygen demand. To counteract this, left ventricular wall thickness increases to maintain a wall thickness to cavity radius ratio that preserves myocardial efficiency. With time, however, left ventricular volume may become enormous. Increasing wall thickness does not keep pace with this increasing left ventricular dilation. Sharply increased wall tension develops, with resulting systolic dysfunction. At this point, an elevation in left ventricular end-diastolic pressure occurs and patients have symptoms (Fig. 7). Acute aortic regurgitation, on the other hand, such as occurs with dissections or endocarditis, leads to extremely high left ventricular end-diastolic pressures as a result of the acute increase in end-diastolic volume in the unconditioned ventricle. In these patients, symptoms develop immediately. Diagnosis Patients with aortic insufficiency have a characteristic pattern on physical examination that results from the wide pulse

Chapter 36: Acquired Cardiac Disorders

711

200 PRESSURE, mmHg

180 160 140 120 100 80 60

A0 LV

40 20 0

Figure 7 Simultaneous left ventricular and aortic pressure–time curves in a patient with severe aortic insufficiency. Note that in this patient with extremely severe aortic insufficiency, the left ventricle has become less and less compliant, and at end-diastole, the aortic pressure and left ventricular enddiastolic pressure have nearly equalized. Abbreviation: LV, left ventricle. Source: From Ref. 57.

pressure associated with this disease. The peripheral pulses rise and fall abruptly (Corrigan’s or water-hammer pulse), the head may bob with each systolic stroke (Musset’s sign), and the capillaries visibly pulsate (Quincke’s sign). Auscultation reveals a soft S2 with a high-frequency, diastolic, regurgitant murmur best heard at the left sternal border. A mid-to-late diastolic rumble can be heard (Austin Flint murmur); this represents rapid diastolic flow across the mitral valve that is becoming narrowed as a result of rapid ventricular filling caused by the aortic insufficiency. Clinical Course In chronic aortic regurgitation, symptoms occur late after left ventricular dilatation and myocardial dysfunction (58). Symptoms occur as a result of elevation in left ventricular end-diastolic pressure, again a situation that occurs later in the course of the disease, because early on, left ventricular volumes increase to maintain compliance. Interestingly, nocturnal angina can occur as the result of a slow heart rate, so that diastolic pressure in the coronary arteries is low, and left ventricular end-diastolic pressure is high, compromising blood flow and oxygen delivery to the endocardium. Acute aortic regurgitation, however, is poorly tolerated, and patients have symptoms almost immediately. This is the result of extremely poor compliance of the ventricle and an excessively high diastolic volume. Management Patients with symptomatic aortic insufficiency require surgical therapy, because survival with medical therapy is only a few years from the onset of symptoms. The patient with no symptoms or mild symptoms but with moderate to severe aortic insufficiency presents a dilemma. Frequently, diuretics and afterload reduction may be able to maintain these patients for a considerable period before they experience symptoms. Without surgery, 75% of patients survive five years from the time of diagnosis, and 50% of patients survive 10 years (Fig. 8) (59). Despite the lack of symptoms, however, irreversible myocardial dysfunction occurs. The goal of the clinician should be to intervene before this happens. When end-systolic volume is less than 30 mL/m2, prognosis after surgical therapy is still excellent. With progressive systolic

Figure 8 Survival of patients with medically treated aortic insufficiency. Unlike with aortic stenosis, cardiac failure from aortic insufficiency occurs much more gradually. Consequently, it is much more difficult to discern where one should intervene, particularly in the patient without symptoms. Source: From Ref. 59.

dysfunction, however, end-systolic volumes may rise above 90 mL/m2, a situation that frequency portends permanent postoperative disability. End-systolic volumes between 30 and 90 mL/m2 have intermediate short- and long-termresults (60). Indications for surgical therapy in the patient without symptoms thus should rest on serial echocardiography or radionuclide ventriculography to discern systolic dysfunction or decreasing ejection fraction. Despite good exercise tolerance, when systolic dysfunction occurs, surgery should be recommended. The mortality rate associated with aortic valve replacement for aortic insufficiency is approximately 4% to 6%, somewhat higher than that seen in aortic stenosis (61–63). As discussed, long-term survival depends on preoperative left ventricular function.

Choice of Prosthetic Aortic Valve Type The Department of Veterans Affairs trial randomized patients between 1982 and 1997 to receive mechanical or bioprosthetic valves. At average follow-up of 15 years, mechanical values were associated with lower mortality and lower reoperation rate. These differences became apparent after 10 years. In addition, the mechanical valves displayed no structural value deterioration, and use of the bioprosthetic valve was associated with fewer bleeding complications. Thus, bioprosthetic valves are at risk for late reoperation, but the avoidance of necessary long-term anticoagulation makes them an attractive option for some subgroups. Generally speaking, patients aged at least 65 to 70 years undergoing only valve replacement should receive a bioprosthetic valve. Patients aged at least 60 years undergoing concomitant procedures such as coronary bypass should also receive a bioprosthetic valve (64).

Mitral Valve Disease Surgical Anatomy The mitral valve appartus is composed of the left ventricular papillary muscles, the mitral valve chordae tendineae, the mitral valve leaflets, and the mitral valve annulus. By means of the chordae tendineae, the mitral leaflets are connected to the apical region of the left ventricle. Normal function of the valve depends on the coordinated interaction of these components. The mitral valve has two leaflets joined at two

medwedi.ru

712

Part Three: The Cardiothoracic System—Heart

commissures. The anterior leaflet (also called the aortic leaflets) is broad and relatively square in shape. It is attached to the anterior one-third circumference of the mitral valve annulus and is in fibrous continuity with the aortic valve annulus. The posterior leaflet (also called the mural leaflet) is narrower and relatively rectangular. It is attached to the posterior two-thirds circumference of the mitral annulas. Each leaflet is attached by chordae to each of two papillary muscles arising from the luminal surface of the left ventricle, the anterior-lateral and the posterior-medial papillary muscles. The blood supply of the anterior-lateral papillary muscle is from the diagonal branches of LAD or by obtuse marginal branches of the circumflex coronary artery. The posterior-medial papillary muscle is supplied by the PDA coronary artery, which is usually the terminal branch of the RCA. The mitral valve functions to permit antegrade blood flow from the left atrium into left ventricle during diastole and to prevent reflux of blood from left ventricle into the left atrium during systole. Blood flows antegrade through the mitral valve when the left atrial pressure exceeds left ventricular pressure. As the ventricle contracts during systole, closure of the valve is affected by several mechanisms. Once the left ventricular pressure exceeds left atrial pressure, leaflet closure is initiated, and the rate of blood flow from the atrium into the ventricle is decelerated. At the same time, contraction of the left ventricular muscle at the base of the heart serves to narrow the mitral annulus; echocardiographic data suggest that the annular area decreases by approximately one-third from end-diastole to mid-systole (65). This reduction in annular area helps achieve leaflet approximation. During systolic contraction, papillary muscle contraction pulls the chordae taut, preventing prolapse of the leaflets. Any disease process that interferes with the normal function of any portion of the mitral valve apparatus may result in mitral stenosis or regurgitation.

Mitral Stenosis Rheumatic fever is the primary cause of mitral stenosis (66). Other etiologies of mitral stenosis are rare and include congenital mitral stenosis and stenosis resulting from collagen vascular diseases such as systemic lupus erythematosus and rheumatoid arthritis. Two-thirds of patients with rheumatoid mitral stenosis are female. After resolution of acute rheumatic fever, most patients remain free of symptoms for at least two decades before development of symptoms of mitral valve disease. Thereafter, patients have progressively worse symptoms (67). The normal mitral valve orifice measures 4 to 6 cm2 in cross-sectional area. A mitral valve area (MVA) of 2 cm2 is considered moderate mitral stenosis. At this degree of narrowing, flow across the mitral valve may be accomplished only by generation of an abnormally high-pressure gradient across the valve. An MVA of 1 cm2 is considered critical mitral stenosis, because flow across the valve (CO) is relatively fixed; even extremely high-pressure gradients across the valve are unable to increase flow (Fig. 9). As with the aortic valve, the MVA may be calculated according to the Gorlin formula (for the mitral valve, the constant is 38 rather than the 44.5 used for the aortic valve): MVA ¼ ðFlow rate across valveÞ= 38ðmean gradient across valveÞ1=2 For any given MVA, the magnitude of the transvalvular gradient is proportional to the square of the transvalvular

Figure 9 The relationship between mean diastolic gradient across the mitral valve and the rate of flow across the mitral valve per second of diastole. When the valve area is 1.0 cm2, little additional flow can be achieved, despite an increased pressure gradient. Source: From Ref. 68.

flow rate; doubling the CO quadruples the transvalvular pressure gradient. Increased left atrial pressure results in increased pulmonary venous pressure, and in turn increased pulmonary capillary pressure. Should the transvalvular gradient culminate in a left atrial pressure greater than 25 mmHg, pulmonary edema may result. For this reason, exertional dyspnea is commonly the first symptom of mitral stenosis. Patients frequently first have symptoms with the onset of AF. Chronically elevated left atrial pressure produces left atrial distention, ultimately producing AF. With the onset of AF, diastolic time is shortened; the same volume of blood must flow from left atrium to ventricle in less time, which further increases left atrial pressure. The atrial kick contributes approximately 30% to the presystolic transvalvular gradient in patients with mitral stenosis. Its loss with the onset of AF eliminates this mechanical advantage, and left atrial pressure rises and CO declines (69). The contractile function of the left ventricle is typically well preserved in mitral stenosis. The hemodynamic features of mitral stenosis are notable for a reduced CO at rest (because of the mechanical obstruction of the stenotic valve), which rises subnormally with exercise along with pulmonary hypertension. The pulmonary hypertension is derived from retrograde transmission of elevated left atrial pressure, pulmonary arterial vasoconstriction, and obliterative structural changes in the pulmonary circulation produced by chronic left atrial hypertension. Pulmonary hypertension may become severe, resulting in impaired right ventricular function and tricuspid regurgitation. Diagnosis Patients with mitral stenosis typically are seen with easy fatigue, dyspnea on exertion, and orthopnea. As noted previously, symptoms may develop with the onset of AF.

Chapter 36: Acquired Cardiac Disorders

A history of rheumatic fever is noted in approximately one half of cases. If the left atrial enlargement is sufficient to compress surrounding structures, patients may report dysphagia or hoarseness. On cardiac auscultation, an opening snap of the mitral valve is common as a result of sudden tensing of the valve leaflets by the chordae, as the valve leaflets achieve their opening excursion. The opening snap may be heard within the first 100 msec after the second heart sound. Mitral stenosis produces a low-pitched, rumbling diastolic murmur best heard at the apex. The murmur is often difficult to appreciate, but may be provoked by maneuvers that increase CO. Pulmonary hypertension is suggested by a loud pulmonary component of the second heart sound. With pulmonary hypertension, an enlarged right ventricle may shift the left ventricle posteriorly, making the murmur extremely difficult to hear (silent mitral stenosis). The chest roentgenogram is significant for left atrial enlargement. There may be elevation of the left main stem bronchus and posterior displacement of the esophagus on the lateral radiographic view. Pulmonary venous hypertension typically results in cephalization of pulmonary blood flow. Two-dimensional echocardiographic evaluation of mitral stenosis reveals thickened mitral valve leaflets and restricted leaflet motion as the valve opens. The left atrium is typically enlarged, and the left ventricular cavity is usually reduced in size. Mitral annular calcification and left atrial thrombus are identifiable on echocardiography. Doppler echocardiography provides a functional estimate of the severity of mitral stenosis. The peak velocity of blood flow across the valve is increased, allowing an estimate of the transvalvular gradient (see the section on the Aortic Valve). Medical Treatment Medical treatment of mitral stenosis is of limited efficacy. The focus of medical treatment is to minimize pulmonary edema with diuretics and to control the ventricular rate with digoxin. Because left atrial thrombus may form, patients in AF should have anticoagulation with warfarin. Surgical Treatment Because of the efficacy of surgical treatment, the natural history of mitral stenosis is now unclear. However, after acute rheumatic fever, most patients remain free of symptoms for 20 to 25 years. Once these patients experience symptoms, at least five years is required for the progression of symptoms from mild to severe. According to the study of Olesen (70) of patients in the presurgical era, 40% of symptom-free patients with mitral stenosis had a significantly worsened condition or were dead within 10 years. Among patients with mild symptoms, the number was 80%. Munoz et al. (71) reported a 45% five-year survival rate for medically treated patients with mitral stenosis and mitral regurgitation. In a comparable population undergoing mitral commissurotomy, five-year survival rate was 80%. The first report of successful surgical correction of mitral stenosis appeared in 1923; Cutler and Levine (72) reported successful relief of mitral stenosis by incision of the valve with a knife introduced through an apical left ventriculotomy. In 1925, Souttar (73) performed the first successful closed mitral commissurotomy through the left atrial appendage. After the reports of Harken et al. (74) in 1948 and Bailey (75) in 1949, closed mitral commissurotomy became widely used for mitral stenosis. Despite excellent long-term results after closed mitral commissurotomy (76), by the mid-1970s, this technique was supplanted by open

713

mitral commissurotomy. Closed mitral commissurotomy is now of historical interest only. Although closed mitral commissurotomy offered good palliation of mitral stenosis, open mitral commissurotomy offers several advantages (77). First, the valvuloplasty may be performed under direct vision. The primary reason for failure of closed mitral commissurotomy was residual stenosis, not restenosis (78,79). In as may as 75% of patients, the subvalvular apparatus of the mitral valve contributes significantly to the stenosis (80). The open technique allows precise and maximal division of fused commissures as well as of fused chordae (81). In addition, calcium may be sharply debrided from the valve, and any residual mitral insufficiency may be corrected at the time of operation. Finally, the closed technique offers the disadvantages of potentially dislodging a left atrial thrombus, resulting in intraoperative embolization and stroke. The results of open mitral commissurotomy are excellent. Operative mortality rate is usually reported as 0.2% to 2%, and in most series, the need for reoperation is reported to be 2% per year (81). Balloon Mitral Valvuloplasty Inoue et al. (82) reported the first successful percutaneous balloon mitral valvuloplasty in 1984. The valvular pathology of mitral stenosis makes the valve unsuitable for balloon dilation. Nonetheless, this procedure is now an alternative to surgical relief of mitral stenosis in a small, select group of patients. After creation of a hole in the interatrial septum, a balloon catheter is introduced through the mitral valve and inflated within its orifice. The procedure is based on the idea that the inflated balloon will split fused commissures. As noted previously, however, the subvalvular apparatus contributes significantly to the stenosis, and this region is not addressed by balloon dilation. Immediate hemodynamic improvement is noted in most patients, with a significant reduction in transvalvular gradient, improved CO, and reduction in pulmonary arterial pressure (39). However, these hemodynamic benefits are not long standing, and the complication rate is significant. Reported mortality rates range from 0% to 4% (83), comparable to that of open mitral commissurotomy. Approximately 30% of patients are left with a significant atrial septal defect (84). Stroke is reported as a complication of the procedure in 3% to 4% (85). Recurrence of mitral stenosis is noted in as many as 30% to 40% of patients within one year (86). The small subset of patients with the best results from balloon mitral valvuloplasty are those with soft, pliable leaflets without calcification and without stenosis of the subvalvular apparatus. Such patents are, of course, rare. Thus, although balloon mitral valvuloplasty attempts to spare the patient a more invasive procedure, the patient is actually exposed to greater risk of complication and death. At the same time, the results are inferior to open mitral commissurotomy, which must be considered the procedure of choice.

Mitral Regurgitation Structural abnormalities of any component of the mitral valve apparatus (mitral leaflets, chordae tendineae, and papillary muscles) may result in mitral regurgitation. Rheumatic fever remains the most common cause of mitral regurgitation; it results in deformity and retraction of the leaflets and shortening of the chordae. Other causes include perforation by trauma and infective endocarditis. Calcification of the mitral annulus may result in annular rigidity, preventing valve closure, and mitral annular dilation resulting from left ventricular dilation may likewise preclude leaflet

medwedi.ru

714

Part Three: The Cardiothoracic System—Heart

apposition during systole. Chordal rupture may result from trauma, endocarditis, rheumatic fever, or diseases of collagen formation. Chordae to the posterior leaflet rupture more frequently than do those to the anterior. Coronary arterial disease may produce infarction of the papillary muscle, resulting in initial regurgitation. Infarction in distribution of the anterior descending coronary artery may be associated with necrosis of the anterior-lateral papillary muscle, whereas the posterior-medial muscle may infarct if blood flow through the PDA artery is interrupted. Mitral regurgitation caused by MI typically is seen as a new murmur several days after infarction. Pathophysiology The regurgitant mitral valve offers an alternative route by which blood may exit from the left ventricle. During both isovolumetric contraction and systole, blood is preferentially ejected into the low-pressure left atrium. The volume of the regurgitant flow (regurgitant fraction) depends on the size of the regurgitant orifice and the afterload against which the left ventricle must work to pump blood through the aortic valve. The regurgitant fraction is increased with increased left ventricular preload and increased afterload, both of which dilate the left ventricle, thereby enlarging the mitral annulus and regurgitant orifice. Because the valve leaks during systole, the volume of regurgitant flow also increases as heart rate (number of systoles per minute) increases. To maintain an adequate systemic blood flow (CO), the left ventricle becomes volume overloaded; it must pump the combined volume of systemic and regurgitant flows. Because the left ventricle is able to beat against the reduced resistance of the left atrium, parameters of systolic function (ejection fraction) are increased in mitral regurgitation. However, as with aortic insufficiency, the left ventricle ultimately fails, with chronic volume overload. In fact, normal values of systolic function indicate significant contractile dysfunction of the left ventricle. An ejection fraction of 40% to 50% in the setting of mitral regurgitation indicates severe left ventricular contractile dysfunction (66). As in mitral stenosis, left atrial hypertension results from mitral regurgitation. This pressure is transmitted in a retrograde fashion into the pulmonary circulation; if high enough, it produces pulmonary hypertension. The magnitude of the left atrial pressure is a function of the compliance of the left atrium (Fig. 10). A normal or low compliance of the left atrium, such as may occur in acute mitral regurgitation, results in a relatively rapid rise in left atrial pressure. On the other hand, chronic, slowly developing left atrial volume overload may create significant enlargement of a compliant left atrium, with relatively low left atrial pressure. Diagnosis Symptoms result from the degree of mitral regurgitation, the rate of its progression, the degree of pulmonary hypertension, and the magnitude of left ventricular contractile dysfunction. Symptoms in patients with chronic mitral regurgitation typically do not occur until the left ventricle begins to fail. Patients with mild mitral regurgitation may remain free of symptoms for most of their lives (88). The onset of AF does impair the patient’s functional status, but not to the same degree as with mitral stenosis. With moderate to severe chronic mitral regurgitation, patients may be free of symptoms for long periods. However, this lack of symptoms may be deceptive, because the contractile function of

Figure 10 Syndrome of mitral regurgitation. When mitral regurgitation occurs abruptly in patients with previously normal heart, left atrial compliance is normal. This results in a rapid increase in left atrial pressure. On the other hand, the insidious development of mitral regurgitation allows the left atrial compliance to increase along with its size, attenuating the rise in left atrial pressure. Abbreviations: LA, left atrium; LV, left ventricle; PA, pulmonary artery; PT, pulmonary trunk; PV, pulmonary vein; RA, right atrium; RV, right ventricle. Source: From Ref. 87.

the left ventricle may be slowly deteriorating. Once symptoms occur, left ventricular contractile dysfunction may be irreversible. The natural history of mitral regurgitation is obscure, because surgical intervention has effectively altered this history. In the presurgical era, however, approximately 80% of patients with severe mitral regurgitation survived five years and 60% survived 10 years (59). On cardiac auscultation, a holosystolic murmur is best heard at the apex and radiates to the axilla and left scapular region. The ECG is notable for left atrial enlargement and, frequently, AF. The chest roentgenogram is significant for cardiomegaly and left atrial enlargement. Pulmonary venous hypertension may be manifested by cephalization of pulmonary blood flow and pulmonary edema. Echocardiography is extremely valuable in confirming the diagnosis and severity of mitral regurgitation. Transesophageal echocardiography is particularly effective in providing an anatomic explanation for the regurgitation, such as perforated leaflets, poor leaflet coaptation, or ruptured chordae. Doppler echocardiography reveals a high-velocity jet of regurgitant blood flow into the left atrium during systole. The severity of the valve regurgitation is a function of the distance from the mitral annulus that the jet can be visualized (into the pulmonary veins) and the size of the left atrium. Contrast ventriculography performed at cardiac catheterization likewise demonstrates regurgitation during systole.

Chapter 36: Acquired Cardiac Disorders

Management The cornerstone of medical management is diuresis and afterload reduction with ACE inhibitors (66). The importance of afterload reduction cannot be overemphasized. Because blood leaving the left ventricle travels the path of least resistance, lowering systemic vascular resistance increases systemic CO. The indications for surgical intervention are (i) symptoms despite medical management or (ii) evidence of deteriorating left ventricular contractile function, as determined by echocardiography or contract ventriculography. Surgical correction of mitral regurgitation should be undertaken before left ventricular contractile dysfunction becomes irreversible; the operative mortality rate increases substantially as the ventricle fails. The two surgical options are repair and replacement of the valve. The final decision regarding which of these options to employ is made during the operation after inspection of the valve. There are several advantages to mitral valve repair rather than replacement. First, with mitral valve replacement, there is loss of the mitral valve apparatus connecting the mitral annulus to the apex of the left ventricle by means of the chordae and papillary muscles. In the long term, this may lead to left ventricular dysfunction. Mitral valve repair preserves this apparatus. Second, the risks associated with a prosthetic valve, such as prosthetic valve endocarditis and thromboembolic complications, are avoided. Third, the operative mortality rate associated with mitral valve repair is 0% to 4%, which is lower than the 2% to 8% reported for mitral valve replacement (80). Finally, mitral valve repair can now be accomplished using minimally invasive techniques with robotic assistance, so that a median sternotomy incision is no longer required. In contrast, median sternotomy is still needed for mitral valve replacement.

715

roughly 18% for ACE inhibitors and 35% for b-blockers compared to control, untreated patients. In patients with extremely poor myocardial function, outpatient inotropes may be used chronically via rate-controlled infusion into a large central vein. In this manner, Milrinone, a cyclic adenosine monophosphate–specific phosphodiesterase inhibitor or Dobutamine (a synthetic catecholamine), may be used to chronically support patients who otherwise would be hospitalized and unable to complete most activities of daily living due to such severe ventricular dysfunction.

Surgical Therapy In patients with a maximal oxygen consumption less than 14 mL/kg/min (normal 30–50), heart transplantation provides the greatest survival advantage (68% 10-year survival) to patients with CHF, but its epidemiologic impact is limited by a severe shortage of donor organs. According to the registry of the International Society for Heart and Lung Transplantation, the number of heart transplants in the United States peaked in 1994 at approximately 4300, and has since fallen to the range of 2000 to 2500 transplants per year. Current efforts to increase the potential number of donor organs for heart transplantation are aimed at increasing public awareness, refinement of end-of-life donation consent policies, improvements in organ preservation techniques, and acceptance of organs previously considered marginal. At least in some part due to the growing shortage of donor organs, a multitude of nontransplantation surgical techniques are being used more frequently to ameliorate CHF. These include cardiac revascularization, mitral valve reconstruction (92), and even left ventricular reconstruction using techniques such as the Batista and Dor procedures. Pathologic geometric remodeling of the left ventricle has been prevented by the CorCap cardiac support device (ACORN Cardiovascular, Inc., St. Paul, Minnesota, U.S.A.) or Myosplint (Myocor, Lie, Maple Grove, Minnesota, U.S.A.). The ACORN device (Fig. 11) is an elastic mesh sleeve that slides

HEART FAILURE Epidemiology CHF is the leading cause of hospitalization and death in the developed world, affecting 0.4% to 2% of the general adult population (89). Approximately 550,000 new cases of heart failure are diagnosed each year, and cause approximately 300,000 deaths per year. In the United States alone, over 34 billion dollars are spent on the medical care of patients with CHF. Among patients in the Framingham Study Group, the mean age at diagnosis was 63 years in the period from 1950 to 1969, and 80 years in the period from 1990 to 1999 (90). The most common cause of heart failure in men is MI, and in women, the most common cause is hypertension (91). Despite recent improvements in medical therapy for this disease, the Framingham Study showed that after the time of diagnosis there was a one-year survival of only approximately 75% and 50% at five years.

Medical Therapy Medical therapy of CHF involves many of the same agents that are used in acute MI. ACE inhibitors are used for chronic unloading of the left ventricle. Chronic use of b-blockers causes myocardial upregulation of b-adrenergic receptors, making the heart more responsive to adrenergic stimulation. The addition of both to the medical regimen of CHF patients is now standard of care with an improvement in survival of

Figure 11 Diagram of ACORN device. During implantation, seam is placed anteriorly and oversewn to allow for the adjustment of circumferential tension, depending on heart size. Holes can be created in the jacket to allow for coronary bypass surgery. One can imagine the potential for postoperative scarring and adhesions making reoperative surgery extremely hazardous. Source: Courtesy of Acorn Cardiovascular, Inc., St. Paul, Minnesota, U.S.A.

medwedi.ru

716

Part Three: The Cardiothoracic System—Heart

Figure 12 (A) Picture of Thoratec HeartMate# left ventricular assist system. This device is available as either a vented electric (XVE, shown) or an implantable pneumatic LVAD. Both devices are approved for use as bridge to transplantation, and the XVE is also approved for use as destination therapy. During implantation, the in-flow cannula is sewn to the ventricular apex and the out-flow cannula is sewn to the aorta. In-flow and out-flow valves as well as internal surfaces are covered with a material which alleviates the need for systemic anticoagulation. The driveline is the only portion of the device that is external to the body. (B) Schematic demonstrating necessary components of portable ventricular assist devices system. This device is capable of pumping up to 10 L/min, and its pump rate can be adjusted to either a fixed-rate mode or a variablerate mode, depending on the body’s needs. Each battery lasts up to six hours, and patients carry multiple batteries at a time. The device weighs approximately 1200 g (2.6 pounds). Abbreviation: LVAD, left ventricular assist device. Source: Courtesy of Thoratec Corporation, Pleasanton, California, U.S.A.

to cover all surfaces of the heart, and provides passive support to help reduce stress on the ventricular wall with prevention of subsequent ventricular dilatation. Biventricular pacing has been shown to improve quality-of-life measures, New York Heart Association functional class, and maximal exercise performance at follow-up of six months in patients with severe heart failure (93). Novel techniques in gene transfection are being developed to improve myocardial cellular dysfunction. Likewise, muscle cells have been injected into damaged myocardium to improve cardiac function (94). Mechanical VADs have gained widespread popularity, used both as a bridge to transplantation for patients in extremis as well in nontransplant candidates as end therapy (referred to as destination therapy). This type of mechanical support is expected to assume an even larger role in the management of heart failure in the future. Initially developed in the 1960s, VADs have undergone significant evolution to gain their current FDA approval. A multicenter trial in the early 1990s demonstrated a 65% survival to transplantation in CHF patients after implantation of VAD compared to 50% survival to transplantation in medically treated patients (95). On the basis of this and other studies, the FDA approved the use of left VADs as a ‘‘bridge’’ to transplantation in 1994. Encouraging initial results of the Randomized Evaluation of Mechanical Assistance Therapy as an Alternative in Congestive Heart Failure trial—in which VADs were placed into CHF patients as ‘‘destination’’ therapy—led to the 2002 FDA approval for VADs to be used for this indication, no longer just as a bridge to transplantation (Fig. 12). Current areas of improvement in VAD design focus on minimizing risk of thromboembolism, reducing postoperative VADrelated infections, and prevention of mechanical device failure. In the arena of heart replacement therapy, the Abiocor (ABIOMED, Danvers, Massachussets, U.S.A.) totally implantable total artificial heart has achieved good initial results, but more widespread, long-term use is dependent on further reduction in the thromboembolism risk.

CARDIAC DYSRHYTHMIAS Cardiac function can be adversely influenced by changes in both cardiac rhythm and cardiac rate, but in actuality,

perturbations in CO are more commonly rate related. Healthy individuals in sinus rhythm have a frequency of cardiac contraction that can vary considerably. In optimally physically conditioned individuals, resting heart rates may be as low as 40 to 50 beats/min (bpm), although most healthy persons range from 60 to 90 bpm. Cardiac rate can vary across a wide range (40 to 150 bpm) without eliciting symptoms. With the induction of exercise, however, symptoms generally occur at each end of this spectrum, and especially in individuals with underlying cardiovascular pathology. Although dysrhythmias can generally be managed medically, certain situations may necessitate surgical intervention.

Bradycardias In patients with symptomatic bradycardia, implantation of a pacemaker may be indicated to increase the heart rate. The common types of symptomatic bradycardia include (i) congenital heart block, (ii) acquired heart block, (iii) iatrogenic heart block, (iv) sick sinus syndrome, (v) AF, and (vi) bradycardia– tachycardia syndrome. Patients with congenital heart blocks are frequently free of symptoms because the heart is in other respects structurally and functionally normal. As the child enters adolescence and early adulthood, maintenance of adequate exercise tolerance may require pacemaker implantation. In elderly patients, in whom acquired heart block usually occurs, ischemic heart disease is commonly the underlying etiology. Symptoms may be evoked with minimal exercise and occasionally arise even under resting conditions. Acquired heart block is a common cause of syncope (Stokes–Adams attacks). Sudden cardiac death may occur in this situation as the rhythm degenerates into asystole as a result of the development of ventricular escape beats from the block and the resultant ventricular tachycardia and fibrillation. Because the arterial supply to the atrioventricular node is derived from a branch of the RCA, acute MI resulting from occlusion of this artery may give rise to heart block. This occurs because the resultant ischemia from the coronary occlusion alters the normal function of the atrioventricular node. Although the heart block associated with acute MI usually resolves, these patients are candidates for prophylactic, temporary pacemakers. Occasionally, permanent pacing is required.

Chapter 36: Acquired Cardiac Disorders

In patients undergoing repair of damaged valves or septal defects, or complex intra-atrial repairs associated with congenital heart disease, postoperative heart block may occur. Not uncommonly, such blockade does not manifest immediately after operation. Because cardiac surgeons have encountered this situation with sufficient frequency, temporary pacing wires are routinely placed in these patients at the time of surgery, so that external pacing can be administered rapidly should circumstances necessitate this approach. Chronic sinus bradycardia is typically referred to as the sick sinus syndrome. In this condition, heart rates in the range of 30 to 40 bpm are characteristic. Although sudden cardiac death is much less likely than with complete heart block, the symptoms are essentially the same. The bradycardia is usually regular but can on occasion be irregular, and it typically occurs in older patients, many of whom have ischemic heart disease, although this is not a requirement for the syndrome to occur. Permanent pacing is usually required in patients with this condition. Although chronic AF is effectively managed medically in most patients, significant bradycardia can at times occur, necessitating pacemaker placement. It must be confirmed, however, that the bradycardia is not related to digitalis toxicity before a pacemaker is placed. This can be determined by stopping the digoxin therapy to see whether the bradycardia is resolved. In patients with the bradycardia–tachycardia syndrome, profound episodes of supraventricular tachycardia requiring digoxin prophylaxis produce profound symptomatic bradycardia related to the digoxin therapy necessary to manage tachycardia. The explanation for this effect is not clear, but the treatment of this syndrome requires the placement of a pacemaker to enable the administration of sufficient doses of digoxin to manage the tachycardia.

Pacemaker Placement When pacemakers were first introduced approximately 40 years ago to manage cardiac dysrhythmias, they were placed in the left side of the chest through a formal thoracotomy. The pacemakers were large and heavy, and the pacing leads were sutured to the ventricular myocardium. Furthermore, the batteries needed to operate these pacemakers were generally short lived and required replacement at least every two years, often more frequently. In addition, the lead systems were undependable. Much progress has been made in the development of pacemakers during the last several decades, so that current pacemakers approach the size and weight of a silver dollar, use lithium batteries that have life spans of 10 or more years, and possess lead systems that are remarkably dependable. Current pacemaker management makes use of both epicardial and endocardial methodologies. Epicardial insertion employs a subxiphoid approach to the pericardium in which the lead is screwed into the undersurface of the right ventricle, and the battery box itself is implanted subcutaneously, usually in the left upper abdominal quadrant. This technique requires general anesthesia for the lead placement, but the battery box can easily be replaced with local anesthesia. The endocardial approach employs a catheter system that uses the cephalic, subclavian, or jugular vein, through which the catheter tip is advanced and impacted into the apex of the right ventricle. In this circumstance, the battery box is implanted in a subcutaneous pocket inferior to the clavicle. Compared with the epicardial approach, this strategy of pacemaker management is less dependable,

717

Figure 13 Schematic representation of the two approaches currently used for pacemaker placement. (A) Epicardial approach employs subxiphoid access in which pacemaker lead is secured to undersurface of right ventricle, and battery box is implanted subcutaneously in left upper abdominal quadrant. (B) Endocardial approach uses subclavian (or cephalic or jugular) vein for access, in which pacemaker tip is impacted into apex of right ventricle, and battery box is implanted subcutaneously inferior to clavicle.

requires more time to position the pacemaker, and is associated with a small but real hazard of perforating the right ventricle. Its major advantage with respect to the epicardial approach is that it can be carried out entirely with local anesthesia. These two approaches are schematically represented in Figure 13. A wide variety of pacemakers are presently available. Despite their current level of sophistication compared with older models, they all fire on ‘‘demand’’ when they do not sense a QRS complex. They all have the capability to be programmed for such modalities as rate, size of electrical impulse, and sensing level after implantation. In recent years, there has been a trend toward dual-chamber pacemakers that pace the atria and ventricles sequentially, as well as pacemakers that sense changes in the native sinus rate (in response to a stimulus such as exercise), and thereby change the rate of ventricular firing. These newer systems, although expensive, have been demonstrated to be extremely beneficial in the vast majority of pacemaker candidates, particularly for patients with exercise intolerance or chronic CHF. Not all patients with dysrhythmias require cardiac pacemaker implantation. Absolute indications for pacemaker implantation include third-degree or advanced seconddegree AV block associated with symptomatic bradycardia, asystolic episodes greater than three seconds or an escape rate less than 40 bpm, or following catheter ablation of AV node (96,97). Relative indications include asymptomatic third-degree bloc and asymptomatic type II second-degree AV block with a narrow QRS complex (96,97). Guidelines for the use of pacemakers are summarized in Table 4.

Tachycardias In addition to problems with bradycardia, tachycardias can also pose difficulties that may require surgical intervention, if medical management is not efficacious.

Supraventricular Tachycardias Supraventricular arrhythmias, the most common rhythm disturbances encountered in surgical practice, usually occur in the postoperative period. Typical arrhythmias of this variety include atrial flutter, paroxysmal atrial tachycardia, and

medwedi.ru

718

Part Three: The Cardiothoracic System—Heart

Table 4 Guidelines for Cardiac Pacemaker Implantation Accepted In patients with symptoms and chronic conditions Atrioventricular block Complete (third-degree) Incomplete (second-degree) Mobitz type I (rare indication) Mobitz type II Incomplete with 2:1 or 3:1 block Sinus node dysfunction (symptomatic) Sinus bradycardia Sinoatrial block, sinus arrest Bradycardia–tachycardia syndrome Controversial In patients with symptoms Bifascicular/trifascicular intraventricular block Hypersensitive carotid sinus syndrome In patients without symptoms Third-degree block Second-degree atrioventricular block Mobitz type II Transient complete or Mobitz type II atrioventricular block with bundle-branch block in selected situations (e.g., acute myocardial infarction) Congenital atrioventricular block Sinus bradycardia with heart rates < 45 beats/min, with long-term drug therapy necessary Overdrive pacing for ventricular tachycardia Not warranted Syncope of undetermined cause Sinus bradycardia, sinoatrial block, or sinus arrest without symptoms Bundle-branch blocks Mobitz type I block (asymptomatic)

Figure 14 Two tachycardias found in patients with Wolff-Parkinson-White syndrome are shown. (A) Reentry type. The wide QRS of preexcitation changes to a narrow QRS during the reentry tachycardia (box). (B) Fast ventricular response during atrial flutter. The rhythm strip shows the rapid ventricular response progressing to ventricular fibrillation (box). Source: From Ref. 99.

Source: From Ref. 98.

AF. The diagnosis of these dysrhythmias is made with ECG testing. Most of these disturbances can be managed medically with drugs such as digoxin, b-blockers, calcium channel blockers, and amiodarone, or with combinations of these agents. On rare occasions, such medical management does not prove efficacious, and because of the rapid ventricular rate emanating from these dysrhythmias, emergency cardioversion is required. A more worrisome supraventricular tachycardia that does not respond as well to medical management is the Wolff-Parkinson-White (WPW) syndrome. This disorder is caused by reentry of cardiac excitation impulses through an anomalous muscle bundle, known as the bundle of Kent, which connects the atrial and ventricular myocardia, that are normally electrically separate (Fig. 14). This bundle has been demonstrated in a variety of positions in the atrioventricular groove or junction of the atrial and ventricular septa, having been previously mapped experimentally. The seriousness of this condition is that the Kent bundle can conduct as many as 400 bpm with degeneration into ventricular responses characterized by tachycardia or fibrillation, with the potential for cardiac arrest. On ECG, patients with the WPW syndrome demonstrate a short PR interval (< 0.12 seconds) and small delta waves at the beginning of the QRS complex. Although a wide variety of antiarrhythmic drugs have been used to manage this syndrome (including procaine, quinidine, propranolol, verapamil, and amiodarone), such therapy has not proved especially successful. Fortunately, a means of ablating the Kent bundle surgically is now available. First introduced at Duke University in 1968, this modality has proved efficacious, and many patients treated with interruption of the Kent bundle have

had successful outcomes and have gone on to live normal lives (100). Recent experience with catheter-delivered radiofrequency ablation of the Kent bundle has also proved effective and has supplanted the surgical approach (101). The success encountered with treating the WPW syndrome surgically has been extended to other mechanisms of tachycardia, such as concealed accessory connections, nodal and atrial tachycardia, and even refractory AF. Treatment of this last arrhythmia, the Cox-Maze procedure, consists of a series of atrial incisions to prevent atrial reentry and allow sinus node impulses to activate the entire atrial myocardium. In so doing, this procedure restores atrioventricular synchrony. This procedure has been reported to have an operative mortality of 2% and to have cured AF in 99% of cases (102). There is a significant occurrence of temporary postoperative AF (38%) and need for pacemaker implantation (15%). More recently, microwave energy and radiofrequency energy have been used intraoperatively in the treatment of AF to create lines of conduction blockade, which mimic the standard Maze incisions, but without the degree of morbidity seen with that procedure. These newer procedures have been observed to cure AF in 70% to 80% of cases (103). Perioperative AF occurs in over 60% of cases, and 30% to 40% of patients leave the hospital in AF, but this does not appear to be long-lasting and patients subsequently convert to sinus rhythm over the ensuing three to four postoperative months. Instrumentation is currently being tested, which will allow these procedures to be performed with less morbidity in an epicardial, thoracoscopic fashion.

Ventricular Tachycardia Ventricular dysrhythmias are much more serious than supraventricular tachycardias because of the rate-induced

Chapter 36: Acquired Cardiac Disorders

depression of CO that can degenerate into life-threatening ventricular fibrillation. Most patients with sustained ventricular tachycardias have significant ischemic heart disease and have had one or more MIs, resulting in varying degrees of both reversible and nonreversible ischemic damage. Among patients surviving MI, significant ventricular tachycardias may occur in as many as 5%. Despite the recent development of new antiarrhythmic drugs, approximately one-third of patients with ventricular tachycardia do not have adequate control with them. In this subset of patients, ‘‘mapping’’ the various areas of the epicardium and endocardium, which induce ventricular tachycardias electrically, and then resecting this area has proved efficacious in controlling the ventricular dysrhythmias (104–106). The mapped areas usually comprise subendocardial scar tissue that, from a surgical standpoint, are relatively easy to resect unless vital structures such as the mitral apparatus, membranous septum, and aortic annulus are involved in the scarred area. In such cases, local cryoablation has been substituted and proved useful. Although the risk associated with this type of surgery is substantial, it is directly related to the degree of left ventricular function. The less dysfunction, the better is the outcome. As many as 70% to 80% of patients surviving this type of surgery have relief of their tachycardia without the need for further drug therapy or have substantial reduction in the drug requirements to manage their ventricular dysrhythmias. Implantable Cardioverterdefibrillator Patients who have had a documented cardiac arrest (sudden cardiac death syndrome) in the absence of a documented MI within the preceding 48 hours and who are not candidates for antiarrhythmic drug therapy, as documented by electrophysiologic study, should have an implantable cardioverterdefibrillator (ICD) implanted (106–108). This device, which is similar in size to a pacemaker, is implanted to sustain any cardioversions for several years. Candidates for ICD placement usually have severe coronary artery disease and prior MI. The infarction zone provides the scarring and slow conduction needed for the re-entrant arrhythmias (ventricular tachycardia or ventricular fibrillation). As expected, this patient population is in extremely debilitated condition, with low ejection fractions and chronic CHF. Consequently, these patients are good candidates for ICD insertion, rather than long-term antiarrhythmic drug therapy, which is associated with negative inotropic effects and other morbid drug reactions. This type of therapy is extremely expensive ($12,000 to $20,000 per generator; $2000 to $8000 per lead system). It is, however, worthwhile for selected individuals at high risk, as it has been shown in selected patients to decrease one-year mortality from 90% to 10%.

Evaluation of Pacemakers Before Attempting Surgery In patients about to undergo general anesthesia and surgery, it is mandatory that the surgical and anesthesia teams determine that the pacemaker is sensing and functioning normally. After the pacemaker has been properly identified, the currently active program can be retrieved by interrogation with the manufacturer’s programmer. The first issue is to identify whether the patient is pacemaker dependent. If the pacemaker fails, does it have a dependable and adequate intrinsic rhythm? If the answer to this question is no or cannot be

719

determined because the pacemaker is not programmable, a backup method of maintaining a heart rate must be defined. This is particularly important because electrocautery can induce pacemaker failure. Most pacemaker manufacturers recommend against the use of electrocautery in any patient without an adequate intrinsic rhythm. Unipolar cautery is far more hazardous than bipolar cautery. Electrocautery can, by its noise level, be misinterpreted by the pacemaker and cause inhibition of the pacemaker that is reversible when the cautery is turned off. Thus, frequently, electrocautery can cause the pacemaker to revert to a backup mode. This usually is a ventricular demand mode. The most severe problem the electrocautery may cause is complete and permanent loss of pacing. The best way to manage a pacemaker during the use of electrocautery is to program the generator to ventricular demand mode at a rate sufficient to minimize competition with the intrinsic heart rate (109). The simplest way to achieve this is to place a permanent magnet over the pacemaker. This prevents inhibition by electrocautery. If a permanent loss of pacemaker function occurs in the operating room, with no intrinsic heart rate, the quickest and most efficient method of inducing an intrinsic rate is to begin intravenous infusion of a b-stimulant such as isoproterenol. After this maneuver, a temporary transvenous pacemaker should be inserted.

PERICARDIAL DISEASE The pericardium is a fibrous sac that surrounds and envelops the heart. Its purpose is to fix the heart anatomically within the mediastinum, act as a barrier to the spread of infection from surrounding structures such as the lungs, and reduce friction between the enclosed heart and surrounding organs (110). In the nondiseased state, the pericardium has little or no effect on cardiac hemodynamics. Two specific pericardial disorders, however, may necessitate surgical intervention. These include pericardial effusion with tamponade and chronic constrictive pericarditis.

Pericardial Effusion with Tamponade Pericardial effusion by itself is not uncommon. It can occur in response to acute viral pericarditis, MI, CHF, and various immune disorders such as rheumatoid arthritis and lupus erythematosus. In these conditions, the effusion is usually moderate and self-limited, and it abates with treatment of the underlying condition. In patients with chronic uremic pericarditis or malignant involvement of the pericardium, such as may occur from neoplastic spread of bronchogenic carcinoma, excessive amounts of effusion may collect in the pericardial sac so that adverse stresses are placed on the contracting heart, and cardiac dynamics are severely impaired. This state of pericardial tamponade can significantly compress the heart, not only by compressing the great veins and atria with substantial reduction of venous return to the ventricles but also by impeding the optimal filling of the ventricles during diastole, so that CO is severely depressed despite normal systolic function. The fluid accumulating in the pericardial sac that gives rise to tamponade may be serous or sanguineous, depending on the underlying cause. Inflammatory disorders, such as viral infections or immune diseases, usually result in a serous fluid. Liquid or clotted blood within the pericardium is commonly associated with uremic pericarditis as well as with malignant pericardial involvement. Occasionally, the pericardial sac fills with blood after cardiac surgery, but this

medwedi.ru

720

Part Three: The Cardiothoracic System—Heart

is rare with modern cardiovascular procedures if proper postoperative drainage techniques are employed. Cardiac trauma from penetrating injury, and rarely from blunt trauma, may also produce pericardial tamponade. In these settings, the pericardium is normal and a relatively small volume of blood (as little as 150–200 mL) may produce the tamponade, in contrast to those sustaining tamponade from more chronic pericardial disease, in which the volume may approach 1 L or more of fluid before symptoms develop. Although uncommon, trauma from within the heart as a result of a perforating transvenous pacemaker lead, the placement of a central venous pressure, or Swan–Ganz catheter can produce unsuspected tamponade. Thus, any patient who becomes hypotensive for unknown reasons in the presence of one of these devices may have a cardiac perforation. The clinical presentation of pericardial tamponade is usually characterized by a triad of physical signs, including arterial hypotension, increased jugular venous pressure, and distant (or muffled) heard sounds. Facial cyanosis may also be present, as well as a paradoxic pulse. This latter sign is a drop in arterial blood pressure of 10 mmHg or more with inspiration. It is usually an exaggeration of the normal response to ventilation and is distinctly more prominent in individuals subjected to positive-pressure ventilation. In patients with suspected pericardial tamponade, management depends on ‘‘how tight’’ the effusion is. This tightness is reflected in the degree of hypotension and elevation of venous pressure from the tamponade. In individuals with only moderate tamponade, a Valsalva maneuver is helpful in determining its seriousness. If palpable radial pulses are not lost with a Valsalva maneuver, the situation is not critical. Another useful approach to determine the seriousness of the tamponade is to test a patient’s blood pressure response to a rapid infusion of intravenous fluid. If the tamponade is only moderate, a significant rise in arterial blood pressure should occur from this fluid bolus; in contrast, more serious degrees of tamponade blunt this response. The presence of an unexplained supraventricular dysrhythmia is a sign of significant tamponade and of the potential for incipient circulatory failure, especially if intermittent sinus arrest exists. It is essential in the analysis of suspected pericardial effusion that an echocardiogram be obtained. This modality is extremely useful in patients with pericardial effusions and potential pericardial tamponade. An echocardiogram can determine the location and characteristics of the fluid (loculated or free floating) and also ascertain to a reasonable extent whether the pericardial tamponade is of physiologic significance. In addition, it can be used to guide the insertion of a needle into the pericardial space to aspirate fluid, especially if this is deemed to be the appropriate treatment. Once significant tamponade has been deemed to exist, fluid drainage may be accomplished percutaneously by pericardiocentesis with either a needle or catheter placement (Fig. 15). Alternatively, surgical intervention through a subxiphoid pericardial window can be performed. Situations in which traumatic hemopericardium exists require a sternotomy or thoracotomy for optimal management. It needs to be emphasized that if the tamponade is considered to be of only modest proportions and is not life threatening, great care should be taken to determine the benefit of the pericardiocentesis. This technique, although useful in urgent tamponade, can result in cardiac puncture and actually worsen the situation. An important principle in managing a patient with tamponade is that endotracheal intubation should be

Figure 15 For pericardiocentesis, a 16-gauge plastic-sheathed needle is introduced beneath the costal margin and passed through the properitoncal fat and into the pericardial cavity through the tendinous part of the diaphragm. Source: From Ref. 111.

avoided. The reason for this is that positive-pressure ventilation frequently causes cardiac arrest in individuals with significant tamponade. Consequently, preparation and draping in the operating room should be carried out prior to induction of anesthesia and intubation, so that rapid decompression may be achieved in the event that it becomes necessary. A generous subxiphoid window, instead of formal pericardiectomy, is usually adequate to decompress the pericardial sac in patients with uremic or malignant pericardial tamponade. After removal of the xiphoid cartilage, the pericardium is opened between two silk stitches and the window is created. The fluid is aspirated and sent for appropriate cultures, while the pericardium is formally sampled for biopsy. An angled chest tube is placed within the pericardial cavity along the diaphragmatic surface and exits through a separate stab-wound incision in the skin. This tube is removed when the drainage ceases. Although pericardial effusions can recur after subxiphoid window, this is distinctly uncommon.

Chronic Constrictive Pericarditis Chronic constrictive pericarditis is the other condition of surgical significance involving the pericardium. This form of pericarditis is produced in response to chronic infectious tuberculosis and histoplasmosis, various collagen-vascular diseases, and, less commonly, after what appears to be uncomplicated cardiac surgery or MI, with the development of Dressler’s syndrome (characterized by fever, pericardial friction rub and pain, and often pericardial effusion). The pericardial–epicardial scarring can be severe, with obliteration of the pericardial space, thickening of the pericardium (sometimes as much a 1 in. or more), and severe fibrosis and calcifications in which calcific deposits may actually grow in the myocardium. Pathophysiologically, this massive

Chapter 36: Acquired Cardiac Disorders

pericardial thickening induces several aberrations, including obstruction of venous return with severe diastolic cardiac dysfunction. Physical signs attendant on this condition are similar to those of severe CHF with elevated venous pressure, edema, hepatomegaly, and ascites. If calcification is not apparent on chest radiography, the diagnosis may not be evident. Cardiac catheterization is usually diagnostic. This latter modality usually shows small ventricular cavities, diastolic pressures within 5 mmHg of each other, jugular venous distention with measured mean arterial pressures above 10 mmHg, and the typical ‘‘dip and plateau’’ pattern of diastolic right ventricular pressure (the square-root sign). Because surgical management of chronic constrictive pericarditis can be difficult and dangerous, and it may tax the skill of the most accomplished cardiac surgeon, a median sternotomy incision should be used with cardiopulmonary bypass (112). The absence of an epicardial– pericardial plane can make this procedure bloody. Therefore, a cell saver and aprotinin should be employed. Careful attention must be paid to freeing the atria and vena cavae as well as the ventricles, with recognition of the fact that the visceral pericardial layer may be as important as the parietal layer. This visceral pericardiectomy is complicated by the occasional ‘‘invasion’’ of the ventricular myocardium itself by calcific deposits. The pericardium should be removed from the phrenic nerve anteriorly, but it also should be removed posterior to the phrenic nerve. Complete removal of the constricting pericardium restores the left ventricular pressure–volume loop to normal or nearly normal. Operative mortality rate for this procedure ranges between 10% and 20%, and is adversely influenced by the severity of heart failure, elevation of right atrial pressure, and comorbid disease. Long-term results are poorest in patients with radiation pericarditis, and in all cases results vary primarily in proportion to the preoperative severity of heart failure.

CARDIAC TUMORS The most common tumor of the heart is a metastatic neoplasm. Approximately 10% to 20% of patients who die of disseminated cancer have cardiac metastases (113,114). The most common tumors to metastasize to the heart are from leukemia (50% of the patients have cardiac metastases), breast cancer, lung cancer, lymphoma, and melanoma. Metastatic disease to the heart usually does not warrant surgical intervention, except if it is associated with pericardial effusion and tamponade. Pericardial drainage is best accomplished in these terminally ill patients through subxiphoid pericardiotomy. This operation is performed with local anesthesia and provides reliable relief of symptoms, a recurrence rate of 3%, and minimal morbidity. Primary tumors of the heart are rare. The incidence ranges between 0.002% and 0.19%. Approximately 75% of primary cardiac tumors are benign, and 15% of these are myxomas (113,114). Although myxomas can arise in any cardiac chamber, 90% occur in the atria; 75% are observed in the left atrium, and 15% to 20% are found in the right atrium. Myxomas are distinctly rare in children. The peak incidence is the third to fourth decade of life, they are more common in women than in men, and 94% are solitary. About 5% of myxomas are familial, with an autosomal dominant inheritance. Familial patients tend to be younger, are equally likely to be male or female, and frequently have multicentric

721

tumors. Most important, familial myxomas have the highest recurrence rate (20–60%). Atrial myxomas arise from the interatrial septum near the oval fossa. Right atrial myxomas are most common in women and are broad based. Left atrial tumors are round, lobulated, gelatinous, and frequently pedunculated with a stalk. Consequently, they are quite mobile. Their color is usually white or yellow–brown, and they frequently are covered with thrombus. The average size is 5 cm. Myxomas arise from endocardium, not from a thrombotic origin as was formerly speculated. Myxomas have developed after cardiac trauma, especially atrial septal defect closure. Constitutional symptoms include weight loss, fever, and lethargy. This clinical presentation is associated with leukocytosis, elevated sedimentation rate, thrombocytopenia, and elevated C-reactive protein. Immunoglobulin G levels and interleukin-6 are also elevated. Clinical presentation is related most commonly to obstruction to blood flow within the heart. Left atrial myxomas mimic mitral stenosis or, less commonly, mitral regurgitation. Right atrial myxomas produce features of right heart failure, including venous distention, ascites, hepatomegaly, and peripheral edema. Systemic embolization, the second most common mode of presentation, occurs in 30% to 40% of patients. Most commonly the tumor embolus goes into an intracranial vessel, producing a transient ischemic attack or complete stroke. Less commonly, embolization to the lower extremity occurs. Histologic examination of surgically removed peripheral emboli can establish a diagnosis of an otherwise unsuspected tumor. The most useful diagnostic test is echocardiography, which establishes a diagnosis in nearly every case (115). Transesophageal echocardiography is particularly sensitive to detect small tumors, and it can be useful in the operating room to make certain that the entire mass has been removed. Surgical resection employs cardiopulmonary bypass and bicaval cannulation, with care taken to avoid manipulation of the heart because myxomas are friable and can embolize (116,117). After aortic cross-clamping and cardioplegic arrest, the left atrium is opened widely, and the location of the myxoma is determined. In most cases, it is attached with a stalk to the interatrial septum. A second incision in the right atrium allows excision of the stalk with the atrial septum, followed by gentle removal of the mass through the left atrium. The surgically created atrial septal defect is closed with autologous pericardium. The operative mortality rate is 1% to 3%, and the recurrence rate in nonfamilial cases is 1% to 5%.

SUMMARY Aberrations in normal cardiac function can occur when disease adversely affects cardiac rate and rhythm, the efficiency of cardiac pumping, and the optimization of cardiac loading. Acting either alone or in various combinations, derangements in each of these physiologic mechanisms can seriously affect circulatory dynamics, affecting the entire process whereby adequate delivery of oxygen and nutrients maintains cellular health and function. Although some acquired cardiac defects lend themselves to nonsurgical management strategies, in many situations the cardiac surgeon plays a key role in restoring normal cardiac physiology. As reviewed in this chapter, in most instances, ischemic heart disease, valvular heart disease, and heart failure are managed initially through medical

medwedi.ru

722

Part Three: The Cardiothoracic System—Heart

therapy but with a reliance on surgical approaches when the initial approach fails or when the pathophysiology dictates an initial surgical approach as with left main coronary artery disease in ischemic syndromes or acute valve failure as seen with papillary muscle rupture. In addition, new technologies are emerging, which will prove increasingly useful in the surgical management of virtually all acquired cardiac disorders, from the realm of arrhythmias to ischemic heart disease, to valvular heart disease, and perhaps most dramatically, now in the treatment of end-stage CHF, where immunology and technical advances can add years to the lives of people who previously faced a terminal prognosis. Whether through a medical or surgical approach, the goal of the cardiac specialist is to restore cardiac function to enable adequate delivery of oxygen to the body. Increasingly, the treatment of cardiac disorders is involving a partnership among all disciplines with the traditional lines between surgery and medicine becoming increasingly blurred.

REFERENCES 1. Peter RH. Coronary arteriography. In: Sabiston DC Jr, Spencer FC, eds. Gibbon’s Surgery of the Chest. 4th ed. Philadelphia: WB Saunders, 1983. 2. Berne RM. The role of adenosine in the regulation of coronary blood flow. Circ Res 1980; 47:807. 3. Robertson RM, et al. Thromboxane A2 in vasotonic angina pectoris. N Engl J Med 1981; 304:998. 4. Glomset JA, Ross R. Atherosclerosis and the arterial smooth muscle cell. Science 1973; 180:1332. 5. McGill H. Risk factors for atherosclerosis. Adv Exp Med Biol 1977; 104:273. 6. The Lipid Research Clinics Program. The Lipid Research Clinics coronary primary prevention trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251:365. 7. Scheuner MT. Genetic predisposition to coronary artery disease. Curr Opin Cardiol 2001; 16(4):251–260. 8. Dimitrova KR, DeGroot K, Myers AK, Kim YD. Estrogen and homocysteine. Cardiovasc Res 2002; 15(3):577–588. 9. Nieman K, Cademartiri F, Lemos PA, et al. Reliable noninvasive coronary angiography with fast submillimeter multislice spiral computed tomography. Circulation 2002; 106(16): 2051–2054. 10. Yang PC, Meyer CH, Terashima M, et al. Spiral magnetic coronary angiography with rapid real-time localization. J Am Coll Cardiol 2003; 41(7):1134–1141. 11. Vaughan CJ, Gotto AM, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 2000; 35(1):1–10. 12. Wilson JD, et al. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill, 1990:957. 13. Flaherty JT, et al. A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1976; 54:766. 14. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systemic overview of individual data from 100,000 patients in randomized trials. Circulation 1998; 97:2202–2212. 15. Ryan TJ, Antman EM, Brooks NH, et al. 1999 Update: ACC/ AHA guidelines for the management of patients with acute myocardial infarction, executive summary and recommendations. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 1999; 100:1016–1030.

16. European Cooperative Study Group for Streptokinase Treatment in Acute Myocardial Infarction. Streptokinase in acute myocardial infarction. N Engl J Med 1979; 301:797. 17. Fry ETA, Sobel BE. Coronary thrombosis. Prog Cardiol 1990; 2:199. 18. Tiefenbrunn AJ, Sobel BE. The impact of coronary thrombolysis on myocardial infarction. Fibrinolysis 1989; 3:1. 19. CURE trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502. 20. TIMI Study Group. Results of thrombolysis in myocardial infarction (TIMI) phase II trial. N Engl J Med 1989; 320:618. 21. Maisel AS, et al. Prognosis after extension of myocardial infarct: the role of W wave on non-Q wave infarction. Circulation 1985; 71:211. 22. Allen BS, et al. Studies on prolonged acute regional ischemia IV. Myocardial infarction with left ventricular failure. J Thorac Cardiovasc Surg 1989; 98:691. 23. Daggett WM, et al. Improved results of surgical management of postinfarctionventricularseptalrupture.AnnSurg1982;196:269. 24. King SB III, Talley JD. Coronary arteriography and percutaneous transluminal coronary angioplasty: changing patterns of use and results. Circulation 1989; 79(suppl 1):19. 25. Teirstein PS, Massuillo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336:1697–1703. 26. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773–1780. 27. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288:2411–2420. 28. Myers WO, et al. Medical versus early surgical therapy in patients with triple-vessel disease and mild angina pectoris: a CASS registry study of survival. Ann Thorac Surg 1987; 44:471. 29. Detre KM, et al. Long-term mortality and morbidity results of the Veterans Administration randomized trial of coronary artery bypass surgery. Circulation 1985; 72(suppl 5):84. 30. Varnauskas E. The European Coronary Surgery Study Group. Twelve-year follow-up of survival in the randomized European coronary surgery study. N Engl J Med 1988; 319:332. 31. Cameron A, Davis KB, Green G, et al. Coronary bypass surgery with internal thoracic artery grafts—effect on survival over a 15 year period. N Engl J Med 1996; 334:216–219. 32. Lytle BW, Blackstone EH, Loop FD, et al. Two internal thoracic artery grafts are better than one. J Thorac Cardiovasc Surg 1999; 117:855–872. 33. Nose Y. The Oxygenator. Vol. 2. St. Louis: Mosby, 1973. 34. Gundry SR, et al. Retrograde continuous warm blood cardioplegia: maintenance of myocardial homeostasis in humans. Ann Thorac Surg 1993; 55:358. 35. Whitman GJ, Hart JC, Crestanello JA, et al. Uniform safety of beating heart surgery using the octopus tissue stabilization system. J Card Surg 1999; 14(5):323–329. 36. Puskas JD, Williams MH, Duke PG, et al. Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: a prospective randomized comparison of two hundred unselected patients undergoing off-pump versus conventional coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125(4):797–808. 37. Rose EA. Are there advantages to off-pump coronary artery bypass surgery? N Engl J Med 2003; 348(5):379–380. 38. Gardlund B, Bitkover CY, Vaage J. Post-operative mediastinitis in cardiac surgery—microbiology and pathogenesis. Eur J Cardiothorac Surg 2002; 21(5):825–830. 39. Grove FL, et al. Factors predictive of operative mortality among coronary artery bypass subsets. Ann Thorac Surg 1993; 56:1296.

Chapter 36: Acquired Cardiac Disorders 40. Barbir M, et al. Coronary artery surgery in women compared with men: analysis of coronary risk factors and in-hospital mortality in a single centre. Br Heart J 1994; 71:408. 41. Lyde BW, et al. The effect of coronary reoperation on the survival of patients with stenoses in saphenous vein bypass grafts to coronary arteries. J Thorac Cardiovasc Surg 1993; 105:605. 42. Braunwald E, Rutherford JD. Reversible ischemic left ventricular dysfunction: evidence for the hibernating myocardium. J Am Coll Cardiol 1986; 8:1467. 43. Aaberge L, Rootwelt K, Blomhoff S, et al. Continued symptomatic improvement three to five years after transmyocardial revascularization with CO2 laser. J Am Coll Cardiol 2002; 39:1588–1593. 44. Yeager M. Comparison of Doppler derived pressure gradient to that determined at cardiac catheterization in adults with aortic valve stenosis: implications for management. In: Weyman AE, ed. Principles and Practice of Electrocardiography. Philadelphia: Lea & Febiger, 1994:525. 45. Gorlin R, Gorlin SG. Hydraulic formula for calculation of area of stenotic mitral valve, other cardiac valves, and central circulatory shunts. Am Heart J 1951; 41:1. 46. Lombard JT, Selzer A. Valvular aortic stenosis. Clinical and hemodynamic profile of patients. Ann Intern Med 1987; 106:292. 47. Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):v61. 48. Olesen KH, Warburg E. Isolated aortic stenosis—the late prognosis. Acta Med Scand 1957; 160:437. 49. Copeland JB, et al. Long-term follow-up after isolated aortic valve replacement. J Thorac Cardiovasc Surg 1977; 74:875. 50. Carabello BA, et al. Hemodynamic determinants of prognosis or aortic valve replacement in critical aortic stenosis and advanced congestive heart failure. Circulation 1980; 62:42. 51. Fifer MA, et al. Myocardial contractile function in the aortic stenosis as determined from the rate of stress development during isovolumic systole. Am J Cardiol 1979; 44:1318. 52. Kennedy JW, Doces J, Stewart DK. Left ventricular function before and following aortic valve replacement. Circulation 1977; 56:944. 53. Pantely G, Morton M, Rahimtoola SH. Effects of successful, uncomplicated valve replacement on ventricular hypertrophy, volume and performance in aortic stenosis and in aortic incompetence. J Thorac Cardiovasc Surg 1978; 75:383. 54. Miller DS, et al. Surgical implications and results of combined aortic valve replacement and myocardial revascularization. Am J Cardiol 1979; 43:494. 55. Safian RD, et al. Balloon aortic valvuloplasty in 170 consecutive patients. N Engl J Med 1988; 319:169. 56. Olson LJ, Subramanian R, Edwards WD. Surgical pathology of pure aortic insufficiency: a study of 225 cases. Mayo Clin Proc 1984; 59:835. 57. Grossman W. Cardiac Catheterization, Angiography, and Intervention. Philadelphia: Lea & Febiger, 1991. 58. Alpert JS. Chronic aortic regurgitation. In: Dalen JE, Alpert JS, eds. Valvular Heart Disease. 2nd ed. Boston: Little, Brown, 1987:283. 59. Rapaport E. Natural history of aortic and mitral valve disease. Am J Cardiol 1975; 35:221. 60. Borrow K, et al. End-systolic volume overload from valvular regurgitation. Am J Med 1980; 68:655. 61. Bonow RO, et al. Survival and function results after valve replacement for aortic regurgitation from 1976 to 1983: impact of preoperative left ventricular function. Circulation 1985; 72:1244. 62. Greves J, et al. Perioperative criteria predictive of late survival following valve replacement for severe aortic regurgitation. Am Heart J 1981; 101:300. 63. Lytle BW, et al. Replacement of aortic valve combined with myocardial revascularization: determinants of early and late risk for 500 patients, 1967–1981. Circulation 1983; 68:1149. 64. Rahimtoola SH. Choice of prosthetic heart valve for adult patients. J Am Coll Cardiol 2003; 41:893–904.

723

65. Rankin JS. Mitral and tricuspid valve disease. In: Sabiston DC Jr, ed. Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 13th ed. Philadelphia: WB Saunders, 1992: 2026. 66. Braunwald E. Valvular heart disease. In: Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders, 1992:1007. 67. Bowe JC, et al. Course of mitral stenosis without surgery: 10 and 20 year perspectives. Ann Intern Med 1960; 52:741. 68. Wallace AG. Pathophysiology of cardiovascular disease. In: Smith LH Jr. Thier SO, ed. Pathophysiology: The Biological Principles of Disease. The International Textbook of Medicine. Vol. 1. Philadelphia: WB Saunders, 1981:1192. 69. Thompson ME, Shaver JA, Leon DT. Effect of tachycardia on atrial transport in mitral stenosis. Am Heart J 1977; 94:297. 70. Olesen KH. The natural history of 271 patients with mitral stenosis under medical treatment. Br Heart J 1962; 24:349. 71. Munoz S, et al. Influence of surgery on the natural history of rheumatic mitral and aortic valve disease. Am J Cardiol 1975; 35:234. 72. Cutler EC, Levine SA. Cardiotomy and valvulotomy for mitral stenosis: experimental observations and clinical notes concerning an operated case with recovery. Boston Med Surg J 1923; 188:603. 73. Souttar HS. The surgical treatment of mitral stenosis. Br Med J 1925; 2:603. 74. Harken DE, et al. The surgical treatment of mitral stenosis. N Engl J Med 1948; 239:801. 75. Bailey CP. The surgical treatment of mitral stenosis (mitral commissurotomy). Dis Chest 1949; 15:377. 76. Ellis LB, Harken DE. Closed valvuloplasty for mitral stenosis. A twelve-year follow-up of 1571 patients. N Engl J Med 1964; 270:643. 77. Montoya A, et al. The advantages of open mitral commissurotomy for mitral stenosis. Chest 1979; 75:131. 78. Higgs LA, et al. Mitral restenosis: an uncommon cause of recurrent symptoms following mitral commissurotomy. Am J Cardiol 1970; 26:34. 79. Harken DE, et al. Reoperation for mitral stenosis. A discussion of postoperative deterioration and methods of improving mitral and secondary operation. Circulation 1961; 23:7. 80. Kirklin JW, Barrett-Boyes BG. Mitral valve disease without tricuspid valve disease. In: Cardiac Surgery. 2nd ed. New York: Churchill Livingstone, 1993:425. 81. Smith WM, et al. Open mitral valvotomy: effect of preoperative factors on result. J Thorac Cardiovasc Surg 1981; 82:738. 82. Inoue K, et al. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg 1984; 87:349. 83. Nishimura RA, Holmes DR Jr, Reeder GS. Percutaneous balloon valvuloplasty. Mayo Clinic Proc 1990; 65:198. 84. Tuzcu EM, Block PC, Palacios IF. Comparison of early versus late experience with percutaneous mitral balloon valvuloplasty. J Am Coll Cardiol 1991; 17:1121. 85. Block PC. Early results of mitral balloon valvuloplasty (MBV) for mitral stenosis: reports from the NHLBI Registry. Circulation 1978; 78(suppl 2):11489. 86. Nobuyoshi M, et al. Indications, complications and short-term clinical outcomes of percutaneous transvenous mitral commissurotomy. Circulation 1989; 80:782. 87. Roberts WC, et al. Nonrheumatic valvular cardiac disease. A clinicopathologic survey of 27 different conditions causing valvular dysfunction. Cardiovasc Clin 1973; 5:403. 88. Stapleton JF. Natural history of chronic valvular disease. In: Frankl WS, Brest AN, eds. Cardiovascular Clinics. Valvular Heart Disease: Comprehensive Evaluation and Management. Philadelphia: FA Davis, 1986:105. 89. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002; 347:1397–1402. 90. Sutton JCS. Epidemiologic aspects of heart failure. Am Heart J 1990; 120:1538–1540.

medwedi.ru

724

Part Three: The Cardiothoracic System—Heart

91. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA 1996; 275:1557–1562. 92. Bach DS, Boiling SF. Improvement following correction of secondary mitral regurgitation in end-stage cardiomyopathy with mitral annuloplasty. Am J Cardiol 1996; 78:966–969. 93. Ahbraham WT, Fisher WG, Smith Al, et al. Cardiac resynchronization in chronic heart failure. New Engl J Med 2002; 346:1845–1853. 94. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe post-infarction left ventricular dysfunction. J Am Coll Cardiol 2003; 41(7):1078–1083. 95. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the Heartmate 1000 IP left ventricular assist device. Ann Thorac Surg 1992; 53:1080–1090. 96. American College of Cardiology/American Heart Association/NASPE Heart Rhythm Society. 2002 Guideline update for implantation of pacemakers and antiarrhythmia devices. J Am Coll Cardiol 2002; 40(9):1703–1719. 97. Belott PH, Reynolds DW. Permanent pacemaker implantation. In: Ellenbogen KA, Kay GN, Wilkoff BL, eds. Clinical Cardiac Pacing. Philadelphia: WB Saunders, 1995:447. 98. AMA Council on Scientific Affairs. The use of cardiac pacemakers in medical practice. JAMA 1985; 254:1952. 99. Sealy WC, Selle JG. Surgical treatment of supraventricular arrhythmias. In: Roberts AJ, Conti CR, eds. Current Surgery of the Heart. Philadelphia: JB Lippincott, 1987. 100. Sealy WC, Anderson RW, Gallagher JJ. Surgical treatment of supraventricular tachyarrhythmias. J Thorac Cardiovasc Surg 1977; 73:511. 101. Ellenbogen KA, Kay GN, Wilkoff BL, eds. Clinical Cardiac Pacing. Philadelphia: WB Saunders, 1995; Furman S, Schwedel JB. An intracardiac pacemaker for Stokes-Adams seizures. N Engl J Med 1959; 261:948. 102. Cox JL, Ad N, Palazzo T, et al. Current status of the Maze procedure for the treatment of atrial fibrillation. Semin Thorac Cardiovasc Surg 2000; 12:15–19.

103. Williams MR, Stewart JR, Boiling SF, et al. Surgical treatment of atrial fibrillation using radiofrequency energy. Ann Thorac Surg 2001; 71:1939–1944. 104. Guiraudon GM, et al. Encircling endocardial ventriculotomy: a new treatment for life-threatening ventricular tachycardia. Ann Thorac Surg 1977; 26:438. 105. Harken AH, Josephson ME, Horowitz LN. Surgical endocardial resection for the treatment of malignant ventricular tachycardia. Ann Surg 1979; 190:456. 106. Bocker D, et al. Do patients with an implantable defibrillator live longer? J Am Coll Cardiol 1993; 21:1638; Lowe JL, Sabiston DC. The surgical management of cardiac arrhythmias. J Cardiovasc Surg 1986; 1:1. 107. Kim SG, et al. Long-term outcomes and modes of death of patients related with nonthoracotomy implantable defibrillators. Am J Cardiol 1995; 75:1229. 108. May CD, et al. The impact of implantable cardioverter defibrillator on quality of life. PACE Pacing Clin Electrophysiol 1995; 18:1411. 109. Levine PA, et al. Electrocautery and pacemakers. Management of the paced patient subject to electrocautery. Ann Thorac Surg 1996; 41:313. 110. Shabetai R. The Pericardium. New York: Grune & Stratton, 1981. 111. Edwards EA, Malone PD, Collins JJ Jr. Operative Management of the Thorax. Philadelphia: Lea & Febiger, 1972. 112. Seifer FC, et al. Surgical treatment of constrictive pericarditis: analysis of outcome and diagnostic error. Circulation 1985; 72(suppl 2):II264. 113. Harvey WP. Clinical aspects of cardiac tumors. Am J Cardiol 1968; 21:328. 114. Heath D. Pathology of cardiac tumors. Am J Cardiol 1968; 21:315. 115. Ensherding R, et al. Diagnosis of heart tumors by transesophageal ochocardiography. Eur Heart J 1993; 14:1223. 116. Miralles A, et al. Cardiac tumors: clinical experience and surgical results in 74 patients. Ann Thorac Surg 1991; 52:886. 117. Murphy MC, et al. Surgical treatment of cardiac tumors: a 25 year experience. Ann Thorac Surg 1990; 49:612.

PART FOUR: The Urinary System

37 Urine Formation: From Normal Physiology to Florid Kidney Failure Akinsan Dosekun, John R. Foringer, and Bruce C. Kone

INTRODUCTION The kidney fulfills several major functions. First, the organ regulates the excretion of several important inorganic and organic ions and participates in the regulation of acid–base balance. Second, the kidneys work in an integrated manner with the cardiovascular and central nervous systems to regulate body fluid osmolality and volume. The control of body fluid osmolality is central to the maintenance of normal cell volume in virtually all tissues. Third, the kidney excretes metabolic by-products and exogenous substances, including certain drugs. Finally, the kidney is an important endocrine organ, producing key hormones involved in the regulation of blood pressure and erythropoiesis, as well as calcium, phosphate, and bone metabolism. The kidney has remarkable functional reserve and, through adaptive changes, can maintain fluid, electrolyte, metabolic, and acid–base balance as the number of functioning nephrons is reduced by injury or disease. However, in response to significant injury, the kidney may undergo maladaptive changes that lead to acute irreversible and/or progressive renal disease. The incidence of acute and chronic kidney failure continues to rise, and despite extensive investigation into the pathophysiology of these disorders, major preventive or therapeutic advances have been infrequent. This chapter examines the anatomy and physiology of the normal kidney and then reviews the pathophysiology, diagnosis, and management of acute and chronic kidney failure, with special emphasis on clinical scenarios commonly encountered in modern surgical practice.

interlobular arteries, which divide at the level of the corticomedullary junction to form the arcuate arteries (Fig. 1). The arcuate arteries lead to interlobar arteries, which branch into the afferent arterioles. The afferent arterioles give rise to the glomerular capillaries that coalesce to form the efferent arteriole. The efferent arterioles become a second capillary network, the peritubular capillaries, which surround the proximal tubules and successive tubular segments of the nephron (Fig. 2). The vasa recta arise from the juxtamedullary efferent arterioles and give rise to the descending vasa recta, which form a dense network of anastomosing, looping vessels that descend in parallel with Henle’s loops to supply the outer and inner medulla. The venous system runs in parallel to the arterial vessels, with blood from the peritubular capillaries flowing sequentially through the stellate vein, the interlobular vein, arcuate vein, interlobar vein, and renal vein, which tracks beside the ureter. Blood from the ascending vasa recta enters the interlobular and arcuate veins. Despite receiving less than 1% of the renal blood flow (RBF), the vasa recta subserve several critical functions, including the return of reabsorbed solutes and water to the systemic circulation, the delivery of oxygen, nutrients, and substances for secretion to nephron segments, and the concentration and dilution of the urine. The total vascular resistance along the renal vascular tree is estimated to be about 25% before the afferent arteriole, 50% along the length of the afferent arteriole, and 30% along the efferent arteriole (1).

Cortex

OVERVIEW OF RENAL PHYSIOLOGY Renal Anatomy and Microanatomy The cut surface of a bisected kidney reveals two major regions: the outer region, termed the cortex, in which the glomeruli reside, and the inner region, termed the medulla. The medulla is divided into 8 to 18 renal pyramids, whose bases begin at the corticomedullary junction and form an apex in a minor calyx of the papilla. The minor calyces drain into major calyces and then into the renal pelvis, an expanded region of the ureter. Smooth muscle contractions by the walls of the calyces, pelvis, and ureters drive the urine to the urinary bladder.

Medulla

Interlobar artery Arcuate artery Interlobular artery Afferent arteriole

Macro- and Microcirculation Although comprising only 0.5% of the total body mass, the kidneys receive roughly 25% of the cardiac output. This disproportionately high rate of blood flow facilitates glomerular filtration. The blood flow is distributed principally to the renal cortex, and diminishes progressively toward the cortex. The renal arteries branch successively into

Figure 1 Organization of the arterial vascular system of the human kidney.

medwedi.ru 725

726

Part Four: The Urinary System

basement membrane itself, the foot processes of the podocytes, and the fenestrae of the glomerular endothelium (Fig. 4). The normal glomerular filtration barrier will allow the passage of molecules with molecular weight <58,000 Da. In addition to molecular size, electrical charge also strongly influences glomerular permselectivity. The glomerular basement membrane carries with it a net negative charge that tends to repel anionically charged proteins such as albumin. Multiple disease states result in the disruption of the glomerular filtration barrier and result in proteinuria. The glomerular capillary network is anchored and organized around the mesangium, a central zone that comprises mesangial cells and extracellular matrix. The capillary lumen is separated from the mesangium by the endothelium, without an interposed glomerular basement membrane. The juxtaglomerular apparatus comprises the macula densa, the extraglomerular mesangial cells, and the rennin-producing granular cells of the afferent arteriole. The juxtaglomerular apparatus participates in the tubuloglomerular feedback (TGF) system, which is involved in autoregulation of RBF and the glomerular filtration rate (GFR). Figure 2 Postglomerular circulation of superficial and juxtamedulllary nephrons. Note that the efferent arteriole gives rise to the peritubular capillaries in both classes of nephrons, but also the vasa recta in juxtamedulllary nephrons. The vasa recta form capillary networks that surround the collecting ducts and ascending limbs of Henle’s loop.

Nephron Structure The functional unit of the kidney is the nephron, which consists of the renal corpuscle (containing the glomerulus and Bowman’s capsule), the proximal tubule, Henle’s loop, distal tubule, and the collecting ducts (Fig. 3). The proximal tubule comprises an initial convoluted segment followed by a straight segment that descends to the medulla. The proximal straight tubule then gives rise to the descending thin limb of Henle, which ends at a hairpin turn to become the ascending thin limb of Henle (in long-looped nephrons), which ascends through the medulla to form the medullary and cortical thick ascending limbs (cTAL) of Henle. A specialized portion of the cTAL, termed the macula densa segment, courses between the afferent and efferent arterioles of the same nephron. The distal tubule begins beyond the macula densa segment and continues to the junction of two or more nephrons at the cortical collecting duct. The cortical collecting duct descends to become the outer medullary collecting duct and inner medullary collecting duct. Nephrons are further subdivided into superficial and juxtamedullary types. For superficial nephrons, the renal corpuscle resides in the outer regions of the cortex, its Henle’s loop is short, and its efferent arteriole branches into peritubular capillaries that form a network around neighboring nephrons. In contrast, juxtamedullary nephrons have renal corpuscles located in the cortex near the medulla, Henle’s loop extends deep into the medulla, and the efferent arteriole forms not only the peritubular capillary network, but also the vasa recta. The glomerular capillaries are lined by the fenestrated endothelium. The endothelium and epithelium are anchored by the continuous glomerular basement membrane (Fig. 4). The foot processes of the podocytes, also termed visceral epithelial cells, cover the outer segment of the capillary wall. The glomerular filtration barrier is formed by the glomerular

Innervation Sympathetic nerves arising principally from the celiac plexus innervate the kidney and participate in the regulation of RBF, GFR, and the reabsorption of salt and water (3). Adrenergic fibers course adjacent to the smooth muscle cells of the interlobar, arcuate, and interlobular arteries, and the afferent and efferent arterioles. The renin-producing granular cells of the afferent arteriole are also innervated and activated by sympathetic nerves. In addition, the proximal tubule, Henle’s loop, distal tubule, and collecting duct are innervated, so that activation of these nerves promotes sodium reabsorption by these segments. There is no parasympathetic innervation.

Lymphatics Lymphatic capillaries form a superficial network just inside the renal capsule and a deeper network between and around the renal vasculature (4). The lymphatic networks inside the capsule and around the renal blood vessels drain into lymphatic channels coursing with the interlobular and arcuate blood vessels. The main lymph channels run in parallel with the main renal arteries and veins to drain into periaortic lymph nodes and lymph nodes near the origin of the renal arteries. While there are a few lymphatic capillaries present in the renal parenchyma, associated with connective tissue, the glomeruli contain no lymphatics.

Urine Formation Urine formation involves the integration of three processes: glomerular ultrafiltration, tubular reabsorption of solutes and water, and tubular secretion of endogenous and exogenous substances.

Renal Blood Flow RBF to each kidney is about 600 mL/min or about 25% of the cardiac output in resting individuals. Roughly 90% of the total renal plasma flow is directed to the cortex, about 9% to the outer medulla, and only about 1% to the inner medulla and papilla. The differences in blood flow among the renal parenchymal zones are under metabolic, hormonal, and sympathetic control. The RBF subserves several important roles: it indirectly sets the GFR, modifies the rate of solute

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

PROXIMAL TUBULE Reabsorbs H2O 65% (osmosis) Na+ 65% (symport, antiport, Na pump) 50% (diffusion) Cl– K+ 65% (diffusion) – HCO3 80-90% (facilitated diffusion) Ca2+ variable (diffusion) Mg2+ variable (diffusion) Urea 50% (diffusion)

727

DISTAL CONVOLUTED TUBULE Reabsorbs H2O 10-15% (osmosis) Na+ 5% (symporters) Cl– 5% (symporters) Ca2+ variable, 1by PTH

Secretes variable (antiporters) H+ NH4+ variable, in acidosis (antiporters) Urea variable diffusion Creat small variable

DCT

Glom

S2 S1 CTAL Cortex

CCD

S3

Outer Medulla

OMCD

MTAL

Inner Medulla IMCD LOOP OF HENLE Reabsorbs H2O 15% (osmosis-DTL) Na+ 20-30% (symporters-TAL) Cl– 35% (symporters-TAL) – HCO3 10-20% (facilitated diffusion) Ca2+ variable (diffusion) 2+ Mg variable (diffusion) Secretes Urea variable (recycles from collecting duct)

DTL

ATL

COLLECTING DUCT Reabsorbs H2O 5-10% (ADH-stimulated H2O channel insertion) Na+ 1-4% (Na+ channel & pump) – 5% (symporetrs) Cl HCO–3 variable, depending on H+ secretion Urea variable (recycling to loop of Henle) Secretes H+ variable (H+ pumps) adjusts fo intake (K+ channels) K+

and water reabsorption in the proximal tubule, delivers oxygen, nutrients, and hormones to cells of the nephron, and removes carbon dioxide and reabsorbed fluid and solutes to the circulation, delivers substrates for urinary excretion, and participates in urinary concentration and dilution. The RBF represents the pressure difference between the renal artery and the renal vein, divided by the renal vascular resistance. RBF and GFR remain relatively constant as mean arterial blood pressure changes over the range of bout 70 to 180 mmHg, a phenomenon known as autoregulation (Fig. 5). At least two mechanisms are responsible for autoregulation: a myogenic mechanism and TGF. There appears to be a dynamic interplay between these two mechanisms. The myogenic mechanism is a pressuresensitive mechanism intrinsic to the vascular smooth muscle in which stretching promotes contraction (1). Thus, elevations in arterial pressure stretch the renal afferent arteriole and the smooth muscle contracts. This increase in resistance offsets the increase in pressure so that RBF and GFR remain constant. TGF is a process in which the NaCl concentration (or another factor) in the tubular lumen is sensed by the

Figure 3 Microanatomy and major segmental functions of of an isolated nephron. The nephron is the functional unit of the kidney and consists of the renal corpuscle, proximal tubule, Henle’s loop, distal tubule, and collecting system. The human kidney typically has more than one million nephrons, which function to filter and modify the blood to produce the final urine. Not drawn to scale. Abbreviations: GLOM, glomerulus; DCT, distal convoluted tubule; S1, S2, S3, segments of the proximal tubule; CCD, cortical collecting duct; MTAL, medullary thick ascending limb of Henle; CTAL, cortical thick ascending limb of Henle; DTL, descending thin limb of Henle; OMCD, outer medullary collecting duct; ATL, ascending thin limb, IMCD, inner medullary collecting duct.

macula densa, which transmits a signal that adjusts in an opposite manner afferent arteriolar resistance and, thereby, GFR. Thus, elevations in NaCl delivery to the macula densa prompt the afferent arteriole to constrict and return RBF and GFR to normal. Conversely, reduced NaCl delivery to the macula densa elicits signals that result in vasodilation of the afferent arteriole so that RBF and GFR increase to normal levels. Adenosine-1 receptors are absolutely required for eliciting. TGF responses in animals, and the background level of angiotensin II (Ang II) appears to be an important determinant for the efficiency of adenosine-1 receptor–induced vasoconstriction. The adenosine source remains unclear, but adenosine may be generated extracellularly from released adenosine triphosphate (ATP) by the action of ectonucleotidases. ATP may also activate P2 receptors in preglomerular vessels, which may contribute to autoregulation of renal vascular resistance. Finally, nitric oxide (NO) generated in macula densa cells opposes the constrictor effect of adenosine, but its exact role in states of TGF-induced hyperfiltration is still unclear (5). In addition to these influences, sympathetic nerves, vasoconstrictor

medwedi.ru

728

Part Four: The Urinary System

Figure 4 Microanatomy of the renal corpuscle and the juxtaglomerrular apparatus. The AA enters and the EA leaves the glomerular capillary tuft. The glomerular filtration barrier comprises the GBM, the fenestrae of the glomerular capillary endothelium (E), and the foot processes of the PO. The primary ultrafiltrate enters the US, which is continuous with the lumen of the proximal tubule (P). The juxtaglomerular apparatus consists of the MD segment, the rennin-producing granular cells of the AA, and the extraglomerular mesangial cells (M). Abbreviations: AA, afferent arteriole; EA, efferent arteriole; GBM, glomerular basement membrane; PO, podocytes; MM, mesangial matrix; PE, parietal epithelium; US, urinary space; MD, macula densa. Source: From Ref. 2.

molecules such as Ang II and endothelin, and vasodilator molecules such as NO, bradykinin, and prostaglandins (particularly prostaglandins E2 and I2) act on the vascular tone of the afferent and efferent arterioles and thus contribute to the regulation of RBF. Ang II plays a key role in the regulation of whole-kidney blood flow, cortical and medullary blood flow, and renal autoregulation. Ang II potently constricts both the afferent and the efferent arterioles, with responses modulated by paracrine and autocrine factors arising from endothelial cells and the macula densa. Ang II promotes vasoconstriction of the efferent arteriole via

Flow Rate (ml/min)

RBF

calcium release from intracellular stores and calcium entry through voltage-independent calcium channels. The hormone promotes comparatively less constriction of the afferent arteriole, which occurs primarily by stimulation of calcium entry via voltage-sensitive L-type channels. The relative changes in resistance of the afferent and/ or efferent arterioles dictate the effects on RBF and GFR. For example, hemorrhage leading to hypotension results in accentuated activity of renal sympathetic nerves, which act by direct actions, and indirectly, through the activation of renin secretion and Ang II production, to constrict the renal arterioles. This results in reduced RBF and GFR and enhanced tubular reabsorption of sodium and water. Importantly, autoregulation is often impaired in patients with severe hypertension and in ischemic acute kidney failure (AKF). In these settings, the kidney is even more vulnerable to subsequent hypotensive or hypertensive insults.

Glomerular Filtration

GFR

0

50

100 150 Arterial Blood Pressure (mm Hg)

200

Figure 5 Relationships among renal blood flow, glomerular filtration rate, and arterial blood pressure. Autoregulation maintains GFR and RBF relatively constant over a wide range of blood pressures.

The initial step in urine formation is the production of an ultrafiltrate by the glomerulus. The ultrafiltrate is virtually devoid of cells and proteins and has concentrations of ions and organic molecules similar to that of plasma. Normally, only 15% to 20% of the plasma entering the glomerulus is actually filtered: the filtration fraction. The remainder courses on through the glomerulus to the efferent arteriole and eventually returns to the circulation via the renal vein. Thus, if the RBF is 600 mL/min per kidney and GFR is roughly 120 mL/min, the filtration fraction would be 0.2. Starling forces (i.e., hydrostatic and oncotic pressures) across the glomerular capillary membrane dictate ultrafiltration; hence, changes in these forces result in altered GFR (6). Because the glomerular filtration barrier excludes substances greater than 70,000 Da, the ultrafiltrate is essentially protein free as it arrives in Bowman’s space, and thus

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

contributes little oncotic pressure (pBS). Accordingly, the glomerular capillary hydrostatic pressure (PGC) is the only force favoring filtration. It is opposed by the minor hydrostatic forces in Bowman’s space (PBS) and the oncotic pressure of the blood in the glomerular capillary (pGC): SNGFR ¼ Kf ½ðPGC PBS Þ ðpGS pBS Þ where SNGFR is the single-nephron GFR, Kf is the product of the intrinsic permeability of the glomerular capillary and the glomerular capillary surface area available for filtration. The net ultrafiltration pressure gradient, representing the difference between the hydrostatic and oncotic pressure gradients, is greatest nearest the afferent arteriole, where the oncotic pressure is the lowest, and becomes progressively lower as the oncotic pressure increases along the glomerular capillaries to the efferent arteriole. Disease states that result in changes in these latter properties result in a reduction in GFR. Similarly, reduction in PGC, as might occur in AKF, or increases in PBS, as might occur in acute urinary tract obstruction, result in reduced GFR. In normal humans, GFR is regulated primarily by alterations in PGC that result from changes in glomerular arteriolar resistance. Therapy to prevent progression of chronic kidney disease (CKD) [i.e., angiotensin-converting enzyme (ACE) inhibitors or Ang II receptor antagonists] is directed at lowering PGC in glomeruli of the remaining functional nephrons to minimize thickening and fibrosis of the glomerular capillary wall. As noted above, GFR is regulated in parallel with RBF, exhibiting autoregulation that is principally controlled by TGF. Factors that influence the vascular tone of the afferent and/or efferent arterioles or the TGF mechanism itself will cause alterations in GFR. Given the prime importance of Ang II, bradykinin, and prostaglandins in controlling vascular tone, pharmacologic interruption of these pathways with ACE inhibitors, Ang II receptor antagonists, or cyclooxygenase inhibitors can disrupt autoregulation and the regulation of GFR.

Tubular Functions Epithelial Transport Mechanisms Because membranes are generally impermeable to ions distributed across them, ion pumps are used to interconvert chemical energy derived from ATP hydrolysis into electrochemical gradients to drive ion transport against a concentration gradient in a process termed ‘‘primary active transport’’ (Fig. 6). In the kidney, the Naþ-Kþ-ATPase is the primary mechanism for primary active transport,

729

functioning to maintain the low concentration of Naþ and high concentration of Kþ in the intracellular environment. In secondary active transport, solutes are transported along an electrochemical gradient, without direct energy consumption (Fig. 6). Thus the energy stored in the steep Naþ gradient generated by the Naþ-Kþ-ATPase can direct Naþ-coupled transport of sugars, amino acids, and other solutes along the nephron. Finally, in tertiary active transport, the energy stored in the Naþ gradient generated by the Naþ-Kþ-ATPase can be indirectly used to drive the transport of other ions and organic molecules. For example, the Naþ/Hþ exchanger, a secondary active transporter driven by the transmembrane Naþ gradient generated and maintained by the Naþ-Kþ-ATPase, couples Naþ influx with the Hþ efflux, and is thus principally responsible for the existence of this Hþ gradient (Fig. 6). This Hþ gradient can then drive the tertiary active transport of Cl across the brush border membrane via a Cl/HCO3exchanger (Fig. 6). NaCl and Water Reabsorption Along the Nephron Under normal conditions, less than 1% of the filtered salt and water are excreted in the urine. In the absence of pharmacological interference, urinary excretion of Naþ can vary between less than 0.1% and no more than 3% of the filtered load. Because spontaneous changes in GFR can dramatically alter the filtered load of Naþ, rapid adjustments in Naþ reabsorption must occur along the nephron to prevent wide fluctuations in urinary Naþ excretion and body Naþ balance. The reabsorption of several important solutes is coupled directly or indirectly to Naþ transport. The proximal tubule reabsorbs about 65% of the filtered Naþ, Kþ, Cl, and water, as well as nearly all of the glucose and amino acids filtered by the glomerulus (Fig. 3). About two-thirds of the Naþ is reabsorbed across the cells (transcellular), with the remainder reabsorbed by paracellular routes. Electrochemical gradients established by the NaþKþ-ATPase in the basolateral membrane of the proximal tubule drive the transport of Naþ coupled with Hþ or organic solutes (Fig. 6) (7). The principal mechanisms of Naþ entry across the apical membrane are the Naþ–Hþ exchanger. The exact amounts of Naþ reabsorbed are determined by many regulatory factors such as glomerulotubular balance, Ang II, endothelin, sympathetic input, acid–base status parathyroid hormone (PTH), dopamine, and others. Starling forces across the peritubular capillaries also influence solute and water transport across the proximal tubule. About 25% of the filtered NaCl is reabsorbed in the thick ascending limb, principally via secondary active

Figure 6 Modes of active solute transport in renal epithelial cells. Models illustrating the different modes of active transport are shown. Primary active transport (in this example, the NaþKþ-ATPase) uses adenosine triphosphate (ATP) hydrolysis to power the transport of solutes across the plasma membrane against their electrochemical gradients. Secondary active transport utilizes the energy inherent in the electrochemical gradient (in this case, the Naþ gradient) generated by the primary active transporter to drive the influx or efflux of a coupled solute. Tertiary active transport couples the transport of a solute (in this example, Cl) to the gradient (in this example, Hþ) created by the secondary active transport process. Abbreviations: ATP, adenosine triphosphate; ADP, adenosine diphosphate.

medwedi.ru

730

Part Four: The Urinary System

transport mediated by the apical Naþ-Kþ-2Cl cotransporter and driven by the Naþ-Kþ-ATPase (Fig. 3). Because the thick ascending limb is impermeable to water, NaCl reabsorption in this segment reduces the osmolality of (‘‘dilutes’’) the tubular fluid. The transport rate is determined by the Naþ load and by several hormones and neurotransmitters, including prostaglandins, PTH, glucagon, calcitonin, antidiuretic hormone (ADH), and adrenaline. The distal tubule reabsorbs about 4% to 5% of the remaining NaCl by the actions of the apical thiazide-sensitive NaCl cotransporter and the basolateral Naþ-Kþ-ATPase. The rate of transport is again determined by the delivered load and by several hormones and neurotransmitters. The collecting duct is the final arbiter of Naþ reabsorption, with Naþ channels mediating Naþ entry. Water reabsorption is a highly integrated and regulated process that can vary between 0.3% and 15% of the amount filtered under physiological conditions. About two-thirds of the filtered water is passively reabsorbed in the proximal tubule (Fig. 3). The driving force for water reabsorption in this segment is the osmotic gradient across the tubule established by solute reabsorption Roughly 15% is then passively reabsorbed in the descending thin limb of Henle (Fig. 3). The remainder of the loop of Henle and the distal tubule do not reabsorb significant amounts of water. The late distal tubule and collecting duct reabsorb variable amounts of the remaining water via constitutive and ADH-regulated water channels, termed aquaporins (Fig. 3). Changes in plasma osmolality and blood volume or pressure stimulate ADH release and thirst (Fig. 7). ADH acts on and binds to vasopressin (V2) receptors on the basolateral membrane of collecting duct cells. Receptor binding evokes an increase in cyclic adenosine monophosphate (cAMP) levels, which ultimately results in the insertion of vesicles containing aquaporin-2 in the apical membrane of the cell (8). Water is absorbed through these apical aquaporin-2 channels and through the basolateral membrane via aquaporin-3 channels, driven by the osmotic gradient built up by the countercurrent concentrating system. With ADH removal, the water channels are again internalized into the cell, rendering the apical membrane impermeable to water (8). The shuttling of the water

Figure 7 Relationships among antidiuretic hormone (ADH) concentration, the plasma osmolality, and the urine osmolality. As plasma osmolality increases above normal, ADH levels increase, which permits maximal urinary conservation of water up to a urine osmolality of about 1200 mOsm/kg water. Further increments in ADH concentration do not increase urine osmolality above this maximum.

channels in response to ADH provides a rapid means to regulate membrane water permeability. Potassium Handling Roughly 98% of total body Kþ content in humans is distributed in the intracellular compartment, the result of active Kþ uptake by the Naþ-Kþ-ATPase. The remaining 2% of Kþ normally resides in the extracellular pool (9). Excretion balances K intake even when intake increases more than 10-fold in normal humans. Normal individuals on a typical Western diet absorb about 90% of intake and excrete an equivalent amount of Kþ in the urine. The remaining 10% of Kþ excretion occurs principally in the stool. Kþ is freely filtered at the glomerulus. The proximal tubule reabsorbs about 67% of the filtered Kþ, and the medullary thick ascending limb of Henle’s loop (mTAL) reabsorbs another 20% as a constant fraction of the amount filtered (Fig. 3). In contrast, cells of the distal tubule and collecting duct have the dual ability to reabsorb and secrete Kþ, processes that are highly regulated by multiple hormones and other factors (Fig. 3). Indeed, the principal mechanism for urinary Kþ excretion is the action of principal cells of the distal tubule and collecting duct to secrete excess Kþ from the blood into the tubular fluid (9). During states of Kþ deficiency, the outer and inner medullary collecting ducts reabsorb Kþ to reclaim all but 1% filtered Kþ before it is lost in the urine. However, the reabsorptive processes are less efficient than they are for Naþ, so that hypokalemia can ensue in states of Kþ restriction. Calcium, Magnesium, and Phosphorus Handling The kidney works in concert with the gastrointestinal (GI) tract and bones to regulate the balance of Ca2þ and inorganic phosphorus. Under normal conditions, 99% of the filtered Ca2þ is reabsorbed by the nephron. Ca2þ excretion by the kidney is determined by the net Ca2þ reabsorption by the intestine, the balance between bone formation and resorption, and the net transport rates by the distal tubule and thick ascending limb (Fig. 3). Calcitonin, calcitriol, and PTH also regulate urinary Ca2þ excretion, with PTH contributing the greatest control. PTH stimulates Ca2þ reabsorption by the thick ascending limb and the distal tubule (10,11). Calcitonin stimulates Ca2þ reabsorption by these segments, but to a quantitatively less degree. Calcitriol enhances Ca2þ reabsorption by the distal tubule. The proximal tubule reabsorbs 70%, and the thick ascending limb of Henle an additional 20% of the filtered Ca2þ (Fig. 3). The distal tubule and collecting duct reabsorb about 9% and 1%, respectively. Ca2þ reabsorption by the proximal tubule occurs via transcellular and paracellular pathways. Changes in Naþ reabsorption result in coordinate changes in Ca2þ reabsorption by the proximal tubule and the thick ascending limb of Henle. Changes in Naþ and Ca2þ reabsorption are not always in parallel in the distal tubule. Mg2þ is the second most common cation in the intracellular fluid. About 80% of the total serum Mg2þ is filtered through the glomerular membrane. The proximal tubule reabsorbs about 10% to 15% of the filtered Mg2þ (Fig. 3). The bulk (approximately 60%) of the filtered Mg2þ is reabsorbed in the cTAL by passive means driven by the transepithelial voltage through the paracellular pathway (Fig. 3) (12,13). The distal tubule reabsorbs significant amounts of Mg2þ via an active transcellular process. Several hormones and nonhormonal factors influence renal Mg2þ reabsorption to variable extent in the cTAL and distal tubule. In states of dietary magnesium restriction, urinary Mg2þ excretion decreases through the adaptation of magnesium transport

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

in both the cTAL and the distal tubule. Elevation of plasma Mg2þ or Ca2þ concentration is sensed by an extracellular Ca2þ/Mg2þ-sensing receptor located on the peritubular side of cTAL and distal tubule cells and acts to inhibit Mg2þ and Ca2þ reabsorption. Metabolic acidosis, potassium depletion, or phosphate restriction results in diminished Mg2þ reabsorption within the cTAL and distal tubule (13). Phosphate excretion is determined principally by glomerular filtration and by regulated reabsorption in the proximal tubule. All but about 10% of the filtered load of inorganic phosphorus (Pi) is reabsorbed, primarily by the proximal tubule (approximately 80%) and the distal tubule (approximately 10%) (14). A secondary active Pi transport mechanism—the brush-border membrane type IIa Na–Pi cotransporter—is the key player in proximal tubular Pi reabsorption, and PTH is the major regulator of Pi excretion. PTH inhibits Pi reabsorption by the proximal tubule, thereby enhancing urinary Pi excretion. Acidosis, volume expansion, and glucocorticoids also stimulate Pi excretion. In contrast, volume contraction, alkalosis, and growth hormone are known to limit Pi excretion in the urine (15). Bicarbonate Reabsorption/Proton Secretion Normal humans on a Western diet of normal caloric intake will generate approximately 20,000 mEq of acid/day in the form of CO2 through fat and carbohydrate metabolism. The lungs eliminate this CO2. Protein catabolism generates about 50 to 60 mEq/day of inorganic, nonvolatile acids (e.g., sulfuric, phosphoric, or hydrochloric acids) that must be excreted by the kidney. In addition, the kidney must reclaim filtered HCO3 to maintain acid–base balance. HCO3 reabsorption of the filtered load is virtually complete along the nephron under normal conditions (Fig. 3). About 80% of the filtered load is reabsorbed in the proximal tubule in a process critically dependent on Naþ–Hþ exchanger isoform NHE3 and carbonic anhydrase at the apical membrane. Hþ secreted into the lumen in exchange for Naþ combines with filtered HCO3, and converted via the action of carbonic anhydrase into CO2 and H2O. The CO2 freely diffuses across the luminal membrane into the cell, where it is hydrated in the presence of carbonic anhydrase to H2CO3. The intracellular H2CO3 then dissociates into HCO3, which is reabsorbed across the basolateral membrane, and Hþ, which is secreted into the luminal fluid. Thus, the bicarbonate actually reabsorbed is not that which was originally in the filtrate, but the net effect is the same as if this were the case. Because of their interdependence, HCO3 reabsorption generally parallels the rate of proximal tubule Naþ reabsorption. An Hþ-ATPase in the apical membrane of the proximal tubule participates in Naþ-independent HCO3 reabsorption. The thick ascending limb of Henle reabsorbs another 15% of filtered HCO3, by transport mechanisms similar to those operating in the proximal tubule (16). The distal tubule and collecting duct reabsorb the small amount of HCO3 that escapes the more proximal segments (17,18). A number of factors, including extracellular fluid volume, Ang II, aldosterone, and plasma Kþ concentration, regulate HCO3 reabsorption along the nephron. Other bases besides HCO3 may buffer Hþ secreted into the distal tubules, and Hþ may combine with ammonia also secreted by the tubules. The principal non-HCO3 base in the tubular fluid is dibasic sodium phosphate (Na2HPO4), which can accept Hþ to form monobasic sodium phosphate (NaH2PO4). Titratable acidity of the urine refers to the

731

amount of urinary Hþ buffered by bases such as HCO3 and phosphate. It is measured by titrating the urine with strong base until the pH of the plasma from which the filtrate is derived is reached. Under physiologic conditions, about two-thirds of the Hþ to be secreted in the urine is in the form of ammonium salts. Ammonia (NH3) is absent from the plasma and glomerular ultrafiltrate, but is formed, along with glutamic acid, from the hydrolysis of glutamine by the enzyme glutaminase. A further molecule of ammonia arises from the deamination of glutamic acid to form glutaric acid, which is then metabolized. The NH3 so formed passes into the lumen where it combines with secreted Hþ to form NH4þ, which, as a charged molecule, is then trapped in the lumen. The NH4þ is excreted in the urine as ammonium salts of excess anions (e.g., chloride, sulfate, and phosphate). Increasing acid accumulation stimulates production of NH4þ by the tubular cells. Thus, Hþ secretion can be considered as the integration of three processes: reabsorption of filtered HCO3 in the proximal tubule, reabsorption of filtered HCO3 in the distal nephron, and formation of monobasic phosphate and ammonium salts. Accordingly, the total tubular Hþ secretion represents the sum of the amount of HCO3 reabsorbed, the amount of titratable acid, and the amount of NH4þ excreted. Secretion of Organic Anions and Cations The proximal tubule secretes a number of endogenous and exogenous (typically drugs) compounds. Anionic compounds include metabolic products such as bile salts, urate, and oxalate, and commonly used drugs, including furosemide, penicillin, and hydrochlorothiazide. Cationic organic molecules secreted by the proximal tubule include creatinine, dopamine, and epinephrine, as well as atropine, morphine, and other drugs. All organic compounds compete for the same transporter in the proximal tubule, so that high plasma levels of one organic ion can limit the secretion of the others (19–21). A transport system for net transepithelial secretion of various hydrophobic organic anions has been described in the proximal tubule. This tertiary active transport process involves an organic anion/a-ketoglutarate exchange process in the basolateral membrane, Naþ–dicarboxylate cotransporters at both membranes, and an inwardly directed Naþ gradient driving a-ketoglutarate uptake generated and maintained by the basolateral Naþ-Kþ-ATPase. The transport of the organic anion into the cells against its electrochemical gradient occurs in exchange for a-ketoglutarate moving out of the cells down its electrochemical gradient. The outwardly directed gradient for a-ketoglutarate is maintained by metabolism and by transport into the cells by Naþ– dicarboxylate cotransporters. The inward Naþ gradient driving a-ketoglutarate uptake is in turn generated and maintained by the basolateral Naþ-Kþ-ATPase. The basolateral organic acid/a-ketoglutarate exchange process appears to be regulated by peptide hormones, growth factors, and the autonomic nervous system (22,23). Sites and Mechanisms of Diuretic Action A number of diuretic agents and other drugs target specific transport proteins or enzymes to effect their action (Table 1). Osmotic diuretics such as mannitol inhibit fluid reabsorption by altering the osmotic driving forces along the nephron (24). These agents are filtered at the glomerulus and are generally not reabsorbed by the tubules, so that they remain in the tubular lumen to exert an osmotic pressure to oppose

medwedi.ru

732

Part Four: The Urinary System

Table 1 Classes and Mechanisms of Diuretic Actions Class Thiazide diuretics (e.g., hydrochlorothiazide) Loop diuretics (e.g., furosemide) Potassium-sparing diuretics [e.g., (a) amiloride, (b) spironalactone]

Site of action

Transport process inhibited

% Filtered Naþ excreted

Early distal tubule

NaCl cotransporter

5–10

MTAL Collecting ducts

Naþ-Kþ-2Cl cotransporter (a) apical Naþ channels; (b) aldosterone-stimulated transepithelial Naþ transport Opposes osmotic gradient for NaCl reabsorption Naþ-Hþ exchange indirectly

20–25 1–2

Osmotic diuretics (e.g., mannitol)

Proximal tubule, TDL

Carbonic anhydrase inhibitors (e.g., acetazolamide)

Proximal tubule

10 5–10

Abbreviations: MTAL, medullary thick ascending limb of Henle; TDL, thin descending limb of Henle.

water reabsorption. This effect is most prominent in the segments that are constitutively water permeable (i.e., the proximal tubule and the thin descending limb of Henle). Other classes of diuretics act on specific membrane transport proteins or enzymes coupled to salt and water transport. Carbonic anhydrase inhibitors (i.e., acetazolamide) inhibit proximal Naþ reabsorption. HCO3 reabsorption depends to a large extent on Naþ (the Na–H exchanger in the proximal tubule apical membrane) (25,26). This enzyme facilitates the formation of Hþ and HCO3 from CO2 and H2O. About one-third of all proximal tubule Naþ reabsorption is related to this process of HCO3 reabsorption. Carbonic anhydrase inhibitors inhibit only 5% to 10% of the filtered Naþ load, in part because more distal segments, in particular the thick ascending limb, increase Naþ reabsorption when Naþ delivery is increased. Loop diuretics (e.g., furosemide, bumetanide, torsemide, and ethacrynic acid) potently inhibit Naþ absorption by blocking the Na-K-2Cl cotransporter of the apical membrane of the thick ascending limb of Henle (27). This action not only inhibits Naþ reabsorption but also limits the kidney’s ability both to concentrate and to dilute the urine. Loop diuretics promote an increase in Naþ excretion that may reach 25% of the filtered load. Thiazide diuretics (e.g., chorothiazide, metolazone, and hydrochlorothiazide) inhibit Naþ reabsorption by blocking the NaCl cotransport in the apical membrane of the early distal tubule (28). Thiazides also reduce the ability to dilute the urine, but because they do not interrupt the countercurrent multiplication system, they do not impair urinary concentration. Natriuresis with thiazides may approach 5% to 10% of the filtered load. By blocking sequential steps in Naþ reabsorption along the nephron, the combined use of a loop diuretic and a thiazide diuretic results in even greater diuretic and natriuretic effect than either agent alone. Kþ-sparing diuretics act on the late distal tubule and cortical collecting duct and work by either antagonizing aldosterone’s action on the principal cells of the collecting duct (e.g., spironolactone) or by inhibiting apical membrane Naþ channels in these cells (e.g., amiloride and triamterene). Accordingly, these agents produce a natriuresis of only about 3% of the filtered load, but concomitantly inhibit Kþ secretion in the collecting duct and thereby limit urinary Kþ wasting (29–31). The ability of a diuretic to promote urinary Naþ excretion is dependent on the diuretic dose, the amount of Naþ typically reabsorbed by the nephron segment it targets, and the capacity of more distal segments to compensate, by increasing reabsorption, for the excess amounts of Naþ. Most diuretics act at the apical membrane of the tubules to impair Naþ entry mechanisms, so that there is a dosedependent relationship between the rate of presentation of

the diuretic to its site of action and the Naþ absorption it inhibits. Loop diuretics are more potent than thiazide or Kþ-sparing diuretics because they target a segment that reabsorbs much more Naþ. Finally, when counter-regulatory responses of more distal segments are fully activated, as they are in congestive heart failure, for example, a given dose of loop diuretic will provoke less natriuresis than in normal subjects because of increased Naþ reabsorption by the distal tubule and collecting duct. Provided the diuretic dose is constant, these counter-regulatory responses typically lead to the establishment of a new steady-state in which Naþ intake balances Naþ excretion within the first two weeks of diuretic therapy. In general, fluid and electrolyte complications associated with diuretics occur within this adaptive two-week period.

Physiologic Compensation for Nephron Loss Progressive loss of renal function, proteinuria, and glomerulosclerosis has been seen in humans with a variety of renal disorders, even after correction of the primary abnormality. In addition, studies of kidney transplant donors, followed for more than a decade, have shown that, while the overall GFR is maintained, there is an increased incidence of proteinuria and hypertension. The kidney maintains near complete regulation of plasma concentrations of Naþ, Kþ, and plasma osmolality until 75% to 90% of the nephrons are lost. HCO3, Ca2þ, and Pi regulation are maintained adequately until 50% to 70% of the nephrons are lost. For these solutes, excretion is not solely a function of the GFR, but also reflects tubular transport. In contrast, plasma concentrations of creatinine and urea increase progressively as nephrons are lost. According to the intact nephron hypothesis (32), remaining nephrons function as intact units within an otherwise diseased kidney. That is, glomeruli do not filter fluid to nonfunctioning tubules, and normal tubules are nonfunctional in the absence of a corresponding functioning glomeruli. As the number of functioning nephrons becomes fewer, the range of solutes and water over which the kidney can regulate excretion is more limited. In addition, the ability of the kidney to respond rapidly to changes in dietary intake may be limited. These factors predispose patients with renal disease to fluid, electrolyte, and acid–base disturbances. Homeostasis for many solutes and water can be maintained, provided intake is restricted to match the limited excretion. Renal disease tends to be progressive when a critical number of nephrons have been destroyed. Brenner and colleagues (33–35) proposed that, following nephron loss from renal disease, surviving nephrons ‘‘hyperfilter’’ to compensate and normalize single nephron GFR. This hemodynamic change results in glomerular capillary hypertension, which is the most studied and most

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

733

GFR. Such a reduction in urine volume may present a normal adaptive response to hypovolemia, tubular injury, or urinary tract obstruction. Conversely, the absence of oliguria does not necessarily imply normal kidney function. Polyuria, or excessive urination, may be caused by diverse etiologies and may be related to severe underlying disorders. Polyuria related to primary water diuresis may be indicative of primary disorders of water balance (central diabetes insipidus, nephrogenic diabetes insipidus, and psychogenic polydipsia) (37). In these settings, there is either a pathological lack of (central diabetes insipidis) or unresponsiveness to (nephrogenic diabetes insipidus) ADH or pathologic water gluttony (psychogenic polydipsia). The two forms of diabetes insipidus are commonly encountered in surgical settings, where brain injury or surgery, or renal tubule injury from nephrotoxic agents may be present. In contrast, solute diuresis may be caused by electrolytes (e.g., sodium chloride and sodium bicarbonate), organic molecules (e.g., glucose and urea), or both (38), or by exogenous agents (e.g., mannitol and certain radiocontrast agents). These solutes produce an osmotic diuresis. Figure 8 Mechanistic roles of angiotensin II in the progression of chronic kidney disease. Abbreviations: TGF-b, transforming growth factor-b; SNGFR, single nephron GFR.

consistent factor in the progression of CKD. High intracapillary pressures damage the capillary wall and generate powerful proinflammatory signals and growth factors that result in mesangial cell proliferation, excessive extracellular matrix production, the recruitment of T-lymphocytes and macrophages, and ultimately glomerular sclerosis and interstitial fibrosis. Unfortunately, however, these adaptations prove to be maladaptive in that they initiate and perpetuate glomerular injury. This vicious cycle, uninterrupted, may end in kidney failure (36). The pace of this injury is determined by the degree of nephron loss. Glomerular capillary hypertension is mediated in large part by Ang II–dependent mechanisms. Besides its hemodynamic effects, several nonhemodynamic effects of Ang II are also important in this process (Fig. 8).

Clinical Assessment of Renal Function Urine Output The volume of urine can vary widely from day to day, even in healthy individuals, as a result of food and fluid intake and extrarenal fluid losses. The daily volume averages 1.5 L, but after exercise in warm weather, it may fall as low as 500 mL, and after excess fluid intake, it may reach three or more liters. Within a 24-hour period, urine output is less in the early hours, is maximal during the first few hours after rising, and peaks after meals. Measurement of urine volume and of the rate of urine output is useful adjuncts in clinical management of fluid volume and the diagnosis of kidney injury. Because many patients may be unable to void spontaneously, bladder catheterization may be needed to assess accurately the urine volume. Anuria refers to the absence of urine output and is relatively uncommon in clinical practice. When anuria is present, however, complete bilateral urinary obstruction or bilateral cortical necrosis from severe ischemic insults is the most common etiology. Oliguria is commonly defined as a urine volume less that 400 mL/24 hr, and it suggests a reduced

Urinalysis Urine Specific Gravity and Osmolality The specific gravity is the weight of the solution compared to the weight of an equal volume of distilled water and is used as an estimate of urine osmolality. Plasma is 0.8% to 1.0% heavier than water, so that its specific gravity is 1.008 to 1.010. Normal urine specific gravity values range from 1.002 to 1.028. Specific gravity differs from the more accurate measurement of urine osmolality, because it is proportional to both the number and the weight of solute particles present in the solution. Hence, excessive amounts of heavier solutes such as glucose or radiocontrast medium will yield urine specific gravity values disproportionately higher than the true osmolality. In these instances, urine specific gravity can exceed 1.030 even when the urine osmolality is 300 mOsm/kg. Thus a random urine specific gravity is of little value as an index of urinary concentration unless it is correlated with plasma osmolality and/or volume status. Urine osmolality determinations may be helpful in determining whether the kidney’s ability to handle water is appropriate in states where plasma osmolality is abnormal. During hypo-osmolar states, urinary water excretion should be maximal and, hence, urine osmolality should be maximally dilute (Fig. 7). If urine osmolality is not low as predicted in this setting, urinary dilution is impaired. Conversely, if isosmolar urine is detected in the presence of plasma hyperosmolality, urinary concentration is impaired. Urinary pH Urinary pH can vary over a wide range (4.4–8.0) depending on the demands of the body to excreted acid or base. An alkaline urine (pH > 7) is commonly encountered in metabolic alkalosis or when urea-splitting organisms are infecting the urinary tract. Mildly alkaline urine with concomitant hyperchloremic metabolic acidosis may reflect renal tubular acidosis. Proteinuria Under normal conditions, the urine contains only very small amounts of protein ( < 50 mg/24 hr). However, the amount of protein in the urine may be increased after exercise, in pregnancy, and in some persons when standing (orthostatic

medwedi.ru

734

Part Four: The Urinary System

proteinuria). A large amount of protein, particularly if in the nephrotic range ( > 3.5 g/24 hr), is typically indicative of glomerular disease, for which there are many etiologies. However, chronic tubulointerstitial disease, polycystic kidney disease, renal vein thrombosis, and other disorders may also present with significant proteinuria. In addition, protein overproduction such as in multiple myeloma may overwhelm the capacity of the proximal tubule to reabsorb protein and escape into the urine. Pigmenturia The urinary dipstick test for heme detects both hemoglobin and myoglobin. With hematuria, erythrocytes are observed on microscopic examination of the urine, and the dipstick test for heme gives a positive reaction. With hemoglobinuria from massive hemolysis (e.g., major blood transfusion reaction), however, no erythrocytes are apparent in the urine but the dipstick is still positive for heme. Similarly, with myoglobuniria resulting from muscle breakdown (e.g., rhabdomyolysis), the dipstick heme test is reactive, and no erythrocytes are evident in the urine. These possibilities can be distinguished by the appearance of the plasma or urine supernatant (clear in myoglobinuria and pink or red in hemoglobinuria) or by the measured urinary myoglobin or hemoglobin. Glycosuria The proximal tubule has a fixed capacity to reabsorb filtered glucose. When this capacity is exceeded as a consequence of hyperglycemia, increased GFR, or proximal tubule injury, glycosuria results. In individuals on normal carbohydrate loads, glycosuria typically indicates that the patient has diabetes mellitus. In some healthy persons, however, there may also be an abnormal amount of glucose in the urine because of a low threshold for tubular reabsorption, without any disturbance of glucose metabolism. Ketone bodies (acetone and acetoacetic acid) may be present in traces in normal urine, but may be present in larger quantities in severe untreated diabetes and in carbohydrate starvation. Urine Microscopic Examination Examination of the urinary sediment may provide not only information on the presence of an underlying renal disorder but clues as to its specific etiology. White blood cells, particularly as casts, commonly indicate infectious (e.g., pyelonephritis) or inflammatory acute tubulointerstitial nephritis (ATIN) disease. Urinary eosinophils detected by Hansel’s stain may be found in acute interstitial nephritis, but have also been found in several other disorders. Red blood cells may arise from either upper or lower tract bleeding. However, the presence of dysmorphic red blood cells or red blood cell casts in a freshly voided urine sample is much more suggestive of glomerulonephritis. Cellular casts derived from the renal tubules may indicate injury, and are commonly present in acute tubular necrosis (ATN). Finally a number of crystals may be apparent in the urine. Calcium oxalate dihydrate crystals typically are colorless squares resembling an envelope. In some cases, they result from increased calcium related to disorders of calcium metabolism. These crystals can also be seen in cases of ethylene glycol intoxication. If seen in large numbers in the urine of a patient with AKF, this diagnosis should be entertained. Uric acid crystals may be seen in gout and uric acid stone formation. They appear and often occur in a diamond shape, but may also be prism or hexagon shaped, or simply as amorphous material. Amorphous phosphates and urates cannot

be distinguished by routine microscopy. Struvite crystals (magnesium ammonium phosphate and triple phosphate) usually appear as colorless, three-dimensional, prism-like crystals (‘‘coffin lids’’). Urinary tract infection with ureasepositive bacteria promotes struvite crystalluria by raising urine pH and increasing free ammonia.

Renal Function Tests Serum Creatinine Concentration and GFR Creatinine is a product of creatine metabolism in muscle. A less significant source of creatinine is dietary meat intake. Creatinine generation therefore directly correlates with muscle mass. Individuals with larger muscle mass, such as a young, muscular males have greater creatinine production; at a given level of glomerular filtration, such individuals will have higher levels of serum creatinine. Individuals with smaller muscle mass (e.g., females, the elderly, malnourished patients with muscle wasting, and patients with chronic liver disease) have lower levels of serum creatinine. In particular, patients with CKD with anorexia, weight loss, and muscle wasting, as well as dietary protein restriction will have serum creatinine levels that underestimate the degree of loss of renal function. Factors that interfere with renal tubular secretion of creatinine or with extrarenal excretion of creatinine also change the relationship of serum creatinine and GFR. Extrarenal elimination of creatinine occurs in the gut by colonic secretion into the lumen followed by its degradation by colonic bacteria. Creatinine clearances by this route vary from 1 to 7 mL/min. Although negligible at near-normal levels of renal function, this becomes a significant fraction of creatinine clearance in severe kidney failure. The relationship between serum creatinine concentration and GFR is valid only in the steady state. In the extreme case in which GFR halts, plasma creatinine will still remain normal for several hours until nonexcreted creatinine has accumulated. The relationship between true GFR and serum creatinine is important to consider. During initial reductions in GFR to about 60 mL/min, enhanced tubular secretion of creatinine maintains serum creatinine levels at near normal levels (Fig. 9). With further reductions in GFR corresponding to plasma creatinine concentrations of 1.5

7.5

Plasma (Cr) (mg/dl)

5.0 2.5 1.0 0

50 100 150 GFR (ml/min)

Figure 9 Correlation between plasma creatinine concentration and glomerular filtration rate (GFR). The amount of creatinine that is filtered (GFR PCr) is equivalent to the amount that is excreted (UCr V). Because creatinine production by skeletal muscle is also relatively constant, creatinine excretion must be constant to maintain equilibrium. Thus, as GFR falls, PCr must increase proportionately to keep the filtration and excretion of creatinine equal to the creatinine production rate.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

to 2.0 mg/dL, however, the tubular secretion of creatinine is saturated, and creatinine concentrations rise proportionate to the fall in GFR. Thus, significant disease progression can occur, while serum creatinine levels remain in the normal or near-normal range. Careful consideration of these factors is needed when attempting to deduce renal functional status from the creatinine level. Two empiric formulae are frequently used to estimate renal function from the serum creatinine level, which are as follows: The Cockroft–Gault equation (39, 40): creatinine clearance (mL/min) ¼ [140age (years)] weight (kg)/72 serum serum Cr (mg/mL) for men, and corrected by a factor of 0.85 for women The MDRD study formula (41): GFR (mL/min per 1.73m2) ¼ 186 (Scr)1.154 (age)0.203 (0.724 if female) (1.210 if African-American), which predicts GFR and not creatinine clearance and takes into consideration race, albumin, and blood urea nitrogen (BUN) levels. Serum creatinine measurements and estimates of creatinine clearance or GFR provide quick and convenient information about renal function. Serial measurements give an idea of the course of disease and the impact of treatment, provided caution is exercised in their interpretation (42). BUN and GFR Like serum creatinine, BUN is excreted by glomerular filtration and tends to vary inversely with GFR. The BUN level is a much less reliable as a marker of GFR than serum creatinine. BUN is greatly influenced by factors other than glomerular filtration. Urea generation is far more variable than creatinine generation: it is elevated with increased protein intake and in states of excessive catabolism—infections, febrile states, and trauma—or decreased during anabolism, as with corticosteroid and tetracycline therapy. Gastrointestinal hemorrhage is of particular clinical importance as a cause of markedly increased urea generation. Conversely, low protein intake, malnutrition, severe liver parenchymal disease, and myxedema are associated with decreased urea generation. Renal handling of urea is more complex than that of creatinine. Urea is freely filtered at the glomerulus, and 35% to 40% of filtered urea is obligatorily reabsorbed in the proximal tubule. Urea is secreted into the tubular lumen in the loop of Henle, and reabsorbed in the medullary collecting duct via urea transporters that are regulated by vasopressin. The state of hydration, RBF rate, and urine flow rates all influence the rate of urea excretion. In states of dehydration or volume depletion, only 35% to 40% of filtered urea appears in the urine, because of increased proximal reabsorption, while in states of volume repletion or diuresis, this proportion may be higher than 80%. Despite these limitations, analysis of BUN can be clinically helpful. A high BUN: serum creatinine ratio ( >20) is suggestive of volume depletion (prerenal azotemia), if renal ischemia, obstruction, or excessive urea generation has been excluded. Clinical Measurement of GFR The GFR is measured by assaying the clearance of creatinine or exogenously administered substances. The most frequently used exogenous substances used in clinical practice are iodinated iothalamate and technetium-labeled diethylenetriaminepentaacetic acid, but several nonradionuclide compounds (e.g., nonradioactive iothalamate) and nonionic iodinated contrast media (e.g., iohexol and iopental) are also used in some instances. The most commonly used method

735

for the routine measurement of GFR is the determination of creatinine clearance. A timed collection of urine is required, which must necessarily be accurate, because an incomplete collection can lead to an underestimation of the GFR. The adequacy of the urine collection can be judged by measuring the total creatinine excretion of the patient, which should approximate 10 to 15 mg/kg/day in women and 15 to 20 mg/kg/day in men. The creatinine clearance is calculated according to the following equations: Assumption: Amount filtered ¼ Amount excreted PCr GFR ¼ UCr V UCr V GFR ¼ PCr (PCr and UCr are the serum and urinary concentrations of creatinine, respectively, and V is the urine flow rate.) Creatinine clearances always overestimate GFR, because they do not take into account the contribution of tubular secretion of creatinine to urinary creatinine excretion. The contribution of tubular secretion is negligible at normal levels of renal function and serum creatinine; creatinine clearance overestimation of GFR in this setting is in the range of 5% to 10% approximately. Drugs that block the tubular secretion of creatinine (e.g., cimetidine) can produce an elevated plasma creatinine concentration without affecting GFR. With severe degrees of kidney failure, however, creatinine clearance overestimation of GFR may be in excess of 100%. Because creatinine clearances markedly overestimate GFR in advanced stages of renal failure, while urea clearances underestimate GFR, the mean of creatinine and urea clearances may sometimes be used to estimate more accurately GFR in advanced stages of renal failure. Clinical Estimation of RBF The measurement of RBF is often required in the management of the post–renal transplant patient and occasionally in the evaluation of renovascular disorders. The renal clearance of substances excreted by both glomerular filtration and tubular secretion is used to estimate effective renal plasma flow. Most commonly used are the radionuclides mercaptoacetyltriglycine, chelated to technetium, and iodohippurate. Doppler ultrasonographic methods are also used to estimate RBF.

ACUTE KIDNEY FAILURE AKF is a common clinical problem associated with considerable morbidity and mortality. AKF is primarily a hospital-acquired disease, occurring in approximately 5% of hospitalized patients, 5% to 15% of patients following coronary artery bypass grafting, and up to 25% of patients in an intensive care unit (ICU). Mortality in AKF is greatly influenced by comorbid events. The high mortality associated with AKF is well described and reaches 65% in ICU patients (43–45). Of the patients who experience AKF requiring dialysis, 5% to 30% will require long-term dialysis therapy, without renal recovery (46). Importantly, AKF is an independent risk factor for morbidity and mortality. AKF is associated with a 5.5 odds ratio of dying (47). Thus AKF should not be viewed solely as a treatable complication of a serious illness. AKF can be defined by a decrease in the GFR that occurs over days to weeks. Commonly used definitions

medwedi.ru

736

Part Four: The Urinary System

include an increase of serum creatinine > 0.5 mg/dL over baseline, an increase of serum creatinine over 50% of baseline, or a reduction in creatinine clearance of 50%. However, no standardization of the definition of AKF has been adopted, and the true magnitude of the problem is likely unrecognized. The GFR can decline rapidly with only small changes in the serum creatinine. Understanding the significance of the relationship between early declines in GFR and changes in serum creatinine may help in the early recognition and treatment of AKF.

Classification of AKF It is useful to subcategorize renal disorders based on clinical and pathologic features. AKF has traditionally been divided into prerenal, renal, or postrenal according to the etiology of the insult (Table 2). Distinguishing these three causes of kidney failure is important to the diagnostic and therapeutic strategy. The majority of hospital-acquired AKF is secondary to prerenal azotemia and ischemic or toxic ATN, an intrinsic renal cause of AKF.

Prerenal Azotemia Prerenal azotemia accounts for approximately 70% of AKF cases in hospitalized patients (48,49). Prerenal azotemia is a normal physiologic response to decreased renal perfusion and rapidly resolves with restoration of glomerular ultrafiltration pressure. The decrease in glomerular ultrafiltration pressure may be secondary to a true reduction in circulating blood volume from bleeding or cutaneous, GI, or urinary losses, or from renovascular disease or dysfunction (Fig. 10). Cirrhosis, congestive heart failure, and sepsis produce effective circulating volume depletion with similar hypoperfusion of the glomerulus. Mean arterial pressures (MAP) below 80 to 90 mmHg will induce a fall in RBF. If the fall in the MAP is promptly corrected, renal parenchymal damage does not typically ensue. If the prerenal state is allowed to continue, however, renal pathology may occur, and ATN can develop. Sustained reduction in RBF results in cellular hypoxia leading to pathologic tubular changes and ATN. Prerenal azotemia and ischemic ATN are opposite extremes of a continuum related to renal hypoperfusion: the

Table 2 Common Causes of Acute Kidney Failure: Urinary Findings and Confirmatory Tests Cause of acute kidney failure Prerenal azotemia Volume depletion

Typical urinalysis No cellular elements or proteinuria

Rapid resolution of ARF with correction of renal hypoperfusion Invasive monitoring—CVP or PCWP

Hematuria without dysmorphic red blood cells, casts, or proteinuria

Abdominal X-ray

Decreased EABV NSAIDs ACE-I or ARB Postrenal azotemia Abdominal or flank pain Palpable bladder Enlarged prostate Nephrolithiasis Urinary frequency, oliguria, or anuria Intrinsic renal azotemia Acute tubulointerstitial nephritis

Hemolysis

Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura Glomerulonephritis

Radiocontrast Rhabdomyolysis

Tumor lysis syndrome Ischemia

Confirmation

Renal ultrasound IVP Retrograde pyelography

WBCs Urine eosinophils White cell cast Red blood cells Rarely red blood cell casts Urine supernatant is pink and heme þ Hemoglobinuria No red blood cells Urine red blood cells Heme þ

Proteinuria Red blood cell casts White blood cell casts May have granular, coarse, or tubule epithelial cell casts Urine supernatant Heme þ without red blood cells Myoglobinuria Urate crystals Muddy brown granular, coarse, or tubule epithelial cell casts

Systemic eosinophilia Renal biopsy Biopsy of skin rash Elevated serum Kþ, PO4, uric acid, LDH Hypocalcemia Peripheral smear with fragmented red blood cells Renal biopsy Peripheral smear with schistocytes and fragmented red cells Thrombocytopenia Renal biopsy Serum antibody test Temporal relationship to the contrast infusion Elevated serum myoglobin, creatine phosphokinase, PO4, uric acid, Kþ Hypocalcemia Elevated serum Kþ, PO4, uric acid Decreased serum Ca2þ Clinical assessment and urine findings usually sufficient

Abbreviations: EABV, effective arterial blood volume; NSAIDs, nonsteroidal anti-inflammatory drugs; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; LDH, lactate dehydrogenase; PCWP, pulmonary capillary wedge pressure; CVP, central venous pressure.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

737

and certain surgical patients. Obstruction can occur at any level of the urinary collecting system from intratubular to bladder outlet obstruction. Common causes of intrinsic tubular obstruction include nephrolithiasis, blood clots, myoglobinuria, hyperuricosuria, drug crystallization, tumors, and papillary necrosis (Table 2). External retroperitoneal disease processes can cause ureteral obstruction including retroperitoneal fibrosis or abscess, cancers, and retroperitoneal hemorrhage. Accidental surgical ligation of a ureter is also a possibility. The most common cause of postrenal azotemia arising from the lower urinary tract is bladder outlet obstruction, usually from prostatic disease or neurogenic bladder. With timely resolution of the obstruction, there is often complete resolution of the azotemia.

Intrinsic Renal Azotemia Figure 10 Pathogenesis and etiologies of prerenal azotemia. Abbreviations: ARB, angiotensin II receptor blocker; ACEI, angiotensin converting enzyme inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs; CO, cardiac output; SVR, systemic vascular resistance; EBV, effective blood volume; ECF, extracellular fluid; CHF, congestive heart failure; MI, myocardial infarction.

severity of the insult will dictate the progression from the normal physiologic response to ischemic tubular damage. Less commonly, prerenal AKF can result from diseases of renal microvasculature, including inflammatory (glomerulonephritis and vasculitis) and noninflammatory insults (malignant hypertension) of the vessel wall, thrombotic microangiopathies, and, rarely, hyperviscosity syndromes (Fig. 10). In many instances, the renal hypoperfusion caused by these disorders progresses from prerenal azotemia to ischemic ATN. Common causes of prerenal azotemia are listed in Table 2 and Fig. 10. The common mechanism leading to a decrease in the GFR is a reduction in the circulating arterial blood volume in the renal vasculature. A reduction in the systemic arterial volume or perfusion pressure causes afferent arteriolar dilation, with concomitant increases in the vasomotor tone of the efferent arteriole. This is accomplished through activation of the renin-angiotensin-aldosterone system. Release of norepinephrine and ADH from the sympathetic nervous system completes the basic neural–hormonal attempt to restore the MAP and circulating blood volume (50,51). The early recognition and correction of prerenal azotemia is paramount in preventing progression to tubular damage from prolonged renal hypoperfusion. In patients with severe hepatic disease, splanchnic vasodilation and reductions in systemic vascular resistance lead to prerenal azotemia. In these patients, however, the decline in GFR is commonly masked by low production rates of urea (from liver disease) and creatinine (from reduced muscle mass). As a result, plasma creatinine concentrations and BUN levels may remain in the ‘‘normal’’ range despite progressive kidney failure. Hepatorenal syndrome is an otherwise unexplained development of AKF in patients with advanced hepatic disease. Mortality is high, unless hepatic function can be improved, as with liver transplantation.

Postrenal Azotemia Postrenal azotemia is defined as AKF secondary to urinary tract obstruction. Postrenal azotemia accounts for less than 5% of all cases of AKF, though the frequency is more common in specific patient populations such as elderly men

The most common cause of renal azotemia is a direct ischemic insult to the kidney usually resulting in ATN. Other common injuries encountered in the surgical patient include pigmented nephropathy from myoglobinuria or hemoglobinuria, direct nephrotoxic insults from medications and intravenous iodinated contrast, and acute interstitial nephritis (Table 2) typically from medications. ATN accounts for approximately 75% of AKF episodes among hospitalized patients. As discussed earlier, ATN differs from prerenal azotemia in that renal hypoperfusion has been severe enough to injure renal parenchymal cells, particularly tubule epithelium, and AKF does not resolve immediately after restoration of RBF as it does in prerenal azotemia. If the ischemic episode is prolonged, cortical necrosis can ensue and lead to irreversible renal failure. Hemoglobinuria and myoglobinuria can lead to direct tubular injury through a pigmented cast nephropathy. Extensive trauma resulting in rhabdomyolysis or mismatched blood transfusions leading to massive hemolysis are two common causes of the pigmented nephropathies. In either circumstance, the myoglobinuria or hemoglobinuria results in accumulation of pigmented cast in the proximal tubular lumen and direct injury to tubular cells. With the proximal tubular obstruction, there is also renal vasoconstriction, and both processes contribute to the decline in GFR (52). Renal atheroembolic disease, often following invasive arterial procedures, can also produce AKF (53). Livido reticularis, peripheral and urinary eosinophilia, hypocomplementemia, and thrombocytopenia are classic clinical manifestations of this disorder. Intravenous iodinated contrast promotes an intense renal vasoconstriction and direct tubular cell injury leading to a prerenal azotemia then progression to an intrinsic renal azotemia and ATN. Patients with preexisting renal disease and/or diabetes mellitus are at greatest risk for developing contrast nephropathy (54,55). The temporal relationship between the decrease in GFR and the exposure to the contrast is the most helpful clinical clue to this diagnosis: decrements in GFR are typically seen within 24 to 48 hours of radiocontrast exposure. Recovery from radiocontrast nephropathy often occurs within two weeks of the insult. Nephrotoxic injury from medications can be caused by a wide array of insults that promote direct tubular damage or injury related to renal vasoconstriction. Common offending agents are the aminoglycoside antibiotics, which can cause a decrease in GFR through multiple mechanisms, including renal vasoconstriction, alterations in glomerular capillary permeability, and direct tubular cell disruption (56). Amphotericin and its lipid-based derivatives cause similar changes in the kidney (57–59). Some medications

medwedi.ru

738

Part Four: The Urinary System

can cause a change in the serum creatinine with or without an acute change in the GFR; two classic examples of this are cimetidine and trimethoprim-sulfamethoxazole. Both drugs can block the secretion of creatinine, resulting in an elevated serum creatinine level despite preserved GFR. However, both can also cause an interstitial nephritis and a true renal azotemia (60–62). ATN can be divided into initiation, maintenance, and recovery phases, the pathophysiology and management of which differs (63). In the initiation phase (hours to days), ischemic injury is evolving. GFR falls because of impaired RBF and glomerular ultrafiltration pressure, disrupted integrity of tubule epithelium with backleak of glomerular filtrate, and obstructed urine flow due to intratubular formation of casts comprising detached epithelial cells and cellular debris. The terminal portion of the proximal tubule and the mTAL are the nephron segments most vulnerable to ischemic injury. Both have high rates of active solute transport and oxygen consumption. Furthermore, both of these segments are located in the outer medulla, an ischemic zone even under basal condition by virtue of the unique countercurrent arrangement of the medullary vasculature. Importantly renal injury can be limited by restoration of RBF during this period. In the maintenance phase (typically 1–2 weeks), during which epithelial cell injury is established, GFR stabilizes at its nadir despite correction of systemic hemodynamics, and uremic complications may arise. In the recovery phase, kidney function is restored to a degree by regeneration and/or repair of kidney parenchymal cells.

Diagnosis In distinguishing prerenal, renal, and postrenal azotemia, the most useful early clinical indices include the timing of the changes in serum creatinine, BUN, and urinary volume following in relation to other clinical events, the urine specific gravity, examination of the urinary sediment, and assessment of the urine electrolytes. In certain circumstances, evaluation of the urine osmolality and special stains for urine eosinophils are valuable. In determining hemodynamic changes from cardiac failure or sepsis, central hemodynamic monitoring is often incorporated into the evaluation of critically ill patients with renal failure. Hourly urine output can be used as a measure of adequate renal perfusion. In a prerenal state with inadequate glomerular perfusion pressure, the urine output will often drop to less than 0.5 mL/kg of body weight. Oliguria, defined by a urine output of less than 400 mL/day, is present in about 50% of AKF cases. In the evaluation of prerenal azotemia, urine indices are predictable based on the effect of norepinephrine, ADH, and Ang II on urine flow rate and sodium and water reabsorption. The BUN-to-creatinine ratio is usually elevated to greater than 20:1 in a prerenal state; it is common to see an elevated BUN in the face of a normal creatinine early in the coarse of glomerular hypoperfusion. In differentiating prerenal azotemia from ATN, the urine sodium and specific gravity are often used, the typical clinical indices are illustrated in Table 3. However, urine sodium, osmolality, and specific gravity, as well as the serum BUN-to-creatinine ratio are relatively insensitive measures for the differential diagnosis of AKF. An alternative method of evaluating the kidneys ability to handle sodium is the fractional excretion of sodium (FENa). The FENa has been adopted to help differentiate, in the oliguric patient, prerenal azotemia from intrinsic renal failure. The FENa utilizes the urine sodium and creatinine

Table 3 Urinary Indices in the Differential Diagnosis of Acute Kidney Failure Index

Normal value

Prerenal azotemia

Acute tubular necrosis

Obstruction

Urinary 0.5 mL/kg/ 0.5 mL/kg/ Variable Variable volume hr hr Urine specific 1.003–1.025 1.020 1.010 Variable gravity Urinary Variable < 20 mEq/L > 40 mEq/L < 40 mEq/L sodium early > 40 mEq/ L late < 1% < 1% > 3% < 1% early FENaa > 3% late BUN: 10:1 > 20:1 Variable Variable creatinine a

Fena ð%Þ ¼ U=PNa U=PCr 100

Abbreviation: BUN, blood urea nitrogen.

with simultaneous measurements of serum sodium and creatinine (Table 3). In the normal kidney, the FENa is less than 1%, indicating that less than 1% of the filtered sodium is excreted in the urine. The same is true in prerenal azotemia in which case the tubules are sodium avid in the face of volume depletion and suppressed atrial natriuretic peptide (ANP) release. In contrast, intrinsic kidney failure from ischemic or nephrotoxic injury typically has a FENa greater than 1% (64,65). However, many confounding factors and conditions can alter the FENa much like the other urine indices mentioned above, including saline infusion, diuretics, or bicarbonaturia rendering it of limited value in the differential diagnosis of AKF (66). The urinalysis can often give clues to the underlying etiology of AKF. Hemoglobinuria and myoglobinuria, as well as infectious causes of AKF are easily identifiable by a positive test for large blood on the urine dipstick, despite minimal or no red blood cells in the urine on microscopic exam. A large amount of protein ( > 3 g/day) is suggestive of an intrinsic kidney, and typically glomerular, injury. Pyuria and white blood cell casts can be secondary to infection, glomerulonephritis, or ATIN; with the latter, urine eosinophilia may be present but is not a specific finding restricted to ATIN. Red blood cell casts suggest glomerulonephritis. ATN is associated with tubular epithelial cells, epithelial cell casts, and coarse granular cast, whereas prerenal azotemia is associated with fine granular and hyaline casts (Table 2).

Prevention Given the limited therapeutic options currently available, a clear understanding of which patients are at risk is the best defense against AKF. Patients at the greatest risk for AKF are those with preexisting kidney disease and diabetes mellitus with or without overt signs of nephropathy. It is also paramount to understand the relationship of measured serum creatinine to GFR. A 75-year-old woman who weighs 55 kg with a ‘‘normal’’ serum creatinine of 1.0 mg/dL actually has a calculated GFR of 44 mL/min and moderate kidney failure. Despite her preexisting kidney disease, it is relatively common for a patient like this with a normal serum creatinine value to receive intravenous iodinated contrast or other nephrotoxic agents. A common theme in the prevention of AKF is fluid resuscitation. Often presurgical patients are placed on

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

restricted fluid intake prior to procedures. Adequate intravenous hydration is important especially if intravenous contrast will be used during radiographic studies, if bowel preparation is needed, or if insensible losses are high from bowel surgery or in burn patients. Medications that interfere with the autoregulation of renal perfusion, such as amphotericin, nonsteroidal anti-inflammatory medications, or ACE inhibitors put the patient at a greater risk for prerenal azotemia and ATN.

Specific Measures N-Acetylcysteine Newer means of protecting against specific injuries such as contrast-induced nephropathy have become commonplace in the clinical setting. Intravenous contrast can cause AKF by a direct reduction in glomerular perfusion pressure through hemodynamic changes and by exerting a direct toxic effect on the tubular epithelial cells. A proposed mechanism of this action is mediated through the production of oxygen free-radical species. Animal models have shown that free-radical scavengers can reduce the oxidant injury in the kidney and prevent AKF (67). N-acetylcysteine is an antioxidant that promotes renal vasodilation by increasing the bioavailability of NO. Based on these properties and the fact that it is generally well tolerated, N-acetylcysteine has been used for the prevention of AKF from radiocontrast agents in high-risk individuals. Several small clinical trials have shown that its administration prior to radiocontrast significantly reduces the rise in serum creatinine values from baseline as compared to the placebo group (68,69). However, whether N-acetylcysteine prevents severe AKF or the need for dialysis has not been determined. In patients at high risk for radiocontrast nephropathy, it is reasonable to provide N-acetylcysteine given the low potential for harm from the therapy. The most important factors in limiting kidney injury from radiocontrast agents, however, still appear to be providing adequate hydration and minimizing contrast dose (70–73). At the time of this writing, there is no evidence to advocate its routine use in preventing other forms of AKF. There is currently no consensus on its benefit in preventing contrast-induced nephropathy. Low-Dose Dopamine In normal human subjects, low-dose (1–3 mg/kg/min) dopamine increases RBF and GFR and acts on the proximal tubule to promote natriuresis. Numerous studies have used lowdose dopamine either to treat or to prevent AKF resulting from radiocontrast administration, repair of aortic aneurysms, orthotopic liver transplantation, unilateral nephrectomy, renal transplantation, and chemotherapy with interferon (INF) (74,75). However, prevention trials have been small, inadequately randomized, and of limited statistical power. Furthermore, low-dose dopamine has been associated with potentially harmful side effects, including tachyarrhythmias, myocardial ischemia, decreased mesenteric blood flow, and suppressed T-cell function (74–76). In diabetic patients treated with low-dose dopamine to prevent radiocontrast nephropathy, there is an associated increase risk of AKF (77). Therefore, it is generally recommended that the use of low-dose dopamine for the prevention of AKF be abandoned. Low-Dose Fenoldopam Fenoldopam is a pure dopamine type-1 receptor agonist that has similar renal vascular hemodynamic effects as

739

dopamine, but without the a- and b-adrenergic stimulation. Animal data have shown that a pure dopamine-1 receptor agonist has the potential to reduce the renal injury induced by hypoperfusion of the kidney. In a hypovolemic dog model, infusion studies with fenoldopam mesylate, a selective dopamine-1 receptor agonist, increases cortical and medullary blood flow and preserves GFR (78). The limited clinical trials available suggest that fenoldopam reduces the occurrence of AKF associated with radiocontrast and aortic aneurysm repairs (79,80). However, there is limited clinical data and, as yet, no large randomized controlled trials to support its indiscriminate use. Diuretics Furosemide is a loop diuretic and vasodilator that may decrease oxygen consumption in the loop of Henle by inhibiting secondary active transport of sodium (69,81). By increasing urine volume, furosemide may reduce intratubular obstruction from cellular debris and reduce backleak of filtrate. This combination of actions in the kidney may lessen the ischemic potential. Clinical studies have shown furosemide to be ineffective in preventing AKF after cardiac surgery (82), but it may actually increase the risk of AKF in patients given radiocontrast (81). Mannitol acts as an osmotic diuretic that can scavenge free radicals. It may have some benefit when added to solutions to preserve organs for transplantation and to protect against AKF associated with rhabdomyolysis (83,84). Like furosemide, mannitol may actually worsen AKF associated with radiocontrast (77). Atrial Natriuretic Peptide ANP increases GFR by causing vasodilatation of the afferent arteriole and constriction of the efferent arteriole, and inhibits tubular sodium reabsorption. Two studies have examined the efficacy of ANP for the prevention of renal dysfunction in renal transplant recipients and found no benefit (85,86). Otherwise, most studies have focused on the treatment of established AKF and found little therapeutic benefit (87). As with low-dose dopamine, furosemide, and mannitol, ANP infusion has been associated with an increased risk of AKF with radiocontrast administration in diabetics (77). Management Management is directed at prevention of ATN in high-risk patients and control or uremic complications with established ATN until spontaneous recovery of renal function (63). In the early management of AKF, quick recognition of the renal insult and resolution of the potential cause are most important. If the patient is volume depleted, volume resuscitation is indicated. It is widely held that the degree of renal injury may be minimized in patients with optimized effective intravascular volume. However, the definition of adequate volume expansion has yet to be determined. Also open to question is the type of fluid that should be utilized. Randomized trials evaluating colloids versus crystalloids have revealed conflicting results (88). Albumin is frequently used for volume expansion, with no clinical evidence of its benefit in critically ill patients. A recent meta-analysis of studies involving albumin use in critically ill patients suggested that albumin infusion actually increases mortality (89). Medications that may inhibit the kidney’s normal ability to autoregulate glomerular filtration pressure, such as ACE inhibitors and Ang II receptor blockers, should be discontinued if possible when AKF is recognized.

medwedi.ru

740

Part Four: The Urinary System

Current evidence suggests that nonoliguric renal failure has a better prognosis than oliguric renal failure. In the nonoliguric patient, volume overload and the potential for prolonged ventilation and poor wound healing are reduced. Volume resuscitation and nutritional support have less potential for complications. Clinical trials have attempted to elucidate if converting oliguric AKF to nonoliguric AKF with pharmacologic measures improves outcome. The use of high doses of loop diuretics early in AKF is common. The potential beneficial effects of loop diuretics include the reduction of intratubular obstruction with cellular debris and limiting oxygen consumption in tubular cells, and thus potentially reducing ischemic tubular damage. The available evidence suggests that using loop diuretics as a continuous infusion will produce a better diuresis than intermittent bolus administration and help manage volume overload (38). While diuretics may simplify patient management, there is no evidence that converting oliguric AKF to nonoliguric AKF with loop diuretics improves renal recovery or patient survival (90,91). Fluid, Acid–Base, and Electrolyte Abnormalities Oliguric AKF is often complicated by derangements in electrolytes and fluid balance. In AKF, water intoxication with resultant hyponatremia is a potential complication if hypotonic solutions are used. If the hyponatremia is significant enough, exacerbation of the effects of uremia on the central nervous system can occur. The critically ill patient is often catabolic; so acute hyperkalemia can arise. Serum potassium levels near 6 mEq/L require therapy, particularly if the patient is symptomatic with muscle cramps or weakness, or has electrocardiographic changes that may be a harbinger of life-threatening cardiac arrhythmias. Immediate temporizing maneuvers should include glucose and insulin infusion (start with 25 g, 50% glucose solution plus 10 U of intravenous regular insulin). If the patient is acidotic, intravenous sodium bicarbonate can be infused. Both the insulin and the bicarbonate are temporary measures to redistribute the potassium into the intracellular space, not to eliminate the potassium from the body. After institution of the acute temporizing measures, attempts should be made to eliminate the total body potassium overload. Ion exchange resins such as sodium polystyrene sulfonate (Kayexalate, 30–60 g given orally or rectally) are effective. Kayexalate acts in the intestinal tract through cationic exchange to increase potassium elimination in the stool. In the postoperative patient, it is advisable to administer sorbitol with Kayexalate to prevent constipation and promote catharsis, especially if the patient is receiving narcotic pain medications. The management of AKF can also be complicated by hypocalcemia, hypermagnesemia, and hyperphosphatemia. Early in AKF, phosphorous levels will rise. The goal of the acute management of hyperphosphatemia is to keep the calcium phosphate product less than 70. As the calcium phosphate product rises above 70, the risk of cardiac conduction abnormalities, vascular endothelial damage, and central nervous system injury increases. Phosphorous binders (calcium carbonate, aluminum hydroxide, or cationic polymers such as sevalamer hydrochloride) given with meals can be used to control dietary phosphorous absorption. The phosphate content of enteral feedings or total peripheral nutrition should be reduced. Hypocalcemia is a rare complication of AKF except in the setting of tumor lysis syndrome or rhabdomyolysis, and ionized calcium levels should be monitored in critically ill patients.

AKF is associated with loss of renal acid–base regulation typically resulting in metabolic acidosis. Sodium bicarbonate infusion can help alleviate the metabolic acidosis, but often the associated volume and sodium load is rate limiting. Common solutions for bicarbonate infusion include D5W with 3 amps NaHCO3, 0.25% NaCl with 2 amps NaHCO3, or 0.45% NaCl with 1 amp NaHCO3. It is important to keep the bicarbonate infusion as near to an isotonic solution as possible to limit infusion of excessive Na. In the face of an organic acid such as lactic acid or ketoacids, bicarbonate infusion will produce carbon dioxide, and in a postoperative patient with poor ventilation, this may produce a respiratory acidosis. Frequently the oliguric patient will be unable to tolerate the volume load associated with sodium bicarbonate infusions, so that dialysis is necessary to control the acidosis.

CHRONIC KIDNEY DISEASE CKD results from the loss of normal renal function arising from any of a wide variety of causes. Table 4 lists the major causes of chronic kidney failure. Whatever the original cause of renal disease, whether primarily glomerular or primarily nonglomerular, CKD tends to worsen because of a progressive loss of functioning nephrons. These processes result in the gradual development of a clinical state of uremia. The rate of progression of renal failure may or may not be predictable depending on the nature of the primary renal disease; however several known ‘‘progression’’ factors—hypertension, tubulointerstitial nephritis, proteinuria, hyperlipidemia, tobacco smoking—are known to influence strongly the process. There is a close correlation between clinical symptoms and the GFR; the GFR has therefore become the clinical marker of the stage of CKD. A clear understanding of the relationship of serum creatinine and GFR is needed so as to make right deductions about the degree of CKD.

Uremic Toxins Traditionally, the uremic state has been viewed as a ‘‘toxic’’ state, the result of retained ‘‘uremic toxins’’ that would otherwise be excreted by normally functioning kidneys. This view received strong support from the early successes of dialysis therapy in improving uremic symptoms, presumably by the removal of such toxins (92–94). More recently, the uremic state has also been viewed as a chronic inflammatory condition. There are ongoing efforts to identify the triggers for this inflammation, its mediators and consequences. Uremic ‘‘retention’’ of toxic compounds or solutes are arbitrarily classified according to molecular weight into low Table 4 Causes of Chronic Kidney Failure Glomerular diseases—primary (idiopathic) and secondary Tubulointerstitial diseases Diabetes mellitus Hypertension Obstructive nephropathies Renal cystic diseases Renovascular diseases Renal involvement in multisystem diseases, including diabetes mellitus and hypertension Renal involvement in congenital and heredofamilial diseases Renal injury secondary to medications, chemicals, drug abuse, radiation, heavy metal

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

(MW < 300 Da; e.g., urea, uric acid, xanthine, and methylguanidine), middle [e.g., b2-microglobuni, complement factor D, leptin, interleukin-6 (IL-6)], and high-molecular-weight molecules (MW > 500 Da). These are further subdivided into non–protein-bound and protein-bound molecules. Dialysis procedures clear the non–protein-bound, low-molecularweight solutes predominantly by diffusive and convective forces. There is some clearance of larger molecules by hemodialysis filters, by the process of adhesion. Middlemolecular-weight-molecules are hypothesized to contribute to some of the features of uremia, though specific toxins have not yet been identified (95). Laboratory abnormalities associated with retention of middle-molecular-weight-molecules include disturbances of lymphocyte proliferation, cell growth, interleukin production, osteoblast mitogenesis, and apolipoprotein (apo) A-1 secretion, while clinical abnormalities such as anorexia, polyneuropathy, and carpal tunnel syndrome may occur (96). In addition, a number of proteinbound molecules have been suggested to account for some of uremic toxicity.

Pathophysiology of CKD Glomerular and tubulointerstitial scarring characterize the renal histopathology of patients with chronic renal failure. These lesions often are similar in appearance, regardless of the nature of the primary renal disease. Decreased glomerular filtration is the result of atubular glomeruli and of increased backleak of filtrate through denuded tubular basement membranes. In all forms of renal disease, both the degree of interstitial infiltration with inflammatory cells and the interstitial fibrosis predict subsequent renal failure more accurately than does glomerular scarring or sclerosis. Interstitial fibrosis therefore represents the final common pathway of response to injury in the kidney, irrespective of the nature of the initial injury (97). Tubulointerstitial fibrosis is characterized by tubular atrophy, tubular dilatation, increased interstitial matrix deposition, and loss of capillaries. Matrix accumulating in the interstitium contains proteins such as collagens l, lll, and V, fibronectin, and laminin. An important phenomenon is the appearance of myofibroblasts, highly fibrogenic and contractile cells that may originate from tubular cells by ‘‘transdifferentiation.’’ Tubulointerstitial fibrosis is initiated by tubular epithelial cell injury and activation, and by the recruitment of inflammatory cells such as CD4þ lymphocytes and macrophages into the interstitium (98,99). Some of the factors known to activate tubular cells include proteinuria, cytokines, ischemia, and reactive oxygen species. Activated tubular cells release cytokines such as macrophage chemoattractant protein-1 (MCP-1), regulated on activation, normal T expressed and secreted (RANTES), TGF-b1 and PDGF, and cell adhesion molecules such as integrins, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, and osteopontin that attract more inflammatory cells into the interstitium. After this initial phase of acute interstitial inflammation, a second phase of inflammatory matrix synthesis ensues with the local release of profibrogenic cytokines and tissue inhibitors of matrix metalloproteinase (TIMPs). Finally, the process of persistent matrix synthesis occurs resulting from sustained action of profibrogenic cytokines and epithelial-mesenchymal transformation (transdifferentiation). The appearance of myofibroblasts in the interstitium is the single worst prognostic predictor of later development of interstitial fibrosis (100,101). The origin of these cells is uncertain. There is evidence to suggest that they are derived from resident interstitial fibroblasts, pericytes, or

741

from transdifferentiated tubular epithelial cells. The major issue awaiting clarification is the mechanism whereby the process of scarring, once initiated, continues even after the original or primary insult is in remission. Of the cytokines produced by resident glomerular, tubular, and interstitial cells, as well as by infiltrating lymphocytes, macrophages, fibroblasts, and myofibroblasts, TGF-b1 is the predominant fibrogenic molecule involved in tubulointerstitial scarring (99). TGF-b1 production is stimulated by a variety of vasoactive compounds (e.g., Ang II and endothelin-1), circulating peptides, shear stress, and ischemia. It promotes transcription of genes encoding matrix components, inhibits matrix-degrading enzymes, promotes the evolution of myofibroblasts, and enhances chemotaxis of fibroblasts and monocytes. The fibrinolytic system (and plasmin) plays a major role in degrading fibrin and extracellular matrix, and its inhibition by plasminogen activator inhibitor (PAI) impairs the repair process while promoting interstitial fibrosis. TGF-b1 stimulates and upregulates the gene expression of PAI. Downstream signaling pathways for TGF-b1 have not been fully characterized. TGF-b1 is thought to bind to the type II receptor on the cell membrane, which in turn phosphorylates the type I receptor. This complex activates Smad proteins and the mitogen-activated kinase pathway (99). In addition to glomerular capillary hypertension, significant, positive correlation is observed between the magnitude of proteinuria and the degree of tubulointerstitial fibrosis. Proteinuria itself is toxic to the renal tubules. Candidate plasma proteins that may be toxic to renal epithelial cells are albumin, complement components, transferrin, and lipoproteins.

Clinical Course of CKD Given the large renal functional reserve and slow progression of most renal diseases, most patients remain asymptomatic until 85% to 90% of renal function is lost. Thus, in its early stages, CKD is a subclinical condition, and represents a loss of renal reserve. Excretory and other functions are well maintained, despite a diminution of GFR up to 50%. The usual clinical laboratory parameters—BUN and serum creatinine—may remain in the normal range. Kidney insufficiency ensues at more severe reductions in GFR. Azotemia, impaired concentrating ability resulting in nocturia, anemia, and an easy vulnerability of the kidneys to hemodynamic insults such as volume (salt) depletion, dehydration, hypotension, congestive heart failure, the administration of ACE inhibitors, NSAIDs, and to catabolic drugs and potassium loads, diagnosed as acute-on-chronic renal failure. The stage of clinically overt kidney failure is characterized by severe anemia, fluid overload, hypertension, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyponatremia, isosthenuria, and hyperchloremia. Hyperkalemia still is generally absent unless the patient is receiving large loads of potassium. At end stage, in uremia, there is a constellation of signs and symptoms that involve all the systems—the uremic syndrome (Table 5). Ideally, the full-blown uremic syndrome should not occur, because renal replacement therapy with dialysis or transplantation has already been initiated. The National Kidney Foundation published ‘‘Clinical Practice Guidelines for Evaluation, Classification, and Stratification of Chronic Kidney Disease’’ in 2002 (102). In this scheme, CKD is defined as (i) kidney damage for more than three months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by either (a) pathologic abnormalities or (b) markers of kidney damage, including abnormalities in the

medwedi.ru

742

Part Four: The Urinary System

Table 5 Uremic Manifestations System

Clinical manifestations

Cardiovascular

Hypertension Pericarditis Anorexia Nausea, vomiting Encephalopathy Peripheral neuropathy Anemia Platelet dysfunction Insulin resistance Hyperlipidemia Decreased fertility Renal osteodystrophy Myopathy Uremic arthropathy

Gastrointestinal Neurologic Hematologic Endocrine

Musculoskeletal

composition of the blood or urine, or abnormalities in imaging tests; and (ii) GFR < 60 mL/min per 1.73 m2 for more than three months, with or without kidney damage. These guidelines propose specific functional stages of CKD (Table 6) and clinical action plans to pursue depending on the stage.

Clinical Manifestations of CKD Gastrointestinal System Gastrointestinal symptoms occur frequently and are prominent in CKD (103) (Table 5). Most common among these are anorexia, nausea vomiting, metallic taste, hiccups, and diarrhea. Additional complications include stomatitis, gastritis, duodenitis, esophagitis, parotitis, and gastroparesis.

such that hyperkalemia occurs earlier and with more severity in the course of progressive renal failure. These conditions, in particular diabetic nephropathy, are mostly associated with the syndrome of hyporenninemic hypoaldosteronism. Table 7 lists some of the conditions that are commonly associated with the syndrome of hyporenninemic hypoaldosteronism as well as additional clinical situations that predispose to hyperkalemia in CKD. Patients with CKD are at risk of hyperkalemia when these conditions are present. Hyperkalemia needs close monitoring and anticipation in these patients. With mild-to-moderate degrees of CKD, there is a limitation of sodium excretory capacity despite adaptive compensatory sodium wasting in surviving nephrons. This is manifested mainly as hypertension. Only in severe kidney failure (GFR < 10–15 mL/min) does edema become evident, provided there are no other causes of edema such as nephrotic syndrome or congestive heart failure. Peripheral pitting edema is the most common finding. But with the often coexisting hypertension and left ventricular hypertrophy (LVH) and dysfunction, pulmonary congestion and edema can supervene. Treatment is by dietary sodium restriction (usually 2 g daily), along with the judicious use of diuretics. With moderate CKD, thiazide diuretics are no longer effective. Because of resistance to diuretic therapy, increasing doses of the loop diuretics may be needed before the required dose is determined. Because of their short duration of action (4–6 hours), loop diuretics often need to be dosed frequently. Torsemide, a long-acting (24 hours) loop diuretic, is more convenient and is effective in a once-a-day regimen. The diuretic effect of loop diuretic therapy may be augmented by concomitant administration of hydrochlorothiazide or metalozone. Table 7 Clinical Conditions That Predispose to Hyperkalemia

Acid–Base, Fluid, and Electrolyte Abnormalities Metabolic acidosis occurs uniformly in CKD. At GFRs in the 20 to 50 mL/min range, there is usually already a mild drop in serum bicarbonate concentration. The main cause of the metabolic acidosis is decreased ammonia synthesis by the surviving nephrons, which occurs despite the fact that there is an adaptive increase in ammonia synthesis per nephron. This diminution of total ammoniagenesis limits the capacity to excrete acid loads. Sustained metabolic acidosis has a number of potential adverse effects for which the clinical evidence remains controversial. In CKD, limitation of the capacity to excrete potassium results in hyperkalemia. Hyperkalemia is usually mild (5.0–5.5 mEq/L), even at GFRs as low as 20 mL/min, and requires only dietary potassium restriction and close monitoring as management. With worsening renal failure, however, hyperkalemia becomes more severe and requires definitive treatment. However, there are a number of diseases that are associated with a tendency to hyperkalemia, Table 6 Stages of Chronic Kidney Disease Stage 1 2 3 4 5

Description

GFR (mL/min/1.73 m2)

Kidney damage with normal or increased GFR Kidney damage with mild decrease in GFR Moderate decrease in GFR Severe decrease in GFR Kidney failure

> 90 60–89 30–59 15–29 < 15/dialysis

Abbreviation: GFR, glomerular filtration rate.

Diseases Diabetic nephropathy Obstructive nephropathy Sickle cell nephropathy Tubulointerstitial nephropathies Systemic lupus erythematosis Renal transplantation Elderly patients Amyloidosis Drugs Potassium chloride, including Kþ-containing salt substitutes Angiotensin-converting enzyme inhibitor; angiotensin II receptor blocker Nonsteroidal anti-inflammatory drugs Spironolactone Amiloride and triamterene b-Adrenergic antagonists Digoxin, particularly in digoxin toxicity Heparin Cyclosporine and tacrolimus Trimethoprim and pentamidine Succinylcholine Arginine chloride Mannitol Glycerol Other clinical conditions Acidosis Hyperglycemia Volume depletion Internal bleeding, especially gastrointestinal bleeding Tissue damage, especially rhabdomyolysis

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

This potent combination should be used with caution because it can rapidly be complicated by volume depletion and acuteon-chronic renal failure, as well as severe hypokalemia. With progressive CKD, there is the loss of the capacity to dilute or concentrate urine, termed isosthenuria. The individual is prone to excessive and inappropriate water loss and therefore hypernatremia, if water intake is restricted or if the patient is unable to have access to water. Conversely excessive water intake or injudicious administration of hypotonic solutions readily leads to water excess and hyponatremia. Elderly patients are particularly prone to these complications.

Abnormalities of Calcium, Phosphate, and Bone Metabolism Several alterations of calcium, phosphate, and bone metabolism occur in CKD. The major bone pathologic lesions are described as uremic osteodystrophy. Modifications of this primary bone lesion arise from the different therapeutic interventions and nutritional factors, as a result of which there is a spectrum of bone abnormalities in uremia. Bone disease is mainly attributed to severe secondary hyperparathyroidism, which is characterized by elevated serum PTH levels and parathyroid gland hyperplasia and hypertrophy. Several possible ‘‘primary’’ abnormalities have been postulated as responsible for secondary hyperparathyroidism: phosphate retention, hypocalcemia, deficiency of 1,25 dihydroxy vitamin D (calcitriol), parathyroid gland resistance to calcitriol and calcium, and bone resistance to PTH (104). The principal skeletal and extraskeletal consequences of secondary and tertiary hyperparathyroidism in the CKD patient are presented in Table 8. Calcitriol deficiency arises not only as a result of loss of nephrons but also by inhibition of its synthetic enzyme, 1a-hydroxylase, by uremic toxins (105). Calcitriol exerts its biologic action by binding to the vitamin D receptor (VDR), the hormone–receptor complex then binding to vitamin D response elements in the DNA. In uremia, parathyroid resistance to calcitriol results in part from reduced expression of VDR as well as altered binding of the hormone– receptor complex to DNA. Similarly, there is parathyroid resistance to calcium associated with reduced expression of the calcium-sensing receptor. Initial diffuse parathyroid hyperplasia and hypertrophy may transform to nodularity of the gland with monoclonal cellular expansion. Allelic loss at loci on chromosome 11 at the location of the MEN-1 gene, which is associated with primary parathyroid hyperplasia, has been described (106). Other mechanisms

Table 8 Clinical Consequences of Secondary/Tertiary Hyperparathyroidism Skeletal High turn-over bone disease

Osteitis fibrosa Mixed osteodystrophy Bone pain Osteopenia Fractures

Extraskeletal Metastatic calcifications (skin, myocardial, vascular, valvular, pulmonary) Bone marrow fibrosis (resistance to erythropoietin) Myocardial hypertrophy and fibrosis Encephalopathy, electroencephalographic changes Peripheral neuropathy Hypertension, hyperlipidemia, glucose intolerance

743

of this transformation include somatic mutation and decreased expression of cell cycle regulatory genes. The principles of treatment and prevention of secondary hyperparathyroidism and renal osteodystrophy derive from the following goals: (i) control of hyperphosphatemia— dietary phosphate restriction: phosphate binders to be taken with meals; (ii) replacement therapy of calcitriol with synthetic 1,25 dihydroxy vitamin D or any of its new analogs; (iii) modulation of dialysate calcium for more effective control of PTH levels; (iv) close monitoring of calcium, phosphate, and PTH levels; and (v) parathyroid surgery or percutaneous ablation for uncontrollable ‘‘tertiary’’ hyperparathyroidism. Ablation can be accomplished by total or subtotal parathyroidectomy, total parathyroidectomy with immediate autotransplantation, total parathyroidectomy with cryopreservation of parathyroid tissue, ultrasoundguided percutaneous ethanol injection directly into the enlarged glands, or ultrasound-guided percutaneous calcitriol injection directly into the enlarged glands. Calcific uremic arteriolopathy (calciphylaxis) is a rare condition involving the calcification of subcutaneous vessels and infarction of the adjacent skin and tissues. Its pathogenesis is not understood, and morbidity and mortality are very high (107,108). Risk factors may include: high calcium phosphate products, severe hyperparathyroidism, adynamic bone disease, excessive doses of calcitriol, hypercoagulable state, and intravenous iron therapy. Debridement of necrotic tissue, control of infection, skin grafting, and hyperbaric oxygen therapy may aid management.

Uremic Arthropathy Monoarticular and polyarticular arthritides and tendinitis are common in uremic patients (108). The causes of articular disease may be classified into crystal-related, related to secondary hyperparathyroidism, related to dialysis therapy (particularly b2-microglobulin amyloid-associated arthropathy), related to underlying or concomitant systemic diseases, and septic arthritis. Diagnosis usually requires diagnostic joint aspiration. Commonly used arthritic medications such as NSAIDs and colchicine need to be avoided or carefully dosed.

Anemia of CKD Anemia is a leading cause of morbidity and mortality in CKD (109). Erythropoietin deficiency is the most common cause of anemia in these patients. Adequate treatment of anemia is essential in CKD, in particular, because of its role in the development of LVH with all of its attendant complications. Recombinant human erythropoietin (r-HuEPO and epoietin) is the mainstay of anemia management, not only in end-stage kidney disease but also in the predialysis patient. Adequate treatment of anemia has been shown to improve morbidity, quality of life, and mortality. It is therefore essential to screen vigorously for anemia and treat in a cost-efficient manner in view of the high cost of this medication. Iron deficiency is the most common cause of a lack of response (resistance) to erythropoietin action, so that iron status needs to be closely monitored and corrected. Other mechanisms that contribute to anemia include blood loss, shortened RBC survival, inhibition of erythropoiesis by uremic toxins, chronic inflammation, and severe hyperparathyroidism. Subcutaneous administration of r-HuEPO is usually more efficient than intravenous, and target hemoglobin levels are about 12 to 13 g/dL. The uremic patient requires iron administration to maintain adequate erythropoiesis

medwedi.ru

744

Part Four: The Urinary System

and responsiveness to epoietin. Transferrin saturations need to be maintained above 20%. A level of transferrin saturation below 20% is considered to represent iron deficiency in this setting. This level of transferrin saturation is often difficult to achieve with oral iron agents, so that intravenous administration is the preferred route (110). Guidelines for intravenous iron therapy and monitoring of iron stores and availability are provided in the DOQI guidelines of National Kidney Foundation (111).

Cardiovascular Complications There is excessive cardiovascular morbidity and mortality in uremia (112,113). In the most recent report of the United States Renal Data System (USRDS) data, all-cause mortality in patients with end-stage kidney disease is about 20% per year; of these, cardiovascular complications account for approximately 50%. Among cardiovascular complications, atherosclerotic events (acute myocardial infarction, ischemic cardiomyopathy, peripheral vascular disease, cerebral infarctions, and mesenteric infarctions) account for at least 50% of deaths. The proportion of atherosclerotic events is even greater if account is taken of the ischemic component of congestive heart failure and sudden death. Cardiac death rates are 10 to 15 times higher in uremic patients than in agematched controls of both genders. Twenty to thirty percent of cardiac deaths are due to myocardial infarctions. Besides the high prevalence rates of coronary artery disease in uremic patients, there is a high fatality rate in these patients, possibly a reflection of poor coronary perfusion reserve. Mortality rates of first myocardial infarctions are higher and of recurrent myocardial infarctions even more so. There is a higher rate of restenosis after PTCA. These data suggest that uremia further exaggerates the risks of coronary artery disease (112,113). Atherosclerosis in uremic patients is thus particularly severe and aggressive. Although there is controversy whether it progresses at an accelerated pace, the term ‘‘accelerated atherogenesis or atherosclerosis’’ is commonly used to describe this phenomenon. The use of these terms is best reserved, for the present, for the observation that atherogenesis is noted at a very early age in uremic patients. More than 80% of young chronic dialysis patients (age 20–30 years) already have severe and progressive coronary artery calcifications as detected by electron beam computed tomography. In the 20 to 40 years age group, coronary artery disease rates are up to 40 times the background population (112,113). There is evidence that the uremic state per se and not dialysis is the major causative factor in accelerated atherosclerosis. Incidence rates and age at first myocardial infarction are similar in predialysis and end-stage kidney disease (ESKD) patients. Nearly 40% of patients have coronary artery disease and congestive heart disease at the start of dialysis. Some of these observations may be attributed to the high incidence of diabetes, and the older age of patients in the ESKD population. LVH and Uremic Cardiomyopathy LVH and an increased left ventricular mass index are highly prevalent in CKD and ESKD patients (114). In the general population and in uremic patients, LVH is the strongest predictor of adverse cardiovascular events. In the general population, vigorous control of hypertension and the use of ACE inhibitors result in a decline in LVH and cardiovascular morbidity. Unfortunately LVH is frequently underdiagnosed, and hypertension is inadequately treated in CKD and ESKD. Both concentric and eccentric LVH occur in combination in

Figure 11 Risk factors for cardiovascular disease in chronic kidney disease and ESKD patients. Abbreviations: CKD, chronic kidney disease; ESKD, end-stage kidney disease.

CKD. Concentric LVH is mainly secondary to hypertension and aortic stenosis; remodeling of the arterial tree with arterial dilatation, wall thickening, and stiffening also results in pressure overload and concentric hypertrophy. On the other hand, volume overload results in eccentric hypertrophy with enlargement of the left ventricular chamber (Fig. 11). The three main factors contributing to volume overload are sodium and water excess, anemia, and the arterio-venous (A-V) access. Myocardial cells are overloaded and have an increased rate of energy expenditure in the presence of impaired coronary circulation and diminished coronary reserve resulting in myocardial cell death. Abnormal induction of proto-oncogenes, which promote and regulate cell proliferation and differentiation, and activation of growth factors that stimulate the proliferation and activity of cardiac fibroblasts result in cardiomyopathy and myocardial fibrosis: a rapid increase in collagen synthesis and extracellular matrix. Myocardial fibrosis is more marked in pressure overload than in volume overload and is favored by factors such as senescence, ischemia, catecholamines, Ang II, and aldosterone. Other factors such as endothelin, PTH, and sympathetic nerve discharge contribute to myocardial fibrosis. Delayed relaxation resulting from slower uptake of calcium by the sarcoplasmic reticulum contributes to diastolic dysfunction and arrhythmias, which are also favored by conduction abnormalities resulting from myocardial fibrosis and hypertrophy. In ESKD patients without preexisting cardiac disease, systolic function is usually well preserved; diastolic function is usually abnormal as a result of LV stiffness and delayed relaxation. Diastolic dysfunction is characterized by marked sensitivity to changes in left ventricular volume. A small increase in LV volume can cause pulmonary congestion, while a small decrement can lead to systolic hypotension and hemodynamic instability. Coronary Artery Disease The prevalence of ischemic heart disease in ESKD patients on chronic hemodialysis is 10 to 20 times that in the general population (115). According to the USRDS, 42% of chronic

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

hemodialysis patients have had an acute myocardial infarction or a coronary revascularization procedure: 20% of cardiovascular deaths in ESKD patients is due to acute myocardial infarction, the excessive risk being highest in the elderly and diabetics. In addition to traditional risk factors, a number of uremia-specific risk factors contribute to coronary atherosclerosis and myocardial ischemia (116) (Fig. 11). In nonuremic patients with suspected myocardial damage, serum levels of myoglobin, creatinine kinase (CK)MB, and troponins are reliable markers for early diagnosis and risk stratification. In chronic hemodialysis patients, there is a high prevalence of silent myocardial ischemia, significant coronary artery disease occurring in 30% to 50% of asymptomatic or mildly symptomatic patients (115). Thus, symptoms of angina pectoris are unreliable. Conversely, because of small-vessel disease and microcirculatory dysfunction, 25% of hemodialysis patients with angina pectoris have no significant stenosis of epicardial coronary arteries. Electrocardiographic findings are often confounded by nonspecific changes due to LVH, electrolyte abnormalities, and uremic pericarditis. Noninvasive ECG stress testing is limited by nonspecific baseline ECG changes, poor exercise tolerance, and excessive hypertension during exercise. Both exercise thallium scintigraphy and pharmacologic stress testing have poor sensitivity and specificity. Dobutamine stress echocardiography is independent of exercise tolerance, and appears to be the most valuable noninvasive test currently available. Coronary angiography is therefore frequently indicated, but with careful consideration of attendant risks. The CKD patient, especially if advanced, is at high risk of contrast nephropathy and acute-on-chronic kidney failure that may require dialysis. Dialysis patients are also at risk of volume overload, pulmonary edema, and bleeding complications. Revascularization Procedures There is a high complication rate associated with coronary bypass surgery. Complications include arrhythmias, myocardial infarction, low-output congestive heart failure, bleeding, and infection. Preoperative risk factors include older age, emergency surgery, LVH and dysfunction, myocardial and coronary calcification, and New York Heart Association class IV. Long-term outcome in dialysis patients undergoing coronary artery bypass surgery is poor. According to the USRDS, in dialysis patients who underwent bypass surgery between 1978 and 1995, five-year survival was 26.5% compared with 90% in nonuremic patients. Balloon angioplasty (PTCA) in dialysis patients is characterized by higher complication rates as well as high rates of recurrent ischemia, myocardial infarction, restenosis, and death (117,118). The lesions are more complex and diffuse; there is extensive vascular calcification and small vessel disease; vessel diameters are smaller; there is more multivessel involvement; there is a higher proportion of diabetes mellitus and hypercoaguability. New techniques may offer particular benefit in these complicated patients, such as coronary artery stenting, newer antiplatelet therapies—the thienopyridines and glycoprotein IIb/IIIa-receptor antagonists—rotational atherectomies, and brachytherapy (117,118). Hypertension It is established that hypertension is a major risk factor for cardiovascular disease in the general population. There is an extremely high incidence of hypertension in CKD (119). Even when hypertension is not currently present, there

745

may have been a prior history with the fall in blood pressure coinciding with the development of severe left ventricular systolic dysfunction. After adjusting for age, diabetes mellitus, ischemic heart disease, hemoglobin, and albumin level, each 10 mmHg rise in MAP was independently associated with a progressive increase in concentric LVH, development of de novo congestive heart failure, and new-onset ischemic heart disease (119). Thus hypertension is a major risk factor for the development of cardiac disease in CKD. Impaired coronary perfusion coupled with ventricular hypertrophy leads to a vicious cycle of impaired left ventricular contraction, left ventricular dilatation, progressive alteration of left ventricular geometry, and systolic dysfunction. Vigorous treatment of hypertension is advocated, and the guidelines for target blood pressure as well as for recommended choice of medications are under intense study. No single class of antihypertensive medication is superior to the other in dialysis patients. Pericarditis Before the advent of chronic dialysis therapy, uremic pericarditis was an agonal development in the course of the disease. With chronic dialysis, uremic pericarditis is less common and is treatable. It however remains a significant cause of morbidity and mortality in CKD. In dialysis patients, uremic pericarditis is associated with inadequate dialysis often in relation to a dysfunctioning vascular access or poor compliance with dialysis prescriptions (120). Pericarditis also frequently occurs in hypercatabolic states such as severe infections, postsurgery. Volume overload has been proposed as a risk factor. Clinical presentation is highly variable and most importantly the patient may be asymptomatic. Dialysis patients with pericarditis often present with fluid retention, an increasing difficulty with fluid removal (ultrafiltration) during dialysis treatments and hypotension. Pleural effusions often accompany uremic pericarditis, considered to be part of a diffuse serositis. The pericardial fluid is exudative and frequently hemorrhagic with a lot of organized fibrin; the fluid is often loculated. Uremic pericarditis is usually successfully treated with intensified dialysis. Pericarditis occasionally occurs in patients who are considered to be adequately dialyzed. This appears to be a dialysis-associated pericarditis, for which heparin used in dialysis anticoagulation may be a risk factor. Much less commonly, a constrictive pericarditis occurs. The mainstays of therapy are a high index of suspicion, intensified dialysis for uremic pericarditis, and close monitoring. Patients with dialysis-associated pericarditis do not respond well to intensive dialysis. Heparin should not be administered with dialysis. NSAIDs or steroids are not effective. Pericardiotomy or pericardiectomy is indicated for the persistent or enlarging effusion or at the earliest sign of hemodynamic compromise (120). Other causes of pericarditis should be in the differential diagnosis—viral, bacterial, and mycobacterial infections, autoimmune diseases, malignancies, and drugs. Lower Extremity PAOD Peripheral arterial occlusive disease (PAOD) is a major cause of morbidity and mortality in end-stage renal disease patients on dialysis (121). In ESKD patients, PAOD confers additional risks for hospitalizations, death within six months of the initiation of chronic dialysis, and death following a myocardial infarction, and poor outcomes following renal transplantation—prolonged hospitalizations, poor allograft survival, and increased mortality rates. The incidence of

medwedi.ru

746

Part Four: The Urinary System

nontraumatic lower extremity amputations after renal transplantation is 10 times higher in ESKD patients than in nonESKD patients even after correction for diabetes mellitus. Lower extremity amputation is the most common vascular complication following renal transplantation. Septicemia secondary to PAOD is one of the leading causes of death among ESKD patients. Risk factors for PAOD include advancing age, diabetes mellitus, hypertension, hyperlipidemia, smoking (tobacco), coronary artery disease as well as numerous novel, nontraditional atherosclerosis risk factors. Vascular calcification is very common. With ‘‘noncritical ischemia,’’ patients are either asymptomatic or present with claudication. With more advanced disease, ‘‘critical stenosis,’’ patients present with rest pain, ischemic ulceration, and gangrene. Diagnostic testing needs to be performed early because history and physical examination are not reliable. Because of heavily calcified peripheral arteries, ankle brachial index may be falsely negative. Other noninvasive screening tests such as toe brachial index, transcutaneous partial pressure of oxygen measurements, and toe pulse volume recording are not affected by lower leg arterial calcifications. Digital arterial calcifications occur in ESKD patients, and this may interfere with the toe brachial, and toe pulse volume tests. Duplex scanning, conventional angiographic studies, and, more recently, peripheral magnetic resonance angiography and CO2 angiography are alternative tests in these settings. Because a high proportion of patients progress to critical stenosis and require surgical intervention, preventive and conservative measures should be vigorously pursued (121). Uremia-Associated Immune Deficiency The uremic state is associated with an immunodeficiency state, the mechanisms of which await full elucidation. This immune abnormality is characterized by a chronic state of activation of all the key components of the immune system—T-cell, B-cell, monocyte/macrophage, and polymorphonuclear neutrophil systems—which paradoxically result in immune deficiency (122). The abnormalities occur early in the predialysis stage and are not reversed by dialysis. Therefore, it is postulated that this abnormally activated immune state is triggered by metabolic derangements resulting from uremia or by nondialyzable ‘‘uremic toxins.’’ Additional factors contributing to the immunodeficiency include malnutrition, vitamin deficiencies, anemia, use of drugs such as intravenous iron especially in the presence of iron overload, and vitamin D, known for its immunosuppressive activity, and hemodialysis therapy especially when bioincompatible dialyzer membranes are used. In summary, in uremia, T-lymphocytes exist in a state of activation but exhibit impaired response capacity; B-lymphocytes are in an activation state but are not capable of sustaining an adequate antibody response; monocytes are activated and produce abnormally high levels of interleukin 1 (IL-1), IL-6, and tumor necrosis factor-a (TNF-a), while polymorphonuclear neutrophils are activated, with increased generation of reactive oxygen species and the increased release of their cytoplasmic proteases. CKD patients are susceptible to a high frequency of bacterial, viral (including hepatitis B and C), and mycobacterial infections, and may exhibit cutaneous anergy. Abnormalities of Coagulation A bleeding tendency is the most common abnormality in uremia (123). Numerous laboratory abnormalities of coagulation have been described in uremia, but platelet dysfunction appears to be the most dominant defect. The bleeding

diathesis improves with dialysis, suggesting that retained dialyzable compounds or toxins may play an important role. Minor or major epistaxis, hematuria, menorrhagia, melena, retroperitoneal hemorrhage, and hemorrhagic pleural or pericardial effusions may be encountered. There is a diminution in number and binding affinity of the platelet membrane glycoprotein receptors llb and llla. Possible mediators of the bleeding diathesis include NO, cAMP, urea, phenols, and guanidinosuccinic acid. Altered blood rheology secondary to a low hematocrit may also contribute to bleeding. CKD appears to be a risk factor for postoperative bleeding in patients undergoing coronary artery bypass graft surgery. Even mild levels of renal impairment were associated with increased risk for postoperative bleeding: patients with a GFR of 40 mL/min or less had six times the odds of postoperative bleeding than patients with a GFR greater than 100 mL/min (124). Thrombosis is uncommon in uremia. However, thrombosis occurs frequently in dialysis A-V grafts as well as in the coronary and cerebrovascular circulations (125). Risk factors for thrombosis include smoking, trauma, immobilization, thrombocytosis, antiphospholipid antibodies, resistance to activated protein C (the factor V Leiden mutation), and hyperhomocysteinemia. Abnormalities of Carbohydrate and Lipid Metabolism Hypertriglyceridemia and hypercholesterolemia with decreased HDL levels and elevated Lp(a) levels are common in ESKD patients (126,127). Hyperinsulinemia is secondary to reduced renal catabolism of insulin and insulin resistance (128). As renal failure progresses, insulin requirements fall. Failure to recognize this can result in severe hypoglycemic episodes. Oral hypoglycemics are prone to cause hypoglycemia. Additional abnormalities include altered peripheral glucose utilization. Neurologic Complications Neurologic complications in uremia are a common cause of morbidity and mortality (129–131). The central nervous system as well as peripheral and autonomic nervous systems are affected. Uremic encephalopathy describes central nervous system dysfunction secondary to chronic renal failure. Differential diagnosis includes electrolyte derangements, particularly of sodium and calcium, drug toxicities, hypertensive disorders, ischemic cerebrovascular syndromes, sepsis, and coexisting hepatic neurologic or other multisystemic diseases. Dialysis dementia is a severe, fatal neurologic complication of dialysis first noted in epidemic form and characterized by difficulties of speech with rapid progression and deterioration and death occurring within months of diagnosis (132). There is strong evidence that dialysis dementia is associated with aluminum exposure and toxicity. This devastating complication is now rare and has been largely controlled by the use of reverse osmosis (RO) in deionization of dialysis water. Dialysis disequilibrium syndrome is a complication of hemodialysis comprising headaches, nausea, vomiting, muscle cramps, tremors disorientation, and seizures during hemodialysis, possibly related to rapid fluxes of urea or other solutes and/or disturbances of brain intracellular pH (133). Uremic peripheral neuropathy is usually distal, symmetric, and mixed (sensory and motor) (134). Autonomic neuropathy is characterized by loss of baroreceptor sensitivity resulting in postural hypotension, hypotension during dialysis unresponsive to volume repletion, paroxysmal

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

hypertension during dialysis, arrhythmias, gastroparesis and other GI motility problems, and sexual dysfunction (135).

Management of Progressive CKD There is currently no convenient, inexpensive method of measuring progression of renal failure. Serial creatinine measurements are unreliable because creatinine levels do not rise until renal failure is quite advanced. The reciprocal of serum creatinine or logarithm of serum creatinine over time has a more linear relationship with GFR, and these are sometimes used, but intermittent estimations of GFR with creatinine clearance measurements or other methods are often required. The mainstays of management include the assessment of severity and stage of renal failure; renoprotection—monitoring and control of progression factors; control of complications, including appropriate drug dosing; and timely recognition of the need to initiate renal replacement therapy (97) (Tables 9 and 10). All of these goals require effort to inform and educate patient and family of the nature of disease and benefits of adherence to the treatment plan.

747

Table 10 Indications for the Initiation of Chronic Dialysis Absolute indications Progressive advanced chronic kidney failure with: Pericarditis/pericardial effusions Severe encephalopathy—confusion, asterexis, coma, myoclonus Severe, difficult-to-control hypertension Refractory volume overload, anasarca, pulmonary congestion and edema Intractable nausea Bleeding diathesis Malnutrition BUN levels > 100 mg/dL (if primarily reflective of reduced GFR) Serum creatinine levels > 10 mg/dL Relative indications Somnolence (daytime) Inability to concentrate Poor memory Restless leg syndrome Anorexia, nausea, vomiting, weight loss Pruritus Increased vulnerability to infection Depression Abbreviations: BUN, blood urea nitrogen; GFR, glomerular filtration rate.

Diagnostic Use of Renal Imaging in CKD Diagnostic imaging may be of value in the diagnosis and management of CKD (136–138). Renal ultrasonography is an integral part of the evaluation of chronic renal failure and is now available in many renal clinics. The renal ultrasound is used to assess (i) renal size, position, and number; (ii) parenchymal disease (echogenicity); (iii) obstruction; (iv) tumors, cysts, inflammation, and abscesses; (v) trauma; (vi) renovascular diseases; (vii) abnormalities of the transplanted kidney; (viii) nephrocalcinosis; and (ix) in ultrasoundguided interventional procedures. Computed tomography (CT) scanning is used in evaluation of (i) renal masses, cysts, inflammation, and cysts; (ii) obstruction and site of obstruction; (iii) perinephric hematomas, abscesses, or other collections; and (iv) renal stones and nonopaque filling defects. Magnetic resonance imaging provides additional anatomic information in the evaluation of renal diseases. MR arteriography is now the diagnostic test of choice in the evaluation of renal artery stenosis in many centers. MRvenograms are also useful in detecting renal vein thrombosis.

Perioperative Management of the CKD Patient Because of their limited capacity to maintain fluid, electrolyte, and acid–base homeostasis, CKD and ESKD patients experience increased perioperative morbidity and mortality Table 9 Management of Chronic Kidney Disease Control of hypertension, with attention to evidence-based optimum Blood pressure reduction and choice of antihypertensive agent Dietary restrictions—phosphate, sodium, potassium, protein, lipid, and fluid Glycemic control in diabetics Control of: Anemia Hyperparathyroidism Dyslipidemia Hyperhomocysteinemia Increased oxidant stress Attention to atherosclerosis, coronary artery and peripheral vascular disease, and left ventricular hypertrophy Timely recognition of need to initiate renal replacement therapy Education of patient regarding treatment modalities and early planning of dialysis access

rates compared to patients with normal renal function (139,140). In CKD and ESKD patients, cardiac arrhythmias and sepsis are the most frequent causes of perioperative mortality. ESKD patient who undergo cardiac surgery tends to require longer postoperative vasopressor support, mechanical ventilation, and ICU and hospitalization stays than patients who do not have kidney disease (141). Meticulous evaluation and management is required in the perioperative period to avoid acute and often catastrophic clinical problems. Previously undetected cardiac or pulmonary disease must be identified and compensated for or corrected in the preoperative period. Preoperative testing may be necessary in patients with cardiac risk factors. The patient must be adequately dialyzed, preferably receiving hemodialysis within 12 to 24 hours of the operative procedure. In the case of CAPD or CCPD, dialysis can generally continue until called to the operating room, at which time the peritoneal cavity is drained. Plasma electrolyte levels, in particular potassium concentrations, must be optimized before surgery, particularly because electrolyte fluxes can be problematic during anesthesia. Preoperative hyperkalemia in ESKD patients is common (142) and can be temporarily improved by the intravenous administration of an insulin–dextrose combination or bicarbonate, and polystyrene-binding resins or dialysis can remove excess stores of potassium. CKD and ESKD patients commonly experience preoperative and intraoperative hypertension. With few exceptions, CKD and ESKD patients with chronic hypertension should continue antihypertensive drug therapy throughout the surgical period. Transdermally administered clonidine two to three days before surgery or intravenously administered agents can potentially substitute for oral agents that cannot be given intravenously. If future vascular access grafting is contemplated, intravenous line placement and blood draws should be avoided in a patient’s nondominant arm. Anesthetics have multiple effects on the renal microcirculation and the release of certain hormones. The volatile anesthetic drugs (e.g., halothane) can reduce cardiac output and blood pressure resulting in glomerular hypoperfusion and prerenal azotemia. The inhaled anesthetics do not appear to directly alter renal autoregulation (143). Renal

medwedi.ru

748

Part Four: The Urinary System

hypoperfusion from volatile anesthetics and increased ADH release associated with surgical procedures may result in intraoperative oliguria. However, in the absence of surgical manipulation, anesthetics are not associated with increased ADH release (144). In addition, halothane and enflurane have been shown to increase renin levels in sodiumdepleted animals (145). Preoperative hydration with normal saline attenuates the prerenal azotemia, and the release of ADH and renin in these clinical settings. Whether inhalation anesthetics cause direct nephrotoxicity is controversial. However, a concentrating defect in the kidney, which can lead to polyuria with dilute urine and associated hypernatremia, has been described with the metabolism of anesthetics such as methoxyflurane, enflurane, and sevoflurane to fluoride (146–149). Patients with CKD have been reported to be at increased risk for worsening renal dysfunction after enflurane inhalation (150). However, there is no evidence that fluoride levels are increased in patients with depressed GFR’s in this circumstance, presumably because of bone uptake of the metabolite. Halothane and isoflurane are not known to be nephrotoxins (151). CKD reduces the clearance of long-acting nondepolarizing muscle relaxants (e.g., pancuronium). The duration of action of vecuronium is unpredictable (152). The clearance of atracurium and mivacurium is not affected by a low GFR, and these agents are safe choices in patients with CKD requiring anesthesia (152). The acetylcholinesterase inhibitors neostigmine, pyridostigmine, and edrophonium are more than 50% excreted in the urine, and CKD may prolong their clearance (153). Careful attention to drug selection and dosing is therefore critical. Because of the increased risk of bleeding related to uremic platelet dysfunction, the ESKD patient should be well dialyzed, and medications with antiplatelet effects should be avoided close to the time of surgery. Bleeding time is the most sensitive indicator of the extent of platelet dysfunction, although test results are variable across laboratories. Bleeding times of greater than 10 to 15 minutes may be associated with a high risk of hemorrhage (154), but a precise correlation between prolonged bleeding times and surgical risk in the ESKD patients has not been clearly established. The synthetic ADH analog, 1-deamino-8-D-arginine vasopressin (DDAVP; 0.3 mcg/kg IV one hour before surgery) (155), cryoprecipitate [10 units over 30 minutes IV; effects generally apparent in one hour (156)], or conjugated estrogens [0.6 mg/kg/day IV or orally for five days; some effect should be apparent in six hours, with peak effect in five to seven days (157,158)] can be administered to improve the bleeding time. Cryoprecipitate can be given repeatedly to effect improvements in bleeding risk, but DDAVP is subject to tachyphylaxis with repeated dosing. Intensive dialysis or transfusion of packed red blood cells to raise the hematocrit to at least 30% may also reduce bleeding risk. Nonetheless, packed blood cell transfusion should generally be reserved for patients with clinically significant anemia, to avoid the potential for antibody formation that may limit the prospects for successful renal transplantation in the future. Many patients with CKD or ESKD receive prophylactic antibiotics for surgical procedures, especially dialysis A-V graft procedures (159), and minor procedures [e.g., dental care (160)]. To avoid bacterial seeding of the grafts before epithelialization occurs, antibiotic prophylaxis using standard endocarditis regimens is recommended for the first several months after synthetic vascular access are placed.

In the postoperative period, strict attention must be paid to volume and hemodynamic status and drug dosing, as well as fluid, electrolyte, and acid–base balance. Surgical trauma, blood product transfusions, and acidosis may promote significant hyperkalemia, which may require emergent treatment. Postoperative hypokalemia is generally not treated unless signs, symptoms, or cardiac dysrhythmias referable to hypokalemia supervene, or the patient requires digitalis therapy. Operative blood losses, third-space volume losses, and fluid losses from drains and fistulae must be carefully evaluated to optimize postoperative care in the renal patient.

Dialysis Different types of dialysis modalities are in clinical use. These can be broadly categorized as intermittent hemodialysis, continuous renal replacement therapy (CRRT), and peritoneal dialysis. The relative advantages and disadvantages of these modalities in various clinical settings are presented in Table 11.

Hemodialysis Hemodialysis became standard treatment for kidney failure in the 1960s. In this process, the blood is circulated through a machine containing a dialyzer (also called an artificial kidney). The dialyzer has two spaces separated by the thin, semipermeable dialysis membrane. Blood passes on one side of the membrane, and dialysis fluid passes on the other. The wastes and excess water pass from the blood through the membrane into the dialysis fluid, which is discarded. The dialyzed blood is returned to the circulation. The process of removing excess fluid is known as ultrafiltration. The blood is circulated and diffused numerous times during a dialysis session. Chronic hemodialysis is commonly performed three or more times a week for four hours or more. Physical Process of Solute and Water Transport Across the Dialyzer Membrane The dialyzer membrane is a semipermeable membrane. Solute molecules and water, the solvent, move across this Table 11 Comparative Advantages (þ) and Disadvantage () of Dialysis Modalities Clinical variable Continuous renal replacement Hemodynamic stability Superior attainment of fluid balance Unlimited nutritional support Superior metabolic control Continuous removal of toxins Limited anticoagulation Stable intracranial pressure Rapid removal of poisons, drugs Need for intensive care nursing support Need for hemodialysis nursing support Ease of operation Patient mobility

Intermittent hemodialysis

Peritoneal dialysis

CRRT

þ

þ

þ

þ þ

þ þ

þ þ þ

þ þ þ þ

þ

þ

þ

þ

þ

þ

þ/

Abbreviation: CRRT, continuous renal replacement therapy.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

membrane under the influence of three physical processes— diffusion, convection, and ultrafiltration. Diffusion is the process of solute movement down a concentration gradient across the membrane. The flux of solute molecules depends on the size and shape of the solute molecule (characteristics that are described in a term called the diffusion coefficient of the solute); the porosity of the membrane, as well as its thickness, and surface area; and the concentration gradient and temperature of the solution. Whereas these factors enable a close prediction of solute fluxes or clearance in simple solutions, protein binding and electrical charge further influence solute flux in vivo. A second mechanism of the movement of solute molecules is convection. Water (solvent) is moved across the membrane by filtration; the flux of water is determined by the balance of hydrostatic and oncotic pressures across the membrane (the transmembrane pressure), and the permeability of the membrane to water molecules (hydraulic permeability) defined in the term, ‘‘coefficient of hydraulic permeability’’ (Kf). Convective movement of solute is the movement of solute molecules with water, a phenomenon known as solvent drag. The convective flux depends on the ultrafiltration rate and the solute concentration, as well as the sieving coefficient of the membrane for the solute. Sieving coefficients of membranes to solutes are determined by a characteristic of the membrane, the reflection coefficient. Dialysis membranes are classified according to ultrafiltration coefficient and solute sieving profiles into high-flux and low-flux membranes. Low-flux membranes are called dialyzers and clear solute mainly by diffusion, while high-flux membranes are called hemofilters and clear solute mainly by convection. The Dialyzer Membrane and Dialyzer Design Several important characteristics are required of the dialyzer membrane. These include adequate clearance of small molecules such as urea; adequate removal of water; retention of large molecules; biocompatibility (i.e., nonthrombogenic, nontoxic, and noninflammatory); capable of sterilization by steam, gamma irradiation, or ethylene oxide; and possessing microscopic structure that confers strength to the high transmembrane pressures required for ultrafiltration. Dialyzer membranes are classified into categories depending on their method of production. Semisynthetic membranes are cellulose derived or modified/regenerated cellulose (cellulose acetate, cellulose diacetate, and cellulose triacetate). Synthetic membranes include those composed of polysulfone, polyamide, polyacrylonitrile, or polymethylmethacrylate. The dialyzer membranes are assembled or bundled in two main designs—hollow fiber and parallel plate. Modern dialyzers are constructed of hollow fiber filters. Hemodialysis Vascular Access A well-functioning, dependable vascular access is needed for hemodialysis. For chronic hemodialysis, the ideal, permanent access is a ‘‘native’’ A-V fistula: the alternative is a synthetic A-V graft. However, in several clinical situations, temporary vascular access is needed. Percutaneous central venous hemodialysis catheters (CVCs) are available for such situations. Central Venous Catheters. The ability of CVCs to provide high blood flow rates (300–400 mL/min) is compromised by the development of very negative pressures at the catheter tip and pores as a result of high blood velocities in the area—the Bernoulli effect. This effect is worsened by additional obstruction from thrombosis and fibrin sheaths and

749

results in the collapse of the venous wall around the catheter. To minimize this problem, catheters are positioned in the right atrium; they are made with a wide internal diameter, multiple pores placed in all directions around the catheter, and the arterial port placed away from the wall of the vein. The ideal CVC should provide adequate blood flows with minimum resistance, pressure drop, and Bernoulli effect; its placement should cause minimal trauma to the vein and its intimal lining; and minimal activation of the coagulation cascade, white cells and platelets, and infection by the migration of bacteria from skin, along the sides of the catheter or through the catheter lumen. The material of the CVC should be able to withstand the negative pressures without collapsing and should not kink, break, or deteriorate with use of antiseptic agents (161,162). The materials of which dialysis CVC catheters are made need to fulfill certain requirements for clinical safety and performance as well as for manufacturing purposes (162). The material should be biocompatible and nonthrombogenic; the body of the catheter must be strong so as not to crack or break easily; it should be able to withstand repeated exposure to alcohol, iodine, and other cleaning and antiseptic chemicals; it should be sufficiently rigid as to enable threading over a guidewire or splitsheath during placement, but not too rigid as to cause injury to the vessel wall; it should resist kinking and collapsing under very negative pressures; it should be flexible so as to negotiate bends, especially in the tunnel; the catheter itself should have as large as possible an internal diameter without being too large so as to minimize trauma to the vessel. For manufacturing purposes, it should be moldable, and bondable for use with other materials used in making of the other parts of components of the catheter. Most catheters in current use are polyurethane. Polyurethane has high material strength—catheters can be made with a very thin wall; it is flexible and can be made very rigid or soft; it is moldable and bonds well with other materials. A main disadvantage is that it is damaged by alcohol and antibiotic ointments such as mupirocin and betadine ointment that contain polyethylene glycol. Common femoral vein cannulation is relatively easy and is preferred in the critically ill patient, where rapid and safe cannulation is required (163). Thus, in the emergency room or ICU, to minimize the risk of pneumothorax in the mechanically ventilated patient, cardiac arrhythmias, hemothorax, and pericardial tamponade, there is a high incidence of catheter-associated bacteremia. Ultrasound guidance or fluoroscopy are usually not required but may be useful in the morbidly obese or where there have been multiple prior cannulations and severe scarring; this may also be useful to determine catheter tip position where there is poor catheter function and high recirculation rates. In this situation, long catheters ( >20 cm) are needed with X-rays to ensure catheter tip placement in the right atrium. Attempts at subclavian vein cannulation are associated with a high rate of severe acute complications—subclavian artery puncture, hemothorax and pneumothorax, and a high rate of subclavian vein stenosis in long-dwelling catheters (164), which will compromise the arm for subsequent placement of A-V accesses. Subclavian vein dialysis catheters are no longer recommended. For internal jugular (IJ) vein cannulation, the right IJ vein is preferred, because it runs straight inferiorly to the superior vena cava. Thus, the risk of malposition and malfunction is minimized, and endothelial injury is minimized so that chronic stenoses and occlusion are less common. There is great anatomic variability in the diameter of the vein and in its relations to the internal carotid artery,

medwedi.ru

750

Part Four: The Urinary System

hence IJ vein placement is preferably done with ultrasound or fluoroscopic guidance or by surgical implantation (where there has been prior extensive neck surgery or multiple cannulations of the IJ with scarring) easily done under local anesthesia to minimize trauma to the vein, and the risk of injury to the IJ artery. The left IJ vein has a tortuous course, and catheters in this vein are complicated more frequently by malfunction, intimal injury, and chronic central venous stenosis, injury to the thoracic duct, pneumothorax, and hemothorax (163). Inadequate Dialysis from Catheter Malfunction and Unreliability. Adequate dialysis delivery requires adequate blood flow (Qb) in the 350 to 400 mL/min range. Access malfunction is therefore not to be tolerated. Blood flow rates as read by the machine tend to overestimate true blood flow rates, more so at more negative pressures. CVCs generate very negative pressures around their ports as a result of direct sucking and of the Bernoulli effect. Thus, machine blood flow readings with CVCs often greatly overestimate the actual blood flow. This, coupled with the fact that CVCs provide blood flows much lower than A-V accesses and have high recirculation rates, explains why CVCs are frequently associated with inadequate dialysis. CVCs are vulnerable to thrombosis, fibrin sheath formation, primary malposition, secondary displacement or dislocation of the catheter tip. Adherence of the catheter tip to the vein wall can be corrected by reversing catheter ports, but this leads to higher recirculation rates. These CVC complications can be successfully managed by interventional radiologic procedures such as changing of the catheter over a guidewire, thrombolysis with tissue plasminogen activator, or fibrin sheath stripping (163). Where chronic hemodialysis has to be done using a CVC, meticulous monitoring of dialysis adequacy with aggressive use of these procedures to optimize catheter function is mandatory (161,165). Hemodialysis Catheter-Related Infections. Catheterrelated bacteremia and septicemia are a major cause of morbidity and mortality in hemodialysis patients (166– 170). The majority of infections are due to Staphylococcus aureus and coagulase-negative staphylococcus. Coagulasenegative S. aureus most commonly colonizes the catheter exit site, but less frequently accounts for sepsis, whereas S. aureus colonization of the exit site is associated with a high incidence of bacteremia. Hemodialysis catheter-related bacteremia is less frequently caused by gram-negative bacteria such as Escherichia coli, Pseudomonas spp., Klebsiella spp., Proteus spp., and Serratia spp. Hemodialysis catheter-related infections due to fungi are not common in chronic dialysis patients; however this complication occurs in long-dwelling dialysis catheters in acute renal failure in hospitalized patients. Adherence of bacteria to the catheter surface is determined by an interplay of host, bacterial, and catheterrelated factors. A layer of thrombin, rich in fibrin and fibronectin, forms around the catheter. S. aureus adheres tightly to fibrin, while coagulase-negative staphylococci adhere tightly to fibronectin and not to fibrin. The bacteria produce a fibrous glycocalyx called extracellular slime; coagulasenegative staphylococci are particularly slime producing. The thrombin and slime are components of a biofilm layer that supports further bacterial adherence and growth and also acts as a barrier protecting the organisms from antibiotics, antibodies, phagocytic neutrophils, and macrophages. The nature of the catheter material also plays a role in biofilm

Table 12 Risk Factors for Catheter-Related Bacteremia Nasal carriage of S. aureus usually associated with skin carriage Catheter hub colonization Duration of catheterization Frequency of catheter manipulation Procedure of dialysis itself, which involves several exposures The conditions of catheter placement and postinsertion catheter care Patient’s personal hygiene Adherence by medial staff to universal precautions, including hand washing, wearing of gloves and masks when catheter is manipulated Catheter clotting Diabetes mellitus Frequent skin needle punctures (e.g., diabetics or drug users)

formation. Following bacterial adherence to the dialysis catheter surface, biofilm organizes into a complex structure regulated by the exchange of chemical signals between bacterial cells, a process known as quorum sensing. This ‘‘multicellular’’ cell–cell communication leads to the emergence of virulence phenotypes. Two quorum-sensing systems are identified in S. aureus, the autoinducer RNAIIIactivating protein (RAP) and its target molecule TRAP; and the peptide pheromone AIP and its receptor AgrC. More understanding of these mechanisms of biofilm formation may lead to novel approaches to the management of CVC. The risk factors for the development of catheter-related bacteremia are presented in Table 12. The Native AVF. The arteriovenous fistula (AVF) is the first choice of hemodialysis vascular access, using the patient’s own artery and vein (171,172). Time, sometimes up to three months, is needed for the vein to arterialize or ‘‘mature.’’ Every effort should be made to create an AVF, in spite of the fact that an increasing proportion of patients needing dialysis are surgically challenging. More dialysis patients are diabetic and elderly, with more severe diffuse atherosclerosis and more venous damage or injury resulting from multiple prior venipuncture for blood draws and intravenous infusions, as well as central vein catheterizations. The radiocephalic AVF, first described by Brescia and Cimino in 1966 (173), is the classical AVF, created at the wrist using the radial artery and the forearm cephalic vein (174) (Fig. 12). In individuals with severe atherosclerosis, the radial artery may not provide adequate blood inflow, and thus it is necessary to use the brachial artery in the antecubital fossa, connected to the lateral upper arm cephalic vein. Careful preoperative evaluation of artery and vein is essential for successful AVF creation. The radial artery usually has a blood flow rate of 20 to 30 mL/min, which increases to 200 to 300 mL/min after AVF creation; by the time of maturation of the AVF, typical blood flows are 600 to 1200 mL/min. This marked increase in blood flow requires a distensible inflow artery, thus the atherosclerotic, thickwalled and calcified artery is a poor candidate for successful AVF creation. The greatest threats to successful maturation of the vein are prior multiple venipunctures, with resulting venous sclerosis, multiple venous tributaries draining blood flow, hypertrophic venous valves, and central venous stenosis or thrombosis, often subclinical or asymptomatic. Preoperative evaluation should include a history taking and physical examination, with careful palpation of arteries and veins, auscultation and blood pressure measurements on both arms, ultrasonographic study of the arteries and veins to evaluate their caliber, wall structure and flow characteristics (this has replaced the Allen test),

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

Figure 12 Potential vascular sites for creation of an endogenous arteriovenous fistula for hemodialysis vascular access. The preferred access site is created at the wrist by anastomosing the radial artery and cephalic vein (A). Other potential sites for access creation include the brachial artery with either the medial cubital vein at the elbow (B) or the cephalic vein at the upper arm (C).

and contrast or magnetic resonance venography in selected cases. Recently, the surgical procedure of transposition of the basilic vein in the upper arm has allowed the use of proximal upper arm vessels for AVF creation (175). The NKF-DOQI Clinical Practice Guidelines for Vascular Access has recommended an AVF rate of approximately 50% in new ESRD patients (176). The high prevalence of diabetic, obese, and elderly patients in the ESRD population in the United States demands particular effort to reach this goal. Most AVFs require approximately three months to mature (cf 2–3 weeks for A-V grafts). Fistulas have a high primary failure rate due to a failure to mature or early thrombosis. A common problem in the dialysis center is that of the patient waiting for long durations for their AVF to mature or having successive AVFs thromboses. These patients are forced to continue with CVCs for long periods, which is not ideal. In order to increase the chances of achieving successful AVF placement, maturation, and function, preoperative vein mapping by sonography, contrast, or magnetic resonance venography is needed. Absolute contraindications to A-V access are severe congestive heart failure with low ejection fraction that may be worsened by the A-V shunt, symptomatic steal syndrome, morbid obesity, chronic and intradialytic hypotension, hypercoagulable states, skin disease, and severe venous hypertension leading to severe edema of the arm.

751

Arteriovenous Graft. The arteriovenous graft (AVG), introduced in mid-1970, is the second option for vascular access. Graft material may be autogenous, heterogenous, or synthetic. Expanded polytetrafluoroethylene is the most commonly used graft material (177). Grafts may be placed in the upper or lower extremities and may be straight or looped, and the anastomosis may be end-to-end, end-toside, or side-to-side. The end-to-side anastomosis is the most commonly used. Graft thrombosis is the most common complication of AVGs (70%); of these, 90% are associated with venous anastomotic stenosis, the result of neointimal hyperplasia. As a consequence, there is a high incidence of access malfunction and poor outcomes in patients with AVGs. In the United States, AVGs account for approximately 70% of all vascular accesses. Recent studies reveal that chronic AVGs are associated with a chronic inflammatory state with higher levels of inflammatory markers such as C-reactive protein (178). In diabetics, AVGs were associated with an overall mortality risk of 1.41; cause-specific relative risks are significantly higher, and the relative risk of death from infection is more than twice that of diabetics with AVFs (179). AVGs develop an aggressive form of venous anastomotic intimal hyperplasia characterized by smooth muscle cell proliferation, extracellular matrix synthesis and deposition, and neointimal and adventitial angiogenesis. There is no effective pharmacological therapy as yet for this lesion. In view of the high rates of graft dysfunction and thrombosis, and the lack of specific therapy, attempts have been made to develop simple and reliable tests of graft function that will give early warning of dysfunction and impending thrombosis. These methods include dynamic pressure measurements, static intra-access pressure measurements, access blood flow measurements using Doppler ultrasound and ultrasound dilution methods, and recirculation measurements using urea-based methods, ultrasound dilution or thermodilution methods. These programs of graft surveillance have proven useful in prolonging graft survival and have ensured adequate delivery of dialysis. Using well-validated criteria of access function, dysfunctioning vascular accesses are then referred for fistulography or graftography and further interventional procedures (172). Management of AVG Dysfunction. Interventional radiology, interventional nephrology, or vascular surgery departments primarily manage the management of graft thrombosis. Procedures can be performed more promptly, and thus with minimal interruptions of the patients’ dialysis treatment schedules, and they are less invasive and they do not require general anesthesia. These procedures allow access sites to be preserved better for future use and also provide more precise anatomic diagnosis of lesions within the access and on both arterial and venous side, up to the central venous system. This more precise diagnosis makes it possible to develop the appropriate treatment plan, and this should be done in a multidisciplinary approach involving the interventionist, nephrologist, and surgeon. More AV accesses are salvaged in this way, longevity of the access is increased, accesses that are not salvageable are more clearly identified and referral to surgery and outcomes are improved. The usual interventional procedures are thrombolysis, usually mechanical, but occasionally with the aid of thrombolytic agents, and angioplasty of venous anastomotic stenotic lesions as well as venous stenotic lesions that may occur all the way up to the central veins (180). Occasionally lesions are detected on the arterial anastomotic

medwedi.ru

752

Part Four: The Urinary System

region, which may be amenable to angioplasty, and stenting of stenotic venous segments is performed where indicated. Surgery is indicated when the interventional approach has failed or is not feasible and is usually carried out with more detailed anatomic data and with a view to preserve access sites for the future and to address the underlying lesion. Surgical procedures include thrombectomies, placement of patch angioplasties, interpositional or jump grafts, or the creation of new AV accesses. Additionally, surgical intervention is required for the management of bleeding, infections, and pseudoaneurysms. Anticoagulation. Activation of the hemostatic system as a result of contact between blood and the foreign surfaces of extracorporeal circulatory systems is a challenge in hemodialysis dialysis therapies. Clotting occurs within the blood compartment of the dialyzer and/or at different vulnerable points along the dialysis blood lines or circuitry. Filter clotting results in treatment interruptions and inefficiency, nursing difficulties, increased cost of treatment, and, most important, inadequacies of clearances and ultrafiltration capacity. Anticoagulation is therefore usually required for the effective delivery of the dialysis prescription. The anticoagulation regimen must be individualized for the needs of each patient. Hospitalized patients, acutely ill with infection, sepsis, post-trauma, surgery, strokes, or myocardial infarctions and such conditions may be hypercoagulable or coagulopathic. Careful consideration of these factors must go into the determination of the requirements for anticoagulation for dialysis. Anticoagulation is usually systemically administered, but where there are serious bleeding risks, it may be done locally or regionally, across the dialyzer only. Regional anticoagulation is particularly preferred with continuous dialysis therapies in the severely ill intensive care patients and also because of the potential for anticoagulants to accumulate with continuous administration. Treatment characteristics that affect clotting include vascular access— catheter diameter, traumatic catheter placement, catheter malposition, and kinking; blood flow rates; ultrafiltration rates; dialyzer membrane material and geometry; and nursing attention to alarms and other warning signs of impending thrombosis. Anticoagulation may be systemic or regional. Sometimes no anticoagulation is used or required. Patients with liver failure, uremic bleeding diathesis, severe thrombocytopenia, consumptive coagulopathy, or patients receiving medications with anticoagulant effect such as the recently introduced activated protein C may require only intermittent saline flushes to maintain patency of the extracorporeal circuit. Water for Dialysis and Dialysate Composition. Water for dialysis is usually municipal water; occasionally only well water is available. The water undergoes a number of filtration steps to remove particles, dissolved organic compounds, chloramines, and chlorine, after which it is pumped through a water softener, and an ion exchange resin to remove calcium and magnesium ions (181,182). Municipal water is allowed to contain up to 100 colony-forming units of microorganisms per mL. Ion exchange resins promote bacterial growth. Next, the water filtered and softened is pumped through an RO unit, for the elimination of up to 99% of all ions present. The hemodialysis machines are connected to the water purification system by polyvinyl chloride tubing. Water stagnation in the tubing promotes bacterial overgrowth as well as biofilm formation, especially from Pseudomonas species, which are a constant source of endotoxins

and other pyrogenic bacterial products. Failure of the water treatment system results in incorrect electrolyte composition of the final dialysate, patient exposure to unwanted chemical contents such as chloramines, fluorides, nitrates, copper, and aluminum, as well as to microorganisms and their products. Salt concentrates, particularly bicarbonate concentrate, are prone to heavy contamination with microorganisms, especially Pseudomonas species. Solid bicarbonate in powder form is now available. Bacterial products back filtrate from dialysate side to the blood side. There is a current effort to provide pyrogen-free (ultra-pure) dialysate by adding pyrogen-adsorbing membranes, or ultraviolet radiation to the water treatment system. The final dialysate is mixed in a proportioning system from dialysate concentrates and the dialysate water. Dialysate composition is individualized according to clinical requirement. The main variables are dialysate sodium, potassium, calcium, and, more uncommonly, bicarbonate and magnesium. It is easy to imagine that errors of dialysate composition from a faulty proportioning system or human error can have severe deleterious clinical effects. Monitoring of ionic conductivity is used as a safety measure against this possibility. Measurement of Dialysis Adequacy. The effort to quantify dialysis adequacy has engaged the interest of nephrologists for many years. Among the first choices of uremic toxins selected for such analysis was urea, representative of small solutes. Several parameters need consideration—dialyzer membrane transport characteristics, blood and dialysate flow rates, duration of treatment, vascular access performance, in particular blood flow recirculation within the access, ultrafiltration rates, hematocrit, etc. These in turn are factored to a measure of patient size. The most successful parameter to date, dialysis dose, and which has been validated as predictive of patient outcome, is the Kt/V urea index (183). This is the clearance of urea factored to total body water. A Kt/V of one indicates urea clearance equal to the volume of total body water. The NKF/DOQI Clinical Practice Guidelines give evidence-based targets of dialysis dosing to be delivered to patients so as to ensure adequate dialysis (184–186).

Continuous Renal Replacement Therapies CRRT have become the most effective treatment modality in critically ill patients (187,188). Several features of these modalities explain their advantages: 24-hour treatment provides continuous removal of toxic compounds that are presumed to be continuously generated; there is a marked overall increase in dialysis clearances; and small hemofilters and small volume extracorporeal circuits are used to minimize blood volume reduction in the hemodynamically unstable patient. The hemofilters have large pore-size with high hydraulic permeability permitting large volume ultrafiltration [continuous veno-venous hemofiltration (CVVHF) and continuous veno-venous hemodiafiltration (CVVHDF)], as well as the passage of middle and some high–molecularweight toxins (up to 30–50 Da): this enables the clearance of inflammatory cytokines, anaphylatoxins (C3 and C5), platelet-activating factor, and substance such as myocardial depressant factors. The capacity for high volumes of ultrafiltration also enables the safe administration of large volumes of fluid required for administration of medications, nutrition, and blood products. Additionally, these techniques offer gradual and continuous correction of electrolyte, acid–base and osmolality abnormalities, as well as the capacity to cope with the severe azotemia of the severely ill and

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

753

Table 13 Potential Indications for Continuous Renal Replacement Therapy Acute renal failure with: Severe hypercatabolism Cerebral edema Cardiovascular failure Acute or chronic liver failure Adult respiratory distress syndrome Tumor lysis syndrome Lactic acidosis Cardiopulmonary bypass Sepsis syndrome Refractory congestive heart failure Acute necrotizing pancreatitis Rhabdomyolysis Acute intoxications Hyperammonemia associated with inborn errors of metabolism

Dialysis catheter Patient

Air embolus monitor

Venous pressure monitor

Ultrafiltrate tubing pump

hypercatabolic patient. It has recently been demonstrated that adsorption is an important mechanism of solute clearance in CRRT. In many cases the clinical significance of such clearances is yet to be understood. Table 13 lists some of the renal failure and nonrenal conditions that have been reported to benefit from CRRT (189). CRRT may be particularly advantageous when AKF is accompanied by refractory volume overload, hypercatabolism, intracerebral edema, hemodynamic instability, or uncontrollable hyperkalemia or metabolic acidosis. The first continuous therapies were continuous arteriovenous, requiring arterial cannulation, with the force for blood flow provided by the arterial blood pressure. With the introduction of a blood pump into the extracorporeal circuit, and the availability of single dual-lumen catheters, continuous veno-venous therapies became possible and are much preferred. The modalities of continuous therapies can now be classified into three categories: convective therapies, dialysis therapies, and continuous ultrafiltration. Convective Therapies: CVVHF and CVVHDF The convective therapies are hemofiltration (CVVHF) and hemodiafiltration (CVVHDF) (Fig. 13) (187,188). The dialyzing membrane is highly permeable to solutes and water. In CVVHF, there is no dialysis fluid, while in CVVHDF, there is a dialysis fluid flow. In both CVVHF and CVVHDF, very large volumes of ultrafiltration are the goal, far in excess of ultrafiltration required for the purposes of volume balance; therefore, in both procedures there is a need for replacement or substitution fluid. Typical ultrafiltration rates are about 30% of blood flow rates; at blood flow rates of 200 to 300 mL/min, typical ultrafiltration rates are 60 to 90 mL/ min. CVVHF and CVVHDF achieve very high clearances of both small and large-molecular-weight solutes. With CVVHF, clearances of small-molecular–weight-solutes depend mainly on ultrafiltration volume; therefore to achieve high small-solute clearances, high blood-flow rates (approximately 500 mL/min) are required. With the availability of online production of substitution fluid, it is possible to achieve such a high blood flow into the hemofilter (e.g., 250 mL/min actual blood flow and 250 mL/min predilution substitution fluid). With CVVHDF, small solute clearance depends not only on ultrafiltration rates but also on diffusion down a concentration gradient; predilution with substitution while increasing ultrafiltration rates also dilutes concentrations of these solutes, thereby reducing diffusive clearances.

Blood pump

Membrane

Drainage Bag

Figure 13 Continuous venovenous hemofiltration (CVVH) circuit. CVVH offers large-volume ultrafiltration in critically ill patients with specific indications. Blood moves from and to the patient via a dual-lumen central venous catheter, with the filtration pressure being provided by a blood pump.

Predilution therefore reduces clearance of small solutes in CVVHDF. Substitution fluid is administered postfilter. Both CVVHF and CVVHDF can only be accomplished by the availability of large volumes of substitution fluid made possible by its online production. There is currently great interest in the development of the continuous convective therapies, for the treatment of acute renal failure in the setting of sepsis or the multiple organ dysfunction syndrome (MODS). Besides the improved small solute clearances, hemodynamic stability, metabolic control, and nutritional support that can be provided, it is suggested that there is improved clearances of middle and large molecules, especially inflammatory mediators and endotoxins (by convection and adsorption), the removal of which will aid the management of sepsis. This has led to novel therapies aimed at the treatment of sepsis or MODS as opposed to AKF. In principle, two main approaches are being pursued: high volume hemofiltration with filtration rates averaging 35 mL/kg/hr or more and ultrahigh-efficiency clearance using plasma filtration and adsorption. The Dialysis Therapies: CVVHD and SLED CVVHD and sustained low-efficiency dialyis (SLED) are diffusion (dialysis)-based techniques as in regular hemodialysis (187,188,190), but unlike routine hemodialysis, dialysate flow rates are lower, rendering the procedure less efficient. With CVVHD, the dialysate flow rates are in the range of 1 to 2 L/hr (17–35 mL/min); blood flow rates are also slowed, averaging 200 mL/min. The dialysate is completely saturated in its passage through the dialyzer, and dialysate flow rate is the limiting factor to clearance. Small solute clearance is the objective in CVVHD. At this rate of dialysate flow, the dialysate is supplied in bags from the manufacturer or custom-mixed in the hospital pharmacy. Because

medwedi.ru

754

Part Four: The Urinary System

of the undesirability of leaving bicarbonate solution sitting for long periods, the alkalinizing agent in these dialysate solutions has been more commonly citrate than bicarbonate, though both types of solution are in use. With SLED, higher dialysate flows can be achieved using bicarbonate for alkalinization as in regular hemodialysis. Ultrafiltration: SCUF Slow continuous ultrafiltration (SCUF) provides low water and sodium removal continuously and can be useful in the management of refractory congestive heart failure, sometimes as a bridging procedure to cardiac transplantation. Complications of CRRT The major complications of CRRT are related to anticoagulation and metabolic disturbances (191). Continuous therapies often require continuous anticoagulation (192,193). This, in the presence of kidney failure, carries the high risk of excessive anticoagulation and bleeding, more so in critically ill patients with other bleeding risks. The trend therefore is to do regional, rather than systemic, forms of anticoagulation. Citrate anticoagulation is the most commonly used of these methods. Recent increased interest in alternatives to heparin is the result of increasing reports of the devastating complication of heparin-induced thrombocytopenia. Pharmacokinetics and Drug Dosing Adjustments During CRRT Drugs are cleared during CRRT mainly by convection and adsorption (194). Drugs that are normally cleared by the kidneys are usually also removed by CRRT. The critically ill patient already has major abnormalities of drug handling from altered absorption, distribution, metabolism, and excretion. Drug dosing in CRRT is best guided by measuring levels where this is applicable. CRRT drug clearances can be measured or estimated; where this is not feasible, drug dosing can be adjusted (according to reference guidelines) using measured CRRT creatinine clearances. With nontoxic drugs, dosing may be done in excess of estimates (approximately 30%), to ensure adequate levels.

Peritoneal Dialysis In peritoneal dialysis, the intra-abdominal peritoneal microcirculation, with its large surface area, blood flow, and the solute and fluid exchange properties of the capillary network, is exploited. Dialysate is injected into the peritoneal space through a two-way catheter. The peritoneal membrane allows waste and fluid to pass from the blood into the dialysate, which is drained out. The peritoneal dialysate contains electrolytes in physiologic concentrations to facilitate correction of acid–base and electrolyte abnormalities. The dialysate glucose concentration can be increased or decreased depending on the desire to promote or restrict, respectively, osmotic movement of fluid from the peritoneal capillaries into the peritoneal space. Urea clearances of 10 to 15 mL/min can be achieved using this method. The amount of solute removal is a function of the degree of its concentration gradient, the molecular size, membrane permeability and surface area, duration of dialysis, and charge. Peritoneal dialysis must be performed everyday and fluid must be in the abdomen at all times to clean the blood adequately. Advantages of peritoneal dialysis over acute intermittent hemodialysis include the fact that in peritoneal dialysis, fluid removal is more gradual and less hemodynamically stressful, dialysis is slower and more continuous so that

electrolyte shifts may be less dramatic, anticoagulation is not required, and less specialized equipment and personnel are required. In the AKF setting, acute peritoneal dialysis is not as efficient as acute intermittent or continuous hemodialysis in correcting metabolic, fluid, and electrolyte abnormalities. Continuous ambulatory peritoneal dialysis (CAPD) exchanges approximately 2 L of dialysate three to six times a day while the patient is active. The patient connects a bag of dialysate fluid to the peritoneal catheter and allows it to infuse into the abdomen. After the dialysate filters for four to six hours (the ‘‘dwell’’ time), the patient drains the fluid and exchanges it for fresh fluid. In automated peritoneal dialysis, also termed ‘‘continuous cyclic peritoneal dialysis’’ (CCPD), a machine exchanges the fluid while the person sleeps. Over the 8- to 12-hour night, the machine exchanges fluid four to eight times. Upon waking, the patient’s fluid is exchanged and used throughout the day. Some patients require a mid-day exchange. Early peritoneal dialysis fluids composed of solutions varying from normal saline to 5% dextrose. Sodium concentrations were varied as required to correct hypo- or hypernatremia. To correct acidosis, bicarbonate, acetate or lactose was used as base. Dextrose in high concentrations (up to 7%) was used as the osmotic agent to provide ultrafiltration. These high concentrations of glucose posed a problem owing to caramelization during sterilization. With the advent of commercially prepared peritoneal fluid, two problems arose. One was the inability of keeping calcium and bicarbonate in solution in storage for long durations (precipitation of calcium carbonate); the second was that bicarbonate solutions are difficult to keep sterile. Thus modern peritoneal dialysis fluids remain buffered with lactate. The technique, in its early history, was hardly suitable for the chronic treatment necessary for ESKD. The first efforts required repeated catheterization of the peritoneum for each treatment. This ‘‘periodic’’ peritoneal dialysis was extremely painful and uncomfortable for the patient, and had a high rate of infections and peritoneal adhesions. Unsuccessful attempts were made to develop devices such as abdominal buttons or other conduits to facilitate the repeated catheterizations. The earliest peritoneal dialysis catheters were made from tubing easily available on the hospital ward—stainless steel sump drains, trochars, and rubber catheters—all of which were unsuitable for longdwelling use. Polyvinylchloride and polyethylene tubing became available in the early 1950s, but these were limited by their tendency to kink, leak, and get blocked. Catheter placement initially required a trochar, but later designs had pointed stylets for convenience of placement. In 1968, Tenckhoff (195) introduced his catheter, a silicone rubber catheter with two Dacron cuffs, designed to be used as a long-term indwelling dialysis catheter. All other peritoneal dialysis catheters designed since have been modifications of the Tenckhoff catheter. The Tenckhoff catheter is, arguably, the single most important device that has made chronic peritoneal dialysis a reality. Peritoneal dialysis catheters can now be placed laparoscopically at the bedside or in the operating room, or by open surgery. Straight, coiled, singleor double-cuffed, Swan Neck, Ash T-fluted, and presternal catheters are all in use. The coil of the catheter gives it weight in its pelvic location, which minimizes the possibility of migration from the pelvis. The Swan Neck design allows a downward direction of the exit site, which markedly reduces the risk of exit site infection. The Dacron cuffs on the catheter are highly fibrogenic and help to secure the catheter in position and minimize the possibility of pericatheter leak

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

and infection. The internal cuff, placed within the rectus abdominus muscle, helps to prevent catheter leak or migration. The coiled intraperitoneal segment helps to prevent catheter migration and minimizes pain from infusion of fluid. Presternal catheters are suitable for the morbidly obese and patients with abdominal ostomies. A variety of peritoneal catheter-related complications may occur (Table 14). At the same time as the indwelling catheter was evolving, efforts in the area of fluid delivery led to the introduction of automatic cycling machines—machines capable of delivering fluid to the patient’s peritoneal cavity in cycles, with varying volume and composition of fluid, duration of inflow, dwell, and outflow. At first, the dialysate was premixed and provided in large containers. Later, the dialysate was available in plastic bags of different dextrose concentrations or strengths, with the possibility of being mixed or matched to provide a final composition appropriate for the patient. Over the years, peritoneal dialysis cyclers have become smaller and more portable. The next major development in peritoneal dialysis was the concept of CAPD proposed by Popovich and Moncrief in 1973 (196). They hypothesized that peritoneal dialysis could be performed on a principle of ‘‘equilibration’’ dialysis: that is, if each exchange of fluid introduced into the peritoneum was allowed to ‘‘dwell’’ there until it equilibrated with the blood and then was drained; they calculated that only a relatively small amount of peritoneal fluid, in a relatively small number of exchanges would be required to provide the necessary amount of solute and fluid clearance. Specifically, they calculated, for example, that exchanges of 2 L, each with an ultrafiltration of 500 mL and thus a drain volume of 2500 mL, four times in the course of a 24-hour period, would result in a 12 L drain volume or effluent. If it is assumed that this volume of dialysis fluid effluent achieved equilibration with blood, then the amounts of urea and creatinine cleared, which can be calculated should be adequate to treat ESKD. The patient in this way achieves steady state chemistries, with minimal fluctuation of serum creatinine or BUN levels. The developments in peritoneal dialysis described thus far formed the basis of modern peritoneal dialysis technique. Further developments have only been the modifications of these principles. Because CAPD requires exchanging peritoneal dialysis fluid four to five times daily, the potential for contamination of fluid and resulting peritonitis is high. Numerous devices and techniques to achieve and maintain sterile connections with minimal risk of contamination have since been developed. Automated cycling machines that can automatically Table 14 Peritoneal Dialysis Catheter-Related Complications Exit-site infections Extrusion of the external cuff Catheter obstruction by: Clot Bowel (constipation) Omentum Adhesions Full bladder Kinks Pericatheter leaks Infusion or drainage pain Peritonitis Migration Cuts, material deterioration and breakdown, organ erosion, and allergic reactions (rare)

755

Table 15 Peritoneal Dialysis as Chronic Renal Replacement Therapy Advantages More liberal diet with less fluid intake restrictions Minimal fluctuation of blood chemistries Better anemia control Better hypertension control Improved sense of well-being Suitable for children in school and employed patients Less cost Disadvantages Catheter malfunction Weight gain Patient fatigue with the procedure Development of abdominal hernias Peritonitis

provide the needed dialysis exchanges, usually at night during sleep, have been developed and are in common use. Evidence-based standards for quantification of peritoneal dialysis, guidelines for adequacy of treatment, and protocols for the diagnosis and treatment of peritonitis, exit site infections, and tunnel infections have also been established. Catheter design and placement techniques and peritoneal dialysis fluid composition and biocompatibility have been improved. As a result of these developments, peritoneal dialysis is now widely available for the treatment of ESKD in most parts of the world, and its use is growing much faster than that of hemodialysis. The advantages and disadvantages of peritoneal dialysis, as well as the indications and contraindications for peritoneal dialysis and factors that influence the choice of hemodialysis versus peritoneal dialysis are presented in Table 15.

RENAL TRANSPLANTATION Kidney transplantation is the treatment of choice for ESKD, and the number of kidney transplants (both cadaveric and living donor) performed in the United States has dramatically increased in the past decade. This reflects an increased availability of living kidney donation, the result of increased public education and awareness. Living unrelated kidney donation is the area of greatest increase in the United States. Although cadaveric kidney donation has not substantially increased, there has been a lowering of the threshold of acceptable cadaveric kidney transplantation, which has been largely responsible for the increase in cadaveric kidney transplantation. Donor organ availability continues to fall short of demand, resulting in long transplant waiting lists.

Transplantation Immunobiology The major barrier to successful allotransplantation is immunologic. Renal allograft rejection remains the major cause of graft loss. The delineation of molecular mechanisms of allograft rejection has led to new classes of biologic agents for the abrogation and control of allograft rejection. Additionally, there is the increasing prospect of achieving transplantation tolerance and of successful xenotransplantation. Central to the question of transplantation immunology are the facts of self-identity of the organism and the ability to differentiate self from nonself and mount an immune response to destroy the non–self-‘‘invader.’’ Most of the proteins of the body are oligomorphic or nonpolymorphic, and as such, lack the necessary variation to distinguish individual members of the species, one from the other.

medwedi.ru

756

Part Four: The Urinary System

The vast polymorphism, of almost limitless extent, that is needed to achieve this ‘‘self-identity,’’ is to be found in the major histocompatibility complex (MHC) structure. Unlike any other region of the chromosome, the MHC gene is highly polymorphic, as are its products, the MHC class I and class II cell surface proteins. Individuals with identical MHC proteins [other than identical (monozygotic) twins] are extremely rare. Histocompatibility antigens can be divided into a single MHC or system and numerous minor histocompatibility (miH) systems. Incompatibility for either MHC or miH antigens between donor and recipient leads to an immune response against the graft, although more vigorous reaction occurs with MHC differences. MHC class I glycoproteins are expressed on the surface of most nucleated cells, although at different levels. They are responsible for activating T-cells bearing the CD8 surface protein (CD8þ cells). MHC class II proteins, which are also membrane-anchored glycoproteins, stimulate T-cells bearing CD4 surface protein (CD4þ cells). Under basal conditions, class II proteins are expressed only in B-lymphocytes, dendritic cells, and some endothelial cells. During an immune or inflammatory response, however, many other cell types may be induced to express MHC class II proteins. Both class I and II proteins form a similar threedimensional structure at the cell surface. Within this structure is a groove flanked by two alpha helices; the amino acids in the groove show the highest polymorphism within a species. During the synthesis and transport of MHC class I and II proteins to the cell surface, they become associated with small peptides that fit into the groove. Class I proteins bind peptides derived from the intracellular compartment, while class II proteins bind peptides derived from the extracellular compartment. The combination of MHC protein and peptide is recognized by the antigen receptor on the T-cell, the T-cell receptor (TCR). Thus, antigenic peptides are recognized by T-cells only when they are presented in the groove of (i.e., in the context of) the MHC; antigen recognition is said to be ‘‘MHC restricted.’’ When the renal allograft is placed, host-specialized antigen-presenting cells take up foreign protein from the graft, process them, and load some of the resulting ‘‘foreign’’ peptides onto their MHC grooves. These are then presented at the cell surface to host T-cell. The class III region of the MHC is large and contains many uncharacterized genes. Genes that have been characterized encode proteins with a variety of functions important in immunity, such as TNF-a and TNF-b. miH antigens (e.g., the male antigen or H-Y) may play a prominent role in graft rejection in a recipient who is given an MHC-compatible graft but in whom preexisting sensitization to miH antigens exists. It may, for example, explain graft rejection and loss in renal transplants performed between human leukocyte antigen (HLA)-identical siblings. Multiple miH differences have been shown to represent an immunogenic stimulus that can be equivalent to that of the MHC. The process of graft rejection begins when recipient CD4þ T-cells are activated by graft alloantigen (197). Graft alloantigen is presented to the recipient T-cells by either of the processes of direct antigen presentation or indirect antigen presentation. The transplanted kidney contains bone marrow–derived leukocyte-like cells called passenger leukocytes. These passenger leukocytes rapidly traffic (migrate) out of the graft, via the lymphatic drainage, to the recipient’s lymphoid organs. Here, they rapidly mature into potent antigen-presenting cells (dendritic-like cells). Non–self MHC class II molecules expressed on these specialized, antigenpresenting cells of the graft, directly activate recipient

CD4þ cells. The peptide-binding grooves of these non–selfMHC molecules may contain peptides derived from graft or recipient proteins. Non–self-MHC are extremely potent transplantation antigens, which activate large numbers of T-cell clones in the recipient. Up to 5% of all clones in the body may respond to a non–self-MHC molecule (198). This process of presentation of donor MHC by donor ‘‘dendritic’’ cells is described as direct antigen presentation. In similar fashion, non–self-MHC class I molecules expressed on many cells in the graft may directly activate recipient CD8þ T-cells. Another example of direct antigen presentation is when recipient T-cells react with endothelial cells of the donor (allograft), which in an activated state express MHC molecules. Direct antigen presentation results in powerful stimulation of the immune system and is thought to be mainly responsible for acute allograft rejection. Direct antigen presentation bypasses antigen processing by recipient antigen-presenting cells. The second mechanism of host T-cell activation involves indirect antigen presentation. In this mechanism, antigen-presenting cells of the recipient migrate into the transplanted kidney, take up graft alloantigens, process the molecules, and present the resulting peptides on selfMHC molecules to T-cells, stimulating and activating them. Conversely donor cells could traffic out of the allograft and interact with recipient APCs in the lymphoid organs. Recipient APCs may also react with soluble ‘‘circulating’’ donor proteins that have been released into the bloodstream as a result of processes within the allograft, e.g., ischemia and inflammation that result in cell injury and/or cell death. Following the binding of antigenic protein by the APC, the protein is taken up into intracellular proteolysosomes and digested into peptide fragments. A relatively small number of these peptide fragments, and which are immunogenic, are selected, placed in the groove of the MHC molecule, and transported as the MHC–peptide complex to the cell surface to be presented to T-cells. With indirect antigen presentation, donor antigen-presenting cells such as dendritic cells and macrophages are involved as intermediaries between recipient T-cells and transplanted donor cells. The results of CD4þ and CD8þ activation, whether by direct or indirect mechanism of antigen presentation, are the generation of cytokine synthesis, and the proliferation and differentiation of T-cells into cytotoxic T-cells (CTLs).

Tests for Histocompatibility Antigens Tissue typing consists of the analysis of histocompatibility antigens of donor and recipient so as to determine the degree of foreignness between the two individuals and thus to predict the outcome of the transplantation. There are several ways to determine the degree of parity or disparity between transplantation antigens: (i) serologic detection of cell surface antigens (lymphocytotoxicity test); (ii) measurement of the reaction between leukocytes from the donor and recipient in the mixed lymphocyte reaction; and (iii) genotyping of transplantation epitopes.

T-Cell Antigen Recognition, Processing, and Signaling The TCR expressed on the surface of the T-cell interacts with the antigenic peptide located in the groove of the MHC molecule on the surface of the APC, but does not transduce a signal. The TCR is associated with a transmembrane coreceptor, the CD4 or CD8 molecule; CD4 and CD8 molecules act as

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

adhesion molecules tightening the binding of T-cells with APCs, and also transduce signals into the cell. Additional costimulatory molecules expressed on APCs bind with their respective ligands on the T-cell, thereby enhancing and sustaining T-cell activation. Other adhesion molecules, the accessory molecules interact in pairs between APC and T-cells, resulting in the formation of the immunological synapse, which allows full activation of the T-cell. Activation of the CD4þ cell results in proliferation, cytokine synthesis and secretion, migration of T-cells from lymphoid tissue into the allograft and differentiation into memory cells, while activation of CD8þ cells results in their differentiation into cytotoxic T-lymphocytes (T-killer cells). Interaction of the TCR and alloantigen brings results in a complex-signaling cascade that lead to the activation of at least two major signaling pathways: the Ca2þ–calcineurin cascade and the protein kinase C (PKC)–Erk cascade. Calcineurin is a serine/threonine phosphatase that dephosphorylates and functionally inactivates key transcription factors such as nuclear factor of activated T cells (NFAT) involved in IL-2 gene transcription. PKC activation, in a multistep signaling pathway, leads to phosphorylation of Erk, which then phosphorylates and activates transcription factors such as c-fos and Elk-1, leading to the initiation of gene transcription.

Cytokines and Chemokines Graft rejection involves interactions among many cells involved in the immune and inflammatory responses and other cells such as endothelial and parenchymal cells. These cells communicate through direct contact using recognition molecules located on their cell surfaces (e.g., MHC, TCR CD4, CD8, CD40L, and FasL). In addition to the numerous cell–cell-based interactions required for T-cell activation, important signals are also delivered through the binding of soluble proteins, the cytokines, to specific cell surface cytokine receptors. A cascade of cytokines is produced that amplifies immune and inflammatory processes after transplantation (199). Cytokines such as IL-1 and IL-12, derived mainly from antigen-presenting cells, sensitize T-cells, by upregulating their expression of receptors for other cytokines, mainly T-cell derived, such as IL-2 and IL-4, which cause proliferation and differentiation. Many of the phenomena observed in the immune response to a transplant are mediated by several cytokines, acting redundantly and synergistically. On the other hand, calcineurin induces many cytokines, including CD40L, calcineurin, cytokine gc chain, and tyrosine-protein kinase receptor torso precursor (TOR), which all serve nonredundant functions. Activation of the calcineurin pathway results in the activation of transcription factors that regulate the transcription of genes encoding for several key cytokines (e.g., IL-2 and IFN-g) and cytokine receptors. Cytokines regulate MHC expression and the peptide generation and processing pathways. Under basal conditions, parenchymal cells express MHC antigens, adhesion molecules, and costimulatory molecules at levels too low to allow T-cell recognition. Certain cytokines may increase the antigenicity of an allograft by inducing the expression of MHC class I and II, adhesion and signaling molecules, and cytokine receptors. Costimulatory signals are also regulated by cytokines. IFN-g increases the transcription of the large mutifunctional protease genes and the genes for transporters associated with antigen processing, which are encoded in the class II region of the MHC, and could influence the peptides available for binding to the class I grooves. The growth factor cytokines such as IL-2 mediate the triggering, commitment, and clonal expansion of T- and

757

B-lymphocytes and the emergence of their effector functions. T-cell receptor triggering is dependent on the presence of costimulatory factors (such as CD28 engaging B7-1/B7-2) and may be promoted by the binding of certain cytokines produced by the APC to their cognate receptors (e.g., IL-2, IL-6, and IL-12) on the T-cell (200). The subsequent lymphocyte differentiation and clonal expansion also require that certain cytokines produced by T-cells (e.g., IL-2, IL-4, IL-7, and IL-13) engage their receptors on T-cells, producing paracrine or autocrine effects. The aggregate strength of those signals may be a rate-limiting step in the immune response. Cytokines also play a crucial role in the organization of inflammation in a rejecting allograft. Cytokines can activate endothelial cells and affect their interactions with leukocytes and platelets, as well as their regulation of vasomotor tone and fluid movement. The primary role of cytokines in an immune response is to initiate proliferation, differentiation, and homing of leukocytes in the generation of immunity. However, certain cytokines also may directly damage tissue acutely or chronically. TNF-a produced by CTLs and macrophages may damage a graft, and blocking the effects of TNF with neutralizing antibodies can prolong organ graft survival. Several chemokines have been identified, which modulate help to determine the extent and kinetics of immune-related transplantation injury and rejection (201). The chemokines are classified into two major groups based on their structure: the cysteine-X-cysteine (CXC) or alpha chemokines (e.g., IL-8 and IFN-g-inducible protein), which primarily attract neutrophils and T-cells, and the CC or beta chemokines (e.g., macrophage inflammatory protein-1a/b (MIP-1a/b, RANTES and MCP-1), which attract T-cells, monocyte/macrophages, dendritic cells, natural killer cells, and some polymorphs. Chemokines orchestrate the trafficking of leukocytes to sites of inflammation. Chemokines and their receptors are important in the development of graft infiltrates as well as in reperfusion injury. They act not only as attractants for various leukocyte populations but also by augmenting the effector functions of leukocytes within the graft.

Migration of Activated Leukocytes into the Graft To enter the site of inflammation or immune response, leukocytes must migrate across the vascular endothelium. This migration process is controlled by the elaboration of chemokines and by cell–cell interactions between leukocytes and the endothelium. The adhesion of leukocytes to the endothelium is a complex multistep process that involves a series of interactions between the surface of the leukocyte and the endothelial cell or its extracellular matrix (202). Activated cells bear adhesion proteins, chemokine receptors, and addressins, which allow homing to and migration into the graft. The expression of many adhesion proteins involved in these interactions is upregulated by proinflammatory cytokines. Ischemic damage alone results in increased expression of several cytokines, and of these, IL-1 upregulates the expression of members of the selectin family. Other adhesion proteins such as ICAM-1, VCAM-1, and E-selectin (endothelial-specific selectin) are known to be upregulated by the type of cytokines also induced after the trauma of transplantation. Antigen-activated lymphocytes may show tissue-specific homing and show preference for sites in which they are most likely to reencounter their specific antigen. This process seems to be facilitated by recognition by the T-cell of MHC class II/peptide complexes on the vascular endothelium. It may be possible to hide the proteins

medwedi.ru

758

Part Four: The Urinary System

involved in leukocyte extravasation, thereby slowing or preventing the rejection process. Blocking the adhesion proteins by using antibodies or inhibiting their expression has been attempted in experimental and clinical transplantation. In general, cocktails of antibodies are more potent than single antibodies.

Destruction of the Graft The immune system generates many different effector mechanisms, most of which are involved in the destruction of the graft. Patients who have been exposed to MHC antigens through transplant, blood transfusions, or pregnancy often develop antibodies reactive to those MHC antigens. These antibodies can cause hyperacute rejection. The conventional cross-match test, however, detects not only harmful MHC-directed cytotoxic antibodies, but also harmless autoantibodies. In most cases, it is now possible to distinguish autoreactive from alloreactive antibodies, and it is now possible to transplant patients across an apparent positive crossmatch, but in whom the reactivity is due to autoantibodies. Many of the changes associated with acute rejection, including arteriolar thrombosis, interstitial hemorrhage, and fibrinoid necrosis of the arteriolar walls, may result from the deposition of antibody and fixation of complement. MHC-mismatched lymphocytes proliferate and produce cytokines that allow the differentiation of precursor CTLs into effector cells that lyse target cells bearing the mismatched MHC antigens. Furthermore, through the elaboration of high levels of IFN-g and other cytokines or chemokines, CTLs are able to recruit and activate cells involved in delayed type hypersensitivity (DTH) lesions, initiating acute or chronic rejection. Macrophages also participate by elaborating proinflammatory and profibrogenic cytokines that may result in the atherosclerotic and fibrotic changes associated with chronic rejection.

Renal Injury During Transplantation Injury to the kidney frequently occurs during transplantation and often manifests clinically as delayed graft function (DGF) (Table 16) (203) or transplant acute tubular necrosis (TxATN). This injury can occur at many stages and also has short- and long-term consequences for the graft. Factors that participate in renal injury include donor hypertension and aging; brain death in the cadaveric donor; injury arising from harvesting, preservation, and implantation; prolonged warm ischemic time; and anastomosis time or rewarm time. The pathology of transplant ATN is not identical to that of native kidney ATN. The extent of tubular necrosis is usually more widespread in transplant ATN, which may be related to the presence of endothelial injury and disseminated intravascular coagulation (DIC) in the brain-dead donor as well as the exposure of the transplant kidney to cold flush and storage. Ischemia/reperfusion injury causes direct injury to the kidney, but also induces an inflammatory response during the phase of healing. Delayed graft function is associated with an increased rate of acute rejection and irreversible graft rejection. Transplant ATN adversely affects survival, while total preservation time and sharing between centers do not predict transplant ATN. Transplant ATN is associated not only with graft loss, but also with patient death and irreversible rejection. These adverse effects of DGF are manifested in the first six months. Pulsatile perfusion is associated with a reduction in DGF. In this era of stronger and improved immunosuppressive therapy, DGF is assuming greater

Table 16 Differential Diagnosis of Delayed Graft Function Prerenal azotemia (e.g., hemorrhage, overdiuresis) Acute tubular necrosis Urologic complications Ureteral anastomotic obstruction Obstruction of the bladder catheter Urine leak, urinoma Vascular complications Hemorrhage Renal artery thrombosis Renal vein thrombosis Renal artery stenosis Calcineurin inhibitor nephrotoxicity (cyclosporine, tacrolimus) Vasoconstriction Thrombotic microangiopathy Other nephrotoxic agents Amphotericin B Aminoglycosides Acyclovir Contrast media Angiotensin-converting enzyme inhibitors Nonsteroidal anti-inflammatory drugs Infection Septicemia Graft pyelonephritis Cytomegalovirus infection Acute rejection Recurrent disease Focal segmental glomerulosclerosis Hemolytic uremic syndrome Other glomerulopathies

importance in graft outcomes. Risk factors for DGF include anastomosis time, total preservation time, black race, donor cerebrovascular accidents, as well as immunological variables such as panel reactive antibodies (PRAs), donorrelated mismatches, and high cytotoxic antibodies. The failure of DGF to recover usually represents severe rejection in an injured transplant. The worst one-year survival rate is recorded in grafts that had both DGF and acute rejection. Evidence suggests that DGF causes an increased frequency of acute rejection, and the real cause of the impaired graft survival is the rejection. Living donor kidneys with extensive HLA mismatching have excellent graft survival, perhaps lacking the injury associated with brain death and prolonged cold storage that accompanies cadaver donation. Several renal syndromes may affect the transplanted kidney (Table 17).

Allograft Rejection Hyperacute rejection is characterized by the sudden, irreversible cessation of graft function minutes to hours after revascularization. Preformed antibodies against donor Table 17 Renal Syndromes Affecting the Transplanted Kidney Hyperacute rejection Accelerated rejection Acute rejection Delayed graft function/transplant acute tubular necrosis Cyclosporine nephrotoxicity Chronic allograft nephropathy Chronic rejection De novo glomerulopathy Recurrent glomerulopathy

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

antigens present on the endothelium mediate this form of rejection (204). One setting for hyperacute rejection is ABO incompatibility, wherein circulating antidonor ABO blood group hemagglutinins bind to glycolipid determinants on endothelial cells. A second setting is the attachment of preformed recipient antidonor HLA antibodies to the vascular lining of the graft. Histologically, there is extensive glomerular and vascular thrombosis. However, routine pretransplant cross-match testing minimizes the risk of hyperacute rejection. Accelerated rejection is characterized by anamnestic responses that occur within five days posttransplant. These responses may include the production of generally lowaffinity antidonor antibodies by presensitized B-cells or the generation of CTLs from memory elements. The immune elements bind to the donor endothelium without the involvement of complement (Type II endothelial activation), leading to disruption of the vascular layer and interstitial hemorrhage. Parenchymal rupture may result in acute pain, tenderness, and swelling of the graft and life-threatening hemorrhage. Accelerated rejection is uncommon with current immunosuppressive strategies, and can often be reversed by antilymphocyte globulin (ALG), plasmapheresis, and cyclophosphamide. Acute rejection is the most common type of rejection in clinical practice, affecting up to 40% of patients. It usually occurs between 7 and 90 days posttransplant, but it may occur later. In the early posttransplant period, there is the activation of alloantigen-specific T-cells, which initiate acute rejection or subclinical graft injury (197). It is often responsive to steroid therapy, but sometimes there is an antibody component, in which cases there is resistance to steroids and a partial response to ALG. Histologically, acute rejection is characterized by intimal arteritis and tubulitis (205). Uncontrolled acute rejection can result in graft swelling, vascular occlusion, and necrosis. Acute rejection episodes that are not completely reversed (to serum creatinine < 1.6 mg/dL) increase the probability of graft loss. Chronic rejection occurs in about half of all renal allografts within 10 years. In contrast to acute rejection, chronic rejection does not respond to immunosuppressive therapy (206). Histopathologically, there is arterial narrowing and hyalinization and interstitial fibrosis. Chronic kidney rejection is often associated with the presence of antidonor antibodies, which correlates with the presence of arterial hyalinization. In addition to these antigen-dependent factors, the development of chronic rejection seems to be influenced by nonimmunological factors associated with ischemia/reperfusion injury, including evidence of cardiovascular compromise in the donor, prolonged cold ischemia time prior to transplantation, and impaired RBF in the recipient. The incidence of chronic rejection may be minimized by aggressive treatment of acute rejection episodes with the goal of achieving complete resolution (207); the use of surveillance biopsies to diagnose subclinical rejection, which if treated could result in better long-term outcomes; matching of HLA antigens; effective maintenance immunosuppression; and vigorous control of hypertension, hyperlipidemia, and diabetes mellitus.

Late Graft Dysfunction In addition to chronic rejection, several disorders can potentially cause graft dysfunction remote from the time of initial transplant: recurrent primary disease, infectious, calcineurin inhibitor–related, and mechanical disorders. Some primary

759

renal diseases recur at a high and predictable rate and may be a relative contraindication to transplantation (e.g., oxalosis). Others recur at a rate that is acceptable for transplantation but sufficient to be seriously considered as a differential diagnosis of late graft dysfunction (e.g., hemolytic uremic syndrome and diabetes mellitus). Immunoglobulin A nephropathy recurs in up to 50% of cases, but is rarely a cause of graft dysfunction. Membranoproliferative glomerulonephritis (especially Type I) also recurs but also rarely causes graft dysfunction. Recurrent focal segmental glomerulosclerosis can occur within minutes of establishing the transplant arterial anastomosis. Acute urinary tract infections may be complicated by transplant pyelonephritis causing allograft dysfunction. Fever, graft tenderness and swelling, rising serum creatinine, and high-ultrasound resistive indices resemble acute graft rejection. Cytomegalovirus (CMV) infection in its most common form presents with fever, malaise, leukopenia, pancytopenia, myalgia, and occasionally renal dysfunction. More severe forms include pulmonary infiltrates, respiratory failure, hepatitis, and renal failure. CMV may directly involve the graft and cause a CMV glomerulopathy (208). The calcineurin inhibitors, cyclosporine and tacrolimus, are nephrotoxic. Chronic interstitial fibrosis in a striped pattern is the classic histologic finding in chronic calcineurin inhibitor nephropathy. Finally, obstructive uropathy can occur by mechanisms that afflict native kidneys, including renal stone disease, but also those peculiar to the transplanted kidney, including ureteral anastomotic stenosis, lymphoceles, and BK virus infection.

Evaluation and Selection of the Living Donor The living donor evaluation begins with education regarding the process of evaluation and donation, followed by a thorough history, physical examination, and psychosocial evaluation. A comprehensive laboratory screening is performed, including complete blood count, chemistry panel, HIV, HBsAg, antihepatitis C virus, CMV, glucose tolerance test (for diabetic families), urinalysis, urine culture, pregnancy test, and two 24-hour urine determinations for creatinine clearance and protein excretion. Chest X ray, electrocardiogram, and exercise treadmill test are performed for patients aged 50 years and older. Psychosocial evaluation, and intravenous pyelogram, renal angiogram, and/or helical CT urogram are performed. Potential donors are tissue typed and cross-matched. Prospective donors are generally excluded if they are less than 18 or more than 65 years of age, or have hypertension, diabetes, proteinuria, reduced GFR, microscopic hematuria, urologic abnormalities, or significant medical or psychiatric conditions (including active substance abuse).

Evaluation of Prospective Kidney Transplant Recipients An extensive pretransplant evaluation of the prospective recipient is performed to detect and treat reversible medical and surgical conditions that might increase the risk of transplantation if left untreated. Ischemic heart disease substantially increases the risk of transplantation. Cancer screening is directed at common cancers for the age group and gender. Screening for colorectal malignancy is accomplished with a stool occult blood test as well as sigmoidoscopy or colonoscopy in older patients. Chest X rays are used to screen for lung cancer. Digital prostate exam and possibly prostatespecific antigen determinations are performed to detect prostate cancer. Women should undergo pelvic exam and a

medwedi.ru

760

Part Four: The Urinary System

Table 18 Contraindications to Renal Transplantation Disseminated malignancy Refractory cardiac failure Chronic respiratory failure Advanced hepatic disease Extensive vascular disease: coronary, cerebral, or peripheral Severe congenital urinary tract abnormality Chronic infection, refractory to therapy Persistent coagulation disorder Severe mental retardation Psychosocial problems: severe psychosis, alcoholism, or drug addiction

Pap smear. Women over 40 years or younger women with a family history of breast cancer should have a mammogram. In patients with a history of cancer, it is generally recommended that a two-year interval for the most invasive cancers elapse before transplantation. Smoking cessation should be accomplished. Screening for esophagitis and peptic ulcer disease can be reserved for patients with symptoms. Evidence for tuberculosis, CMV, or HIV infection should be established. Pulmonary function studies may be indicated in patients with chronic lung disease. Urologic evaluation can generally be reserved for patients with chronic bladder dysfunction or recurrent infection. Renal ultrasound, computerized tomography, or magnetic resonance imaging study is probably needed to screen for renal malignancies or other structural problems. Psychosocial evaluation is obtained to ensure that the patient is capable of providing informed consent and can comply with the posttransplant immunosuppression regimen. Despite these potential contraindications (Table 18), selection criteria are generally less restrictive than in past, and more patients with significant comorbidity and older patients are receiving renal transplants. The donor and recipient should be ABO blood group compatible and have no preformed antibodies. Antibodies directed against a random panel of lymphocytes from the general population are assayed, and the percentage of these lymphocytes that incite a reaction from the recipient— termed the percent PRA—is measured. Transplant recipients with a high PRA are more likely to have preformed antibody against a donor kidney and thus more susceptible to hyperacute rejection. When a potential donor kidney becomes available, the recipient’s serum is tested for reaction against cells from the potential donor. If the potential recipient’s serum reacts with the donor, transplantation is usually contraindicated. MHC antigens are also measured on cells from both the donor and the recipient. In the United Network for Organ Sharing protocol for organ allocation, highest priority is given to kidneys with no MHC antigen mismatches. Because the average waiting time currently exceeds two years, periodic reevaluation of the recipient may be needed in the interval.

Immunosuppressive Agents The search for the optimal chronic immunosuppression regimen for renal transplant patients continues to evolve as new immunosuppressive agents are introduced and new combinations of therapies tried. All of these agents have therapeutic effects, toxicities related to immunodeficiency (i.e., increased infection and malignancies), and nonimmune toxicities (e.g., nephrotoxicity, hyperlipidemia, and diabetes). The initial period after transplantation requires intense immunosuppression. During the ‘‘induction’’ period, high doses of combinations of calcineurin inhibitors,

mycophenolate mofetil (MMF), rapamycin, or azathioprine, and glucocorticoids are often used. The reversal of acute rejection also requires intense immunosuppression with high doses of glucocorticoids, but also in more severe cases, with anti-CD3 of polyclonal ALG or ATG. Maintenance immunosuppression can generally be achieved after three to six months, and now usually involves cyclosporine or tacrolimus in combination with MMF, rapamycin or azathioprine, and/or steroids. However, drug regimens and treatment guidelines are constantly evolving. Corticosteroids downregulate the expression of several genes that encode for inflammatory cytokines, inhibit leukocyte migration to sites of inflammation, promote apoptosis of lymphocytes and eosinophils, and reduce expression of MHC class II molecules, thereby inhibiting T-cell activation and function. Azathioprine blocks RNA and DNA synthesis by inhibiting inosinic acid, the precursor for the purines adenylic and guanidylic acids. Chlorambucil and cyclophosphamide alkylate DNA and interfere with DNA metabolism. These compounds are cytotoxic to lymphocytes and are thus immunosuppressive. The cytotoxic effects of these compounds are not limited to the immune system; however, they have a wide range of side effects (e.g., anemia, leukopenia, thrombocytopenia, intestinal damage, and hair loss) that may limit the dosage and duration of therapy. Cyclosporine and tacrolimus exert their pharmacologic effects by inhibiting the activity of calcineurin, an intracellular phosphatase essential for transcriptional activation of IL-2 gene, and ultimately T-cell activation. In contrast, sirolimus inhibits a different pathway required for full T-cell activation by blocking the phosphorylation of p70(s6) kinase and the eukaryotic initiation factor-4E-binding protein, PHAS-1 (209). Cyclosporine is effective before transplantation, but is ineffective in suppressing ongoing rejection. Both cyclosporine and tacrolimus are nephrotoxic and associated with a higher risk of cancer in patients who take the drugs long term. Sirolimus is minimally nephrotoxic when given alone; thrombocytopenia and severe dyslipidemia are its major side effects. Leflunomide blocks T-cell activation by inhibiting the activity of tyrosine kinases associated with cytokine receptors. This agent also prevents T-cell proliferation by inhibiting de novo pyrimidine synthesis (210). ALG, prepared in horses immunized with human lymphocytes, has been used to treat acute rejection. It can cause serum sickness. Monoclonal antibodies are less immunogenic than ALG and can be more specifically targeted. OKT3 is a ‘‘humanized’’ mouse antibody directed against CD3 that is in common use. Antibodies to the IL-2 receptor (CD25) on activated T-cells, and to CD4 are also in use. MMF inhibits the de novo synthesis of purines, crucial to cell cycling of T- and B-cells. It thus blocks clonal expansion of T- and B-cells, preventing antibody production and the generation of CTLs, as well as other effector T-cells (211). In contrast to other immunosuppressive drugs, MMF also inhibits antibody production by B-cells. There seems to be a trend toward better graft survival at three years post-transplant (211).

Complications of Renal Transplantation Transplant patients are at risk of numerous medical and surgical complications (Table 19). Infectious complications, arising mainly as a result of immunosuppressive therapy, are among the most common and significant. Infections may be classified according to duration after transplantation, or by organism or system involved. The main risk factors for

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure

761

Table 19 Complications of Renal Transplantation

SUMMARY AND CONCLUSIONS

Surgical complications

The kidney is an extremely complex organ with tightly integrated functions that are critically involved in the maintenance and restoration of normal physiology of humans over a wide range of clinical conditions. Perhaps more than any other organ, the physiology and pathophysiology of the kidney is directly tied to numerous, significant clinical disorders. The kidney is vulnerable to both acute and chronic injury, which poses a multitude of potential problems for the management of fluid, mineral, electrolyte, acid–base, and metabolic balance, blood pressure, and anemia, particularly in critically ill surgical patients experiencing acute renal decompensation or in ESKD patients undergoing surgery. The trend toward increasingly aggressive resuscitation and life support measures, growing numbers of trauma victims, and the growth in the rate of surgical procedures performed on patients with significant comorbidities will continue to increase the incidence of AKF in the surgical setting. Given the explosive growth in the incidence rates for CKD and ESKD, surgeons will also encounter an increasing proportion of patients with chronically impaired renal function presenting for surgical interventions of other organ systems. Unfortunately, no therapies to date have been shown to reverse renal injury, so that emphasis must be placed on prevention, early detection, prompt correction of precipitating, contributing, or exacerbating factors, and appropriate timing and choice of renal replacement therapy when indicated. Fortunately, continuous dialysis therapies are evolving, which will continue to facilitate advanced therapeutic options for critically ill surgical patients with AKF, and advances in kidney transplantation have allowed it to become applicable to a much broader population of ESKD patients. The Holy Grail, of course, remains the discovery of methods for therapeutic recovery of renal function.

Medical complications

Urologic Cardiovascular Obstruction Coronary artery disease Stricture Hypertension Edema Metabolic Blood clot Hyperparathyroidism Stone Hyperkalemia Excess ureter redundancy Hypomagnesemia Tumor Hyperuricemia and gout Infection (fungus ball, viral) Posttransplant diabetes mellitus Indwelling ureteric stent Hepatic Fluid collections Viral hepatitis (hepatitis B and C) Lymphocele Drug-induced liver dysfunction (e.g., Hematoma cyclosporine, azathioprine, and, Urinoma rarely, mycophenolate mofetil; Abscess antimicrobials) Urine leaks Hematologic Calyceal Anemia Renal pelvic Polycythemia (usually associated Ureteral with transplant renal artery stenosis) Leukopenia (azathioprine, mycophenolate Ureteroneocystostomy mofetil, ganciclovir, and Vesical cytomegalovirus infection) Vascular Infectious Renal artery thrombosis Intravenous catheter associated Renal artery stenosis Pulmonary Renal vein thrombosis Gastrointestinal infections Complications of Central nervous system infections percutaneous Neurologic allograft biopsy Diffuse encephalopathies Arteriocalyceal fistulas Focal neurological disorders Arteriovenous fistulas Seizure disorders Iliac or mesenteric Peripheral nerve disorders vascular Cancer lacerations Skin cancers Perirenal hematomas Posttransplant lymphoproliferative disease Pseudoaneurysms Sarcomas Gross hematuria Carcinomas of the vulva, anus, cervix, liver Intra-abdominal organ injury

infection are immunosuppressive therapy, the immunocompromised state of uremia, and major surgery involving urologic and vascular procedures. Other risk factors include DGF and acute rejection, hyperglycemia, diabetes, splenectomy, and hepatitis B infection. Infections may be transmitted from the donor. Pretransplant screening for infections is critical as are prophylactic measure post-transplant. The timing of infections posttransplant is of diagnostic importance. Infections within the first month posttransplant are associated with the surgical procedure, usually bacterial infections of the urinary tract, respiratory tract, perinephric space, surgical wound, and vascular access sites (line sepsis). Herpes simplex virus (HSV) infections may occur at this time. From one to six months, the most common infection is due to CMV; other infectious agents during this interval include opportunistic organisms such as pneumocystis carinii, cryptococcus, aspergillus and other fungal infections, nocardia, toxoplasma, listeria, nontyphoid salmonella, tuberculosis, and viral infections, including primary or reactivated CMV, Epstein–Barr virus (EBV) varicella-zoster virus, and adenovirus. After six months, communityacquired infections predominate. Persistent viral infections (e.g., CMV, HSV, EBV, hepatitis B and C, and HIV) can assume great importance in the transplant patients.

REFERENCES 1. Just A, Arendshorst WJ. Dynamics and contribution of mechanisms mediating renal blood flow autoregulation. Am J Physiol Regul Integr Comp Physiol 2003; 285:R619–R631. 2. Venkatachalum MA, Kriz W. Anatomy. In: Heptinstall RH, ed. Pathology of the Kidney. 4th ed. Boston: Little, Brown and Co., 1992:35. 3. DiBona GF, et al. Neural control of the kidney: functionally specific renal sympathetic nerve fibers. Am J Physiol Regul Integr Comp Physiol 2000; 279:R1517–R1524. 4. Cockett AT. Lymphatic network of kidney. I. Anatomic and physiologic considerations. Urology 1977; 9:125–129. 5. Schnermann J, Levine DZ. Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide. Annu Rev Physiol 2003; 65:501–529. 6. Navar LG. Renal autoregulation: perspectives from whole kidney and single nephron studies. Am J Physiol 1978; 234: F357–F370. 7. Aronson PS. Ion exchangers mediating NaCl transport in the renal proximal tubule. Cell Biochem Biophys 2002; 36:147–153. 8. Nielsen S, Frokiaer J, Marples D, et al. Aquaporins in the kidney: from molecules to medicine. Physiol Rev 2002; 82:205–244. 9. Giebisch GH. A trail of research on potassium. Kidney Int 2002; 62:1498–1512. 10. Loffing J, Kaissling B. Sodium and calcium transport pathways along the mammalian distal nephron: from rabbit to human. Am J Physiol Renal Physiol 2003; 284:F628–F643. 11. Hoenderop JG, Nilius B, Bindels RJ. Molecular mechanism of active Ca2þ reabsorption in the distal nephron. Annu Rev Physiol 2002; 64:529–549.

medwedi.ru

762

Part Four: The Urinary System

12. Yu AS. Evolving concepts in epithelial magnesium transport. Curr Opin Nephrol Hypertens 2001; 10:649–653. 13. Quamme GA, de Rouffignac C. Epithelial magnesium transport and regulation by the kidney. Front Biosci 2000; 5: D694–D711. 14. Murer H, Hernando N, Forster I, et al. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev 2000; 80:1373–1409. 15. Friedlander G. Autocrine/paracrine control of renal phosphate transport. Kidney Int Suppl 1998; 65:S18–S23. 16. Good DW. The thick ascending limb as a site of renal bicarbonate reabsorption. Semin Nephrol 1993; 13:225–235. 17. de Mello-Aires M, Malnic G. Distal tubule bicarbonate transport. J Nephrol 2002; 15(suppl 5):S97–S111. 18. Hamm LL, Hering-Smith KS. Acid-base transport in the collecting duct. Semin Nephrol 1993; 13:246–255. 19. Russel FG, Masereeuw R, van Aubel RA. Molecular aspects of renal anionic drug transport. Annu Rev Physiol 2002; 64:563–594. 20. Masereeuw R, Russel FG. Mechanisms and clinical implications of renal drug excretion. Drug Metab Rev 2001; 33:299–351. 21. Berkhin EB, Humphreys MH. Regulation of renal tubular secretion of organic compounds. Kidney Int 2001; 59:17–30. 22. Dantzler WH. Renal organic anion transport: a comparative and cellular perspective. Biochim Biophys Acta 2002; 1566: 169–181. 23. Dresser MJ, Leabman MK, Giacomini KM. Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 2001; 90:397–421. 24. Lang F. Osmotic diuresis. Ren Physiol 1987; 10:160–173. 25. Brater DC. Pharmacology of diuretics. Am J Med Sci 2000; 319:38–50. 26. Preisig PA, Toto RD, Alpern RJ. Carbonic anhydrase inhibitors. Ren Physiol 1987; 10:136–159. 27. Prandota J. Furosemide: progress in understanding its diuretic, anti-inflammatory, and bronchodilating mechanism of action, and use in the treatment of respiratory tract diseases. Am J Ther 2002; 9:317–328. 28. Velazquez H. Thiazide diuretics. Ren Physiol 1987; 10:184–197. 29. Ryan MP. Magnesium and potassium-sparing diuretics. Magnesium 1986; 5:282–292. 30. Doggrell SA, Brown L. The spironolactone renaissance. Expert Opin Investig Drugs 2001; 10:943–954. 31. Suki WN. Use of diuretics in chronic renal failure. Kidney Int Suppl 1997; 59:S33–S35. 32. Bricker NS. On the meaning of the intact nephron hypothesis. Am J Med 1969; 46:1–11. 33. Anderson S, Brenner BM. The role of intraglomerular pressure in the initiation and progression of renal disease. J Hypertens Suppl 1986; 4:S236–S238. 34. Brenner BM. Nephron adaptation to renal injury or ablation. Am J Physiol 1985; 249:F324–F337. 35. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int 1996; 49:1774–1777. 36. Brenner BM, Mackenzie HS. Nephron mass as a risk factor for progression of renal disease. Kidney Int Suppl 1997; 63: S124–S127. 37. Halperin ML, Bohn D. Clinical approach to disorders of salt and water balance. Emphasis on integrative physiology. Crit Care Clin 2002; 18:249–272. 38. Oster JR, Singer I, Thatte L, et al. The polyuria of solute diuresis. Arch Intern Med 1997; 157:721–729. 39. Robertshaw M, Lai KN, Swaminathan R. Prediction of creatinine clearance from plasma creatinine: comparison of five formulae. Br J Clin Pharmacol 1989; 28:275–280. 40. Vervoort G, Willems HL, Wetzels JF. Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: validity of a new (MDRD) prediction equation. Nephrol Dial Transplant 2002; 17:1901–-1913. 41. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate

42.

43.

44.

45. 46.

47.

48.

49. 50.

51.

52.

53.

54. 55.

56.

57. 58. 59. 60.

61. 62.

63. 64. 65.

from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130:461–470. Manjunath G, Sarnak MJ, Levey AS. Estimating the glomerular filtration rate. Dos and don’ts for assessing kidney function. Postgrad Med 2001; 110:55–62; quiz 11. van Bommel EF, Leunissen KM, Weimar W. Continuous renal replacement therapy for critically ill patients: an update. J Intensive Care Med 1994; 9:265–280. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ. Acute renal failure in intensive care units—causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure. Crit Care Med 1996; 24:192–198. Albright RC Jr. Acute renal failure: a practical update. Mayo Clin Proc 2001; 76:67–74. Silvester W. Outcome studies of continuous renal replacement therapy in the intensive care unit. Kidney Int Suppl 1998; 66:S131–S141. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996; 275: 1489–1494. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983; 74:243–248. Anderson RJ, Linas SL, Berns AS, et al. Nonoliguric acute renal failure. N Engl J Med 1977; 296:1134–1138. Yared A, Kon V, Ichikawa I. Mechanism of preservation of glomerular perfusion and filtration during acute extracellular fluid volume depletion. Importance of intrarenal vasopressinprostaglandin interaction for protecting kidneys from constrictor action of vasopressin. J Clin Invest 1985; 75:1477–1487. Guazzi MD, Agostoni P, Perego B, et al. Apparent paradox of neurohumoral axis inhibition after body fluid volume depletion in patients with chronic congestive heart failure and water retention. Br Heart J 1994; 72:534–539. Slater MS, Mullins RJ. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review. J Am Coll Surg 1998; 186:693–716. Scolari F, Tardanico R, Zani R, et al. Cholesterol crystal embolism: a recognizable cause of renal disease. Am J Kidney Dis 2000; 36:1089–1109. Porter GA. Contrast-associated nephropathy. Am J Cardiol 1989; 64:22E–26E. Parfrey PS, Griffiths SM, Barrett BJ, et al. Contrast materialinduced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med 1989; 320:143–149. Alexandridis G, Liberopoulos E, Elisaf M. Aminoglycosideinduced reversible tubular dysfunction. Pharmacology 2003; 67:118–120. Kaloyanides GJ, Pastoriza-Munoz E. Aminoglycoside nephrotoxicity. Kidney Int 1980; 18:571–582. Porter GA, Bennett WM. Nephrotoxic acute renal failure due to common drugs. Am J Physiol 1981; 241:F1–F8. Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother 2002; 49(suppl 1):37–41. Richman AV, Narayan JL, Hirschfield JS. Acute interstitial nephritis and acute renal failure associated with cimetidine therapy. Am J Med 1981; 70:1272–1274. Dutt MK, Moody P, Northfield TC. Effect of cimetidine on renal function in man. Br J Clin Pharmacol 1981; 12:47–50. Berglund F, Killander J, Pompeius R. Effect of trimethoprimsulfamethoxazole on the renal excretion of creatinine in man. J Urol 1975; 114:802–808. Esson ML, Schrier RW. Diagnosis and treatment of acute tubular necrosis. Ann Intern Med 2002; 137:744–752. Espinel CH, Gregory AW. Differential diagnosis of acute renal failure. Clin Nephrol 1980; 13:73–77. Miller ED Jr, Ackerly JA, Peach MJ. Blood pressure support during general anesthesia in a renin-dependent state in the rat. Anesthesiology 1978; 48:404–408.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure 66. Zarich S, Fang LS, Diamond JR. Fractional excretion of sodium. Exceptions to its diagnostic value. Arch Intern Med 1985; 145:108–112. 67. Bakris GL, Lass N, Gaber AO, Jones JD, Burnett JC Jr. Radiocontrast medium-induced declines in renal function: a role for oxygen free radicals. Am J Physiol 1990; 258:F115–F120. 68. Durham JD, Caputo C, Dokko J, et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int 2002; 62:2202–2207. 69. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002; 162:329–336. 70. Briguori C, Manganelli F, Scarpato P, et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002; 40:298–303. 71. Boccalandro F, Amhad M, Smalling RW, Sdringola S. Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Catheter Cardiovasc Interv 2003; 58:336–341. 72. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343:180–184. 73. Kay J, Chow WH, Chan TM, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA 2003; 289:553–558. 74. Denton MD, Chertow GM, Brady HR. "Renal-dose" dopamine for the treatment of acute renal failure: scientific rationale, experimental studies and clinical trials. Kidney Int 1996; 50:4–14. 75. Segal JM, Phang PT, Walley KR. Low-dose dopamine hastens onset of gut ischemia in a porcine model of hemorrhagic shock. J Appl Physiol 1992; 73:1159–1164. 76. Burton CJ, Tomson CR. Can the use of low-dose dopamine for treatment of acute renal failure be justified? Postgrad Med J 1999; 75:269–274. 77. Weisberg LS, Kurnik PB, Kurnik BR. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 1994; 45:259–265. 78. Halpenny M, Markos F, Snow HM, et al. Effects of prophylactic fenoldopam infusion on renal blood flow and renal tubular function during acute hypovolemia in anesthetized dogs. Crit Care Med 2001; 29:855–860. 79. Tumlin JA, Wang A, Murray PT, Mathur VS. Fenoldopam mesylate blocks reductions in renal plasma flow after radiocontrast dye infusion: a pilot trial in the prevention of contrast nephropathy. Am Heart J 2002; 143:894–903. 80. Sheinbaum R, Ignacio C, Safi HJ, Estrera A. Contemporary strategies to preserve renal function during cardiac and vascular surgery. Rev Cardiovasc Med 2003; 4(suppl 1):S21–S28. 81. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994; 331:1416–1420. 82. Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hiesmayr M. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol 2000; 11:97–104. 83. Better OS, Rubinstein I, Winaver JM, Knochel JP. Mannitol therapy revisited (1940–1997). Kidney Int 1997; 52:886–894. 84. Bonventre JV, Weinberg JM. Kidney preservation ex vivo for transplantation. Annu Rev Med 1992; 43:523–553. 85. Ratcliffe PJ, Richardson AJ, Kirby JE, Moyses C, Shelton JR, Morris PJ. Effect of intravenous infusion of atriopeptin 3 on immediate renal allograft function. Kidney Int 1991; 39: 164–168. 86. Sands JM, Neylan JF, Olson RA, O’Brien DP, Whelchel JD, Mitch WE. Atrial natriuretic factor does not improve the outcome of cadaveric renal transplantation. J Am Soc Nephrol 1991; 1:1081–1086.

763

87. Allgren RL, Marbury TC, Rahman SN, et al. Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 1997; 336:828–834. 88. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids versus colloids in fluid resuscitation: a systematic review. Crit Care Med 1999; 27:200–210. 89. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. BMJ 1998; 317:235–240. 90. Kellum JA. The use of diuretics and dopamine in acute renal failure: a systematic review of the evidence. Crit Care (Lond) 1997; 1:53–59. 91. De Vriese AS. Prevention and treatment of acute renal failure in sepsis. J Am Soc Nephrol 2003; 14:792–805. 92. Deppisch RM, Beck W, Goehl H, Ritz E. Complement components as uremic toxins and their potential role as mediators of microinflammation. Kidney Int Suppl 2001; 78: S271–S277. 93. Miyata T, Sugiyama S, Saito A, Kurokawa K. Reactive carbonyl compounds related uremic toxicity (‘‘carbonyl stress’’). Kidney Int Suppl 2001; 78:S25–S31. 94. Dhondt A, Vanholder R, Van Biesen W, Lameire N. The removal of uremic toxins. Kidney Int Suppl 2000; 76:S47–S59. 95. Vanholder R, De Smet R, Vogeleere P, Ringoir S. Middle molecules: toxicity and removal by hemodialysis and related strategies. Artif Organs 1995; 19:1120–1125. 96. Ringoir S. An update on uremic toxins. Kidney Int Suppl 1997; 62:S2–S4. 97. Yu HT. Progression of chronic renal failure. Arch Intern Med 2003; 163:1417–1429. 98. Stahl PJ, Felsen D. Transforming growth factor-beta, basement membrane, and epithelial-mesenchymal transdifferentiation: implications for fibrosis in kidney disease. Am J Pathol 2001; 159:1187–1192. 99. Bottinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol 2002; 13:2600–2610. 100. Badid C, Vincent M, Fouque D, Laville M, Desmouliere A. Myofibroblast: a prognostic marker and target cell in progressive renal disease. Ren Fail 2001; 23:543–549. 101. Norman JT, Fine LG. Progressive renal disease: fibroblasts, extracellular matrix, and integrins. Exp Nephrol 1999; 7: 167–177. 102. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002; 39: S1–S246. 103. Krawiec DR. Managing gastrointestinal complications of uremia. Vet Clin North Am Small Anim Pract 1996; 26:1287– 1292. 104. Drueke TB. Abnormal skeletal response to parathyroid hormone and the expression of its receptor in chronic uremia. Pediatr Nephrol 1996; 10:348–350. 105. Ho LT, Sprague SM. Renal osteodystrophy in chronic renal failure. Semin Nephrol 2002; 22:488–493. 106. Sato K, Obara T, Yamazaki K, et al. Somatic mutations of the MEN1 gene and microsatellite instability in a case of tertiary hyperparathyroidism occurring during high phosphate therapy for acquired, hypophosphatemic osteomalacia. J Clin Endocrinol Metab 2001; 86:5564–5571. 107. Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial 2002; 15:172–186. 108. Bardin T. Musculoskeletal manifestations of chronic renal failure. Curr Opin Rheumatol 2003; 15:48–54. 109. Obrador GT, Pereira BJ. Anaemia of chronic kidney disease: an under-recognized and under-treated problem. Nephrol Dial Transplant 2002; 17(suppl 11):44–46. 110. Agarwal R, Warnock D. Issues related to iron replacement in chronic kidney disease. Semin Nephrol 2002; 22:479–487. 111. Bickford AK. Evaluation and treatment of iron deficiency in patients with kidney disease. Nutr Clin Care 2002; 5: 225–230.

medwedi.ru

764

Part Four: The Urinary System

112. Jaradat MI, Molitoris BA. Cardiovascular disease in patients with chronic kidney disease. Semin Nephrol 2002; 22:459–473. 113. Paparello J, Kshirsagar A, Batlle D. Comorbidity and cardiovascular risk factors in patients with chronic kidney disease. Semin Nephrol 2002; 22:494–506. 114. Levin A. Anemia and left ventricular hypertrophy in chronic kidney disease populations: a review of the current state of knowledge. Kidney Int 2002; 80(suppl):35–38. 115. Goldsmith DJ, Covic A. Coronary artery disease in uremia: etiology, diagnosis, and therapy. Kidney Int 2001; 60: 2059–2078. 116. Uhlig K, Levey AS, Sarnak MJ. Traditional cardiac risk factors in individuals with chronic kidney disease. Semin Dial 2003; 16:118–127. 117. Logar CM, Herzog CA, Beddhu S. Diagnosis and therapy of coronary artery disease in renal failure, end-stage renal disease, and renal transplant populations. Am J Med Sci 2003; 325:214–227. 118. Elsner D. How to diagnose and treat coronary artery disease in the uraemic patient: an update. Nephrol Dial Transplant 2001; 16:1103–1108. 119. Levin A. Identification of patients and risk factors in chronic kidney disease—evaluating risk factors and therapeutic strategies. Nephrol Dial Transplant 2001; 16(suppl 7):57–60. 120. Alpert MA, Ravenscraft MD. Pericardial involvement in endstage renal disease. Am J Med Sci 2003; 325:228–236. 121. O’Hare A, Johansen K. Lower-extremity peripheral arterial disease among patients with end-stage renal disease. J Am Soc Nephrol 2001; 12:2838–2847. 122. Cohen G, Haag-Weber M, Horl WH. Immune dysfunction in uremia. Kidney Int Suppl 1997; 62:S79–S82. 123. Weigert AL, Schafer AI. Uremic bleeding: pathogenesis and therapy. Am J Med Sci 1998; 316:94–104. 124. Winkelmayer WC, Levin R, Avorn J. Chronic kidney disease as a risk factor for bleeding complications after coronary artery bypass surgery. Am J Kidney Dis 2003; 41:84–89. 125. Casserly LF, Dember LM. Thrombosis in end-stage renal disease. Semin Dial 2003; 16:245–256. 126. Crook ED, Thallapureddy A, Migdal S, et al. Lipid abnormalities and renal disease: is dyslipidemia a predictor of progression of renal disease? Am J Med Sci 2003; 325:340–348. 127. Prinsen BH, de Sain-van der Velden MG, de Koning EJ, Koomans HA, Berger R, Rabelink TJ. Hypertriglyceridemia in patients with chronic renal failure: possible mechanisms. Kidney Int 2003; 84(suppl):S121–S124. 128. Hall JE, Brands MW, Henegar JR, Shek EW. Abnormal kidney function as a cause and a consequence of obesity hypertension. Clin Exp Pharmacol Physiol 1998; 25:58–64. 129. Brown TM, Brown RL. Neuropsychiatric consequences of renal failure. Psychosomatics 1995; 36:244–253. 130. Fraser CL, Arieff AI. Metabolic encephalopathy as a complication of renal failure: mechanisms and mediators. New Horiz 1994; 2:518–526. 131. Fraser CL, Arieff AI. Nervous system complications in uremia. Ann Intern Med 1988; 109:143–153. 132. Mach JR Jr, Korchik WP, Mahowald MW. Dialysis dementia. Clin Geriatr Med 1988; 4:853–867. 133. Arieff AI. Dialysis disequilibrium syndrome: current concepts on pathogenesis and prevention. Kidney Int 1994; 45:629–635. 134. Pirzada NA, Morgenlander JC. Peripheral neuropathy in patients with chronic renal failure. A treatable source of discomfort and disability. Postgrad Med 1997; 102:249–250, 255–247, 261. 135. Kurata C, Uehara A, Sugi T, et al. Cardiac autonomic neuropathy in patients with chronic renal failure on hemodialysis. Nephron 2000; 84:312–319. 136. Herts BR. Imaging for renal tumors. Curr Opin Urol 2003; 13:181–186. 137. Prasad S, Bannister K, Taylor J. Is magnetic resonance angiography useful in renovascular disease? Intern Med J 2003; 33:84–90.

138. Ather MH, Noor MA. Role of imaging in the evaluation of renal trauma. J Pak Med Assoc 2002; 52:423–428. 139. Kellerman PS. Perioperative care of the renal patient. Arch Intern Med 1994; 154:1674–1688. 140. Horst M, Mehlhorn U, Hoerstrup SP, Suedkamp M, de Vivie ER. Cardiac surgery in patients with end-stage renal disease: 10-year experience. Ann Thorac Surg 2000; 69:96–101. 141. Lissoos I, Goldberg B, Van Blerk PJ, Meijers AM. Surgical procedures on patients in end-stage renal failure. Br J Urol 1973; 45:359–365. 142. Deutsch E, Bernstein RC, Addonizio P, Kussmaul WG III. Coronary artery bypass surgery in patients on chronic hemodialysis. A case-control study. Ann Intern Med 1989; 110: 369–372. 143. Bastron RD, Perkins RM, Pyne JL. Autoregulation of renal blood flow during halothane anesthesia. Anesthesiology 1977; 46:142–144. 144. Philbin DM, Coggins CH. Plasma antidiuretic hormone levels in cardiac surgical patients during morphine and halothane anesthesia. Anesthesiology 1978; 49:95–98. 145. Miller TR, Anderson RJ, Linas SL, et al. Urinary diagnostic indices in acute renal failure: a prospective study. Ann Intern Med 1978; 89:47–50. 146. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose response in man. JAMA 1973; 225:1611–1616. 147. Cousins MJ, Greenstein LR, Hitt BA, Mazze RI. Metabolism and renal effects of enflurane in man. Anesthesiology 1976; 44:44–53. 148. Creasser C, Stoelting RK. Serum inorganic fluoride concentrations during and after halothane, fluroxene, and methoxyflurane anesthesia in man. Anesthesiology 1973; 39: 537–540. 149. Behne M, Wilke HJ, Harder S. Clinical pharmacokinetics of sevoflurane. Clin Pharmacokinet 1999; 36:13–26. 150. Loehning RW, Mazze RI. Possible nephrotoxicity from enflurane in a patient with severe renal disease. Anesthesiology 1974; 40:203–205. 151. Cousins MJ, Skowronski G, Plummer JL. Anaesthesia and the kidney. Anaesth Intensive Care 1983; 11:292–320. 152. Hunter JM, Jones RS, Utting JE. Comparison of vecuronium, atracurium and tubocurarine in normal patients and in patients with no renal function. Br J Anaesth 1984; 56: 941–951. 153. Morris RB, Cronnelly R, Miller RD, Stanski DR, Fahey MR. Pharmacokinetics of edrophonium in anephric and renal transplant patients. Br J Anaesth 1981; 53:1311–1314. 154. Steiner RW, Coggins C, Carvalho AC. Bleeding time in uremia: a useful test to assess clinical bleeding. Am J Hematol 1979; 7:107–117. 155. Chen KS, Huang CC, Leu ML, Deng P, Lo SK. Hemostatic and fibrinolytic response to desmopressin in uremic patients. Blood Purif 1997; 15:84–91. 156. Davenport R. Cryoprecipitate for uremic bleeding. Clin Pharm 1991; 10:429. 157. Vigano GL, Mannucci PM, Lattuada A, Harris A, Remuzzi G. Subcutaneous desmopressin (DDAVP) shortens the bleeding time in uremia. Am J Hematol 1989; 31:32–35. 158. Livio M, Mannucci PM, Vigano G, et al. Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 1986; 315:731–735. 159. Manian FA. Vascular and cardiac infections in end-stage renal disease. Am J Med Sci 2003; 325:243–250. 160. Werner CW, Saad TF. Prophylactic antibiotic therapy prior to dental treatment for patients with end-stage renal disease. Spec Care Dentist 1999; 19:106–111. 161. Work J. Hemodialysis catheters and ports. Semin Nephrol 2002; 22:211–220. 162. Ash SR. The evolution and function of central venous catheters for dialysis. Semin Dial 2001; 14:416–424. 163. Trerotola SO. Hemodialysis catheter placement and management. Radiology 2000; 215:651–658.

Chapter 37: Urine Formation: From Normal Physiology to Florid Kidney Failure 164. Okadome K, Komori K, Fukumitsu T, Sugimachi K. The potential risk for subclavian vein occlusion in patients on haemodialysis. Eur J Vasc Surg 1992; 6:602–606. 165. Akoh JA. Central venous catheters for haemodialysis: a review. Niger Postgrad Med J 2001; 8:99–103. 166. Saad TF. Central venous dialysis catheters: catheter-associated infection. Semin Dial 2001; 14:446–451. 167. Kovalik EC, Schwab SJ. Treatment approaches for infected hemodialysis vascular catheters. Curr Opin Nephrol Hypertens 2002; 11:593–596. 168. Berns JS. Infection with antimicrobial-resistant microorganisms in dialysis patients. Semin Dial 2003; 16:30–37. 169. Kuti J. Antibiotic treatment of catheter-related bacteremia in the hemodialysis patient. Conn Med 2003; 67:85–88. 170. Sandroni S, McGill R, Brouwer D. Hemodialysis catheterassociated endocarditis: clinical features, risks, and costs. Semin Dial 2003; 16:263–265. 171. Cooper SG, Sofocleous CT. Dialysis access. Semin Roentgenol 2002; 37:327–342. 172. Konner K. Vascular access in the 21st century. J Nephrol 2002; 15(suppl 6):S28–S32. 173. Brescia MJ, Cimino JE, Appel K, Hurwich BJ. Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. N Engl J Med 1966; 275:1089–1092. 174. Burkhart HM, Cikrit DF. Arteriovenous fistulae for hemodialysis. Semin Vasc Surg 1997; 10:162–165. 175. Paulson WD, Ram SJ, Zibari GB. Vascular access: anatomy, examination, management. Semin Nephrol 2002; 22:183–194. 176. NKF-DOQI clinical practice guidelines for vascular access. National Kidney Foundation-Dialysis Outcomes Quality Initiative. Am J Kidney Dis 1997; 30:S150–S191. 177. Santoro TD, Cambria RA. PTFE shunts for hemodialysis access: progressive choice of configuration. Semin Vasc Surg 1997; 10:166–174. 178. Nassar GM, Fishbane S, Ayus JC. Occult infection of old nonfunctioning arteriovenous grafts: a novel cause of erythropoietin resistance and chronic inflammation in hemodialysis patients. Kidney Int 2002; 80(suppl):49–54. 179. Konner K. Increasing the proportion of diabetics with AV fistulas. Semin Dial 2001; 14:1–4. 180. Cynamon J, Pierpont CE. Thrombolysis for the treatment of thrombosed hemodialysis access grafts. Rev Cardiovasc Med 2002; 3(suppl 2):S84–S91. 181. Levin R, Hoenich NA. Running water: measuring water quality in a dialysis facility. Part 2. Nephrol News Issues 2003; 17:25–26, 78. 182. Levin R, Miller L. Running water: designing the dialysis clinic water room. Part 1. Nephrol News Issues 2003; 17:65, 68–70. 183. Oreopoulos DG. Beyond Kt/V: redefining adequacy of dialysis in the 21st century. Int Urol Nephrol 2002; 34:393–403. 184. I. NKF-K/DOQI Clinical Practice Guidelines for Hemodialysis Adequacy: update 2000. Am J Kidney Dis 2001; 37:S7–S64. 185. DOQI guidelines/fourth in a series. Adequacy HD dose, reuse, compliance. NKF-Dialysis Outcomes Quality Initiative. Nephrol News Issues 1997; 11:52–53. 186. NKF-DOQI clinical practice guidelines for hemodialysis adequacy. National Kidney Foundation. Am J Kidney Dis 1997; 30:S15–S66. 187. Gibney RT, Kimmel PL, Lazarus M. The Acute Dialysis Quality Initiative—part I: definitions and reporting of CRRT techniques. Adv Ren Replace Ther 2002; 9:252–254. 188. Ronco C, Bellomo R. Continuous renal replacement therapy: evolution in technology and current nomenclature. Kidney Int Suppl 1998; 66:S160–S164.

765

189. van Bommel EF. Should continuous renal replacement therapy be used for ’non-renal’ indications in critically ill patients with shock? Resuscitation 1997; 33:257–270. 190. Kes P. Slow continuous renal replacement therapies: an update. Acta Med Croatica 2000; 54:69–84. 191. Locatelli F, Pontoriero G, Di Filippo S. Electrolyte disorders and substitution fluid in continuous renal replacement therapy. Kidney Int Suppl 1998; 66:S151–S155. 192. Davenport A, Mehta S. The Acute Dialysis Quality Initiative—part VI: access and anticoagulation in CRRT. Adv Ren Replace Ther 2002; 9:273–281. 193. Hidalgo N, Hynes-Gay P, Hill S, Burry L. Anticoagulation in continuous renal replacement therapy. Dynamics 2001; 12:13–17. 194. Bugge JF. Pharmacokinetics and drug dosing adjustments during continuous venovenous hemofiltration or hemodiafiltration in critically ill patients. Acta Anaesthesiol Scand 2001; 45:929–934. 195. Tenckhoff H, Schechter H. A bacteriologically safe peritoneal access device. Trans Am Soc Artif Intern Organs 1968; 14: 181–187. 196. Moncrief JW, Popovich RP, Nolph KD. The history and current status of continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1990; 16:579–584. 197. Divate SA. Acute renal allograft rejection: progress in understanding cellular and molecular mechanisms. J Postgrad Med 2000; 46:293–296. 198. Kamoun M. Cellular and molecular parameters in human renal allograft rejection. Clin Biochem 2001; 34:29–34. 199. Bunnapradist S, Jordan SC. The role of cytokines and cytokine gene polymorphism in T-cell activation and allograft rejection. Ann Acad Med Singapore 2000; 29:412–416. 200. Dai Z, Lakkis FG. The role of cytokines CTLA-4 and costimulation in transplant tolerance and rejection. Curr Opin Immunol 1999; 11:504–508. 201. Inston NG, Cockwell P. The evolving role of chemokines and their receptors in acute allograft rejection. Nephrol Dial Transplant 2002; 17:1374–1379. 202. Solez K, Racusen LC, Abdulkareem F, Kemeny E, von Willebrand E, Truong LD. Adhesion molecules and rejection of renal allografts. Kidney Int 1997; 51:1476–1480. 203. Shoskes DA, Halloran PF. Delayed graft function in renal transplantation: etiology, management and long-term significance. J Urol 1996; 155:1831–1840. 204. Bohmig GA, Exner M, Watschinger B, Regele H. Acute humoral renal allograft rejection. Curr Opin Urol 2002; 12:95–99. 205. Robertson H, Kirby JA. Post-transplant renal tubulitis: the recruitment, differentiation and persistence of intra-epithelial T cells. Am J Transplant 2003; 3:3–10. 206. Joosten SA, Van Kooten C, Paul LC. Pathogenesis of chronic allograft rejection. Transpl Int 2003; 16:137–145. 207. Knight RJ, Burrows L, Bodian C. The influence of acute rejection on long-term renal allograft survival: a comparison of living and cadaveric donor transplantation. Transplantation 2001; 72:69–76. 208. Soderberg-Naucler C, Emery VC. Viral infections and their impact on chronic renal allograft dysfunction. Transplantation 2001; 71:SS24–SS30. 209. Brunn GJ, Hudson CC, Sekulic A, et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997; 277:99–101. 210. Pascual J, Orte J, Marcen R, Burgos J, Ortuno J. Use of leflunomide in human renal transplantation. Transplantation 2001; 72:1709. 211. Mele TS, Halloran PF. The use of mycophenolate mofetil in transplant recipients. Immunopharmacology 2000; 47:215–245.

medwedi.ru

38 Urinary Tract Obstruction J. Robert Ramey and Deborah T. Glassman

INTRODUCTION Urinary tract obstruction may result from numerous etiologies and at various levels within the urinary system. Sources may be congenital or acquired, benign or malignant. Moreover, patients’ presenting symptoms will vary not only by the location of obstruction, but also with the time course over which the blockage has developed. This chapter systematically addresses the physiologic alterations to renal and bladder function that result from obstruction of normal urinary flow, the pathologic processes that may produce obstruction, and the varied options for restoring proper drainage of the urinary tract.

THE UPPER URINARY TRACT Normal Physiology of the Renal Pelvis and Ureter The upper urinary tract is a closed drainage system that functions to deliver urine from the kidney to the bladder. It begins at the level of the minor calyces. Each minor calyx receives urine from a single renal papilla and drains via an infundibulum into one of the major calyces (Fig. 1). These major calyces, usually numbering two to three, fuse to form the renal pelvis. The ureter and renal pelvis join at the ureteropelvic junction (UPJ), and the ureter then courses inferiorly through the retroperitoneum to empty into the bladder. These anatomic divisions do not exist on a functional basis; however, they do provide a useful framework for understanding upper tract obstruction (1) and planning correctional interventions. The contractile force that propels each bolus of urine downstream to the bladder is provided by the smooth muscle cells enveloping the mucosa of the upper tract. The smooth muscle of the ureter is arranged into inner longitudinal and outer circumferential layers. Individual

Major calyx

Minor calyces

Renal pelvis Ureteropelvic junction

Ureter

Infundibuli

Figure 1 Anatomy of the renal collecting system.

cells are connected via intermediate junctions (2,3), producing a functional syncytium (4) that allows the conduction of electrical signals down the ureter. Specialized pacemaker cells are found at the pelvicalyceal junction (5). Action potentials generated by these cells are propagated downstream via diffusion. These waves of depolarization produce peristaltic contractions of the renal pelvis and ureter, which serve to propel urine into the bladder (4).

Unilateral vs. Bilateral Ureteral Obstruction Complete unilateral ureteral obstruction (UUO) has been well studied in a variety of animal models and produces consistent alterations in renal hemodynamics and ureteral function (6–8). There is a triphasic response consisting of an acute increase in both renal blood flow (RBF) and ureteral pressure resulting from preglomerular vasodilation followed by a period of decreasing RBF, during which ureteral pressures remain elevated. Chronically, both ureteral pressure and RBF are maintained at below normal levels secondary to preglomerular vasoconstriction (6,9). These changes are mediated by intrarenally produced prostaglandins, with prostaglandin E (PGE2) producing the initial vasodilation and thromboxane A2 responsible for the subsequent vasoconstriction (10). Bilateral ureteral occlusion (BUO) produces slightly different alterations in RBF as well as ureteral pressure. Initially, rapid increases in both RBF and ureteral pressure occur as with unilateral obstruction; however, unlike UUO, chronic BUO results in decreased RBF with persistently elevated ureteral pressures (10–12). These chronically elevated ureteral pressures are responsible for the reduction in glomerular filtration rate (GFR) during BUO rather than the preglomerular vasoconstriction seen in phase 3 of UUO (12). These divergent responses to BUO and UUO are mediated by elevated levels of atrial natriuretic peptide (ANP) present during BUO, but not UUO (13–15). ANP is secreted in response to atrial stretch that occurs in volume-overloaded states (13). In an unobstructed system, ANP increases GFR by producing afferent arteriolar vasodilation along with efferent arteriolar constriction (16). During BUO, ANP counteracts the thromboxane A2–mediated preglomerular vasoconstriction seen in phase 3 of UUO, while maintaining efferent arteriolar vasoconstriction, thereby producing the elevated ureteral pressures seen with BUO (10,11,13). Chronic obstruction of one or both ureters results in hydroureteronephrosis proximal to the level of obstruction. The degree of dilation that develops varies depending on the duration and degree of obstruction, as well as the anatomy of the collecting system. The ureteral walls become unable to coapt due to the dilation, thus rendering peristaltic contractions ineffective. Subsequently, urine must drain from the obstructed system in a passive fashion via gravity or

medwedi.ru 767

768

Part Four: The Urinary System

pyelovenous backflow (17). Histologically, obstructive nephropathy results in obliterative interstitial fibrosis, with subsequent loss of functional cortex (18).

Presentation and Diagnosis of Upper Tract Obstruction Signs and Symptoms of Ureteral Obstruction The signs and symptoms of upper tract obstruction vary greatly with the time course over which the obstruction occurs. Acute obstruction produces flank pain on the affected side due to distension of the collecting system and renal capsule. The common innervation of the distal urinary tract and genitalia often results in radiation of the pain to the patient’s ipsilateral testicle/labia. Similarly, obstruction in the proximal urinary tract can radiate to the shoulder or across the abdomen due to shared innervation with the gastrointestinal tract. Generally colicky in nature, the pain is often accompanied by nausea and vomiting. Patients are restless and on physical examination have extreme costovertebral angle tenderness on the affected side. If the urine becomes infected, fevers may develop along with bacteremia and even overt sepsis. Gross hematuria may accompany intrinsic obstructing lesions, such as calculi or transitional cell carcinomas. Complete BUO, or UUO of a solitary kidney, will produce anuria. Chronic obstruction often develops asymptomatically. Some patients may have signs of uremia, or vague complaints of lethargy or abdominal discomfort. It may be discovered serendipitously as hydronephrosis seen on abdominal imaging performed for unrelated complaints, or during investigation of previously unrecognized renal failure. Patients may also present with complaints of recurrent urinary tract infections (UTI) or pyelonephritis. Laboratory analysis should include serum chemistries, complete blood count, and urinalysis with culture. Blood urea nitrogen and creatinine allow monitoring of renal function, while leukocytosis may accompany systemic infection. Specific gravity on urinalysis reveals the kidneys’ concentrating ability, while white blood cells and bacteria may indicate a UTI. Crystals may be present on microscopic examination of the urine from patients with renal calculi. Empiric antibiotics may be initiated; however, all infections should be confirmed with a culture.

Diagnostic Studies Renal ultrasonography is often the initial study performed in the evaluation of renal failure. Due to the absence of ionizing radiation, ultrasound is also frequently used during pregnancy and with pediatric patients, as well as for patients with iodinated contrast allergies. It provides anatomic detail of the renal parenchyma and is fairly accurate in detecting the presence of hydronephrosis, especially in the setting of chronic obstruction. However, unless one of the above conditions exists, ultrasound is not the diagnostic study of choice in obstruction because its sensitivity as well as specificity is less than that of intravenous urography (IVU) (19). Duplex Doppler interrogation with calculation of resistive indices improves the ability of ultrasound to diagnose obstruction, yet this technique still falls short of IVU (20). For years, IVU has been the ‘‘gold standard’’ for diagnosing ureteral obstruction, providing both anatomic and functional information. In the setting of acute obstruction, delayed uptake and excretion of contrast by the kidney, along with dilation of the collecting system, are seen. If present, extravasation of contrast indicates the presence of

forniceal rupture. IVU will often reveal cortical thinning, along with a dilated collecting system and tortuous ureter containing a standing column of contrast in chronically obstructed systems (17). Unenhanced computed tomography (CT) scans provide the most sensitive study for the detection of calculi (21,22). Hydroureteronephrosis, perinephric stranding, and periureteral edema indicate the presence of ureteral obstruction (23). CT scans provide excellent anatomic detail of the entire abdomen, and IV contrast may be given following the acquisition of unenhanced images to perform a CT urogram, producing a functional study of the kidneys and making it an ideal study for potentially complex cases. Nuclear medicine renal scans may also be employed in the evaluation of potentially obstructed urinary systems. Using radiolabeled tracers that are given intravenously and excreted by the kidney, the drainage of each system may be assessed by the half-life (t1/2) for tracer transit from renal pelvis to bladder during diuresis. A prolonged t1/2 (more than 20 minutes) is diagnostic of obstruction. Prior to the development and refinement of noninvasive diuretic nuclear renography, the Whitaker test was routinely utilized to demonstrate obstruction. The study is performed by measuring the pressure within the renal pelvis during the infusion of a saline and contrast solution via a percutaneously placed cannula with a Foley catheter in place to drain the bladder. A pressure difference between renal pelvis and bladder greater than 22 cmH2O at a flow rate of 10 cc/min is diagnostic of obstruction. The addition of contrast to the infusate allows fluoroscopic images to be obtained during the study revealing anatomic information regarding the level and degree of obstruction (17). The test remains useful in patients with poor renal function or marked hydronephrosis, because both of these hinder the interpretation of diuretic renograms (24).

Relieving Obstruction Once a renal unit is determined to be obstructed, the physician must decide whether to temporarily drain the system or proceed directly with definitive repair. Indwelling ureteral stents or catheters may be placed endoscopically, while nephrostomy tubes can be inserted percutaneously for temporary relief of ureteral obstruction. Patients with signs of infection should undergo drainage and antibiotic therapy prior to proceeding with definitive repair. Ureteral stents function well in cases of intrinsic obstruction from such etiologies as calculi and strictures; however, in the face of extrinsic compression from retroperitoneal fibrosis (RPF) or malignant lesions, percutaneous nephrostomy tubes usually provide more reliable drainage (25).

Etiologies of Upper Urinary Tract Obstruction Numerous processes may ultimately result in either UUO or BUO. Table 1 lists various sources of urinary tract obstruction, while Figure 2 depicts the locations of common lesions. Determining whether obstruction is due to extrinsic compression or internal blockage is vital in planning definitive correction. The following section addresses some of the more common sources of ureteral occlusion and the surgical options for management.

Extrinsic Compression Retrocaval Ureter During normal embryologic development, the infrarenal inferior vena cava (IVC) arises from the supracardinal vein.

Chapter 38:

Table 1 Common Causes of Urinary Obstruction Intrinsic diseases of the urinary tract

Extrinsic obstruction of the ureter

Congenital disorders Vascular lesions Ureteropelvic junction lesions Accessory vessels Primary megaureter Aortic, Iliac aneurysms Ectopic ureter Ovarian vein syndrome Ectopic ureterocele Circumcaval (retrocaval) ureter Neuropathic bladder disease Pelvic and retroperitoneal masses Urethral valves Pregnancy Detrusor-sphincter dyssynergia Enlarged uterus—benign, malignant Ureteral dysplasia (prune-belly disorders syndrome) Hydrometrocolpos Ovarian lesions Metabolic and inflammatory disorders Embryologic remnants (cysts of Urinary calculi Gartner’s duct) Blood clots Pelvic and retroperitoneal tumors, Fungus balls primary and metastatic Sloughed papillae (papillary Pelvic lipomatosis necrosis) Lymphocele Renal, ureteral, or vesical Uterine prolapse tuberculosis Inflammatory diseases Urethral strictures Retroperitoneal fibrosis Prostatic inflammatory diseases Retroperitoneal abscess Meatal stenosis Retroperitoneal hemorrhage Foreign body Tubo-ovarian abscess; pelvic inflammatory disease Neoplastic disorders Appendiceal or diverticular abscess Benign prostatic hyperplasia Endometriosis Renal pelvic and ureteral tumors Bladder tumors Granulomatous (Crohn’s) disease Prostatic tumors of the bowel Urethral tumors Traumatic disorders Ureteral stricture (postsurgical) Urethral stricture

When this segment forms from the subcardinal vein instead, a portion of the ureter comes to lie in a retrocaval position where the IVC exerts extrinsic compression producing partial obstruction. Contrast-enhanced CT scan is the study of choice for evaluation of this anomaly. Surgical correction involves transection of the ureter with reanastomosis anterior to the IVC, though cases with severe obstructive nephropathy and a nonfunctional kidney may require nephrectomy (26).

Urinary Tract Obstruction

769

has been established pathologically, definitive therapy may be initiated. Surgical ureterolysis provides the best longterm results for correction of ureteral obstruction (29). Successful medical management utilizing corticosteroids (30) and tamoxifen has been reported in patients who are poor surgical candidates (28,31–33). Long-term indwelling ureteral stents or nephrostomy tubes may be employed for relief of obstruction in patients unfit for surgery. Malignancy Various malignancies may produce ureteral obstruction via extrinsic compression from the primary tumor (carcinoma of the prostate, cervix, ovaries, or bladder) or retroperitoneal lymphadenopathy due to metastatic disease (leukemia, lymphoma, and testicular neoplasm). Regardless of tumor origin, malignant ureteral obstruction portends a poor prognosis because median survival is less than seven months (34). Percutaneous nephrostomy tube placement is often required for palliation of malignant obstruction, because more than half of patients with pelvic malignancies will fail internal drainage with ureteral stents (25).

Intrinsic Obstruction UPJ Obstruction Obstruction at the UPJ may present at any age, though it represents the most common cause of upper urinary tract obstruction in children (35). Patients frequently complain of flank pain that may be intermittent or chronic in nature. Additionally, there may be a history of UTI or stones. The etiology of UPJ obstruction (UPJO) remains an area of some dispute with both congenital and acquired conditions implicated (36). IVU and diuretic renal scan are typically utilized in the diagnosis and treatment planning of UPJO (37). Surgical correction via open pyeloplasty has a 90% success rate, while antegrade endopyelotomy via percutaneous nephrostomy tract produces equivalent results initially (37). Advances in ureteroscopic and laparoscopic instrumentation and techniques have allowed these minimally invasive approaches to yield similar success without the morbidity of open incisions or nephrostomy tubes (36,38).

Arterial Aneurysm Acquired aneurysmal lesions of the abdominal aorta and iliac arteries may also result in ureteral obstruction. Perianeurysmal fibrosis involving the ureter produces occlusion of the lumen (27). CT scan is a valuable tool to evaluate the ureter’s anatomic relationship to vascular structures prior to surgery. If necessary, ureterolysis may be performed prior to aneurysm repair, or concomitantly (17).

Ureteral Stricture Ureteral strictures may develop in response to numerous insults including ischemia, instrumentation, radiation, and calculi. While a diuretic renogram confirms obstruction, it does not provide anatomic detail as to the length or level of the stricture. This information is easily obtained with either an IVU or retrograde pyelogram. Distal and midureteral strictures may be managed endoscopically with balloon dilation or endoluminal incision. Mid-ureteral strictures occasionally require ureteroureterostomy, while distal lesions not amenable to minimally invasive techniques can be corrected via ureteroneocystotomy.

Idiopathic Retroperitoneal Fibrosis RPF is a benign inflammatory process that produces an intense fibrotic infiltrate that may encompass and compress one or both ureters, and the great vessels. Radiographic imaging will reveal a large retroperitoneal mass in addition to hydronephrosis. Excretory urography (IVU or CTurogram) often reveals medial deviation of the involved ureter(s) (28). Biopsy of the mass to rule out malignancy should be performed. This may be accomplished surgically via either an open or laparoscopic approach, or percutaneously under CT or ultrasound guidance (17). Once the diagnosis of RPF

Calculi When a given solute reaches supersaturation in the urine, it precipitates out of the solution, forming a calculus. Calcium stones are most common, but uric acid, struvite, and cystine stones are also seen in humans. A nonenhanced helical CT scan is the study of choice when considering the diagnosis of stone disease (21,22), because it provides details regarding the size, location, and number of stones, all vital information for planning intervention. Extracorporeal shock wave lithotripsy (ESWL) produces excellent results for renal stones less than 2.0 cm, and proximal ureteral stones less than

medwedi.ru

770

Part Four: The Urinary System

Figure 2 (A) Causes of upper urinary tract obstruction. (B) Causes of lower urinary tract obstruction. Source: Courtesy of J. N. Corriere Jr., from Chapter 43 in the Second Edition.

1.0 cm that do not pass spontaneously (39). Distal ureteral calculi, proximal calculi larger than 1.0 cm, and residual fragments from calculi previously treated with ESWL should be treated with ureteroscopic lithotripsy, because patients undergoing ESWL in these cases are more likely to require multiple procedures to be rendered stone free (39,40).

THE LOWER URINARY TRACT Normal Anatomy of the Urinary Bladder and Urethra The detrusor muscle of the bladder overlies a transitional cell mucosa. Its myofibrils are arranged into fasicles oriented in random directions, in contrast to the more organized smooth muscle of the ureter (41). At the lateral aspect of the bladder base, the ureters tunnel through the detrusor obliquely, producing functional antireflux valves. The ureteral orifices then open into the bladder at the posterolateral corners of the trigone. Arising from the bladder neck, the urethra extends to the external meatus. In women, the urethra is relatively short and runs within the distal one-third of the anterior vaginal wall, while the male urethra covers a much longer

course and is comprised of four segments: prostatic, membranous, bulbous, and penile urethra. The smooth muscle of the urethra is arranged into a thick inner layer of longitudinal fibers and a sparse outer layer of circumferential muscle (42). The external sphincter also encircles the urethra; however, it comprises striated muscles and is thus under volitional control.

The Micturition Cycle The intact bladder provides a highly compliant reservoir for urine storage during the filling phase of the micturition cycle. Emptying requires the coordination of detrusor contraction with relaxation of the internal and external sphincters. The pons, located within the brainstem, houses the micturition center responsible for organizing the normal voiding reflex. Spinal sympathetic and somatic reflex arcs are initially inhibited producing relaxation of the internal and external sphincters, respectively. Parasympathetic stimulation subsequently results in the coordinated contraction of the detrusor leading to complete emptying of the intact, unobstructed lower tract (43). Thus, pathologic processes that increase resistance to the outflow of urine or decrease bladder contractility may result in voiding dysfunction. The

Chapter 38:

remainder of this chapter focuses on the diagnosis and treatment of common lesions that produce increased resistance to urine flow, and thus lower urinary tract obstruction.

Bladder Outlet Obstruction Benign Prostatic Hyperplasia As men age, the prostate gland undergoes hyperplasia, with the prevalence of benign prostatic hyperplasia (BPH) increasing from 0% in those below 30 years of age to 88% in men in their 80s (44). Common complaints include urinary frequency and urgency, hesitancy and intermittency of urinary stream, incomplete voiding, and nocturia. This symptom cluster is frequently referred to as the lower urinary tract syndrome, or LUTS. Traditionally, patients with enlarged prostates and significant LUTS have been treated with transurethral resection of the prostate (TURP). However, over the past decade, this ‘‘gold standard’’ has been challenged by the introduction of medical therapies and novel surgical procedures. Medical therapies target alpha1-adrenergic receptors in the smooth muscle of the prostate and bladder neck or the 5-alpha-reductase enzyme. Alpha-blockers relax the smooth muscle within the prostate, prostatic capsule as well as periurethral fibers, thereby decreasing outlet resistance. Meanwhile, 5-alpha-reductase inhibitors prevent the conversion of testosterone to dihydrotestosterone (DHT), the principal active androgen in the prostate. Reduced DHT levels result in decreased prostate volume with long-term therapy (45). Various transurethral techniques have also been introduced to challenge TURP. All aim to produce equivalent reduction in LUTS, with decreases in TURP-associated morbidities (bleeding, infection, and hospitalization). Radio frequency [transurethral needle ablation (TUNA)], microwave energy [transurethral microwave thermal therapy (TUMT)], and various laser media have been utilized to destroy hyperplastic prostate tissue in a minimally invasive fashion (45,46). Smaller glands (prostate volume < 50–60 cc) may be treated effectively with transurethral incision (TUI), rather than formal resection (46). Prostate glands larger than 80 cc may best be treated with open simple prostatectomy.

Bladder Neck Contracture Resection of the prostate via open or endoscopic techniques may result in scarring and contracture of the bladder neck, which subsequently produces bladder outlet obstruction (BOO). Bladder neck contracture (BNC) occurs in 0.48% to 32% of patients undergoing radical prostatectomy (47) versus 0.14% to 20% with TURP (48). Transurethral dilation and endoscopic incision of the contracture are equally effective treatment options (47).

Detrusor–External Sphincter Dyssynergia During normal voiding, the pontine micturition center coordinates relaxation of the striated muscle of the external sphincter with contraction of the detrusor. Lesions between the pons and sacral spinal cord resulting from traumatic spinal cord injury, transverse myelitis, multiple sclerosis, etc. may interfere with this coordination (49). The uncoupling of detrusor contraction and external sphincter relaxation is termed dyssynergia and is commonly referred to as DESD. DESD produces a functional obstruction that often results in elevated voiding pressures and decreased bladder compliance. Chronically, this may lead to vesicoureteral reflux and renal parenchymal deterioration, especially in

Urinary Tract Obstruction

771

patients with voiding pressures greater than 40 cmH2O (50). Urodynamic evaluation consists of cystometrography and external sphincter electromyography (EMG). Uninhibited detrusor contractions with concomitant increased EMG activity in the external sphincter confirm the diagnosis. Treatment options include anticholinergics and selfcatheterization, transurethral external sphincterotomy, and stenting of the external sphincter (49,51,52).

Urethral Obstruction Posterior Urethral Valves With an estimated incidence between 1:3000 and 1:8000, posterior urethral valves (PUV) are the most common congenital cause of lower urinary tract obstruction. Renal insufficiency and failure due to renal dysplasia are common, while pulmonary hypoplasia with respiratory failure may be seen in neonates with a history of oligohydramnios secondary to obstruction (53). Neonates classically presented with palpable abdominal masses from either a distended bladder or hydronephrotic kidneys, or in pulmonary distress secondary to hypoplasia of the lungs. Later in life, UTI or obstructive voiding symptoms are often the presenting complaint. Presently, most cases are discovered as bilateral hydronephrosis seen on prenatal ultrasonography (54). Voiding cystourethrogram (VCUG) is the diagnostic test of choice for PUV. In addition to upper tract damage, PUV result in a hypertrophied, trabeculated, and noncompliant detrusor that may produce vesicoureteral obstruction as well (53). Thus, initial management should consist of temporary drainage with a Foley catheter, and patients who fail to reach a serum creatinine nadir of less than 2 mg/dL should be considered for upper tract diversion via nephrostomy tube or cutaneous ureterostomy (54). Primary transurethral endoscopic valve ablation is currently the treatment of choice, though patients with significant bilateral reflux may benefit from temporary cutaneous vesicostomy prior to valve ablation (55).

Urethral Stricture Urethral strictures represent scar formation in response to injury of the urethral mucosa and corpus spongiosum (56). Prior to the advent of effective antibiotic therapy, the vast majority of stricture disease was secondary to gonococcal urethritis; however, presently, most strictures result from trauma due to straddle injury, or iatrogenic instrumentation (57–59). Patients present with obstructive voiding complaints such as straining to void, decreased stream, and terminal dribbling. Radiographic evaluation should include dynamic fluoroscopic retrograde urethrogram and VCUG. Some urologists advocate transperineal ultrasonography because they feel it provides further information regarding stricture length, location, and degree of fibrosis within the corpus spongiosum (59). A myriad of treatment options exist for stricture disease including dilatation, endoscopic internal urethrotomy, and open urethroplasty. Ultimately, the procedure of choice is determined by the characteristics of the given stricture (i.e., length, location, and degree of fibrosis). Various models of rigid dilators exist; however, balloon-dilating catheters provide the least traumatic dilatation (57). Unfortunately, with strictures other than the most superficial, membranelike lesions, dilation is rarely curative. In selected patients with short strictures (1.0–1.5 cm) of the bulbous urethra and relatively little spongiofibrosis, internal urethrotomy provides cure rates in excess of 90% (58). Bulbous urethral

medwedi.ru

772

Part Four: The Urinary System

strictures of slightly longer length (< 2.0–3.0 cm) may be successfully managed via excision with a spatulated primary anastomosis (56). Longer strictures and those of the penile urethra require more complex open urethroplasty techniques, which employ various onlay grafts or tissue flaps to reconstruct the urethra (57,58).

Post-Obstructive Diuresis Following the relief of bilateral upper tract obstruction or urinary retention due to lower tract obstruction, patients should be closely monitored for postobstructive diuresis (POD). The tubular dysfunction resulting from obstruction results in an inability to excrete acid and concentrate urine; thus prior to release of obstruction, patients typically present with a hyperchloremic, hyperkalemic metabolic acidosis (9). Signs of volume overload and severe renal impairment with encephalopathy should alert the clinician to the potential for significant POD (60). Retained sodium and urea may both provoke POD. Urea-provoked diuresis is usually selflimited, whereas salt-induced POD may perpetuate into a pathologic state with ensuing dehydration, hypotension, electrolyte disturbances, and death if not recognized and treated appropriately (61). ANP has also been implicated in POD because levels are elevated in patients with obstructive uropathy and return to normal following relief of obstruction with ensuing natriuresis and diuresis (13,62). Recognition and management of POD requires that clinicians maintain a high index of suspicion. Based on clinical examination and serum studies, patients may be categorized as low, medium, or high risk for developing POD (61). The low- and medium-risk patients have minimal to no signs of volume overload, azotemia, or encephalopathy and may be managed with oral rehydration alone unless urine output exceeds 200 cc/hr or signs of hemodynamic instability or mental status changes develop. Patients with significant volume overload, mental confusion, or chronic BOO are at high risk for developing POD. Their urine output should be replaced 1/2 cc:cc with hypotonic saline solution containing 20 mEq KCl/L. If hyponatremia is present on initial serum chemistry, normal saline should be used for replacement of urine output (9,60). Serum electrolytes should be monitored closely and any derangements corrected appropriately. Excessive fluid replacement should be avoided because this may iatrogenically prolong diuresis following recovery of renal function.

SUMMARY Urinary tract obstruction can occur at any age and in either sex, but is most commonly encountered in pediatric patients and those 60 years or older. Symptoms can be acute or chronic and have minimal or significant adverse effects on underlying renal function. The most serious complication of obstruction is renal failure with its attendant life-threatening effects. Fortunately, the refinement in current imaging techniques has enabled early diagnosis of this condition and exact determination of the site of obstruction so that optimal therapy can be rendered in a timely fashion. In the unfortunate subset of patients in whom significant renal dysfunction has occurred, relief of obstruction may still enable recovery of enough function so that dialysis is not needed. Even when intermittent dialysis becomes essential, current approaches to this treatment option will make possible longer life and better quality of living.

REFERENCES 1. Kabalin JN. Surgical anatomy of the retroperitoneum, kidneys, and ureters. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:3–40. 2. Uehara Y, Burnstock G. Demonstration of ‘‘gap junctions’’ between smooth muscle cells. J Cell Biol 1970; 44:215–217. 3. Libertino JA, Weiss RM. Ultrastructure of human ureter. J Urol 1972; 108:71–76. 4. Weiss RM. Physiology and pharmacology of the renal pelvis and ureter. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. Philadelphia: Saunders, 2002:377–409. 5. Dixon JS, Gosling JA. The fine structure of pacemaker cells in the pig renal calices. Anat Record 1973; 175:139–153. 6. Vaughn ED, Sorenson EJ, Gillenwater JY. The renal hemodynamic response to chronic unilateral complete ureteral occlusion. Investig Urol 1970; 8:78–90. 7. Moody TE, Vaughn ED, Gillenwater JY. Relationship between renal blood flow and ureteral pressure during 18 hours of total unilateral ureteral occlusion. Investig Urol 1975; 13:246–251. 8. Dal Canton A, Stanziale R, Corradi A, Andreucci VE, Migone L. Effects of acute ureteral obstruction on glomerular hemodynamics in rat kidney. Kidney Int 1977; 12:403–411. 9. Bruce RG, Waid TH, Lucas BA. Understanding postobstructive diuresis. Contemp Urol 1997; 9:53–66. 10. Wilson DR. Pathophysiology of obstructive nephropathy. Kidney Int 1980; 18:281–292. 11. Moody TE, Vaughn ED, Gillenwater JY. Comparison of the renal hemodynamic response to unilateral and bilateral ureteral occlusion. Investig Urol 1977; 14:455–459. 12. Dal Canton A, Corradi A, Stanziale R, Maruccio G, Migone L. Glomerular hemodynamics before and after release of 24-hour bilateral ureteral obstruction. Kidney Int 1980; 17:491–496. 13. Gulmi FA, Matthews GJ, Marion D, Von Lutterotti N, Vaughn ED. Volume expansion enhances the recovery of renal function and prolongs the diuresis and natriuresis after release of bilateral ureteral obstruction: a possible role for atrial natriuretic peptide. J Urol 1995; 153:1276–1283. 14. Purkeson ML, Blaine EH, Stokes TJ, Klahr S. Role of atrial peptide in the natriuresis that follows relief of obstruction in rat. Am J Physiol 1989; 256:F583–F589. 15. Fried TA, Lau AT, Ayon MA, Stein JH. Elevation of atrial natriuretic peptide (ANP) in ureteral obstruction in the rat. Clin Res 1986; 34:596A. 16. Cogan MG. Renal effects of atrial natriuretic factor. Annu Rev Physiol 1990; 52:699–708. 17. Gulmi FA, Felsen D, Vaughn ED. Pathophysiology of urinary tract obstruction. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. Philadelphia: Saunders, 2002:411–462. 18. Nagle RB, Bulger RE. Unilateral obstructive nephropathy in the rabbit. II. Late morphologic changes. Lab Investig 1978; 38: 270–278. 19. Laing FC, Jeffrey RB, Wing VW. Ultrasound versus excretory urography in evaluating acute flank pain. Radiology 1985; 154:613–616. 20. Deyoe LA, Cronan JJ, Breslaw BH, Ridlen MS. New techniques of ultrasound and color Doppler in the prospective evaluation of acute renal obstruction. Do they replace the intravenous urogram? Abdominal Imaging 1995; 20:58–63. 21. Smith R, Rosenfield A, Choe K, et al. Acute flank pain: comparison of non-contrast-enhanced CT and intravenous urography. Radiology 1995; 194:789–794. 22. Yilmaz S, Sindel T, Arslan G, et al. Renal colic: comparison of spiral CT, US, and IVU in the detection of ureteral calculi. Eur Radiol 1998; 8:212–217. 23. Youssefzadeh M, Katz DS, Lummerman JH. Unenhanced helical CT in the evaluation of suspected renal colic. Am Urol Assoc Updates 1999; 28:203–207. 24. Whitaker RH, Buxton-Thomas MS. A comparison of pressure flow studies and renography in equivocal upper urinary tract obstruction. J Urol 1984; 131:446–449.

Chapter 38: 25. Feng MI, Bellman GC, Shapiro CE. Management of ureteral obstruction secondary to pelvic malignancies. J Endourol 1999; 13:521–524. 26. Rubinstein I, Cavalcanti AG, Canalini AF, Freitas MA, Accioly PM. Left retrocaval ureter associated with inferior vena caval duplication. J Urol 1999; 162:1373–1374. 27. Lindblad B, Almgren B, Bergqvist D, et al. Abdominal aortic aneurysm with perianeurysmal fibrosis: experience from 11 Swedish vascular centers. J Vasc Surg 1991; 13:231–239. 28. Bourouma R, Chevet D, Michel F, Cercueil JP, Arnould L, Rifle G. Treatment of idiopathic retroperitoneal fibrosis with tamoxifen. Nephrol Dial Transplant 1997; 12:2407–2410. 29. De Luca S, Terrone C, Manassero A, Rocca-Rossetti S. Aetiopathogenesis and treatment of idiopathic retroperitoneal fibrosis. Ann Urol 1998; 32:153–159. 30. Kadar AH, Kattan S, Lindstedt E, Hanash K. Steroid therapy for idiopathic retroperitoneal fibrosis: dose and duration. J Urol 2002; 168:550–555. 31. Frankhart L, Lorge F, Donckier J. Tamoxifen for retroperitoneal fibrosis. Postgrad Med J 1997; 73:653–654. 32. Owens LV, Cance WG, Huth JF. Retroperitoneal fibrosis treated with tamoxifen. Am Surgeon 1995; 61:842–844. 33. Clark CP, Vanderpool D, Preskitt JT. The response of retroperitoneal fibrosis to tamoxifen. Surgery 1991; 109:502–506. 34. Russo P. Urologic emergencies in the cancer patient. Semin Oncol 2000; 27:284–298. 35. Snyder HM, Lebowitz RL, Colodny AH, Bauer SB, Retik AB. Ureteropelvic junction obstruction in children. Urol Clin North Am 1980; 7:273–290. 36. Streem SB, Franke JJ, Smith JA. Management of upper urinary tract obstruction. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002: 463–512. 37. Meretyk I, Meretyk S, Clayman RV. Endopyelotomy: comparison of ureteroscopic retrograde and antegrade percutaneous techniques. J Urol 1992; 148:775–783. 38. Soroush M, Bagley DH. Ureteroscopic retrograde endopyelotomy. Tech Urol 1998; 4:77–82. 39. Lam JS, Greene TD, Gupta M. Treatment of proximal ureteral calculi: holmium: YAG laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. J Urol 2002; 167:1972–1976. 40. Pace KT, Weir MJ, Tariq N, Honey RJD. Low success rate of repeat shock wave lithotripsy for ureteral stones after failed initial treatment. J Urol 2000; 164:1905–1907. 41. Donker PJ, Droes JP, Van Alder BM. Anatomy of the musculature and innervation of the bladder and urethra. In: Chisolm GO, Williams DI, eds. Scientific Foundations of Urology. Chicago: Year Book Medical, 1982:404–441. 42. Chancellor MB, Yoshimura N. Physiology and pharmacology of the bladder and urethra. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:831–886. 43. Wein AJ. Pathophysiology and categorization of voiding dysfunction. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002: 887–899.

Urinary Tract Obstruction

773

44. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479. 45. Holtgrewe HL. Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia. Urology 1998; 51(suppl 4A):1–7. 46. Jepsen JV, Bruskewitz RC. Recent developments in the surgical management of benign prostatic hyperplasia. Urology 1998; 51(suppl 4A):23–31. 47. Borboroglu PG, Sands JP, Roberts JL, Amling CL. Risk factors for vesicourethral anastomotic stricture after radical prostatectomy. Urology 2000; 56:96–100. 48. Kulb TB, Kamer M, Lingeman JE, Foster RS. Prevention of post-prostatectomy vesical neck contracture by prophylactic vesical neck incision. J Urol 1987; 137:230–231. 49. Kim YH, Kattan MW, Boone TB. Bladder leak point pressure: the measure for sphincterotomy success in spinal cord injured patients with external detrusor-sphincter dyssynergia. J Urol 1998; 159:493–497. 50. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126:205–209. 51. Rivas DA, Chancellor MB, Bagley D. Prospective comparison of external sphincter prosthesis placement and external sphincterotomy in men with spinal cord injury. J Endourol 1994; 8:89–93. 52. Chancellor MB, Kaplan SA, Blaivas JG. Detrusor-external sphincter dyssynergia. Ciba Foundation Symp 1990; 151:195–206. 53. Yohannes P, Hanna M. Current trends in the management of posterior urethral valves in the pediatric population. Urology 2002; 60:947–953. 54. Gonzales ET Jr. Posterior urethral valves and other urethral anomalies. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:2207–2230. 55. Walker RD, Padron M. The management of posterior urethral valves by initial vesicostomy and delayed valve ablation. J Urol 1990; 144:1212–1214. 56. Jezior JR, Schlossberg SM. Excision and primary anastomosis for anterior urethral stricture. Urol Clin North Am 2002; 29:373–380. 57. Jordan GH, Schlossberg SM. Surgery of the penis and urethra. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Campbell’s Urology. 8th ed. Philadelphia: Saunders, 2002:3886–3954. 58. Jezior J, Jordan GH. Management of the bulbous urethral stricture. AUA Update Ser 2002; 22(1):1–7. 59. Gallentine ML, Morey AF. Imaging of the male urethra for stricture disease. Urol Clin North Am 2002; 29:361–372. 60. Vaughan ED, Gillenwater JY. Diagnosis, characterization and management of post-obstructive diuresis. J Urol 1973; 109: 286–292. 61. Baum N, Anhalt M, Carlton CE, Scott R. Post-obstructive diuresis. J Urol 1975; 114:53–56. 62. Gulmi FA, Mooppan UMM, Chou SY, Kim H. Atrial natriuretic peptide in patients with obstructive uropathy. J Urol 1989; 142:268–272.

medwedi.ru

39 Neurogenic Lower Urinary Tract Dysfunction Hari Siva Gurunadha Rao Tunuguntla and Unyime O. Nseyo

INTRODUCTION The normal function of the urinary bladder is to store and expel urine in a coordinated, controlled fashion. This coordinated activity is regulated by the central and peripheral nervous systems. Neurogenic bladder is a term applied to a malfunctioning urinary bladder due to neurogenic dysfunction or insult emanating from internal or external trauma or disease. Neurogenic lower urinary tract dysfunction (NLUTD) is the new term currently applied to ‘‘neurogenic bladder dysfunction’’. NLUTD is a multi-facetted pathology and an important clinical as well as public health problem that is associated with complex management issues. Therefore, knowledge of the anatomy and pathophysiology of NLUTD remains the prerequisite for the safe and appropriate surgical–medical management of this disorder.

ANATOMY AND PHYSIOLOGY OF CONTINENCE AND MICTURITION Anatomy and Physiology of the Bladder Outlet Functionally, the lower urinary tract (LUT) (bladder and its outlet, the urethra) works in an integrated fashion for a normal voiding cycle to occur. The normal voiding cycle includes bladder filling and storage at a low pressure and without urinary incontinence. The subsequent voluntary and active voiding also occurs at a relatively low pressure. The bladder is one of the most compliant organs in the body, and allows normal filling to occur with only a gradual rise in intravesical pressure independent of large urine volumes. Increased tension in the external urethral sphincter, the so-called rhabdosphincter or striated sphincter (SS), occurs during the bladder filling and ensures continence even with increased intra-abdominal pressure. Urine storage ends when sensory tracts transmit to the central nervous system (CNS) the sensation of bladder fullness. Under appropriate sociocultural environment control, micturition occurs by coordinated neural activities leading to detrusor contraction, funneling of bladder neck, and relaxation of the bladder outlet. Cessation of neural activity leads to relaxation of the external SS during the micturition phase. As voiding ends, neural activities and tension return to the bladder outlet and relaxation of detrusor muscle occurs and a new urine storage cycle begins. Embryologically, the bladder is derived from the urogenital sinus, the anterior portion of the cloacal membrane. The urogenital sinus is further divided into upper and lower segments at the level of the insertion of the fused distal portion of the mullerian ducts. In the male the ventral or pelvic segment forms the bladder and the prostatic urethra above the verumontanum, whereas in the female this portion forms the bladder and the entire urethra. Anatomically,

the bladder may be divided into the detrusor and trigone. However, neuropharmacologically the bladder may be conceived as comprising both a body and base, which differ substantially (1). The urinary bladder wall is organized into three layers: inner epithelial layer, or ‘‘mucosa’’ lined by specialized transitional epithelium called the urothelium, which is impervious to fluids and ions; smooth muscle layer (detrusor); and the outer serosal layer comprising of connective tissue. The urothelium characteristically unfolds and expands during bladder filling. The detrusor smooth muscle layer has a heterogeneous composition of smooth muscle cells, fibroblasts, elastin, collagens, and proteoglycans. The actual smooth muscle composition ranges from 50% to 60% and may diminish during bladder outlet obstruction (1). The bundles of the detrusor muscle merge into the trigone and bladder base. These bundles lack uniform orientation during the resting phase. However, reorientation occurs during stretch. Also, at rest and during passive bladder filling, these smooth muscle bundles occlude the bladder outlet. Realignment and coordinated relaxation of these smooth muscle bundles must occur to allow efficient opening of the bladder outlet and the low voiding pressure of less than 40 cm of H2O. The adult female urethra averages 5 cm in length and 6 mm in diameter. Its wall is composed of an outer muscular layer and an inner epithelial layer. The inner epithelial layer forms internal folds, which then form a mucosal seal and contribute to the continence mechanism. The outer longitudinal muscle extends the entire length of the inner epithelial layer. Most investigators have accepted the existence of an inner longitudinal smooth muscle layer. However, the notion by Tanagho of the outer longitudinal layer representing a direct continuation of the detrusor remains controversial (2–4). The middle third of the female urethra contains the intrinsic striated skeletal muscle, which loops around the urethral lumen, probably in an oblique fashion as in the male. Both the intrinsic and extrinsic components of the SS surround the inferior aspect of the female urethra. The distal end of the intrinsic rhabdosphincter aborts in the bulky skeletal muscle of the so-called ‘‘external urinary sphincter.’’ Future research may offer succinct explanation for the presence of a very robust urethral muscle tone that contributes to urinary continence in the female. Anatomically, the male urethra is divided into the anterior component, which contains a penile and bulbar urethra. The posterior urethra contains the membranous and the prostatic urethra, which measures 3 to 4 cm in length. Inner longitudinal and outer circular layers of smooth muscle comprise the wall of the male posterior and membranous urethra. These two layers of smooth muscle extend beyond the apex of the prostate to the bulbar urethra distally. Many investigators believe that the smooth muscles of the trigone extend into the urethra (Fig. 1). Consequently, these proponents

medwedi.ru 775

776

Part Four: The Urinary System

Figure 2 Detrusor–external sphincter dyssynergia. Note the increased activity of the external urethral sphincter on electromyogram during detrusor contraction; video showing detrusor contracting against contracting external urethral sphincter, the resulting high detrusor pressure leading to bilateral (right > left) vesicoureteral reflux.

Figure 1 Anatomy of the bladder and its outlet as defined by Gosling and Dixon versus El badawi and co-workers. Source: From Ref. 5.

hypothesize that this anatomic arrangement facilitates funneling of the urethrovesical angle for efficient micturition. The contraview is that the trigone is physiologically and neuropharmacologically unique to allow functional funneling of the opening of the bladder neck during micturition. The striated muscle component of the urethra has an intrinsic layer (the so-called ‘‘rhabdosphincter’’) within the urethra, and also tends to wrap around the lumen of the urethra in an obliquely spiral fashion. The rhabdosphincteric fibers interdigitate with fibers of the external component of the extrinsic skeletal muscle intimately to the levator ani muscle group and separate from the urethral wall (3). Anatomically no ‘‘sphincter’’ is observable at the bladder neck, which remains rich with collagen and elastin that co-mingle with smooth muscle bundles. The patency and closing of the bladder neck at rest depends heavily on the passive forces of the components of the extracellular matrix (ECM) and active tone of the smooth muscle. The intrinsic tone in the bladder neck region and the proximal urethra leads to higher urethral pressure than intravesical pressure during bladder filling. The decrease in the internal urethral pressure occurs at the onset of micturition and leads to voiding at a low detrusor pressure. The competence of this ‘‘internal sphincteric mechanism’’ of the smooth muscle is very essential for continence. The external SS works in concert with the so-called internal sphincter of the bladder neck to ensure urinary continence. Unlike in the female urethra, both the intrinsic and extrinsic components of the SS surround the proximal male urethra. The involuntary contraction of the striated external sphincter during bladder contraction leads to striated detrusor– sphincter dyssynergia (DSD) (Fig. 2) common among patients with neurologic disease. This condition manifests also in the presence of a lesion between the brain and sacral cord. The only non-neurologic condition associated with DSD is the so-called Hinman Syndrome, common in children (6).

Innervation of the Urinary Bladder Voiding is an autonomic reflex and involuntary in the infant. However, normal neural maturation leads to somatic control of the LUT in due course. Central and peripheral nervous systems (Figs. 3 and 4) coordinate the complex interactions between the smooth muscle of the detrusor, bladder neck, and urethra during micturition. The contemporary literature supports the ‘‘urogenital short nervous system’’ (USNS), which contains postganglionic neurons that innervate the LUT (1). The USNS arises from the ganglia within or intimately proximal to the bladder wall. Classically, the sympathetic autonomic system leaves the preganglionic neurons of the thoraco-lumbar spinal segment to reach the first synapse in the following ganglia: (i) adjacent to the vertebral bodies (paraganglia), (ii) between the vertebral bodies and the organ (preganglia), and (iii) within the end organ (peripheral ganglia) (1). There is some evidence that urogenital neuronal fibers may connect the muscle with efferent neurons via the peripheral ganglion, which allows function that is

Brain Pontine Micturition Center

Onuf's Nucleus in Spinal Cord

S2, S3, S4

Detrusor Contraction

Figure 3 Micturition pathway.

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

Figure 4 Innervation of the lower urinary tract.

independent of the spinal cord. Also the sympathetic system may affect the parasympathetic ganglia via alpha-receptors, which modulate motor activity to the bladder. In addition to the traditional autonomic neurotransmitters of acetylcholine and norepinephrine, the noncholinergic and nonadrenergic neurotransmitters include adenosine triphosphate, serotonin, histamine, prostaglandins, peptides, and nitric oxide (1). These transmitters most certainly play a critical role in autonomic neurotransmission most likely through the principle of ‘‘cotransmission,’’ with one molecule/peptide altering the postjunctional cell for the primary neurotransmitter (1). The postsynaptic cell membrane of the smooth muscle contains receptors that recognize the neurotransmitter. The resulting specific binding generates the process of excitation–contraction in the effector cell, accompanied by a rise in the free cytosolic calcium concentration. The cholinergic receptor membrane proteins that bind acetylcholine predominate in neurons of somatic fibers, all preganglionic autonomic fibers, and all postganglionic parasympathetic fibers. The cholinergic receptors are divided into nicotinic (nicotine, a mimicry of acetylcholine) and muscarinic (alkaloid muscarinic inhibitor of acetylcholine). The nicotinic receptors abound in skeletal muscle motor end plates and autonomic ganglia. They may also have control over bladder function. The muscarinic receptors are widely distributed in all autonomic effector cells in sweat glands, large and small bowel, gall bladder, and urinary bladder. Molecular biochemists have defined five subtypes of the muscarinic receptors based on the type of protein, ‘‘M,’’ and mRNA’s (1). Structural differences are difficult to delineate; however, their functions are distinct. The urinary bladder contains only 20% of the muscarinic receptor density. The muscarinic receptor subtype, M2, predominates in the urinary bladder. Nevertheless, activation of M3 subtypes initiate bladder contraction, and activation of M2 subtype inhibits adrenergic pathway, which leads to force generation (1,7). The conditions that affect the density of the muscarinic cholinergic receptors of the bladder include pregnancy (downregulation), estrogen (upregulation), spinal cord injury, acute urinary tract obstruction, and diabetes. The adrenergic receptors bind to the catecholamines (e.g., norepinephrine) and predominate in most postganglionic sympathetic fibers. Classification of the adrenergic receptors is based on physiologic functions referred to as alpha or

777

beta. The alpha-receptors mediate nasal congestion and smooth muscle contraction. Stimulation of beta-adrenergic receptors leads to increased myocardial contractility and smooth muscle relaxation. The alpha-receptors have wellcharacterized subtypes, alpha-1 (postsynaptic) and alpha-2 (pre- and postsynaptic). Adrenergic sites in the bladder are predominantly beta-subtypes (1,7,8). They also are localized in the trigone, with sparse distribution in the bladder body. Adrenergic innervation predominates in the smooth muscle of the bladder neck and the proximal urethra. The betaadrenergic receptors exist in several major forms: beta-1, -2, and -3. Affinity of beta-1 receptors remains high for norepinephrine, whereas epinephrine has a greater affinity for beta-2 receptors. Beta-2 receptors predominate in the presynaptic and postsynaptic membranes and in the urinary bladder. Stimulation of beta-2 receptors results in relaxation of the smooth muscle in the urinary bladder. The SS is innervated by the pudendal nerves, which originate from the S2 to S4 spinal cord segments. Somatic control of the SS is responsible for the physiologic increase in activity during bladder filling and abortion of this activity at the initiation of and throughout micturition. Supratrigonal mechanoreceptors control somatic activity of the SS, which explains the failure of the external sphincter in paraplegic patients. The cholinergic receptors for smooth muscle are muscarinic whereas those associated with SS contraction are nicotinic. Anticholinergic agents such as oxybutynin act at muscarinic sites, and therefore, have no effect on SS. The muscarinic receptors of SS can be blocked by endoscopic injection of botulinum toxin to treat refractory voiding dysfunction or as an alternative to sphincterotomy. Less is known about the sensory innervation of the LUT. Afferent nerve fibers have been demonstrated in the pelvic, pudendal, and hypogastric nerves. Sensation of distention originates in the bladder wall and travels in the pelvic nerves. Mechanoreceptors are present in the hypogastric nerves. These nerves carry afferent nociceptive stimuli. The afferent neurons from the sphincter (SS) and urethra carry sensations of pain, temperature, and urinary distention. Denervation leads to increased sensitivity of smooth muscle to neuro-humoral stimuli. This supersensitivity is often associated with injury involving the postganglionic fibers. Injury involving the preganglionic nerve fibers leads to decentralization. Neuronal injuries during radical hysterectomy or abdominal perineal resection constitute examples of decentralization injuries. In summary, the adrenergic efferent neurons modulate the bladder storage function as follows: (i) stimulation of alpha-receptors of the bladder base and urethra increase bladder outlet resistance and facilitate urinary storage, (ii) stimulation of beta receptors in the bladder body engenders increase in bladder compliance and facilitates storage, and (iii) adrenergic fibers and involved alpha-receptors suppress parasympathetic transmission in the pelvic ganglia and inhibit bladder contractions. The classic concept of deGroat maintains that the role of the adrenergic system favors urinary storage at low pressures (9). McGuire (10) and El Badawi (4) endorse the concept, and emphasize that the storage phase of micturition is controlled principally by the sympathetic system and the voiding phase by parasympathetic vesicourethral innervation. The challenge to deGroat’s classic concept centers on the observations that patients on alpha-blockers for hypertension do not loose bladder capacity; and retroperitoneal lymphadenectomy for testicular cancer in normal individuals does not result in urinary incontinence/voiding dysfunction (2).

medwedi.ru

778

Part Four: The Urinary System

CNS Control of Urinary Storage and Micturition Normal voiding essentially is a spinal reflex that is modulated by the CNS (brain and spinal cord) (Fig. 3), which coordinates the functions of the bladder and urethra. The bladder and urethra are innervated by three sets of peripheral nerves arising from the autonomic nervous system (ANS), the somatic nervous system, and the CNS, which comprises the brain, brain stem, and the spinal cord (Figs. 5 and 6).

SUPRAPONTINE CENTERS

Brain

CORTICAL /DIENCEPHALIC

+ –

The brain is the master control of the entire urinary system. The micturition control center is located in the frontal lobe of the brain. The primary activity of this area is to send inhibitory signals tonically to the detrusor muscle to prevent the bladder from emptying (contracting) until a socially acceptable time and place to urinate are available. The signal transmitted by the brain is routed through two intermediate centers (the brainstem and the sacral spinal cord) prior to reaching the bladder. Certain cerebral lesions or diseases, such as stroke, cancer, and dementia, often derange the control of the normal micturition reflex.

Brainstem The brainstem is located at the base of the skull. Within the brainstem is a specialized area known as the pons, a major relay center between the brain and the bladder. The pons is responsible for coordinating the activities of the urinary

PONTINE MICTURITION CENTER

INHIBITS SPHINCTER REFLEXES

+ LUMBAR CORD HYPOGASTRIC NERVE

– BLADDER

PELVIC NERVE + –

+

SACRAL CORD

+

EXTERNAL SPHINCTER

PUDENDAL NERVE

Figure 5 Representation of sphincter reflexes. Distention of bladder during filling produces low-level afferent firing, which triggers (1) hypogastric outflow to the bladder, and (2) pudendal outflow to the external urethral sphincter. Hypogastric pathways may promote urine storage by mediating relaxation () of the bladder body via beta-adrenegic receptors and contraction (þ) of the bladder base and urethra via alpha adrenoceptors. Hypogastric input may also inhibit ganglionic transmission in some species. During voiding, inhibition of hypogastric and pudendal pathways promotes complete bladder emptying. Source: From Ref. 11.

PONTINE MICTURITION CENTER

Aδ-MYELINATED BLADDER AFFERENTS

BLADDER +

SPN

SACRAL SPINAL CORD

Figure 6 Schematic of supraspinal micturition reflex pathway. Bladder distention activates unmyelinated Ad fiber afferents. Ascending input is relayed to a region of the pons termed the pontine micturition center. Depending on cortical input, excitatory descending input activates neurons in the sacral parasympathetic nucleus, which cause bladder contraction. Evidence for a spinobulbospinal pathway exists in the cast (de Groat and Ryall, 1969) and rat (Mallory et al, 1989).

sphincters and the bladder so that they work in synergy. The mechanical process of urination is coordinated by the pons in the area known as the pontine micturition center (PMC). The PMC coordinates the urethral sphincter relaxation and detrusor contraction to facilitate urination. The conscious sensations associated with bladder activity are transmitted to the pons from the cerebral cortex. The PMC controls a variety of excitatory and inhibitory neuronal systems and functions as a relay switch in the voiding pathway. Stimulation of the PMC causes the urethral sphincters to open, while facilitating the detrusor to contract and expel the urine. When the bladder becomes full, the stretch receptors of the detrusor muscle send a signal to the pons, which in turn notifies the brain. Patients perceive this signal (bladder fullness) as a sudden desire to go to the bathroom. Under normal situations, the brain sends an inhibitory signal to the pons to inhibit the bladder from contracting until a bathroom is found. Deactivation of the PMC leads to disappearance of the urge to urinate, allowing the patient to delay urination until locating a suitable bathroom. Within the appropriate environment, the brain sends excitatory signals to the pons, allowing the urinary sphincters to open and the detrusor to contract for bladder emptying.

Spinal Cord The spinal cord extends from the brainstem down to the lumbosacral spine. It is located in the spinal canal and is protected by the cerebrospinal fluid, meninges, and the vertebral column. It is approximately 14-inches long in an adult. Along its course, the spinal cord sprouts off many nerve branches to different parts of the body. The spinal cord functions as a long communication pathway between

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

the brainstem and the sacral spinal cord (Figs. 5 and 6). When the sacral cord receives the sensory information from the bladder, this signal travels up the spinal cord to the pons and then ultimately to the brain. The brain interprets this signal and sends a reply via the pons that travels down the spinal cord via the sacral cord to the bladder. In the normal cycle of bladder filling and emptying, the spinal cord acts as an important intermediary between the pons and the sacral cord. An intact spinal cord is critical for normal micturition. If the spinal cord is severely injured or severed, the affected individual will exhibit constant urinary leakage because of uncontrollable detrusor contracture with bladder spasms, a condition called detrusor hyper-reflexia (Table 1). In a condition of complete spinal cord transection, the patient will demonstrate symptoms of urinary frequency, urgency, and urge incontinence, but will be unable to empty his or her bladder completely. This occurs because the urinary bladder and the external urethral SS are both overactive, a condition termed DSD with detrusor hyper-reflexia (DSD–DH) (Fig. 2; Table 1). The sacral spinal cord is the terminal portion of the spinal cord situated at the lower back in the lumbar area. This is a specialized area of the spinal cord known as the sacral reflex center, which is responsible for bladder contractions. The sacral reflex center (Fig. 3) is the primitive voiding center and the only functional ‘‘micturition center’’ in the infant. In infants, the higher center of voiding control (the brain) is not mature enough to command the bladder, which is why control of urination in infants and young children comes from signals sent from the sacral cord. The full infant bladder triggers an excitatory signal that goes to the sacral cord. The sacral cord responds by signaling the spinal reflex center to automatically trigger detrusor contraction, which results in involuntary coordinated voiding. A continuous cycle of bladder filling and emptying occurs, which is why infants and young children are dependent on diapers until they are toilet trained. As the child’s brain matures and develops, it gradually dominates the control of the bladder and the urinary sphincters to inhibit involuntary voiding until complete control is attained. Voluntary continence usually is attained by age three to four years. By this time, control of the voiding process has been relinquished by the sacral reflex center of the sacral cord to the higher center in the brain. If the sacral cord becomes severely injured (e.g., spinal tumor and herniated disc), the bladder may not function. Affected patients may develop urinary retention, termed ‘‘detrusor areflexia’’ Table 1 Neurogenic Bladder Dysfunction According to the Neurologic Abnormality Level of the lesion Brain Pontine micturition center; S2; lumbar, thoracic, cervical spinal cord lesions Pontine micturition center S3,4 spinal cord lesions S2,3,4 peripheral nerves a

Type of neurogenic bladder dysfunction Detrusor hyper-reflexiaa Detrusor hyper-reflexiaa/detrusor sphincter dyssynergia Detrusor hyper-reflexiaa/detrusor sphincter dyssynergia Detrusor hyporeflexia (hypocontractile detrusor) Detrusor hyporeflexia (hypocontractile detrusor)

Neurogenic detrusor overactivity, according to the current International Continence Society (ICS) nomenclature.

779

(Table 1). The detrusor lacks the ability to contract, resulting in inability to urinate and urinary retention.

Peripheral Nerves Peripheral nerves form an intricate network of pathways for sending and receiving information throughout the body. The nerves originate from the main trunk of the spinal cord and branch out in different directions to cover the entire body. Nerves convert the internal and external environmental stimuli to electrical signals so that the human body can understand stimuli as one of the ordinary senses (i.e., hearing, sight, smell, touch, taste, and equilibrium). The bladder and the urethral sphincters are under the influence of their corresponding nerves. The ANS lies outside of the CNS, and regulates the actions of the internal organs (e.g., intestines, heart, and bladder) under involuntary control. The ANS is divided into the sympathetic and the parasympathetic nervous system. Under appropriate conditions, the bladder and the internal urethral sphincter (bladder outlet) primarily are under sympathetic nervous system control (7,8). When the sympathetic nervous system is active, it causes the bladder to increase its capacity without increasing detrusor resting pressure (accommodation) and stimulates the internal urinary sphincter/bladder neck to remain tightly closed. The sympathetic activity also inhibits parasympathetic stimulation, that is, detrusor contraction. The parasympathetic nervous system functions in a manner opposite to that of the sympathetic nervous system. In terms of urinary function, the parasympathetic nerves stimulate the muscarinic (M) receptors that mediate detrusor contraction, leading to bladder emptying (1,7). Immediately preceding parasympathetic stimulation, the sympathetic influence, that is, the activity of the adrenergic receptors on the internal urethral sphincter, becomes suppressed so that the internal sphincter relaxes and opens. In addition, the activity of the pudendal nerve is inhibited to cause the external urethral SS to open, resulting in the facilitation of voluntary urination. Like the ANS, the somatic nervous system is a part of the nervous system that lies outside of the central spinal cord. The somatic nervous system regulates the actions of the muscles under voluntary control. Examples of these muscles are the external urethral SS and the pelvic diaphragm. The pudendal nerve originates from the nucleus of Onuf and regulates the voluntary actions of the external urinary sphincter and the pelvic diaphragm. Activation of the pudendal nerve causes contraction of the external sphincter and the pelvic floor muscles, which occurs with activities such as Kegel exercises. Difficult or prolonged vaginal delivery may cause temporary neuropraxia of the pudendal nerve and stress urinary incontinence. Conversely, suprasacral-infrapontine spinal cord trauma can cause overstimulation of the pudendal nerve that results in urinary retention.

Physiology of LUT Normal bladder function consists of two phases—filling and emptying. The normal micturition cycle requires that the urinary bladder and the urethral sphincter work together as a coordinated unit to store and empty urine. During urinary storage, the bladder acts as a low-pressure receptacle, while the urinary sphincter maintains high resistance to urinary flow to keep the bladder outlet closed. During urine elimination, the bladder contracts to expel urine while the urinary sphincter opens (low resistance) to allow unobstructed urinary flow and bladder emptying.

medwedi.ru

780

Part Four: The Urinary System

Filling Phase During the filling phase, the bladder accumulates increasing volumes of urine while the pressure inside the bladder remains low. As the bladder initially fills, a small rise in intravesical pressure, which is never greater than 10 cm of H2O, occurs (Fig. 7) (12). The filling of the urinary bladder depends on the inherent viscoelastic properties of the bladder and the inhibition of the parasympathetic nerves. Thus, bladder filling primarily is a passive event. However, the sympathetic nerves also facilitate urine storage by (i) inhibiting the parasympathetic nerves from triggering bladder contractions, (ii) directly causing relaxation and expansion of the detrusor muscle, and (iii) causing the closure of the bladder neck by constricting the inner urethral SS. This sympathetic input to the LUT remains very active during bladder filling. As the bladder fills, the pudendal nerve becomes excited. Stimulation of the pudendal nerve results in contraction of the external urethral SS. Contraction of the external sphincter, coupled with that of the internal smooth muscle sphincter, maintains the urethral pressure (resistance) higher than normal bladder pressure. The combination of both urinary sphincters constitutes the purported continence mechanism. The pressure gradients within the bladder and urethra play an important functional role in normal micturition and continence. As long as the urethral pressure is higher than the bladder pressure, urinary continence is ensured. However, abnormally low urethral pressures or abnormally high intravesical pressures result in urinary incontinence. Physical activities, coughing, sneezing, or laughing often result in the sharp rise of pressure within the abdomen, which is transmitted to both the bladder and urethra. As long as the pressure is evenly transmitted to the bladder and urethra, urine will not leak. However, when the pressure transmitted to the bladder is greater than that transmitted to the urethra, stress urinary incontinence results.

Emptying Phase The storage phase of the urinary bladder can be switched to the voiding phase either involuntarily (reflexly) or voluntarily. Involuntary reflex voiding occurs in an infant when the volume of urine exceeds the voiding threshold. When the bladder is filled to capacity, the stretch receptors within the bladder wall signal the sacral cord. The sacral cord, in

turn, sends a message back to the bladder indicating that it is time to empty the bladder. Concurrently, the pudendal nerve causes relaxation of the levator ani so that the pelvic floor muscles relax. The pudendal nerve also signals the external sphincter to open. The sympathetic nerves send a message to the internal sphincter to relax and open, resulting in a lower urethral resistance. As the urethral sphincters relax and open, the parasympathetic nerves trigger contraction of the detrusor. The bladder contracts and the detrusor pressure overcomes the urethral pressure, resulting in urinary flow. These coordinated series of events allow automatic and unimpeded emptying of the bladder. A repetitious cycle of bladder filling and emptying occurs in newborn infants. The bladder empties as soon as it fills because the brain of an infant has not matured enough to regulate the urinary system. Because urination is unregulated by the infant’s brain, predicting when the infant will urinate is difficult. As the infant brain develops, the PMC also matures and gradually assumes voiding control. During childhood (usually at the age of three to four), this primitive voiding reflex becomes suppressed and the brain dominates the control of bladder function, which is why toilet training usually is successful at ages three to four. However, this primitive voiding reflex may reappear in people with spinal cord injuries.

PATHOPHYSIOLOGY OF LUT DYSFUNCTION The bladder appears to be the only human visceral organ that requires an intact central neural system for function and survival of the individual. Any abnormality within the nervous system affects the entire voiding cycle, and any part of the nervous system may be affected, including the brain, pons, spinal cord, sacral cord, and peripheral nerves. Consequently, voiding dysfunction occurs with different symptoms, which range from acute urinary retention to an overactive bladder, or a combination of both. Urinary incontinence results from a dysfunction of the bladder, the sphincter, or both. Bladder hyperactivity (spastic bladder) is associated with the symptoms of urge incontinence, whereas urethral sphincteric hypoactivity (decreased resistance) results in symptomatic stress incontinence. A combination of detrusor hyperactivity and sphincteric deficiency (hypoactivity) may result in mixed symptoms of urge and stress incontinence in the same individual.

Brain Lesions

PRESSURE (cmH2O)

100

50

Voluntary bladder contraction 1st sensation of bladder filling

100

200

400 300 VOLUME (mL)

Figure 7 Normal cystometrogram.

500

Lesions of the brain above the pons may destroy or impair the primary cortical micturition center, resulting in the complete or variable loss of voiding control. However, the voiding reflexes of the LUT—the primitive voiding reflexes—remain intact. Affected individuals show signs of urge incontinence, or spastic bladder (detrusor hyperreflexia) (Table 1). The bladder empties too quickly and too often, with relatively low volumes. Consequently, the storage function of the bladder is deranged, marked clinically by day- and night-time (nocturia) urinary frequency, urgency, and urge incontinence. Typical brain lesions include stroke, brain tumor, Parkinson’s disease, hydrocephalus, cerebral palsy, and Shy–Drager syndrome. The latter disorder is a rare condition associated with open bladder neck, and is discussed later in this chapter.

Lesions of the Spinal Cord Diseases or injuries of the spinal cord between the pons and the sacral spinal cord also result in spastic bladder or

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

overactive bladder (neurogenic detrusor overactivity) (Table 1). People who are paraplegic or quadriplegic have lower extremity spasticity. Acute spinal cord trauma results in the acute spinal shock syndrome; the patient enters a spinal shock phase which the nervous system shuts down the vesical–neural axis. After 6 to 12 weeks, the nervous system gradually reactivates. This reactivation results in heightened stimulation of the affected organs. For example, the legs become spastic. The bladder suffers a voiding disorder, primarily urinary frequency and urge incontinence, which is similar to that of the brain lesion except that the external SS may have paradoxical contractions as well. If both the bladder and external sphincter become spastic at the same time, the affected individual will sense an overwhelming desire to urinate but only a small amount of urine may dribble out. This is DSD because the bladder and the external SS function in discordance. Spinal cord injury may result from a motor vehicle accident, diving accidents, and gun-shot wounds. Multiple sclerosis (MS) is a common systemic cause of spinal cord disease in young women. Children born with myelomeningocele may have spastic bladders and/or an open urethra. Conversely, some children with myelomeningocele may have hypotonic instead of a spastic bladder.

Sacral Cord Injury Selected injuries of the sacral cord and the corresponding nerve roots arising from the sacral cord may prevent the bladder from emptying. A sensory neurogenic bladder presents with a loss of sense of bladder fullness. In the case of a motor neurogenic bladder, the patient retains the sense of bladder fullness; however, the detrusor may not contract, a condition known as detrusor areflexia (acontractile detrusor). Consequently, there is the failure to empty with associated overflow urinary incontinence and bladder decompensation. Typical causes include sacral cord tumor, herniated disc, crush pelvic injuries, lumbar laminectomy, radical hysterectomy, and abdominoperineal resection. Tethered cord syndrome must be ruled out in a teenager with sudden onset of voiding dysfunction. The spinal cord injury in this syndrome is marked by the tip of the sacral cord being stuck near the sacrum and hence being unable to stretch as the child grows taller. Ischemic changes of the sacral cord associated with the tethering cause the manifestation symptoms of dysfunctional voiding.

Peripheral Nerve Injury Diabetes mellitus and AIDS cause peripheral neuropathy that results in dysfunctional voiding (Table 1). These diseases destroy the nerves to the bladder, resulting in a silent, painless distention of the urinary bladder. Patients with chronic diabetes first lose the sensation of bladder filling and fullness, prior to bladder decompensation. Similar to the case of injury to the sacral cord, affected individuals will have difficulty urinating, with the attendant problems of overflow incontinence and bladder decompensation. Other diseases manifesting this condition are poliomyelitis, Guillain–Barre syndrome, genitoanal herpes, pernicious anemia, and neurosyphilis (tabes dorsalis).

DEFINITION OF COMMON TERMS IN NEUROGENIC VOIDING DYSFUNCTION Neurogenic bladder is a malfunctioning bladder due to any type of neurologic disorder.

781

Detrusor overactivity refers to overactive bladder symptoms due to a neurologic (suprapontine upper motor neuron neurologic)/non-neurologic disorder. In neurologic detrusor overactivity, the external sphincter functions normally. There is functional synergy between the bladder and the external urethral SS. However, the patient often presents with frequency, urgency, and urge incontinence. DSD–DH refers to overactive bladder symptoms due to neurologic upper motor neuron disorder of the suprasacral spinal cord. Paradoxically, the patient is in urinary retention. Both the detrusor and the SS are contracting at the same time, that is, synchronous activation of both parasympathetic and pudendal nerves, which act in dyssynergia (lack of coordination). Detrusor overactivity with impaired contractility refers to overactive bladder symptoms, but the detrusor cannot generate enough pressure to allow complete emptying. The external sphincter is in synergy with detrusor contraction. The detrusor is too weak to mount an adequate contraction for proper voiding to occur. The condition is similar to urinary retention, but irritating voiding symptoms are prevalent. Acontractile/hypocontractile detrusor is a complete inability of the detrusor to empty due to a lower motor neuron lesion (e.g., sacral cord and peripheral nerves). Urinary retention is the inability of the urinary bladder to empty, and the problem of failure to empty may have neurologic or non-neurologic etiology.

SPECIFIC NEUROLOGIC LESIONS Supraspinal lesions Supraspinal lesions refer to those lesions of the CNS above the pons, which include cerebrovascular accidents, brain tumors, Parkinson’s disease, and Shy–Drager syndrome (13).

Cerebrovascular Accidents After a stroke, the brain may enter into a temporary acute cerebral shock phase. During this time, the urinary bladder will be in retention due to detrusor areflexia. About 25% of stroke victims develop acute urinary retention. Following the cerebral shock phase, the bladder demonstrates detrusor overactivity with coordinated urethral sphincter activity, because the PMC is released from the cerebral inhibitory center. The symptoms of detrusor overactivity/hyperactivity/ hyper-reflexia often include urinary frequency, urgency, and urge incontinence. The treatment for the cerebral shock phase is indwelling Foley catheter or clean intermittent catheterization (CIC). The resultant hyper-reflexic bladder is often managed with anticholinergic medications to facilitate bladder filling and storage. Detrusor hyper-reflexia (Fig. 8) with coordinated urethral SS is the most commonly observed urodynamic pattern associated with a brain tumor (Fig. 8). Any associated hyper-reflexia is managed similarly with anticholinergic medications.

Parkinson’s Disease This is a degenerative disorder of pigmented neurons of the substantia nigra of the cerebrum, associated with dopamine deficiency and increased cholinergic activity in the corpus striatum. Patients with Parkinson disease manifest symptoms of bradykinesia, skeletal muscle tremor, cogwheel rigidity, and masked facies. Symptoms specific to the urinary bladder include urinary frequency, urgency, nocturia, and urge incontinence. Typical urodynamic findings are

medwedi.ru

782

Part Four: The Urinary System

Figure 8 Detrusor overactivity/hyper-reflexia. Note the phasic detrusor overactivity reflected in the detrusor pressure curve (Pdet); this may or may not be associated with urinary leak (incontinence). Detrusor overactivity is of two types: neurogenic (spinal cord injury) and non-neurogenic. Terminal detrusor overactivity with leak is characterized by end-filling detrusor overactivity.

consistent with detrusor hyper-reflexia (Fig. 8) and urethral SS bradykinesia, that is, the striated urethral sphincter often demonstrates poorly sustained contraction. Similar to other supraspinal lesions, the treatment of voiding dysfunction associated with Parkinson disease is to facilitate bladder filling and promote urinary storage with anticholinergic agents. If Parkinson disease coexists with symptoms of bladder outlet obstruction due to benign prostatic hyperplasia (BPH), the diagnosis of BPH must be confirmed by multichannel urodynamic studies (UDS). The most common cause of postprostatectomy incontinence in the patient with Parkinson disease is detrusor hyper-reflexia. If transurethral resection of the prostate (TURP) is performed without urodynamic confirmation of obstruction, the patient may become totally incontinent after the TURP procedure.

Shy–Drager Syndrome Shy–Drager syndrome is a rare, progressive, and degenerative disease affecting the ANS with multisystem organ atrophy. In addition to Parkinson-like symptoms, cerebellar ataxia and autonomic dysfunction are common. Affected individuals demonstrate orthostatic hypotension, anhidrosis, and urinary incontinence. Degeneration of the nucleus of Onuf results in denervation of the external SS. Sympathetic nerve atrophy causes a nonfunctional bladder and an open bladder neck. Urodynamic evaluation often reveals neurogenic detrusor overactivity (Fig. 8), although a few individuals may have acontractile detrusor (Fig. 9) or poorly sustained bladder contractions. Often, the bladder neck (internal smooth sphincter) will be open at rest, while there is SS denervation. The treatment for Shy–Drager syndrome is to facilitate urinary storage with anticholinergic agents coupled with CIC or indwelling catheter. Patients with Shy–Drager syndrome should avoid undergoing TURP, because the risk of total incontinence is high.

Spinal Cord Lesions Spinal Cord Injury A spinal cord injury from a diving accident or motor vehicle injury results in the initial response of acute spinal shock.

Figure 9 Pressure–flow study in hypocontractile/acontractile bladder (detrusor hyporeflexia). Note the low detrusor-voiding pressure with low urinary flow rate; one of the patterns in spinal cord injury.

During this acute spinal shock phase, the patient experiences flaccid paralysis below the level of injury, and the somatic reflex activity is either depressed or absent. The anal or bulbocavernosus reflex is typically absent. The autonomic activity is depressed, resulting in acute urinary retention and constipation. Urodynamic findings are consistent with acontractile detrusor (Fig. 9). The internal smooth and external urethral striated sphincteric activities, however, are normal. The spinal shock phase typically lasts for 6 to 12 weeks; it may be prolonged in some cases. The urinary bladder is managed either by indwelling urethral catheter or by CIC. The bladder function returns with reflex excitability and detrusor hyper-reflexia following the spinal shock phase (Fig. 8). Depending on the level of the lesion, the individual may develop DSD–DH and urinary leakage between CIC. Periodic UDS is indicated to monitor the effect of this alteration on detrusor behavior. During UDS, intravesical instillation of cold saline may indicate return of reflex activity or help better characterize the lesion. Suprasacral lesions may result initially in acontractile detrusor, which progresses to detrusor overactivity over time. Conversely, sacral cord lesions are associated with acontractile bladders, which may become hypertonic over time.

Spinal Cord Lesions (Above the Sixth Thoracic Vertebrae) A complete cord transection above the sixth thoracic vertebrae (T6) most often will result in urodynamic findings of neurogenic detrusor overactivity and striated and smooth muscle sphincter dyssynergia (Fig. 2). A unique complication of T6 injury is autonomic dysreflexia. Autonomic dysreflexia is an exaggerated sympathetic response to any stimuli below the level of the lesion. This occurs most commonly with lesions of the cervical cord. Often, the inciting event is instrumentation of the urinary bladder or the rectum, causing visceral distention. Symptoms of autonomic dysreflexia include sweating, headache, hypertension, and reflex bradycardia. Acute management of autonomic dysreflexia is to decompress the bladder or rectum. Decompression usually will reverse the effects of unopposed sympathetic outflow. If additional measures are required,

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

parenteral ganglionic or adrenergic blocking agents, such as chlorpromazine, may be used. Oral blocking agents, including terazosin, may be used for prophylactically treating patients with autonomic dysreflexia. Alternatively, a spinal anesthetic may be used as a prophylactic measure whenever bladder instrumentation is considered.

Spinal Cord Lesions (Below T6) Spinal cord lesions below T6 level reveal urodynamic findings of detrusor hyper-reflexia (Fig. 8), SS dyssynergia (Fig. 2), and smooth sphincter dyssynergia but no autonomic dysreflexia. Neurologic evaluation reveals skeletal muscle spasticity with hyper-reflexic deep tendon reflexes, extensor plantar response, and positive Babinski sign, and above all, incomplete bladder emptying secondary to DSD, or loss of facilitatory input from higher centers. The cornerstone of treatment involves CIC and anticholinergic medications.

Multiple Sclerosis MS is caused by focal demyelination of the CNS. It most commonly involves the posterior and lateral columns of the cervical spinal cord. Usually, poor correlation exists between the clinical symptoms and urodynamic findings. Thus, using UDS to evaluate patients with MS is critical. The most common urodynamic finding is detrusor hyperreflexia (Fig. 8), occurring in as many as 50% to 90% of MS patients. About 50% of these patients will demonstrate DSD–DH. Detrusor areflexia occurs in 20% to 30% of cases. The optimum therapy for a patient with MS and neurogenic voiding dysfunction must be individualized, based on the urodynamic findings.

783

ganglia or the sacral nerves. Sacral nerve involvement leads to impairment of detrusor function. The early stages of herpes infection are associated with LUT symptoms of urinary frequency, urgency, and urge incontinence, whereas the late stage is characterized by decreased bladder sensation, increased residual urine, and urinary retention. Urinary retention is self-limited and will resolve spontaneously with resolution of the herpes infection.

Herniated Disc Slow and progressive herniation of the lumbar disc may cause irritation of the sacral nerves resulting in detrusor hyper-reflexia. Conversely, acute compression of the sacral roots associated with deceleration trauma or pathologic fracture impairs nerve conduction, which results in detrusor areflexia. A typical urodynamic finding of sacral nerve injury is acontractile detrusor with intact bladder sensation (Fig. 9). Association with internal sphincter denervation may occur. Damage of the peripheral sympathetic nerves results in an open and nonfunctional internal sphincter. Peripheral sympathetic nerve damage often occurs in association with detrusor denervation. The SS, however, is preserved.

Pelvic Surgery Major pelvic surgery such as radical hysterectomy, abdominoperineal resection, proctocolectomy, or total exenteration will usually result in varying degrees of bladder dysfunction postoperatively. Most commonly, postsurgical symptoms of acontractile detrusor occur. However, spontaneous recovery of function occurs within six months after surgery in about 80% of the patients.

Peripheral Nerve Lesions

CLASSIFICATION OF NLUTD

Peripheral nerve lesions due to diabetes mellitus, tabes dorsalis, herpes zoster, herniated lumbar disk disease, and radical pelvic surgery result in detrusor areflexia.

Numerous schemes have been proposed to classify neurological voiding dysfunction (Table 2) (14–20). Neurourological classifications are predicated based upon descriptive detrusor pathophysiology as well as the site of the neurologic disease. Table 2 summarizes the historic six classification schemes, from the ‘‘neurologic’’ of Bradley to the ‘‘functional’’ of Wein. We have adopted for this chapter the functional classification proposed by Wein (20), which is based on the ability of the patient to either store urine in the bladder or empty the bladder completely. This classification must depend on the technological advances in modern urodynamics including videofluoroscopy and electromyography (EMG), which allow descriptive urodynamic interpretation of McClellan–Lapides nomenclature (1,20). The specific urodynamic interpretation enables appropriate therapeutic intervention for the patient with NLUTD.

Diabetic Cystopathy Usually, neurogenic bladder dysfunction occurs 10 or more years after the onset of diabetes mellitus. Neurogenic bladder occurs because of autonomic and peripheral neuropathy. A metabolic derangement of the Schwann cell results in segmental demyelination and impaired nerve conduction. The first symptoms of diabetic cystopathy are loss of sensation of bladder fullness followed by loss of motor function. Classic urodynamic findings associated with this condition are elevated residual urine, decreased bladder sensation, impaired detrusor contractility, and, eventually, acontractile detrusor (Fig. 9). Paradoxically, DHIC may occur. Treatment of diabetic cystopathy is CIC, long-term indwelling catheterization, or urinary diversion.

Tabes Dorsalis (Neurosyphilis) In tabes dorsalis, central and peripheral nerve conduction is impaired, resulting in decreased bladder sensation and increased voiding intervals. The most common urodynamic finding associated with neurosyphilis is detrusor areflexia with normal striated sphincteric function.

Herpes Zoster Herpes zoster is a neuropathy associated with painful vesicular eruptions in the dermal distribution of the affected nerve. The herpes virus lies dormant in the dorsal root

DIAGNOSIS OF NLUTD History Both in congenital and acquired NLUTD, early diagnosis and treatment are essential because irreversible changes may occur in children with myelomeningocele, but also in patients with traumatic spinal cord injury. Symptoms of neurogenic bladder range from detrusor underactivity to overactivity, depending on the site of neurologic insult. The striated urinary sphincter also may be affected, resulting in sphincter underactivity or overactivity and loss of coordination with bladder detrusor function. The appropriate therapy and a successful outcome are predicated upon accurate diagnosis through thorough history and physical

medwedi.ru

784

Part Four: The Urinary System

Table 2 Major Classification Schemes Bradley (14) Loop 1: Frontal lobe Brainstem

Loop 2: Brainstem–detrusor nucleus (sacral cord) Loop 3: Detrusor–pudendal nucleus (sacral cord)

Loop 4A: Frontal lobe– pudendal nucleus 4B: Pudendal-pudendal

Gibbon (15)

McClellan/Lapides (17,18)

Krane/Siroky (19)

Wein (20)

Suprasacral lesion

Upper motor neuron lesion—complete vs. incomplete; balanced vs. imbalanced

Uninhibited NB Reflex NB

Detrusor hyper-reflexia (or normoreflexia) Coordinated sphincters Striated sphincter dyssynergia Smoother sphincter dyssynergia

Failure to store bladder outlet

Sacral lesion Motor sensory

Lower motor neuron lesion—complete vs. incomplete; balanced vs. imbalanced Mixed lesion

Autonomous NB Motor paralytic bladder Sensory NB

Detrusor areflexia Coordinated sphincters Nonrelaxing striated sphincter

Failure to empty bladder outlet

Mixed lesion

Bors/Comarr (14)

Denervated striated sphincter

Abbreviation: NB, neurogenic bladder.

examination with a variety of clinical evaluations, including urodynamics and selective radiographic imaging studies. The general history should include questions relevant to neurological and congenital abnormalities, information on the previous occurrence and frequency of urinary infections, and on relevant past surgery. Specific urinary history consists of symptoms related to both the storage and emptying functions of the LUT. The onset and the nature of the NLUTD (acute or insidious) should be determined. Specific symptoms and signs must be assessed in NLUTD and, if appropriate, be compared with the patient’s condition before the NLUTD developed. Voiding symptoms of hesitancy, stranguria, decrease in the force and caliber of urinary stream, incomplete bladder emptying, or frank urinary retention suggest differential diagnosis that must include bladder outlet obstruction due to benign prostatic enlargement, prostate cancer, or urethral stricture and neurologic bladder disease. Specific signs such as pain, dysuria, infection, hematuria, or fever may justify further specialized work-up. The history must rule out congenital anomalies or metabolic disorders with possible neurological implications. Also, the history must include present medications, particularly those with known or possible effects on the LUT, and lifestyle factors such as smoking, alcohol, or addictive drug use. The general history should also include the assessment of menstrual, sexual, and bowel function, and obstetric history. Importance of bowel history must be stressed here because patients with NLUTD may suffer from a related neurogenic condition of the lower gastrointestinal tract. The bowel history also must address symptoms related to the storage and the evacuation functions and specific symptoms and signs including anorectal symptoms, previous defecation pattern, fecal incontinence, and rectal sensation. Mode and type of defecation must be compared with the patient’s condition before the neurogenic dysfunction developed. Hereditary or familial risk factors should be recorded. Like the bowel function, the sexual function may also be impaired because of the neurogenic condition. The details of this history of course differ between men and women. However, such a focused evaluation should elicit information on genital or sexual dysfunction symptoms, previous sexual function, sensation in the genital area, and

for sexual functions and erectile, orgasmic, or ejaculatory dysfunction. Specific neurologic history should concentrate on eliciting information regarding acquired or congenital neurologic conditions, neurological symptoms (somatic and sensory), with onset, evolution, and therapy, as well as spasticity or autonomic dysreflexia (lesion level above T6).

Physical Examination A complete and thorough general physical examination must be performed with special emphasis on the urologic and neurologic systems. Performance of a general urological and, when appropriate, gynecological examination is expected in every case. Attention should be paid to the patient’s physical and possible mental handicaps with respect to planned diagnostic investigations. Impaired mobility, particularly in the hips, or extreme spasticity may lead to problems in patient positioning in the urodynamics laboratory. Patients with very high neurological lesions may suffer from a significant drop in blood pressure when moved in a sitting or standing position. Subjective indications of bladder-filling sensations may be impossible in retarded patients. Prostate palpation or observation of pelvic organ descensus is made. The neurourologic examination should investigate the motor and sensory functions of the body and —the limbs, and the hand function. The examination should include the assessment of perineal sensation, the perineal reflexes supplied by the sacral segments S2 to S4, and anal sphincter tone and control.

Laboratory and Radiologic Evaluation In the patient with LUT dysfunctional voiding, laboratory evaluation must include urinalysis and urine culture to rule out urinary tract infection (UTI) that can cause irritative voiding symptoms and urge incontinence. Urine cytology must exclude the diagnosis of carcinoma-in-situ of the urinary bladder, particularly in those patients with hematuria and/or irritative voiding symptoms that are out of proportion to the overall clinical presentation. Cystoscopy is also indicated in the evaluation of this subset of patients. Determination of serum creatinine and blood urea nitrogen

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

allows important assessment of renal function, which could be impaired in the patient with neurologic bladder dysfunction. Fasting blood glucose may be necessary to rule out diabetes mellitus, and serum serologic test for syphilis may be indicated. Intravenous urogram (IVU) has remained the standard imaging modality to assess the upper urinary system for changes due to neurologic bladder disease. Renal sonogram, which is the screening modality of choice in children, and magnetic resonance imaging (MRI) can be utilized in the patients who may have a contraindication to IVU or impaired renal function. Imaging study is indicated to rule out hydronephrosis, urinary tract stones, and renal scarring from chronic pyelonephritis. Voiding cystourethrogram (VCUG) is indicated to rule out vesicoureteral reflux in children with congenital neurological defect such as myelodysplasia. Additional specialized neurological studies such as head or spine computed tomography scan, MRI, myelogram, or EMG may be indicated to rule out or confirm specific neurological disease. However, long-term follow-up of these patients should include regular periodic imaging of the kidneys and the bladder to rule out stones, hydronephrosis, or masses.

Voiding Studies Uroflometry (UFR) (Fig. 10) with assessment of postvoid residual (PVR) urine remains a useful test to rule out bladder obstruction in the differential diagnosis of LUT dysfunction. This test gives a first impression of the voiding function and is mandatory before any invasive urodynamics is planned. For reliable information, it should be repeated at least two to three times. Possible pathologic findings include low flow rate, low voided volume, intermittent flow, hesitancy, and elevated PVR urine (Fig. 11). Care must be taken in judging the results in patients who are not able to void in a normal position. Both the flow pattern and the flow rate may be modified by inappropriate position and by any construction to divert the flow. More often, UFR and PVR are performed as a part of the complex UDS, which generates other useful clinical parameters such as intravesical pressure, pelvic floor EMG, and VCUG monitored with fluoroscopy.

785

Figure 11 Pressure–flow study in bladder outlet obstruction. Note the high detrusor-voiding pressure and low urinary flow rate; the computergenerated graph is compared to the International Continence Society Standards and Schafer’s Nomograms to objectively document the degree of obstruction.

cord injury above T6 may exhibit autonomic dysreflexia, which is characterized by hypertension, bradycardia, sweating, pounding headache, and piloerection among others following certain stimuli such as bladder distension and stimulation of lower portions of the body. Such patients should have blood pressure monitored during the study. The rectal ampulla should be empty of stool before the UDS. Drugs that influence the LUT function should be discontinued, if feasible, at least 48 hours before the investigation or otherwise be taken into account for the interpretation of the data. All urodynamic findings must be reported in detail and performed according to the International Continence Society technical recommendations and standards.

Urodynamic Tests Cystometry Cystometry is the method by which the pressure–volume relationship of the bladder is measured and is used to assess

Urodynamic Studies UDS (Fig. 12) objectively assesses the LUT function. It is important to know that during UDS patients with spinal

25 ml/s Flow Rate

0

10

20

30 Time (s)

25 ml/s Flow Rate

0

10

20

30

40 Time (s)

Figure 10 Normal free uroflow curve (‘‘bell-shaped’’). The uroflow curve is bell shaped; important parameters to note include maximum flow rate (Qmax), voided volume, and postvoid residual volume.

Figure 12 Normal pressure–flow study. Pdet is normally very low until the end-filling stage of the pressure–flow study, and there is a sustained and effective detrusor contraction with the command to void resulting in urinary flow and relaxation of the external urethral sphincter.

medwedi.ru

786

Part Four: The Urinary System

detrusor activity, sensation, capacity, and compliance (Figs. 7 and 12). Filling Cystometry. An average adult bladder holds approximately 350 to 500 mL of urine. During the test, provocative maneuvers help to unveil bladder instability (Fig. 13A and B). Filling cytometry is important if combined with bladder pressure measurement during micturition (pressure– flow study) and videourodynamics. The latter is necessary to document the status of the LUT function during the filling phase. The bladder should be empty at the start of filling. A relatively physiologic filling rate (< 35 mL/min) should be used with body-warm saline, because fast-filling and room-temperature saline are provocative. Possible pathologic findings during filling cystometry include detrusor overactivity, low detrusor compliance, abnormal bladder sensation, and incontinence and incompetent or relaxing urethra.

Figure 14 Valsalva (abdominal) leak point pressure measurement. The lowest abdominal pressure (Pabd) at which leak is noted with Valsalva maneuver during bladder filling is called valsalva (abdominal) leak point pressure; VLPP of less than 20–30 cmH2O indicates severe intrinsic sphincter deficiency and results in stress urinary incontinence. Abbreviation: VLPP, Valsalva leak point pressure.

LPP Measurements Abdominal or Valsalva Leak Point Pressure. The abdominal pressure (Pabd) at which leak is noted during bladder filling is known as abdominal (or Valsalva) leak point pressure (VLPP) (Fig. 14). This test is useful in patients with urinary incontinence and helps to assess intrinsic sphincter dysfunction. In addition, VLPP of more than 70 to 80 cmH2O carries the risk of upper tract damage. However, there is currently no uniform consensus regarding the methodology of measurement LPP. Detrusor Leak Point Pressure (DLPP). This specific investigation is important to estimate the risk for the upper urinary tract or for secondary bladder damage. The DLPP greater than 40 cmH2O places the upper tract at risk of damage. The DLPP is only a screening test, because it lacks information on the duration of the high pressure that might have more impact on the upper urinary tract. A high DLPP warrants further testing, including videourodynamics to document any associated vesicoureteral reflux.

Figure 13 (A) Normal stable detrusor with normal compliance during filling cystometry. Note the stable detrusor during the filling stage with low detrusor pressure and normal compliance. (B) Poor detrusor compliance. Note the rise in the detrusor pressure (Pdet) during the filling stage; this may be seen in spinal cord injury and interstitial cystitis and may coexist with detrusor overactivity.

Pressure–Flow Study Pressure–flow study reflects the coordination between the detrusor and the urethra or pelvic floor during the voiding phase. This is the only test that can assess bladder contractility and the severity of a bladder outlet obstruction. Pressure–flow study simultaneously records the voiding detrusor pressure and the rate of urinary flow (Fig. 9). Pressure–flow studies can be combined with voiding cystogram and videourodynamics for complicated cases of urinary incontinence. It is even more powerful in combination with filling cystometry and videourodynamics. Possible pathologic findings include detrusor underactivity/ contractility, DSD, nonrelaxing urethra, and residual urine. Most types of bladder obstruction caused by NLUTD are due to DSD or static/nonrelaxing urethra or bladder neck. Pressure–flow analysis mostly assesses the severity of the mechanical obstruction caused by the urethra’s inherent mechanical or anatomic obstruction, and has limited value in patients with NLUTD. Sphincter EMG The cystometrogram may be performed simultaneously with EMG to assess the activity of the external urethral SS, the periurethral striated musculature, the anal sphincter, or

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

787

the striated pelvic floor muscles during micturition (Fig. 2). Normally, the pelvic floor striated muscle electromyographic activity diminishes at the onset of bladder detrusor contraction. Bladder outlet obstruction due to detrusor–external sphincter dyssynergia is diagnosed by persistence of the activity on the EMG during voiding or attempt to void.

also pivotal in the prevention of UTI and perineal area skin infections. Despite the varied neuropathies detected in the patient with NLUTD, a simple practical scheme for their management is based on the premise that NLUTD results primarily in failure to either empty or store urine.

Video Urodynamics This combination of filling cystometry and pressure–flow study with LUT imaging is the gold standard urodynamic investigation in NLUTD. This complex testing combines VCUG and multichannel urodynamics (Fig. 2). The procedure enables documentation of the anatomic and functional integrity of the LUT, as well as the functional pressure–flow relationship between the bladder, the bladder outlet, and urethra. The VCUG can identify a bladder diverticulum, urethral diverticulum, urethral obstruction, and vesicoureteral reflux.

Failure to Empty Assisted Bladder Emptying

Provocative Tests During Urodynamics Coughing, triggered voiding, or anal stretch can provoke LUT dysfunction. Fast-filling cystometry with cooled saline (the ‘‘ice water test’’) is considered a discriminative test between an upper motor neuron lesion (UMNL) and a lower motor neuron lesion (LMNL). Patients with UMNL with intact detrusor muscle will exhibit detrusor contraction, whereas patients with LMNL will not. The test gives false-positive results in young children (21) and may not be fully discriminative in other patients (21). A positive bethanechol supersensitivity test (detrusor contraction more than 15 cmH2O over baseline) was presumed to prove detrusor denervation hypersensitivity, the intactness of the motor innervation of the bladder, and the muscular integrity of an acontractile detrusor. The test often gives equivocal results, and other clinical conditions such as cystitis magnify its false positivity. A recent variation of this method was reported with intravesical electromotive administration of the bethanechol (8). This test turned out to be both selective and predictive for successful oral bethanechol treatment.

Incomplete bladder emptying is a serious risk factor for UTI, for developing high intravesical pressure during the filling phase, and for incontinence. The method of choice to improve the voiding process should be based on practicality, the subject’s compliance, and, most importantly, on longterm clinical impact. Third-Party Bladder Expression (Crede´ Maneuver) Regretfully, this method is still applied, foremost in infants and young children with myelomeningocele and sometimes in tetraplegics. The suprapubic downward compression of the lower abdomen leads to an increase in the intravesical pressure, but also causes a compression of the urethra and thus a functional obstruction that may reinforce an already existing high bladder outlet resistance and lead to inefficient emptying. Because of the high pressures that may be created during this maneuver, it is potentially hazardous for the urinary tract, and thus is contraindicated. Although it is a noninvasive method, its use should be discouraged unless urodynamics shows intravesical pressures to stay within the safe range. Abdominal Straining (Valsalva) In recommending voiding by abdominal straining, the considerations mentioned under Crede´ above also hold for the Valsalva maneuver. Most of these patients are unable to scale the pressure they exert on the bladder during Valsalva; therefore, there is the inherent risk of exceeding the safe range.

MANAGEMENT OF NLUTD The primary aims for treatment of NLUTD include protection of the upper urinary tract, improvement of urinary continence, improvement of the patient’s quality of life, and restoration of the normal LUT function. Preservation of the upper urinary tract function is of paramount importance. Until 25 years ago, renal failure remained the primary long-term cause of mortality in the spinal cord–injured patient surviving the initial trauma. This has led to the golden rule in the treatment of NLUTD: assure that the detrusor pressure remains within safe limits during both the filling phase and the voiding phase. This approach has indeed significantly reduced the mortality and morbidity from urological complications in this patient group. Bladder dysfunction can result in hydronephrosis, vesicoureteral reflux, infections, or stones. In patients with high detrusor pressure during the filling phase (detrusor overactivity, low detrusor compliance, etc.) or during the voiding phase (DSD and other causes of bladder outlet obstruction), therapy is aimed primarily at the conversion of an active, aggressive high-pressure bladder into a passive low-pressure reservoir despite the resulting residual urine, which can be managed by CIC. Therapy of urinary incontinence is important for the social rehabilitation of the patient and thus contributes substantially to the quality of life, but is

Triggered Reflex Voiding Stimulation of the sacral or lumbar dermatomes in patients with UMNL can elicit reflex contraction of the detrusor. Morbidity occurs more often during the first decades of treatment. This method may be used in patients in whom it is urodynamically safe.

Catheter Drainage Indwelling Continuous Catheter Drainage Indwelling continuous catheter drainage (urethral or suprapubic), in general, remains attractive for practicality and effectiveness in the short term. The most common use of a suprapubic catheter is in individuals with spinal cord injuries (paraplegic and quadriplegic) and a malfunctioning bladder. A long-term suprapubic catheter remains an attractive alternative to a long-term indwelling urethral catheter. However, use of smaller (e.g., 14F and 16F) tubes is recommended for either drainage method. In male patients, longterm continuous urethral catheterization is associated with high complication rates of urethral strictures, fistulas, bladder stones, and infection. Although rare, malignancy can also occur with chronic indwelling urethral catheters. This is especially true in paraplegic women (21). In 6 out of 59 patients who had a chronic indwelling urethral catheter

medwedi.ru

788

Part Four: The Urinary System

(22), squamous cell carcinoma developed. In another study, squamous metaplasia and leukoplakia developed in 11 out of 81 spinal cord–injured patients with a chronic indwelling catheter (23). Bacteriuria occurs within 72 hours of placement of a continuous indwelling urethral catheter, and consequently chronic inflammation can result in a contracted fibrotic bladder. Finally, urinary incontinence associated with bladder spasms often is treated by increasing the balloon size with some traction on the catheter, which predisposes to erosion of the bladder neck. Potential complications with chronic suprapubic catheterization are similar to those associated with indwelling urethral catheters, including leakage around the catheter, bladder stone formation, UTI, and catheter obstruction. However, with a suprapubic catheter, the risk of urethral damage is eliminated; because the catheter comes out of the lower abdomen rather than the penis or vaginal area, a suprapubic tube is more patient-friendly. Bladder spasms occur less often because the suprapubic catheter does not irritate the trigone, as does the urethral catheter. In addition, suprapubic tubes are more sanitary for the individual, and bladder infections are minimized because the tube is away from the perineum. Nonetheless, suprapubic tube neither prevents bladder spasms from occurring in unstable bladders nor improves the urethral closure mechanism in an incompetent urethra. If the suprapubic tube falls out inadvertently, the exit hole of the tube will seal up and close quickly within 24 hours if the tube is not replaced with a new one. Regardless of the method employed, the catheter should be changed very regularly, at least once a month. Management with chronic continuous catheter drainage is a risk factor also for renal deterioration. Investigators have reported significant differences in renal scarring and caliectasis in spinal cord–injured patients managed by chronic catheterization versus those using a reflex avoiding method (24,25). Because of the deleterious effects of chronic continuous catheter drainage in this particular patient subgroup, it should be avoided at all costs. Intermittent Catheterization Intermittent catheterization or self-catheterization is a mode of draining the bladder at timed intervals, as opposed to continuous bladder drainage. Intermittent catheterization has become a healthy alternative to indwelling catheters for individuals with chronic urinary retention due to an obstructed bladder, a hypocontractile bladder, or a nonfunctioning bladder. Of the three possible options, i.e., urethral catheter, suprapubic tube, and intermittent catheterization, the latter is the best solution for bladder decompression of a motivated individual who is not physically handicapped or mentally impaired. A prerequisite for self-catheterization is the patient’s ability to use their hands and arms; however, in a situation in which a patient is physically or mentally impaired, a caregiver or health professional can perform intermittent catheterization for the patient. Many studies of young individuals with spinal cord injuries have shown that intermittent catheterization is preferable to indwelling catheters (i.e., urethral catheter and suprapubic tube) for both men and women, including young children with myelomeningocele. Intermittent catheterization may be performed using a soft red-rubber catheter or a short, rigid, plastic catheter. The use of plastic catheters is preferable to red rubber catheters, because they are easier to clean and last longer. The bladder must be drained on a regular basis, either based on a timed interval (e.g., on awakening, every three to six hours during the day, and before bed) or based

on bladder volume, which must be kept at less than 400 to 500 cc during each session. CIC results in lower rates of infection than the rates noted with indwelling catheters. However, all patients should be placed on an antibiotic prophylaxis using an agent such as nitrofurantoin for the initial few weeks, to allow the LUT acclimatization to the bacterial colonization.

Pharmacologic Therapy Aiding Bladder Emptying Acetylcholine mediates the stimulation of the muscarinic, M3-subtype receptors of the detrusor smooth muscles, which results in physiologic bladder contraction and voiding. Activation of the M2-subtype receptor inhibits bladder relaxation through inhibition of the signal transduction pathways, leading to accumulation of cyclic adenosine monophosphate (1,12). Neural injury or denervation leads to upregulation of the M2 receptors. Pharmacologic manipulation involving direct stimulation of the muscarinic receptors would enhance detrusor contraction and bladder emptying. Therefore, useful agents would seem to be those that mimic the action of acetylcholine. Bethanechol chloride is the most commonly recommended acetylcholine-like drug for those patients with failure to empty due to impaired detrusor contractility. Bethanechol exhibits relative selectivity in the bladder, with minimal effect at the level of neural ganglia and cardiovascular targets. Furthermore, bethanechol in doses of 5 to 10 mg has been employed in the treatment of patients with postoperative or postpartum urinary retention. Although, it has remained for many decades the primary therapy in those patients with atonic or hypotonic bladders (26), doubts have continually persisted about its clinical efficacy in aiding bladder emptying. Controversy has also surrounded the use of bethanechol for inducing reflex bladder contraction in patients with supraspinal spinal cord injury, and experience has shown that this agent should not be recommended in those patients with overactive bladder associated with poor compliance, because of the potential deterioration of the upper tract by the rising intravesical pressure. Overall, there is no solid clinical evidence to support the use of bethanechol as a parasympathomimetic agent to aid in the physiologic emptying of the neurogenic bladder. Decreasing Bladder Outlet Resistance In contrast to using a parasympathomimetic agent to stimulate bladder emptying, alpha-blockers have been used with partial success in an attempt to decrease bladder outlet resistance in patients with neurovesical dysfunction. The rationale for these drugs is that increased bladder outlet resistance occurs in response to the stimulation of sympathetic reflexes, and the alpha-adrenergic receptors primarily inhibit the pelvic parasympathetic ganglionic transmission with a resultant increased relaxation of the bladder body and efficient urine storage. Prazosin hydrochloride, terazosin, doxazosin, and alfuzosin are antihypertensive agents with affinity for the postsynaptic a1-adrenergic receptors. These a1-receptor antagonists relax the smooth muscle of the bladder outlet and urethra, and thus lower the outlet resistance. Terazosin and doxazosin are the commonly used alpha-blockers for lowering the outlet resistance and aiding in bladder emptying. Further, these drugs have longer half-lives (12 hours), which improve compliance, and are thus well tolerated. The commonest side effects include asthenia, orthostatic hypotension, and dizziness.

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

The doses are usually titrated from 1 to 10 mg with the average dose at 5 mg; the patients are usually instructed to take it at bedtime to minimize the side effects.

789

the stimulation parameters, this method can also induce defecation or erection.

Surgical Management Decreasing Outlet Resistance at the SS The centrally acting muscle relaxants such as chlordiazepoxide, methocarbamol, orphenadrine, and diazepam are oral agents that cause relaxation of the striated muscles of the pelvic floor. Dantrolene sodium, which is the most commonly used skeletal muscle relaxant in patients with classic detrusor–SS dyssynergia, has been successful in facilitating voiding in these patients. The recommended adult therapy begins with the dose of 25 mg twice daily, and slowly titrated to the maximum daily divided doses of 400 mg. Sedation is the most common side effect; however, potential adverse events include euphoria, dizziness, diarrhea, and hepatitis. The later is related to high dosage and long-term use. Baclofen, a gamma-amino-amino butyric acid agonist has been used commonly as a centrally acting agent to relax the external urethral sphincter. The purported mode of action is the inhibition of the primary afferent fibers terminal in the spinal cord, thereby abolishing any monosypnatic or polysynaptic spinal reflex activity. Treatment is usually started with a dose of 5 mg, three times a day, and titrated to a total daily dose of 60 mg. The reported benefits of baclofen in the management of neurogenic voiding dysfunction include reduction in SS activity, decrease in residual urine, abolition of hyper-reflexia and nocturia, and increase in bladder compliance. Side effects include lower extremity flaccidity (at the therapeutic doses), respiratory depression, erectile dysfunction, and constipation. Drowsiness, insomnia, rash, pruritus, dizziness, weakness, hallucination, and seizures are other potential complications of baclofen therapy.

Electrical Stimulation Currently, direct electrical stimulation to aid in complete bladder emptying in a patient with neurogenic urinary retention remains an attractive alternative to intermittent catheterization, but clinical application has been limited because of poor results and unwanted side effects. Fifty to sixty percent of patients have been reported to exhibit low residual urine volumes following application of direct electrical stimulation to treat their hypotonic or acontractile bladders. However, the collateral spread of electrical current to other pelvic organs with a low stimulus threshold often results in abdominal, pelvic, and perineal pain, desire to defecate, contraction of pelvic and leg muscles, and erections and ejaculations, making this approach less than ideal. To overcome such undesirable effects, investigators have designed devices to stimulate individual sacral nerve roots (27,28), or employ a tripolar electrode in the differential stimulation of large and small fibers with low current, e.g., anode blockade (29). Development of a patient-friendly device, low morbidity, and nearly complete bladder emptying remain the elusive goals of electrostimulation in the management of incomplete bladder emptying in patients with NLUTD. Sacral anterior root stimulation (SARS) is aimed at producing a detrusor contraction. The urethral sphincter efferents are also stimulated, but as the striated muscle relaxes faster than the smooth muscle of the detrusor, the so-called ‘‘poststimulus voiding’’ will occur. This approach has only been successful in highly selected patients. Unfortunately, by changing

External Sphincterotomy The therapeutic destruction of the external urethral SS is primarily indicated in males with incomplete bladder emptying due to suprasacral lesions, and when other management methods have failed or are impractical. The prerequisites are that there is an adequate involuntary detrusor contraction and an adequate penile shaft to anchor the external collection device, usually a condom catheter. Many patients, particularly paraplegics, with detrusor–SS dyssynergia can be successfully managed with CIC; however, recurrent episodes of UTI and upper urinary tract deterioration warrant recommendation for external sphincterotomy. External sphincterotomy has replaced pudendal neurectomy as the surgical treatment of choice for these patients. A successful acute sphincterotomy will result in a substantial improvement in bladder emptying in 70% to 90% of cases, a stable upper urinary tract, resolution of existing vesicoureteral reflux, and maintenance of sterile urine in patients with low volumes and without indwelling catheters. External sphincterotomy is usually performed endoscopically with a knife or loop electrode, or laser, preferably with laser evaporization. Tissue destruction should occur preferably at the 12 o’clock position deep through the bulk of the SS anterior-laterally from the level of verumontanum to the bulbomembranous junction. To minimize the chance of penile (paired carvenosal nerves) nerve injury with resultant impotence, the incision must avoid the 2 to 3 o’clock position on the right and the 9 to 10 o’clock position on the left urethra. Complications of this procedure include impotence in 5% to 30% of patients and urinary extravasation (30). Hemorrhage is unlikely to occur with high-powered (40–60 W) laser evaporization (Nseyo, unpublished data, 2003). Long-term complications include failure of the procedure in 50% of patients, including renal deterioration, condom catheter problems, and decreased bladder compliance. This long-term failure rate of external sphincterotomy has diminished its appeal and engendered interest in urinary diversion in the management of neurogenic urinary retention in many NLUTD patients. Cutaneous Vesicostomy CIC remains the most widely used and attractive method for the management of failure to empty in young children with neurogenic bladders. However, cutaneous vesicostomy has been an effective alternative to CIC in managing those children with a poorly emptying bladder and persistent UTIs and upper tract deterioration. The decision to perform vesicostomy should be individualized and based on clinical grounds and a satisfactory radiographic response to catheterization. In children, the dome of the bladder is easily mobilized through a small transverse skin incision; a button of the detrusor is excised and the bladder wall is sutured to the skin. This Blocksom technique, popularized by Duckett (31), has replaced the old technique, which involved a skin flap that was internalized and sutured to the bladder. The Blocksom technique has fewer complications including stromal stenosis and vesical herniation. Vesicostomy is managed with drainage of urine into the diaper and prophylactic antibiotics. At an appropriate age, when the patient can perform CIC, the vesicostomy can be closed.

medwedi.ru

790

Part Four: The Urinary System

Failure to Store

Clean Intermittent Catheterization

Patients with NLUTD who fail to store urine and therefore are incontinent tend to exhibit either uninhibited bladder contractions or decreased resistance in the bladder neck and urethra. Generally, this group of patients is more difficult to treat than those whose primary problem is failure to empty.

As discussed above, often the patient with neurogenic urinary incontinence secondary to NLUTD can be treated with anticholinergic agents to induce urinary retention (failure to empty). CIC is then initiated to empty the bladder and prevent the bladder from ever reaching a volume that exerts the high reflex activity leading to urinary incontinence.

Pharmacologic Therapy

Continuous Catheter Drainage

Acetylcholine is the principal neurotransmitter that mediates bladder detrusor contractions; therefore, uninhibited bladder contractions associated with reflex NLUTD can be treated with anticholinergic agents. Clinically, the commonly used anticholinergic agents are nonselective for the muscarinic receptors, M2 and M3 subtypes, which are functionally important in the human bladder (1,12). All available anticholinergic agents with atropine-like actions bind with equal effectiveness to all subtypes of the muscarinic receptors. Treatment leads to an atropine-like response against detrusor hyperactivity with urodynamic evidence of increased volume at first sensation, decreased amplitude and uninhibited contractions, and increased total bladder capacity or compliance with attendant reduction in symptoms of urgency and urgency incontinence. Anticholinergic agents generally do not cure patients of their underlying neurogenic symptoms. In some spinal cord injury patients with decreased detrusor compliance, these agents are often used in combination with intermittent catheterization. Such a strategy may prevent loss of bladder compliance due to change in the ECM secondary to chronic urinary retention. The commonly used anticholinergic agents include oxybutynin, which has both short- and long-acting formulations, tolterodine (standard and extended releases), probantheline, and hyoscyamine. The newer formulations in recent years (darefenacin, solefenacin, trospium) have not eliminated the common side effects of anticholinergic therapy, namely dry mouth (inhibition of secretions of salivary glands), pupillary dilatation (blockade of the ocular iris sphincter muscle), blurred vision (dysfunction of the ciliary muscle of the ocular lens), tachycardia, drowsiness, and decreased gut motility. These agents also exhibit a central effect by inducing confusion in the elderly and restlessness in children. Dental problems, especially in the elderly, are attributable to dry mouth caused by the anticholinergic agents. In an effort to improve effectiveness and minimize side effects, an intravesical formulation of oxybutynin is being investigated. It should be noted that all antimuscarinic agents are contraindicated in patients with narrow-angle glaucoma and symptomatic benign prostatic enlargement. Drugs that increase bladder outlet resistance, such as the alpha-adrenergic receptor agonists, phenyl propanolamine, ephedrine, and pseudoephedrine have been used with variable results to increase adrenergic activities to achieve urine storage. The tricyclic antidepressants, such as imipramine hydrochloride, have been used to facilitate urine storage. This agent has three pharmacologic actions: (i) exhibits central and peripheral anticholinergic effects at some selective sites, (ii) blocks, at the presynaptic nerve terminals, the reuptake of neurotransmitters serotonin and noradrenaline, and (iii) binds to glutamate receptors in the CNS. The net effect of these actions is the enhancement of adrenergic activity peripherally, which leads to increased sympathomimetic action. This results in increased bladder outlet resistance (a-adrenergic receptor stimulation) and relaxation of bladder body (b-adrenergic receptor stimulation).

As discussed previously, chronic long-term continuous catheter drainage should not be the treatment of choice for dysfunctional voiding irrespective of the underlying pathophysiology. When indicated, as in the elderly, the principles and catheter care program outlined previously should be practiced.

Artificial Urinary Sphincter Selection of appropriate patients for implantation of an artificial urinary sphincter (AUS) requires a thorough neurourologic work-up to discern the uniqueness of the patient’s incontinence. The patient should appropriately meet the specific criteria of intrinsic sphincteric deficiency with normal detrusor contractility and compliance. The most commonly used AUS consists of an inflatable cuff placed around the bulbous urethra of the adult male or the bladder neck with the pressure balloon reservoir placed beneath the fascia of the abdominal muscle or in the space of Retzius (Fig. 15). The pump control is placed in the scrotum or labia. Activation occurs by compressing the pump chamber, and deactivation can be achieved by pressing the button on the side of the control assembly. Significant rises in intra-abdominal pressure during vigorous exercises or lifting will trigger urinary leakage. Overall, the success rate is reported at 97% for social dryness, with a reoperation rate of approximately 30%. However, this rate is about 55% in patients with a history of prior radiation (32).

Bladder Augmentation or Substitution (Augmentation or Substitution Cystoplasty) Bladder augmentation, by procedures such as the clam cystoplasty, is a valid option to decrease detrusor pressure and increase bladder capacity whenever more conservative approaches have failed (12,32). The results of the various procedures are very good and comparable. Scaffolds, probably of tissue-engineered material for bladder augmentation or substitution or alternative techniques are promising

Figure 15 Artificial urinary sphincter. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

future options. Replacing or expanding the bladder by intestine or other passive expandable coverage will increase the detrusor compliance and reduce the pressure effect of the detrusor overactivity. Therefore, patients with NLUTD who develop a noncompliant bladder and are at high risk for vesicoureteral reflux, hydronephrosis, and deterioration of renal function are potential candidates when conservative measures fail. Bladder substitution to create a low-pressure reservoir may be indicated in patients with a severely thick and fibrotic bladder wall. The surgical technique includes resecting most of the anterior hemisphere of the bladder and sparing the trigone, ureteric orifices and the bladder neck. The ‘‘augmentation patch’’ could be an isolated piece of ileum (ileocystoplasty), colon (colocystoplasty), or stomach (gastrocystoplasty, particularly in children) (Table 3), which is then sutured onto the residual bladder (Fig. 16). Another method known as the detrusor myectomy (autoaugmentation) is aimed at improving the shrunken bladder that is enlarged by removal of lateral detrusor tissue to free the entrapped ureter in a nonfunctional fibrotic detrusor. This procedure reduces the detrusor overactivity and increases the compliance. The augmented bladder must be emptied by CIC. Contraindications for augmentation cystoplasty include renal insufficiency, bowel disease, and inability or lack of resources to perform CIC. The inherent complications associated with these procedures include recurrent infection, stone building, perforation, diverticulum formation, possible malignant changes, and intestinal metabolic abnormalities such as mucus production and impaired bowel function.

Neural Manipulation Electrical stimulation, neuromodulation, denervation, and deafferentation constitute various neural manipulations to achieve urinary storage in patients with NLUTD and urinary incontinence. A strong contraction of the urethral sphincter and/or pelvic floor, as well as anal dilatation, manipulation of the genital region, and physical activity reflexly inhibit micturition. Whereas the first mechanism is affected by activation of efferent fibers, the latter ones are produced by activation of afferents. Electrical stimulation of the pudendal nerve afferents produces a strong inhibition of the micturition reflex and the detrusor contraction. This stimulation then might support the restoration of

Table 3 Bowel Segments Used in Various Urinary Diversion Techniques Type of urinary diversion Incontinent diversion Continent diversions Indiana pouch Kock pouch Reddy pouch Mainz pouch UCLA pouch Neobladder

Ureterosigmoidostomy Sigma-rectum pouch

Bowel segment used Ileum (Bricker’s conduit), colon (transverse colon, sigmoid colon) Cecum, ascending colon, and terminal ileum Ileum Colon Cecum, ascending colon, and terminal ileum Right colon, hepatic flexure, and terminal ileum Ileum (Studer pouch, Camey procedure, ‘‘S’’ pouch, and ‘‘M’’ pouch), colon Sigmoid colon Sigmoid colon and rectum

791

Figure 16 Augmentation cystoplasty. An isolated segment of bowel is opened along its antimesenteric border and used as a ‘‘patch’’ to reconstruct the bladder. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

the balance between excitatory and inhibitory inputs at the spinal or supraspinal level, and it might imply that patients with incomplete lesions will benefit, but patients with complete lesions will not. Stimulation of the tibial nerve afferents has not been applied in patients with NLUTD. Sacral rhizotomy, also known as sacral deafferentation, has achieved some success in reducing detrusor overactivity, but it is used nowadays mostly as an adjuvant to SARS (27,28).

Sacral Nerve Neuromodulation (InterstimTM) (33) During sacral nerve stimulation or sacral neuromodulation, the bladder afferents are stimulated, which probably restores the correct balance between excitatory and inhibitory impulses from and to the pelvic organs at a sacral and suprasacral level, thus reducing the detrusor overactivity. It is used either as a temporary procedure using foramen electrodes with an external stimulator, with the expectation of perseverance of the changes after treatment, or as a chronic procedure with an implanted stimulator. In the latter case, a test procedure, the percutaneous nerve evaluation, with an external stimulator is performed before the implant to judge the patient’s response. This procedure also has considerable success in selected patients.

DEVICE THERAPY Inflow Device to Empty the Bladder A rare cause of incontinence is a situation where the bladder never empties completely and overflows. This problem is seen most commonly with nerve problems affecting the bladder, such as MS and spinal cord injury. Thus far, the most effective treatment to empty the bladder is CIC, three to four times per day. The inflow device, an alternative approach, sits in the urethra and allows the bladder to empty with a pump design activated by an external controller without having to catheterize to empty the bladder. The early results with this device are quite encouraging in selected patients.

medwedi.ru

792

Part Four: The Urinary System

URINARY DIVERSION When no other therapy has been successful, urinary diversion must be considered for the protection of the upper tracts and for the patient’s quality of life.

Continent Diversion This should be the first choice for diversion. In patients for whom indwelling catheterization or suprapubic catheterization is the only feasible treatment option, the change to a continent diversion may be a better prospect. Some patients with limited dexterity prefer a cutaneous stoma above using the urethra for catheterization. The continent cutaneous stoma is created following various reservoir techniques (Table 3). They are constructed to create a low-pressure reservoir for urine storage and contain antireflux and continence mechanisms. The patients empty the reservoirs by periodic catheterization of the continent cutaneous stoma. The continent reservoirs are created generally from segments of ileum or colon, or combination of the segments that have been detubularized and folded into a cistern to obtain the low-pressure systems. The detubularization helps to eliminate the unidirectional peristalsis. An example of an ileal-based diversion is the Studer’s diversion (Table 3), which uses 50 to 60 cm of terminal ileum, which results in the creation of a low-pressure reservoir of 300 cc and an antireflux limb. The Indiana pouch consists of the detubularized segment of the proximal colon (cecum, ascending and a portion of the transverse), which is folded into the low-pressure reservoir (Table 3). The ureters are tunneled into the colon with an antireflux technique, whereas the ileocecal valve provides the continent mechanism, and the ileal segment is doubly imbricated or stabled over a 14-French catheter to configure the catheterizable stoma. All of the forms of continent diversion do show frequent complications, including leakage or stenosis of the ureterointestinal anastomosis or the stoma. The short-term continence rates are over 80%, and good protection of the upper urinary tract is achieved. For cosmetic reasons, the umbilicus is often used for the stoma site, but this may have a higher risk of stomal stenosis. An example of continent urinary diversion is shown in Figure 17.

Incontinent Diversion If catheterization is impossible, incontinent diversion with a urine-collection device is indicated. Fortunately, nowadays, this indication is seldom needed because many appropriate

Figure 17. Continent urinary diversion. A low-pressure reservoir is created and is emptied by intermittent catheterization of the efferent limb. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

alternatives can be offered. Ultimately, it could be considered in patients who are wheelchair bound or bed-ridden with intractable and untreatable incontinence, in devastated LUTs, and when the upper urinary tract is severely compromised, and in patients who refuse other therapy. Various techniques have been described for creating an incontinent urinary diversion; however, several basic principles must be observed in their construction (Table 3). The ureters are first mobilized from the deep pelvis and detached from the bladder, and one ureter is tunneled behind the colonic mesentery to lie next to the contralateral ureter. An adequate ileal or colonic segment is used for the conduit that contains the ureters implanted by the ureteral mucosa–to–bowel mucosa technique into the distal ileal portion, whereas in the colonic conduit, the ureters are tunneled to create antireflux. The proximal end of the conduit is then exteriorized and sutured to the skin to mature the cutaneous intestinal stoma. The continuity of the bowel that was chosen as the conduit is reestablished by bowel–bowel anastomosis. Urine drains continuously into a collection device over the stoma, so the surrounding skin must be protected from urine contact to prevent the aggravation of squamous metaplasia and bleeding. In ureterosigmoidostomy, the ureterointestinal anastomosis is performed similar to the colonic procedure with tunneling of the ureters and the creation of antireflux. Example of these various types of supravesical urinary diversion are shown in Figure 18.

QUALITY OF LIFE The issue of quality of life should remain a paramount consideration in the global scheme of managing patients with NLUTD. Apart from the limitations that relate directly to the neurologic pathology, the NLUTD can be treated adequately in the majority of patients and must not interfere with social independence. The life expectancy of the patient does not need to be impaired by the NLUTD. With appropriate and adequate treatment, and consequent neurourological care over the patient’s lifetime, the quality of life can be assured.

FOLLOW-UP NLUTD is an unstable condition and can vary considerably even within a relatively short period. Meticulous follow-up

Figure 18. Types of supravesical urinary diversion. (A) ileal conduit. (B) colon conduit. (C) ureterosigmoidostomy. Source: Courtesy of George S. Benson, MD, from Chapter 45 of the Second Edition.

Chapter 39: Neurogenic Lower Urinary Tract Dysfunction

and regular evaluation are necessary. Depending on the type of the underlying neurological pathology, the current clinical condition, and the stability of the NLUTD, the interval between the specific follow-up investigations should not exceed one to two years. In patients with MS and acute spinal cord injury, this interval is, of course, much shorter. Urine dipsticks should be available for the patient, and urinalysis should be performed at least every second month to check for signs of infection. The upper urinary tract, the bladder shape, and residual urine should be checked every six months. Physical examination and laboratory assessments of blood and urine should take place every year. Any sign indicating a risk factor warrants specialized investigation and/or referral to a specialist.

SUMMARY Neurogenic bladder dysfunction comprises a spectrum of diseases that can be categorized into two broad subgroups: (i) failure to empty urine properly, and (ii) failure to store urine adequately. With careful history taking and physical examination, and the prudent use of UDS, the specific abnormality in a given patient can usually be identified. Previously, supravesical urinary diversion was the common means of managing most patients with complicated neurogenic bladder disease. Newer therapeutic modalities have obviated the need for this approach except under the most unusual of circumstances. For patients with bladder emptying problems, intermittent self-catheterization and/or pharmacotherapy have offered effective therapy for most conditions. When these approaches have failed, external sphincterotomy has proved useful in selected adults, and cutaneous vesicostomy in children. In patients with bladder storage dysfunction, intermittent self-catheterization has again proved useful in many, either alone or in combination with various forms of pharmacologic manipulation. When these approaches have failed or proved inadequate, artificial urinary sphincter (AUS) implantation or augmentation cystoplasty are often warranted.

REFERENCES 1. Zderic SA, Chacko S, DiSanto ME, Wein AJ. Voiding function: relevant anatomy, physiology and molecular aspects. In: Gillenwater JY, Grayback JT, Howards SS, Mitchell ME, eds. Adult and Pediatric Urology. Philadelphia: Lippincott, Williams and Wilkins, 2002:1061. 2. Tanagho TA. The anatomy, and physiology of micturiction. Clin Obstet Gynecol 1978; 5:3. 3. Gosling JA, Chilton CP. The anatomy of the bladder, urethra and pelvic floor. In: Mundy AR, Stephenson TP, Wein AJ, eds. Urodynamics: Principles, Practice and Application. London: Churchill Livingston, 1984:3. 4. El Badawi A. Autonomic muscular innervation of the vesical outlet and its role in mictirution. In: Himnam F Jr, ed. Benign Prostatic Hypertrophy. Berlin: Springer-Verlag, 1983:330.. 5. Torrens M, Morrison JFB. The physiology of the urinary bladder. Berlin: Springer-Verlag, 1987:1. 6. Hinman F Jr. Syndromes of vesical incoordination. Urol Clin North Am 1980; 7:311. 7. Gosling JA, Dixon JS. The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra. Br J Urol 1975; 47(5):549.

793

8. Bharia NN, Bradley WE. Neuroanatomy and physiology: innervation of the urinary tract:. In: Raz S, ed. Female Urology. Philadelphia: WB Saunders, 1989:12. 9. deGroat WC. A neurologic basis for the overactive bladder. Urology 1997; 50(6A):36. 10. McGuire EJ, Herlihy E. Bladder and urethral responses to sympathetic stimulation. Invest Urol 1979; 17:9. 11. de Groat WC, Booth AM: In: Dyck PK, et al., eds: Peripheral Neuropathy, 2d ed. Philadelphia: WB Saunders, 1984:289. 12. Benson GS. Neurogenic bladder and urinary diversion. In: Miller TA, 2nd ed. Physiology Basis of Surgical Practice. 13. Steers WD, Barrett O, Wein AJ. Voiding dysfunction: diagnosis, classifications and management. In: Gillenwatter JY, Grayback JT, Howards SS, Mitchell ME, eds. Adult and Pediatric Urology. Philadelphia: Lippincott, Williams and Wilkins, 2002:1061. 14. Bors E, Comarr AE. Neurologic Urology. Baltimore: University Park Press, 1971. 15. Gibbon NOK. Nomenclature of neurogenic bladder. Urology 1976; 8:423. 16. Krane RJ, Siroky MB. Classification of neuro-urologic disorders. In: Clinical Neuro-Urology. Boston: Little, 1979: Brown. 17. Lapides J. Neuromuscular vesical and urethral dysfunction. In: Campbell MF, Harrison JH, eds. Urology. Vol. 2. 3rd ed. Philadelphia: WB Saunders, 1970. 18. McClellan FC. The Neurogenic Bladder. Springfield, IL: Charles C. Thomas, 1979. 19. Krane RJ, Siroky MB. Classification of neuro-urologic disorders. In: Krane RJ, Siroky MB, eds. Clinical Neuro-Urology. Boston: Little, Brown, 1979:143. 20. Wein AJ. Classification of neurogenic voiding dysfunction. J Urol 1981; 125:605. 21. Baldew J, Van Gelderen HH. Urinary retention without a cause in children. Br J Urol 1985; 55:200. 22. Dolin P, Darby S, Beral V. Paraplegia and squamous cell carcinoma of the bladder in the young women: findings from a case control study. Br J Cancer 1984; 70:167. 23. Jacobs SC, Kaufman JM. Complications of permanent catheter drainage in spinal cord injury patients. J Urol 1978; 119:740. 24. Broecker BH, Klein FA, Hackler RH. Cancer of the bladder in spinal cord injury patients. J Urol 1981; 125:196. 25. Chai T, Chung AK, Belville WD, et al. Compliance and complications of clean intermittent catheterization in the spinal cord injured patient. Paraplegia 1995; 33:161. 26. Timoney AG, Shaw PJ. Urological outcome in female patients with spinal cord injury: the effectiveness of intermittent catheterization. Paraplegia 1990; 28:556. 27. The clinical use of urecholine in dysfunctions of the bladder. J Urol 1949; 62:300. 28. Tahagho E, Schmidt R, Orvis B. Neural stimulation for control of voiding dysfunction: a preliminary report on 22 patients with serious neuropathic voiding disorders. J Urol 1989; 142:340. 29. Schmidt RA. Advances in genitourinary neurostimulation. Neurosurgery 1986; 18:1041. 30. Rijkholl NJM, Wijkstra H, van Kerrebroeck PEV, et al. Selective detrusor activation by sacral ventral nerve-root stimulations: results of intraoperative testing in humans during implantation of a Finetech-Brindley system. World J Urol 1998; 16:337. 31. Madersbacher H, Scott FB. Twelve o’clock sphincterotomy; technique, indications, results. Urol Int 1975; 30:75. 32. Duckett JW Jr. Cutaneous vesicostomy in childhood: the Blocksom technique. Urol Clin North Am 1974; 1:485. 33. Bushman W. Spinal cord Injury. In: Gillenwatter JY, Grayback JT, Howards SS, Mitchell ME, eds. Adult and Pediatric Urology. Philadelphia: Lippincott, Williams and Wilkins, 2002:1217. 34. Wyndale JJ, Michelsen D, Van Dromme S. Influence of sacral neuromodulation on electrosensation of the lower urinary tract. J Urol 2000; 163:221–224.

medwedi.ru

PART FIVE: The Central and Peripheral Nervous Systems

40 Pathophysiology and Management of Head Injury Egon M. R. Doppenberg, M. Ross Bullock, and William C. Broaddus

INTRODUCTION Data on multiple causes of death, as collected and provided by the National Center for Health Statistics, show that of all injury-related deaths, at least 28% involve significant injury to the brain (1). The patients at highest risk for brain injury are between 15 and 24 years of age, with males far more often affected than females. About two million Americans are treated at hospitals in the United States every year because of a head injury, making it the most common cause of death and severe disability in adults under the age of 40 (2,3). Although 80% to 90% of those patients who are admitted to the hospital with a head injury sustain only a mild or moderate injury, the remainder will sustain permanent disability, or die after mild/moderate injury, due to secondary brain damage, caused by ischemia and/or hematoma (4,5). The great majority of death and disability occurs in those with severe head injury, which affects 200,000 people per year in the United States. Even in this severe head injury group, about a third of the patients who die will have spoken at some point during their clinical course after the injury, suggesting that secondary mechanisms are responsible for death (4,6,7). This indicates that there is a window of opportunity for intervention to treat the pathophysiology and try to restore normal physiology before secondary insults could potentially further develop. The quest for understanding the derangements in brain physiology after head injury has resulted in many gradual improvements in the medical and surgical treatment of the head-injured patient. The greatest decrease in mortality due to head trauma has occurred in patients with mild to moderate injuries. In addition to better management strategies, better imaging and diagnostic tools have contributed to the improvement in outcome for these patients (8). However, despite these advances, the outcome for severe head injury patients still remains poor, with death and severe disability affecting close to 50% (6). The limited understanding of the pathophysiological mechanisms following severe head injury is a major reason for this poor outcome after severe head injury. Better strategies to monitor and treat these patients are only possible if the pathophysiology is better understood. In neurotrauma, not only the primary impact injury but also secondary and delayed mechanisms are important to understand and treat, as a means of trying to reduce the damage that results from the injury. The present chapter focuses on these considerations.

PATHOPHYSIOLOGY General Considerations Our current understanding of the pathophysiological events in human head injury has been developed mainly from post mortem exams, in vitro and in vivo studies in the laboratory, and studies of head-injured patients during life through imaging and monitoring. Each of these modalities has its limitations in showing the derangements in biological and structural status of the brain after head injury. For example, post mortem studies are limited due to the fact that ischemia is usually far more pronounced due to global, agonal reduction in cerebral blood flow (CBF). Therefore, more subtle and focal ischemic changes, which take place between the time of injury and the actual death, might go undetected. Also, animal models do not exactly mimic the complex mechanisms that occur in human head injury, and most often there is a combination of cascades taking place, which affect one another. Therefore, multiple trauma models are currently in use to address different aspects of trauma (9–11). The events concerned with intracellular energy metabolism, maintenance of neuronal membrane potential, and homeostasis at synapses all have been shown to play a role in various degrees in the derangements seen after human head injury. Different insults to the brain, from intracranial hematomas/contusions, ischemia or shear injury, result in different types of disturbances of the biological homeostasis of the brain. Most often, these insults play a role simultaneously in varying severity, therefore resulting in a pathophysiological state that evolves from different mechanisms.

Intracranial Hematomas and Contusions Intracranial hematomas (epidural and subdural hematomas, and hemorrhagic contusions) occur in about 30% to 45% of severely head-injured patients. They are by far the most important cause for preventable delayed secondary brain damage. Epidural and acute subdural hematomas are usually formed within the first hour after the injury, although they may enlarge over time (5,7). These mass lesions compromise the cerebral microcirculation, resulting in secondary ischemia and brain swelling. Subsequently, shifting of the brain occurs, and further occlusion of cerebrospinal fluid (CSF) pathways leads to increased intracranial pressure (ICP). In this way, a vicious cycle can begin with more ischemia and brain swelling. Epidural hematomas are usually the result of focal impact to the skull with an accompanying fracture of the cranial vault in over 80% of cases (Fig. 1). The middle

medwedi.ru 795

796

Part Five: The Central and Peripheral Nervous Systems

Figure 2 Traumatic subarachnoid hemorrhage over the right convexity, with associated small acute subdural hematoma.

Figure 1 Head computed tomography scan demonstrating bilateral epidural (lentiform-shaped) hematomas with obvious depressed skull fracture over the left convexity.

meningeal artery is classically involved with temporal bone fractures, although venous hemorrhage can also cause or contribute to epidural hematomas. These hematomas can rapidly enlarge due to the frequent ‘‘arterial’’ nature of the bleeding and therefore, emergent evacuation is usually indicated. When evacuated promptly, secondary injury to the underlying brain can often be prevented, and therefore excellent outcome is frequently possible with this type of hematoma. The acute subdural hematoma is usually caused by the tearing of the bridging veins that enter the sagittal sinus or by bleeding from surface vessels as a result of focal contusions and laceration of the pia (Fig. 2) (5,12). The acute subdural hematoma has a poor prognosis with a 60% rate of death or severe disability (13). Interestingly, over 50% of all patients with an acute subdural hematoma have had a period after the injury during which they were conscious, suggesting that secondary insults are taking place, resulting in further deterioration. One explanation is that in the acute subdural hematoma model in the rat, there is a zone of focal cerebral ischemia underneath the hematoma. In this zone, a sevenfold increase in glutamate was found, leading to increased metabolic activity and further ischemic insults to the brain (10,13,14). Severe contusions may undergo delayed hemorrhage over the intermediate period from minutes to hours after impact, especially with coagulopathy (Fig. 3). Zones of ischemically damaged pyknotic shrunken neurons and swollen astrocytes are found to extend many millimeters around the margins of contusions, and this is usually associated with reduced CBF and increased metabolism leading to a flow-metabolism mismatch in the ‘‘penumbra’’ surrounding the contusion. This area may be potentially salvageable in the early stages before cell death and necrosis take place. However, the mechanisms involved in this process are not yet fully understood (5,15,16).

Supratentorial contusions and hematomas may induce brain shift either laterally or in a rostrocaudal direction. Lateral shift causes subfalcine herniation with consequent ischemic damage to the cingulate gyrus of the limbic system (6). Uncal transtentorial herniation is a combination of lateral and rostrocaudal shift, which pushes the medial para-hippocampal gyrus of the temporal lobe through the tentorial hiatus alongside the brain stem. This process causes, ipsilaterally, a fixed dilated pupil, as the

Figure 3 Head computed tomography scan. Right posterior temporal contusions. Note the hypodens surrounding edema.

Chapter 40: Pathophysiology and Management of Head Injury

797

Figure 4 (A) Head computed tomography (CT) scan of a two-year old unrestrained female involved in a motor vehicle accident, with massive traumatic subarachnoid hemorrhage. A cerebral angiogram was performed, excluding traumatic aneurysm. (B) Same patient two months later. Head CT scan shows severely enlarged ventricles due to communicating hydrocephalus.

cardinal clinical sign for a mass lesion. If there is not an immediate decompression, irreversible ischemic damage occurs within the brain stem, and may be associated with the classical ‘‘flame-shaped’’ hemorrhage of Duret in the pons. Such brainstem hemorrhages are ominous and these patients usually die or remain in a persistent vegetative state. Herniation seldom occurs when ICP is less than 40 mmHg (normal 4–12 mmHg), but it may develop sooner in the presence of mass lesions within the temporal lobe and when there has been swelling of bilateral, frontal, and temporal lobes to cause anteroposterior shift. Vasospasm has been shown to occur in about 30% of patients with severe head injury (17). It is more frequent in patients who have suffered an extensive subarachnoid hemorrhage (Fig. 4A). The proximal vessels on the pial surface, or around the Circle of Willis are frequently involved. If imaging studies reveal a significant amount of blood in the subarachnoid spaces in a patient, a cerebral angiogram may be warranted to exclude a traumatic arterial aneurysm. Traumatic aneurysms typically arise at the skull base or from distal anterior or middle cerebral arteries or branches consequent to direct mural injury or to acceleration-induced shear. Once diagnosed, these aneurysms should be treated immediately either through surgical or through an endovascular approach. Posttraumatic hydrocephalus (accumulation of CSF and dilatation of the cerebral ventricular system) due to traumatic subarachnoid hemorrhage is a frequent phenomenon that clearly worsens outcome. The blood load can cause arachnoiditis of the villi and result in communicating hydrocephalus, in which ventricular dilatation develops due to poor CSF re-absorption (CSF communication between lateral ventricles and spinal canal is retained, hence the name). This can develop as late as two to three years after the initial injury. Therefore, previously head-injured patients who arrest or regress in their recovery should always be evaluated for increased ICP due to hydrocephalus with a head computed tomography (CT) scan (Fig. 4B). A careful evaluation should be made on imaging studies to not confuse the radiographic findings with ex vacuo hydrocephalus (type of hydrocephalus in which CSF replaces

volume of tissue lost) due to brain atrophy, commonly seen in patients with diffuse axonal injury. The imaging studies should show enlargement of the ventricles, transependymal flow, and effacement of the sulci. A spinal tap may be performed to measure the ICP.

Ischemia Ischemic brain damage is by far the dominant finding in patients who die after head injury, and its distribution is predominantly focal rather than global (6). The interrelationship between metabolic substrate delivery and substrate demand after traumatic brain injury (TBI) has been extensively studied both in animals and in humans. It is known that in the early phase after TBI, CBF is reduced in up to one-third of the patients (18). At the same time, glutamate release is massively increased in subgroups of patients (19). This increase in glutamate then results in increased neuronal activity. This rise in excitatory activity requires an increased metabolic rate and therefore leads to an increased substrate demand. In the absence of a commensurate increase in local CBF (the source of metabolic substrates), a flowmetabolism mismatch occurs. Massive Kþ efflux has been shown to further increase aerobic metabolism, and thereby further deteriorating the already existing discrepancy between supply and demand in brain metabolism (20). Yoshino et al. showed a marked early increase in glucose utilization, followed by a hypometabolic state after animal brain injury (21). Recently, positron emission tomography (PET) studies have shown a hyperglycolytic state of the brain after severe human head injury in as many as 56% of the patients (22). Altogether, these results clearly suggest a coupling between an increased metabolism for glucose and increased extracellular release of glutamate after TBI. Thus, the increase in lactate production seen after TBI is explained by a flow-metabolism mismatch because the increase in substrate demand cannot be met by CBF, resulting in anaerobic glycolysis and lactate generation. However, Andersen and Marmarou have shown that lactate generation is increased, following TBI in the cat, as measured by magnetic resonance (MR) spectroscopy, even when CBF was adequate to ensure substrate delivery (23). This implicates factors other than ischemia as a cause of lactate generation after TBI. This early

medwedi.ru

798

Part Five: The Central and Peripheral Nervous Systems

Figure 5 Intraoperative photo of a 56-year-old man who sustained a fall from a ladder. Massive brain swelling is seen, with hemiation of brain tissue through the craniotomy defect.

patients, probably a relatively small number of axons are immediately torn at the moment of impact, but varying numbers are subjected to stretching due to shear forces. The majority of axonal disruption is then a consecutive delayed event that occurs over the first 24 to 48 hours after injury in humans (26). The pathological hallmark of diffuse axonal injuries is a histological picture described as retraction balls and microglial stars, and they are not seen until 12 to 24 hours after injury. Diffuse shearing injury causes widespread changes in neurotransmitter function and ionic homeostasis throughout the neuraxis and this results in instantaneous loss of axonal transport, disruption of energy metabolism, and coma or altered consciousness. Several animal studies using fluid percussion injury models have shown that the impact is immediately followed by massive release of neurotransmitters, including catecholamines, acetylcholine, and glutamate into the extracellular space (11,27). This may cause widespread depolarization with the influx of sodium and calcium ions into cells, and efflux of potassium into the extracellular space (20). This may then cause swelling of neurons and glia, which may proceed to cause brain edema, and high ICP.

Penetrating Head Injury increase in glucose utilization and lactate generation may be a consequence of the massive glutamate release, in accordance with the hypothesis of Pellerin and coworkers. They showed under physiological conditions in an in vitro study that glutamate release due to physiological stimulation results in increased lactate generation (24).

Brain Swelling Brain swelling, as diagnosed by either cistern effacement on CT scan, or by measured raised ICP, occurs in about 70% of patients with severe head injury at some time during the clinical course (Fig. 5). Even though the cause of brain swelling is not fully understood, four pathophysiological mechanisms are thought to play a role. They are vasogenic edema, cytotoxic edema, vascular engorgement, and venous occlusion. Delayed blood–brain barrier disruption is seen more frequently in patients with contusions, and is delayed for days after injury (5). In the early phase after injury, cytotoxic edema seems to be the most important component in the development of brain swelling. Vascular engorgement (hyperemia) is usually a reactive response to a prior focal or global ischemic event. One explanation is that the hyperemic response can only occur in relatively normal tissue, which has not undergone severe ischemic damage, sufficient to cause severe edema, and ‘‘low density’’ on CT (18,25). Vascular engorgement may occur in response to the release of mediators such as lactate, Hþ, adenosine diphosphate, or inflammatory products, such as cytokines, and substance P.

Diffuse Axonal Injury Brain tissue does not have the supporting structures that other organs possess, such as a collagen stroma, and it is therefore much more vulnerable to deformation and injury due to forces during trauma. Previously, diffuse axonal injury was thought to be an acute event in which widespread physical and functional disruption of axons occurred at the moment of impact. However, in severely head-injured

Penetrating head injury has become increasingly common due to increased availability of firearms. The pathophysiology of these injuries is at least in part distinctly different from that of the previously described closed injuries. The injuries can vary from those resulting from low velocity bullets (mostly civilian hand guns) and sharp objects to high velocity bullets and shrapnel in military injuries (Fig. 6A and B). Also, hematomas, cerebral contusions and, sometimes, significant vascular injuries to major blood vessels can occur. Arterial as well as venous injuries may be present, resulting in hematomas and/or subarachnoid hemorrhage. Delayed hemorrhage may also occur, due to development of pseudo aneurysms, arterial dissection, or direct laceration of a vessel or venous sinus. Intracerebral hematomas are the most frequent, followed by subdural hematomas and, to a lesser extent, epidural hematomas (28). High-velocity injuries, especially, may result in extensive fractures of the cranium. Penetrating injuries often cause a variety of injuries, including scalp lacerations and skull base fractures, sometimes complicated by transient or persistent CSF leak. ICP studies have been carried out in animal models demonstrating an immediate peak in pressure after the injury. The ICP then lowers but does not return to baseline (29). At the same time, cardiac output may be impaired despite adequate fluid resuscitation. This is thought to be due, in part, to the effects on the brain stem either through direct impact or through the ‘‘shock wave’’ produced by the traversing projectile. This combination of increased ICP and decreased cardiac output can significantly impair cerebral perfusion, leading to secondary insults with cerebral ischemia with further brain swelling and further impairment of cerebral perfusion.

GENERAL CONSIDERATIONS IN THE CARE OF THE HEAD-INJURED PATIENT The acutely injured brain has been shown to be vulnerable to so-called secondary insults (30). These insults include ischemia, hypoxia, and hypercarbia. The latter can result in increased cerebral blood volume and consequent increased ICP, leading in turn to further ischemia. The

Chapter 40: Pathophysiology and Management of Head Injury

799

Figure 6 (A) and (B) Lateral skull X-ray and head computed tomography scan (bone window) showing a 45-year-old man with a penetrating crossbow arrow entering through the right orbit into the skull, ending just anterior of the brain stem. An emergent cerebral angiogram was performed, which was negative for vascular injury. The arrow was removed in the operating theatre through the entry site. This patient made a full recovery.

autoregulation of the brain to maintain its constant supply of oxygen and glucose is impaired in the head-injured patient (31). This leads to hypoperfusion of the already vulnerable brain during episodes of systemic hypotension. Several studies have shown that a large number of head-injured patients who present to a trauma center will have hypotension and/or hypoxia, resulting in a tremendous increase in morbidity and mortality from secondary injury to the brain (32–36). Airway establishment is thus the first priority in the head-injured patient. It should also be kept in mind that approximately 7% of all patients with a Glasgow coma score (GCS) of 8 or less will have a concomitant cervical spine fracture (37). Intubation should be accomplished while the patient is in a rigid collar or preferably with in-line manual cervical immobilization. Recently, several studies have been completed in which inspired oxygen fraction (FiO2) was increased in the head-injured patient. This improves brain biochemistry and outcome in animals. Also, this maneuver appears not to increase free-radical production in the injured brain tissue in animal models, despite concerns to the contrary (38–40). Systemic hypotension should be treated aggressively and rapidly, with intravenous fluid (Ringers or normal saline). Hypovolemia is the most common etiology and only rarely is the hypotension caused by the primary brain injury. The choice of intravenous fluids remains a focus of debate. Hypertonic saline has been shown to redistribute extravascular fluids back into the intravascular compartment, resulting in increased cardiac output and blood pressure (41–43). However, in the injured brain where the blood–brain barrier is disrupted, the extracellular fluid may increase with the use of hypertonic solutions, possibly exacerbating the development of cerebral edema. Contrariwise, some data from animal studies show that there may be a beneficial effect on ICP in severely head-injured patients with the use of these hyperosmotic agents (44). To date, there have been no randomized clinical trials to show a clear-cut benefit (as well as risk) for their use in head-injured patients. The main goal in the multitrauma patient is to maintain normotension and volume expansion to normal status, to ensure adequate cerebral perfusion. It is important to recognize that the fear of inducing increased ICP through aggressive fluid resuscitation to normovolemic status has been proven to be unfounded (45–47).

Furthermore, hyperglycemia may occur in diabetic and nondiabetic patients as a consequence of the physiologic stress response, which is directly related to the severity of the head injury. For this reason, hyperglycemia should be treated appropriately in the acute setting. Increased glucose levels have been linked to a worsened prognosis in animal models of brain injury, independent of the severity of the initial injury (48).

SPECIFIC MANAGEMENT OF THE HEAD-INJURED PATIENT Historically, head-injured patients have been categorized into three main subgroups using the GCS. Mild injury is categorized as 14 or 15, moderate as 9 to 13, and severe as eight or less. The details of this scoring system are summarized in Table 1. The neurological examination of the severely headinjured patient in the acute phase consists at a minimum of establishment of this score. Findings should be interpreted with the knowledge of concomitant injuries. These Table 1 Glasgow Coma Score Response Eye opening Spontaneous To sound To pain None Motor response Obeys commands Localizes pain Normal flexion (withdrawal) Abnormal flexion (decortication) Extension (decerebration) None Verbal response Oriented Confused conversation Inappropriate words Incomprehensive sounds None Source: From Ref. 49.

medwedi.ru

Points 4 3 2 1 6 5 4 3 2 1 5 4 3 2 1

800

Part Five: The Central and Peripheral Nervous Systems

Table 2 Admission Criteria for Patient with Mild Head Injury (GCS 14 or 15) History of loss of consciousness Amnesia No reliable supervision at home Skull fracture CSF leak Penetrating head injury Abnormal CT scan No CT scanner available Deteriorating neurological status Moderate/severe headache Inability to reach medical facility quickly while at home Alcohol/drugs intoxication Abbreviations: CSF, cerebrospinal fluid; GCS, Glasgow coma score; CT, computed tomography.

include spinal cord injuries, which can impair motor response, as well as trauma to the orbit/globe, possibly resulting in iridoplegia. Also, intoxication by alcohol or other drugs, and the use of paralytics or other pharmacological agents such as atropine need to be taken into consideration. Unfortunately, the use of paralytic agents is very common, making a reliable neurological exam impossible at times. Eighty percent of the total number of patients with head trauma can be categorized as minor, meaning that they have a GCS of 14 or 15. These patients will need to be admitted for observation if they show any of the findings listed in Table 2. The moderately head-injured patient with a GCS of 9 to 13 will always require close observation, and therefore admission. These are the patients who require skillful clinical judgment and careful, close observation, usually requiring a stay in the intensive care unit (ICU). If necessary, intubation should be performed to protect the airway, with the use of continuous short-acting sedation (e.g., propofol), to ensure the possibility of intermittent neurological exams. The severely head-injured patient, with a GCS of eight or less, is by definition comatose. He is unable to follow simple commands. This patient will always require intubation, because studies have shown that up to 30% of these patients are hypoxemic on arrival in the emergency room (35). Furthermore, these patients require continuous evaluation of their volume status and therefore require continuous blood pressure monitoring as well as central venous pressure or pulmonary artery pressure monitoring. Arterial lines and central venous lines are often placed for these reasons. Mannitol should be given to patients who show localizing signs or who have a fixed pupil when they are hemodynamically stable, even prior to obtaining a CT scan. The osmotic effects of this agent can reduce ICP by decreasing edema in cerebral tissue and therefore decrease ICP and improve cerebral perfusion. Also, the rheological effects play a role in improving cerebral perfusion and therefore potentially might reduce secondary insults to the vulnerable brain (50,51). As soon as the patient is stable enough for transport to the CT scanner, a CT of the head without contrast is to be performed. In general, patients who have a significant mass lesion, with brain compression and shift of normal structures, and who are not fully neurologically intact, require emergent evacuation of these lesions through a craniotomy or craniectomy. This at times can cause ‘‘conflict of interest’’

between the neurosurgeon and trauma surgeon. Patients with a high suspicion of a mass lesion resulting in rapidly deteriorating neurological status and who are suspected to have significant thoracoabdominal injury should undergo a chest X-ray and abdominal CT, and, if necessary, should be taken the operating room to prevent secondary neurological deterioration due to cerebral hypoperfusion. For cranial surgery, the main goal of intervention is to restore the supply of substrate for brain metabolism to the brain. This implies that mass lesions causing increased intracerebral pressure, and therefore decreased cerebral perfusion pressure (CPP), will need to be evacuated as soon as possible. The effects of evacuation of these lesions on brain metabolism have been described in patients recently (52). The exact surgical techniques to perform are beyond the scope of this chapter, but aggressive decompression through a generous bone flap, together with removal of clots and nonviable brain tissue, is mandatory. The neurosurgeon may also elect to leave the bone flap out (craniectomy) for reimplantation later, after subsidence of cerebral edema. In this way, the ICP in the patient will be potentially more manageable in the days after the initial impact when the effects of secondary brain injury may develop. A large bone window can ensure that the swollen brain can expand through the craniectomy site with less chance of dramatic increases in ICP. Overall surgical treatment of gunshot wounds is similar to closed head injury with a few exceptions. First, the rule also applies that when a mass lesion is present, this should be evacuated when it causes significant compression or shift of brain structures and the patient is not fully neurologically intact. Also, bullet and skull fragments should be removed when they are readily accessible and not located in eloquent areas. Studies from Vietnam War patients have shown that less than 5% of patients developed a delayed cerebral abscess, because aggressive entry and debridement was mandatory (53). However, from these studies it became clear that the presence of retained fragments did not result in increased risk of seizures later in life. Also, obvious nonviable brain tissue in penetrating brain injury should be removed because this may help to manage ICP problems in the days after injury. Finally, dura and scalp repair or reconstruction are helpful in the prevention of CSF leak and/or infection. The surgical management of stab wounds is grossly similar to that of gun shot wounds. Debridement and dural closure are the goals during surgery. However, removal of a penetrating object requires careful evaluation of the location of the weapon. Evaluation of vascular structures, especially, is important prior to removal. Cerebral angiography or CT-angiography is mandated, whenever major intracranial vessels maybe injured, and should be performed before removal when feasible. Prophylactic perioperative ‘‘triple’’ antibiotics are frequently used, although no randomized study has shown clinical benefit.

Treatment of Increased Intracranial Pressure There is no absolute critical threshold for ICP. However, prolonged raised ICP over 20 mmHg has been shown to correlate with worsened outcome in head injury patients, and thus should be treated promptly (54). In conjunction with this, maintenance of adequate CPP (defined as mean arterial pressure minus ICP) has been shown to improve outcome (36). Obviously, every severely head-injured patient requires

Chapter 40: Pathophysiology and Management of Head Injury

close monitoring in an ICU with trained nurses who have the expertise to deal with the challenges that come with these patients. Every patient requires continuous monitoring of all ‘‘basic’’ vital signs, including ventilation parameters [oxygen saturation and end tidal carbon dioxide (CO2)], arterial blood pressure, and central venous pressure. Furthermore, ICP needs to be monitored and any elevation should be aggressively treated. Intracranial hypertension can lead to further damage through direct mechanical impact during herniation of brain tissue as well as through further decrease of blood flow, which in turn leads to ischemia. The goal of treatment is to prevent these events. Currently several devices are available commercially to monitor the ICP reliably. Patients who should be considered for this type of monitoring are the ones with a GCS of 8 or less. Also, patients with a moderate head injury and an abnormal CT, who cannot be neurologically evaluated due to other factors, should undergo ICP monitoring. An intraventricular catheter (ventriculostomy) may be used for this purpose as previous studies and experience have validated (55). Also available are intraparenchymal transducer-tipped monitors that are more easily inserted and may be useful in patients with small ventricles. The ventriculostomy is advantageous in that it can allow treatment of elevated ICP by CSF drainage. However, the procedure to place the catheter is slightly more invasive and difficult. Both monitoring modalities are an acceptable way of following the ICP. The treatment of increased ICP is best done by a stepwise process. First and foremost, one should ensure that any increase in ICP is not due to non-neurological causes such as inadequate ventilation, labile blood pressure, agitation, or pain. Positioning with slight elevation of the head of the bed (approximately 20 degrees) can be helpful, and the use of constricting devices, such as tight cervical collars, or tape to secure the endotracheal tube around the neck, should be avoided. Second, the possibility of an expanding mass lesion needs to be ruled out through a head CT. When a ventriculostomy is in place the next step is to drain CSF to treat raised ICP. Mannitol can be given, with monitoring of electrolytes and renal function after each dose. One should also consider that patients with unexplained raised ICP do not have subclinical seizures, which may occur despite anticonvulsant therapy. Evaluation of intractable ICP elevation may also require evaluation of serum anticonvulsant levels, as well as an electroencephalogram (EEG) to exclude seizures. If the above-mentioned measures do not control the ICP, sedation and paralysis are indicated. The benefit of this is twofold. These measures will decrease cerebral metabolic rate, and ventilation is more easily managed. The arterial oxygen and CO2 partial pressures can now be more effectively controlled. For sedation, several agents can be used. First, morphine will act as both a sedative and pain reliever. However, it should not be used unless the head-injured patient is intubated and ventilated, due to the potential increase in arterial CO2. Sedatives such as propofol or midazolam decrease the cerebral metabolic rate and therefore decrease the amount of metabolic substrate delivery that is required by the brain to maintain homeostasis. This is especially of value because there may already be a flowmetabolism mismatch present in the injured brain. Propofol has the advantage that it is very short acting and therefore can be stopped intermittently to examine the patient. Midazolam is longer acting but is currently less expensive, and

801

has the theoretical advantage of reducing seizure activity, which may not be clinically noticeable. Because these sedatives have no analgesic effect, a pain reliever such as morphine should always be used in conjunction with either of these agents. All of these agents may cause hypotension to some extent, and close monitoring of the blood pressure should be maintained. Paralytic agents are also frequently used, in conjunction with sedatives and analgesia for optimal ventilation, CO2 control, and reduction of elevated ICP. Vecuronium is one example of a short-acting nondepolarizing neuromuscular blocker that can be given by continuous intravenous administration. The use of an external nerve stimulator allows for monitoring adequate levels of paralysis. Hyperventilation is a means of decreasing ICP. However, there is now more and more evidence that aggressive and/or prolonged hyperventilation causes cerebral vasoconstriction, decreases CBF, and therefore worsens outcome (56,57). The use of moderate hyperventilation is appropriate and can be extremely helpful to treat elevated ICP. The recommended lower threshold for arterial CO2 is 30 to 32 mmHg (55). Mean arterial pressure needs to be maintained to ensure adequate CPP. This is primarily done by preventing/ treating hypovolemia. If there is doubt about the volume status of the patient, a Swan–Ganz catheter can be used. Usually normovolemia or slight hypervolemia will ensure adequate CPP when ICP is treated. If further increase in mean arterial blood pressure is needed to maintain CPP, pressors may be used. Dopamine and/or phenylephrine are generally effective in doing so. Dobutamine might be used in patients with decreased cardiac output. In general, based on anecdotal evidence, a CPP over 70 mmHg is accepted as adequate for the severely head-injured patient without signs of vasospasm. Moderate hypothermia (32–33 C) has failed to show improved outcome in severely head-injured patients in a recent clinical trial (58). However, it may reduce ICP. This is at least in part due to decreasing cerebral metabolic rate and possibly subsequently reducing the release of excitatory amino acids such as glutamate (59). However, the side effects are significant; they include cardiac arrhythmias and increased risk of systemic infections due to suppression of the immune system, as well as coagulopathies. Nevertheless, the use of hypothermia remains to be more fully evaluated, as a potentially useful tool whenever the abovedescribed measures fail to control the raised ICP.

Other Measures to Reduce ICP Further measures to reduce ICP may be used after the above-described treatments have failed to improve the intracranial hypertension. Their efficacy is less well proven. Decompressive craniectomies are used to give the injured brain ‘‘space to swell’’ as a method to reduce the ICP. A large bone flap is created and the dura is patched with a graft. The brain can now herniate out through the defect. There is some evidence that this measure improves outcome both in terms of morbidity and mortality (60). Induced barbiturate coma is a way to minimize brain activity and therefore the need for substrate delivery, which is compromised in these patients. It requires bedside EEG monitoring to regularly evaluate brain activity. In this way, the cerebral metabolic rate is reduced and the existing flow-metabolism mismatch is positively influenced (61). Unfortunately, this comes with the risk of major complications, such as reduced cardiac output, myocardial infarction,

medwedi.ru

802

Part Five: The Central and Peripheral Nervous Systems

and serious systemic infections, and is therefore reserved for situations when all other measures have failed. There is no role for corticosteroid use in the treatment of raised ICP in the severely head-injured patient (62). It is now clear that the edema resulting from trauma to the brain is cytotoxic in nature and therefore not susceptible to the use of steroids that mainly acts on vasogenic edema (63).

Pharmacologic Intervention As previously stated, both shearing injury and ischemic damage have been shown to result in calcium-mediated damage to intracellular structures, massive release of glutamate, and also generation of free radicals (64–66). Selective pharmacological antagonists for both presynaptic release and postsynaptic receptor binding of glutamate have been developed. The most powerful evidence in support of glutamateinduced neurotoxicity in focal ischemia comes from many neuroprotection studies, performed with different N-methyl-D-aspartate (NMDA) and non-NMDA glutamate antagonists (67–69). NMDA antagonists are most effective when administered before the insult (especially competitive antagonists), but others have been effective when given up to two hours after the ischemic event. Newer glutamate antagonists, which block release of glutamate from presynaptic vesicles, may also show protection after global ischemia, which could not be demonstrated with the previous NMDA antagonists. Unfortunately, trials in humans using free-radical scavengers and glutamate antagonists so far have not shown significant benefit. Clearly, it is now becoming accepted that mechanism-driven trials in which individual pathophysiological mechanisms are targeted may be preferable in this heterogeneous patient population. The degree of brain penetration, the safety and tolerability of the compound, and end points used for outcome assessment are major influences upon the success of these new drugs.

MONITORING THE INJURED BRAIN In the last two decades, major advances have been made in understanding the pathophysiological mechanisms following TBI. However, the impact on clinical monitoring and management of cerebral metabolism in severely headinjured patients of this progress has been modest. The only well-established and accepted method currently available is ICP monitoring. Unfortunately, this is a relatively crude technique, and changes in ICP are only seen after major changes and derangements previously have taken place in the physiology and anatomy of the brain. As a consequence, only the final results (brain swelling) of the disturbance of the intracranial milieu are monitored. Clinically, this means that measurements that are being taken to intervene in these harmful events are by definition done relatively late, and may be too late to prevent permanent injury. This lack of sufficient monitoring for brain injury has resulted in a search for more elegant techniques, in the last decade. Another important issue is the time course of events, following trauma. However, in humans, it remains impossible to study the first events taking place immediately after injury. New monitoring devices and imaging techniques have improved the assessment of brain physiology; they include microdialysis to study the extracellular fluid content in the brain parenchyma. In this way, one can assess the levels of metabolites, amino acids, and free-radical

production in the injured brain. Measurements of brain oxygen, CO2, and pH are also being performed more widely and this has the advantage that continuous monitoring of brain is available in the ICU (19,39,40). Also, more advanced imaging studies are now deployed to evaluate these patients. For example, PET scanning is now used to study the brain metabolism in combination with its supply of nutrients, as well as MR diffusion-weighted imaging to evaluate the water/edema seen after head injury in the parenchyma (16,22,63). However, the data and results of these new monitoring devices require careful evaluation and interpretation before their use in actual treatment of these patients will be clinically helpful. Notwithstanding these findings, before any conclusions can be made from data obtained by means of these devices, a thorough and critical analysis is needed to better understand what exactly is measured and whether or not these labor-intensive and expensive techniques are helpful in understanding and treating the derangements in physiology seen after TBI.

SUMMARY Traumatic brain injury is the most common cause of death and severe disability in adults under the age 40. Because a third of patients who die from this injury will have spoken at some point during their clinical course, it seems clear that a window of opportunity exists to treat the underlying pathophysiology before secondary insults develop, which irreversibly prevent restoration of normal physiology. Although much still needs to be learned about the cascade of events that are set in motion following a traumatic brain injury, our current understanding of the pathophysiologic mechanisms that previously led to death or severe disability has been effectively utilized to institute treatment strategies so that many of these patients can become productive individuals leading normal or near normal lives. Thus, adequate fluid resuscitation to ensure euvolemia, antiseizure prophylaxis, and optimization of the blood’s oxygencarrying capacity have all contributed greatly to managing these patients. Other therapeutic measures that have evolved include the prevention of hyperthermia, maintenance of cerebral perfusion pressure above 70 mmHg, and sedation. Early ventricular drainage for elevated ICP and mild hyperventilation (PCO2 of approximately 35 mmHg) have been found to be especially beneficial in patients with a GCS of less than 8. As research continues in this important area of human disease, it is envisioned that other therapeutic alternatives will become available to salvage even more individuals in the early stages of injury when the ‘‘window of opportunity’’ is most advantageous.

REFERENCES 1. Collins JG. Types of injuries by selected characteristics: United States, 1985–1987. Vital Health Stat 1990; 10:175. 2. Kalsbeek WD, Mclaurin RL, Harris BS. The national head and spinal cord injury survey: major findings. J Neurosurg 1980; (Suppl 53):S19–S31. 3. Kraus JF. Epidemiology of head injury. In: Cooper PR, ed. Head Injury. Baltimore: Williams & Wilkins, 1993:1–25. 4. Blumberg PC, Jones NR, North JB. Diffuse axonal injury in head trauma. J Neurol Neurosurg Psychiatry 1989; 52:38–842. 5. Bullock R, Teasdale GM. Head injuries-surgical management: traumatic intracranial hematomas. In: Braakman R, ed. Vinken

Chapter 40: Pathophysiology and Management of Head Injury

6.

7. 8.

9.

10.

11.

12.

13.

14.

15.

16.

17. 18.

19.

20.

21.

22.

23. 24. 25.

26.

27.

and Bruyn’s Handbook of Clinical Neurology. 24. Head Injury. Amsterdam: Elsevier Science Publishers, 1991:249–298. Adams JH, Graham DI, Gennarelli TA. Head injury in man and experimental animals: neuropathology. Acta Neurochir 1983; 32:15–30. Jennett B, Carlin J. Preventable mortality and morbidity after head injury. Injury 1978; 10:31–39. Klauber MR, Marshall LF, Luerssen TG, Frankowski R, Tabaddor K, Eisenberg HM. Determinants of head injury mortality: importance of the low risk patient. Neurosurgery 1989; 24:31–36. Kirino T, Tamura A, Sano K. Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol 1984; 64:139–147. Miller JD, Bullock R, Graham DI, Chen MH, Teasdale GM. Ischemic brain damage in a model of acute subdural hematoma. Neurosurgery 1990; 27:433–439. Hayes R, Jenkins LW, Lyeth BG. Neurotransmitter mediated mechanisms of traumatic brain injury: acetylcholine and excitatory amino acids. J Neurotrauma 1992;(Suppl 9):S173. Stone JL, Rifai MHS, Sugar O, Lang RGA, Oldershaw JB, Moody RA. Subdural hematomas. Acute subdural hematoma: progress in definition, clinical pathology, and therapy. Surg Neurol 1983; 19:216–231. Chen MH, Bullock R, Graham DI, Miller JD, Mcculloch J. Ischemic neuronal damage after acute subdural haematoma in the rat: effects of pretreatmant with a glutamate antagonist. J Neurosurg 1991; 74:944–950. Kuroda Y, Inglis FM, Miller JD, Mcculloch J, Graham DI, Bullock R. Transient glucose hypermetabolism after acute subdural hematoma in the rat. J Neurosurg 1992; 76:944–950. Schroder ML, Muizelaar JP, Kuta AJ. Documented reversal of global ischemia immediately after removal of an acute subdural hematoma. J Neurosurg 1994; 80:324–327. Hovda DA, Lee SM, Smith ML, et al. The neurochemical and metabolic cascade following brain injury: moving from animal models to man. J Neurotrauma 1995; 12:903–906. Cruz J. Brain ischemia in head injury. J Neurosurg 1993; 78: 522–523 (letter). Bouma GJ, Muizelaar JP, Stringer WA, Choi SC, Fatouros PP, Young HF. Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 1992; 77:360–368. Zauner A, Daugherty WP, Bullock MR, Warner DS. Brain oxygenation and energy metabolism: Part I. biological function and pathophysiology. Neurosurgery 2002; 51(2):289–301; discussion 302. Katayama Y, Becker DP, Tamura T, Hovda DA. Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 1990; 73:889–900. Yoshino A, Hovda DA, Kawamata T, Katayama Y, Becker DP. Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state. Brain Res 1991; 561(1):106–119. Bergsneider M, Hovda DA, Shalmon E, et al. Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg 1997; 86(2):241–251. Andersen BJ, Marmarou A. Post-traumatic selective stimulation of glycolysis. Brain Res 1992; 585(1–2):184–189. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG. Energy on demand. Science 1999; 283(5401):496–497. Muizelaar JP, Marmarou A, De Salles AAF, Ward JD, Zimmermann RS. Cerebral blood flow and metabolism in severely head-injured children. Part 1: relationship with GCS score, outcome, ICP and PVI. J Neurosurg 1989; 71:63–71. Povlishock JT, Erb DE, Astruc J. Axonal response to traumatic brain injury: reactive axonal change, deafferentation, and neuroplasticity. J Neurotrauma 1992; 9(Suppl 1):S189–S200. Faden AI, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989; 244:798–800.

803

28. Clark WC, Muhlbauer MS, Watridge CB, Ray MW. Analysis of 76 civilian craniocerebral gunshot wounds. J Neurosurg 1986; 65(1):9–14. 29. Crockard HA, Brown FD, Johns LM, Mullan S. An experimental cerebral missile injury model in primates. J Neurosurg 1977; 46(6):776–783. 30. Jenkins LW, Moszynski K, Lyeth BG, et al. Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 1989; 477(1–2): 211–224. 31. Bruce DA, Langfitt TW, Miller JD, et al. Regional cerebral blood flow, intracranial pressure, and brain metabolism in comatose patients. J Neurosurg 1973; 38(2):131–144. 32. Shackford SR, Mackersie RC, Davis JW, Wolf PL, Hoyt DB. Epidemiology and pathology of traumatic deaths occurring at a Level I Trauma Center in a regionalized system: the importance of secondary brain injury. J Trauma 1989; 29(10):1392–1397. 33. Graham DI, Ford I, Adams JH, et al. Ischaemic brain damage is still common in fatal non-missile head injury. J Neurol Neurosurg Psychiatr 1989; 52(3):346–350. 34. Graham DI, Adams JH, Doyle D, et al. Quantification of primary and secondary lesions in severe head injury. Acta Neurochir Suppl (Wien) 1993; 57:41–48. 35. Miller JD, Sweet RC, Narayan R, Becker DP. Early insults to the injured brain. JAMA 1978; 240(5):439–442. 36. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993; 34(2):216–222. 37. Hills MW, Deane SA. Head injury and facial injury: is there an increased risk of cervical spine injury? J Trauma 1993; 34(4):549–553; discussion 553–554. 38. Doppenberg EM, Rice MR, Di X, Young HF, Woodward JJ, Bullock R. Increased free radical production due to subdural hematoma in the rat: effect of increased inspired oxygen fraction. J Neurotrauma 1998; 15(5):337–347. 39. Menzel M, Doppenberg EM, Zauner A, et al. Cerebral oxygenation in patients after severe head injury: monitoring and effects of arterial hyperoxia on cerebral blood flow, metabolism and intracranial pressure. J Neurosurg Anesthesiol 1999; 11(4): 240–251. 40. Menzel M, Doppenberg EM, Zauner A, Soukup J, Reinert MM, Bullock R. Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury. J Neurosurg 1999; 91(1):1–10. 41. Smith GJ, Kramer GC, Perron P, Nakayama S, Gunther RA, Holcroft JW. A comparison of several hypertonic solutions for resuscitation of bled sheep. J Surg Res 1985; 39(6):517–528. 42. Auler JO Jr, Pereira MH, Gomide-Amaral RV, Stolf NG, Jatene AD, Rocha e Silva M. Hemodynamic effects of hypertonic sodium chloride during surgical treatment of aortic aneurysms. Surgery 1987; 101(5):594–601. 43. Battistella FD, Wisner DH. Combined hemorrhagic shock and head injury: effects of hypertonic saline (7.5%) resuscitation. J Trauma 1991; 31(2):182–188. 44. Gunnar W, Jonasson O, Merlotti G, Stone J, Barrett J. Head injury and hemorrhagic shock: studies of the blood brain barrier and intracranial pressure after resuscitation with normal saline solution, 3% saline solution, and dextran-40. Surgery 1988; 103(4):398–407. 45. Schmoker JD, Shackford SR, Wald SL, Pietropaoli JA. An analysis of the relationship between fluid and sodium administration and intracranial pressure after head injury. J Trauma 1992; 33(3):476–481. 46. James HE, Schneider S. Effects of acute isotonic saline administration on serum osmolality, serum electrolytes, brain water content and intracranial pressure. Acta Neurochir Suppl (Wien) 1993; 57:89–93. 47. Rosner MJ, Daughton S. Cerebral perfusion pressure management in head injury. J Trauma 1990; 30(8):933–40; discussion 940–941.

medwedi.ru

804

Part Five: The Central and Peripheral Nervous Systems

48. Lam AM, Winn HR, Cullen BF, Sundling N. Hyperglycemia and neurological outcome in patients with head injury. J Neurosurg 1991; 75(4):545–551. 49. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practice scale. Lancet 1974; 2:81. 50. Burke AM, Quest DO, Chien S, Cerri C. The effects of mannitol on blood viscosity. J Neurosurg 1981; 55(4):550–553. 51. Muizelaar JP, Wei EP, Kontos HA, Becker DP. Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes. J Neurosurg 1983; 59(5):822–828. 52. Doppenberg EM, Watson JC, Broaddus WC, Holloway KL, Young HF, Bullock R. Intraoperative monitoring of substrate delivery during aneurysm and hematoma surgery: initial experience in 16 patients. J Neurosurg 1997; 87(6):809–816. 53. Rish BL, Dillon JD, Weiss GH. Mortality following penetrating craniocerebral injuries. An analysis of the deaths in the Vietnam Head Injury Registry population. J Neurosurg 1983; 59(5):775–780. 54. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in severe head injuries. Part I: the significance of intracranial pressure monitoring. J Neurosurg 1979; 50(1):20–25. 55. Bullock R, Chesnut RM, Clifton G, et al. Guidelines for the management of severe head injury. Brain Trauma Foundation. Eur J Emerg Med 1996; 3(2):109–127. 56. Marion DW, Bouma GJ. The use of stable xenon-enhanced computed tomographic studies of cerebral blood flow to define changes in cerebral carbon dioxide vasoresponsivity caused by a severe head injury. Neurosurgery 1991; 29(6):869–873. 57. Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 1991; 75(5):731–739. 58. Marion DW. Moderate hypothermia in severe head injuries: the present and the future. Curr Opin Crit Care 2002; 8(2):111–114. 59. Busto R, Dietrich WD, Globus MY, Ginsberg MD. The importance of brain temperature in cerebral ischemic injury. Stroke 1989; 20(8):1113–1114.

60. Gaab MR, Rittierodt M, Lorenz M, Heissler HE. Traumatic brain swelling and operative decompression: a prospective investigation. Acta Neurochir Suppl (Wien) 1990; 51:326–328. 61. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988; 69(1):15–23. 62. Dearden NM, Gibson JS, McDowall DG, Gibson RM, Cameron MM. Effect of high-dose dexamethasone on outcome from severe head injury. J Neurosurg 1986; 64(1):81–88. 63. Marmarou A, Portella G, Barzo P, et al. Distinguishing between cellular and vasogenic edema in head injured patients with focal lesions using magnetic resonance imaging. Acta Neurochir Suppl 2000; 76:349–351. 64. Benveniste H, Drejer J, Schousboe A, Diemer NH. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 1984; 43:1369–1374. 65. Butcher SP, Bullock R, Graham DI, Mcculoch J. Correlation between amino acid release and neuropathological outcome in rat striatum and cortex following middle cerebral artery occlusion. Stroke 1990; 1:1727–1733. 66. Shimada N, Graf R, Rosner G, Heiss WD. Ischemia-induced accumulation of extracellular amino acids in cerebral cortex, white matter, and cerebrospinal fluid. J Neurochem 1993; 60:66–71. 67. Meldrum B. Protection against ischemic neuronal damage by drugs acting on excitatory neurotransmission. Cerebrovasc Brain Metab Rev 1990; 2:27–57. 68. Bullock R, Fujisawa H. The role of glutamate antagonists for the treatment of CNS injury. J Neurotrauma 1992(suppl 9): S3443–S3461. 69. Kuroda Y, Fujisawa H, Strebel S, Graham DI, Bullock R. Effect of neuroprotective N-methyl-d-aspartate antagonists on increased intracranial pressure: studies in the rat acute subdural hematoma model. Neurosurgery 1994; 35:106–112.

41 Spinal Cord Injury Kangmin Lee and R. Scott Graham

INTRODUCTION Spinal cord injury (SCI) is an important cause of morbidity and mortality in modern society. Injuries result in significant and permanent neurologic deficits, and the functional consequences can be devastating. Although there are a number of causes, the focus of this chapter is on traumatic cord injury. The following is a summary of the prevailing concepts in pathophysiology and treatment of traumatic SCI.

EPIDEMIOLOGY Approximately 10,000 SCIs occur each year in the United States. Although the true incidence is unknown, the range has been estimated to be between 28 and 55 per million population (1,2). Data from the Olmsted County, Minnesota study from 1935 to 1981 reported an age- and sex-adjusted incidence rate of 54 injuries per million population. This figure was reduced to 34 per million if immediate deaths before reaching the hospital were not included (3). In comparison, the incidence rate in other developed countries ranges from 2 to 53 per million population (1,4). In the United States, injuries are due to motor vehicle accidents (36–48%), violence (5–29%), falls (17–21%) and recreational activities (7–16%) (5–7). Average age at time of injury for each cause of SCI was 30 years for motor vehicle accidents, 27 years for violence, 24 years for recreational activities, and 42 years for falls. Monetary costs are significant, and a recent study estimated total direct costs in the value of the 1995 dollar for all causes of SCI in the United States at $7.7 billion (6). Data from the Major Trauma Outcome Study (5) showed that traumatic SCI occurred in one of every 40 injured persons presenting to trauma centers. Patients with SCI and multitrauma were more common than those with isolated spine injuries. In those with isolated SCI, 65% had cervical cord injury. In those with multiple injuries, cervical cord injury was seen in 52%. Motor vehicle accidents, pedestrian accidents, and falls were associated with the highest percentage of cervical injury, 56% to 65%. Gunshot wounds and motorcycle accidents were associated with the lowest percentage of cervical injury, 30% and 39% respectively (5).

PATHOPHYSIOLOGY

injury can have prognostic significance, while the severity of secondary injury can limit the potential of rehabilitative processes and contribute to the overall morbidity and mortality.

Primary Mechanisms The primary mechanical injury occurs by way of penetration, laceration, shear, compression, and/or distraction. Depending on the mechanism of injury, duration can be either transient or persistent. Impact with transient compression is often seen with hyperextension injuries in individuals with underlying spondylosis. Burst fractures with canal compromise, fracture dislocations, and disc ruptures are examples of impact with persistent compression. The extent of the primary injury can be used to group patients into severity categories (neurologic grades). Mechanism of injury, spinal level, and neurologic grade on admission to the hospital are important prognostic indicators (8,9). The American Spinal Injury Association (ASIA) SCI grading scale is a common scale used for this purpose (Table 1). The primary mechanical injury has a tendency to damage the central gray matter of the cord. This is probably due to its softer consistency and greater vascular requirements. Within the white matter, axons that pass through the injured segment may be physically disrupted or exhibit a decrease in myelin thickness, resulting in impaired conduction of action potentials. Mechanical disruption of venules and capillaries may result in early hemorrhage within the cord. Larger vessels such as the anterior spinal artery are relatively spared from direct mechanical injury, and the location of vascular damage is primarily in the intramedullary vascular system (8–10).

Secondary Mechanisms The initial mechanical insult serves as the impetus for a cascade of deleterious events. Current understanding of these

Table 1 American Spinal Injury Association Impairment Scale A ¼ Complete: No motor or sensory function is preserved in the sacral

segments S4–S5 B ¼ Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4–S5 C ¼ Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3 D ¼ Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 or more E ¼ Normal: Motor and sensory function are normal

Similar to current concepts in traumatic brain injury, the pathophysiology of SCI involves a primary mechanism with initial mechanical damage and local tissue destruction and a complex cascade of secondary mechanisms. The secondary mechanisms are initiated by the primary injury and encompass systemic, cellular, and biochemical processes that lead to cellular damage and cell death. The severity of primary

medwedi.ru 805

806

Part Five: The Central and Peripheral Nervous System

mechanisms has evolved over the past three decades, and many corollaries to recent advances in cerebral trauma and ischemia have helped to mold understanding. Numerous studies have shown that the central nervous system responds to injury in a prototypical fashion. Vascular changes, ionic derangements, neurotransmitter accumulation, free-radical production, and apoptosis as well as various other cellular and biochemical events have been shown to compromise the spinal cord after injury (Table 2). A thorough discussion of each event is beyond the scope of this chapter, but animal models point to posttraumatic ischemia as a common denominator for secondary processes following SCI. Other mechanisms such as glutamate excitotoxicity and free-radical and apoptotic mechanisms have been shown to be important sequellar posttraumatic ischemia.

Spinal Cord Ischemia Following the initial insult, a number of systemic and local events are initiated; of primary concern is an acute reduction in blood flow to the area of the lesion. Although the precise mechanism behind this hypoperfusion is unclear, it has been shown to persist in rats and monkeys for at least 24 hours. It is speculated that vasospasm or possibly the release of a vasoactive amine is partially responsible. However, it is likely that the mechanism involves a combination

Table 2 Primary and Secondary Mechanisms of Spinal Cord Injury Primary injury mechanisms Compression Impact Missile Stretch Laceration Shear Secondary injury mechanisms Systemic effects Heart rate: brief tachycardia and then prolonged bradycardia Blood pressure: hypertension and then prolonged hypotension Decreased peripheral vascular resistance Decreased cardiac output Increased catecholamine release and then decrease Hypoxia Hyperthermia Local vascular changes Loss of autoregulation Neurogenic shock Hemorrhage (especially in the gray matter) Loss of microcirculation Vasospasm Thrombosis Electrolyte changes Increased intracellular calcium Increased intracellular sodium Increased extracellular potassium Neurotransmitter accumulation Catecholamines Glutamate Arachidonic acid release Free-radical production Eicosanoid production Lipid peroxidation Edema Apoptosis Source: Modified from Ref. 11.

of processes such as hemorrhagic ischemia, thrombosis, endothelial swelling, and edema formation (8,10,12). Normally, gray and white matter blood flow is maintained at a 3:1 ratio, reflecting the greater vascular requirements of the gray matter relative to the adjacent white matter. The metabolic requirement of spinal cord gray and white matter has important implications for understanding the response to secondary injury. Perfusion to the peripheral white matter is typically reduced within the first five minutes postinjury, with a return to normal flow within 15 minutes. In contrast, hemorrhage is often seen in the central gray matter within the first five minutes postinjury, and perfusion virtually halts within the hour. This vascular stasis has been confirmed using microangiography and fluorescent tracer studies (11,13). It is believed that the central gray matter is irreversibly damaged within the first hour after injury, and that white matter damage is irreversible beyond the first 72 hours postinjury (8). Studies by Tator and Koyanagi using silicone rubber microangiography have elucidated some of the vascular changes in SCI. They have shown that the central area of the cord is supplied by the sulcal arteries and encompasses the anterior gray matter, the anterior half of the posterior gray matter, the inner half of the anterior and lateral white columns, and the anterior half of the posterior white columns. The peripheral white matter and the posterior portion of the posterior gray matter are supplied by the posterior spinal and pial arteries. There is also an intermediate watershed zone representing the vascular overlap between the pial and sulcal arterial systems (10). This anatomical arrangement may help to explain the hemorrhagic and ischemic changes seen in the gray matter of traumatized spinal cords. Hemorrhage in the gray matter of traumatized spinal cords has been well documented in clinical and experimental studies. Sekhon and Fehlings have proposed that it may be that obstruction or mechanical disruption of the anterior sulcal arteries leads to the hemorrhagic necrosis and subsequent central myelomalacia seen at the site of injury (11).

Impaired Autoregulation In many cases of SCI, the primary injury is not severe enough to cause the hemorrhagic necrosis discussed above. However, vascular alterations with cord ischemia have been shown to occur in milder forms of injury as well. Loss of autoregulatory homeostasis (i.e., a decreased ability to maintain constant blood flow over a wide range of pressures) and endothelial dysfunction are additional vascular sequelae of SCI. Endothelial dysfunction leads to increased vascular permeability with the leakage of proteinaceous fluid into the interstial space and edema at the injury site. Endothelial damage occurs early after injury, and cellular changes are observed in as early as one to two hours (12). In the setting of a markedly swollen spinal cord, ischemia may be further aggravated by the limited cross-sectional area of the bony spinal canal and rising tissue pressures. Neurologic deterioration due to spinal cord edema is well documented in SCI and may be potentially reversible in the subacute period.

Neurotransmitter Excitotoxicity The notion of glutamate excitotoxicity is a concept that has been implicated in the pathophysiology of head trauma. As the primary excitatory neurotransmitter in the central nervous system, toxic levels are known to initiate a highly disruptive

Chapter 41: Spinal Cord Injury

process known as glutamate excitotoxicity. This process has been implicated in SCI as well. Glutamate has been shown to flood out of injured spinal neurons, axons, and astrocytes, causing an over excitation of neighboring neurons. Glutamate acts on N-methyl-D-aspartate (NMDA) and non-NMDA receptors on neurons or glial cells, causing an influx of Ca2þ. This triggers a series of highly destructive events directly and indirectly through the production of numerous agents such as free-radicals. The ischemia that results from vascular changes may also be instrumental to glutamate accumulation. Hypoxia results in adenosine triphosphate depletion, which then impairs cellular uptake mechanisms. Glutamate receptor activation also appears to result in early accumulation of intracellular Naþ and Ca2þas well (8).

Free-Radical–Mediated Cell Injury Free-radical formation is also known to be an important secondary injury mechanism in SCI. After injury, oxygen freeradicals are formed and have been shown to cause cell membrane peroxidation. Important phospholipid-dependent enzymes can be impaired disrupting ionic gradients and causing membrane lysis (8).

807

(18,19). According to the ASIA, an SCI is defined as complete when there is absence of sensory and motor function in the lowest sacral segment. In contrast, an incomplete injury is defined by the presence of sensory and/or motor function at the lowest sacral segment (‘‘sacral sparing’’). Sacral sensation includes pinprick or light touch sensation at the anal mucocutaneous junction, as well as deep anal sensation with digital exam. The test of motor function is marked by the ability to contract the external anal sphincter on digital exam. Among the SCI classification schemes, there is some disagreement regarding definition of the ‘‘level’’ of a SCI. ASIA criteria defines neurologic level as the most caudal segment of the spinal cord with normal sensory and, at least, antigravity strength (greater than or equal to three out of five motor strength) on both sides (20). The severity of SCI is rated by a simple five-level (A–E) ASIA impairment scale (Table 1). The standards for neurological and functional classifications of SCI assess motor function in ten muscle groups (arms: C5-T1, legs L2-S1) and sensation (light touch and pinprick) in 28 dermatomes (C2-S4/5) on both sides of the body (Fig. 1).

CLASSIC INJURY PATTERNS

Apoptosis Recent research has implicated the process of programmed cell death in a number of neurological disorders including SCI. Apoptosis can be triggered by a variety of initiating factors including cytokine release, inflammatory insults, free-radical damage, and excitoxicity. Days or weeks after initial trauma, a wave of cell suicide or apoptosis sweeps through neurons, oligodendrocytes, microglia, and, perhaps, astrocytes. This wave can affect cells as many as four segments away from the initial trauma site (8,14,15).

Additional Pathophysiologic Considerations Spinal Shock The term ‘‘neurogenic’’ or ‘‘spinal shock’’ has been used in several ways. For references made in this chapter, spinal shock will refer to a sudden loss of peripheral vascular tone. This results in pooling of blood in the extremities and inadequate central venous return. The unopposed parasympathetic effects of the vagus nerve results in bradycardia, which is in marked contrast to the tachycardia associated with hemorrhagic shock. Although the pathophysiology of spinal shock is not completely understood, it is most probably due to a conduction blockade resulting from cellular Kþ ion leakage. Impulse conduction would then be dependent upon restoration of normal Naþ and Kþ gradient (16).

EVALUATION Neurologic Assessment All individuals with SCI should have a thorough neurologic examination. Traumatic brain injury has been shown to coincide with nearly half of all traumatic SCIs (17). Multilevel injury to the spine is also common, and a thorough examination of the entire spine is warranted, once the diagnosis of SCI is made. The evaluation of a spinal cord–injured patient begins by determining whether the injury is complete or incomplete. This information is important for determining prognosis and often useful clinically in determining the risk and benefit ratio of early surgery

Age, level of injury, and neurologic grade have been demonstrated to be the most important premorbid factors for survival after acute SCI (21). Approximately 45% of SCIs are complete injuries (22). These injuries are more likely to be due to fracture dislocations rather than burst or compression fractures (17). It is generally accepted that thoracic injuries will more frequently produce complete SCIs than cervical or lumbar injuries. When complete injuries do occur, the greatest neurologic recovery occurs in the more rostral injuries. Cervical injuries therefore, have exhibited the greatest degree of recovery following initial complete injury (23).

Complete Spinal Cord Injuries Complete injuries at or above the C3 level result in immediate respiratory arrest, and death will result within minutes if artificial respiration is not instituted (Fig. 2). Additionally, high cervical cord injuries are frequently accompanied by hemodynamic instability, which is the result of sudden loss of sympathetically mediated vasomotor tone, blood loss, and bradycardia from unopposed parasympathetic activity. Patients with complete injuries between the C5 and T1 levels can usually be weaned from mechanical ventilation. Prolonged ventilator support and possible tracheostomy are often necessary during the initial weeks following the injury. The reversible dysfunction of the spinal cord above the level of the injury is presumably due to effects of edema and the secondary pathways discussed earlier in this chapter.

Central Cord Syndrome Central cord syndrome is one of the most well-recognized and common SCI injury patterns. The pattern of injury is classically characterized by disproportionate motor deficit in the upper extremities as compared to deficit in the lower extremities. Bladder dysfunction and varying degrees of sensory loss below the level of the lesion also occur. Injury typically involves hyperextension in the cervical spine,

medwedi.ru

808

Part Five: The Central and Peripheral Nervous System

Figure 1 Standard neurological classification of spinal cord injury.

usually in association with preexisting cervical spondylosis. These injuries can occur even without apparent damage to the bony spine, but have also been described in association with vertebral body fractures or fracture-dislocation

injuries. The natural history of recovery following central cord syndrome is a gradual return of neurologic function in the early stages followed by a plateau. Some patients experience late deterioration often complicated by spasticity

Figure 2 Radiographic findings in a case of complete spinal cord transection just below the cervicomedullary junction due to a gunshot wound. (A) computed tomography (CT) scout tomogram shows the bullet fragment at the angle of the mandible and a markedly comminuted C2 fracture. (B) Sagittal T2-weighted magnetic resonance imaging demonstrates transection of the spinal cord and thick subarachnoid hemorrhage from injury to the vertebral artery. (C) Axial CT shows the comminuted fractures of C1 and C2. (D) Postoperative lateral radiograph shows the stabilizing titanium loop and tracheostomy in place.

Chapter 41: Spinal Cord Injury

809

or pain. Although the prognosis is favorable, recovery is usually incomplete. Impaired intrinsic muscle function of the hand is a common permanent deficit with this injury pattern. Several retrospective studies have shown that increased age and poor initial motor exam are the most important predictive variables (Fig. 3) (24–29).

Conus Medullaris Syndrome Conus medullaris syndrome is another common SCI pattern (Fig. 4). This syndrome most often results from thoracolumbar burst fractures. It involves injury to the distal portion of the spinal cord at the T12 through L2 spinal levels. The clinical presentation of this injury can occasionally be confused with cauda equina syndrome. Patients typically present with severe lower back pain at the level of the fractured vertebra. This may be accompanied by neuropathic pain in the thighs, distal lower extremities, and perineum. Motor and sensory deficits are also seen in a roughly symmetric distribution involving the distal lower extremities. Bladder and sphincter function are usually impaired with severe injuries and are the least likely deficits to regain function. Anatomically, the injured neural elements consist of the terminal portion of the conus (central nervous system) and the cauda equina (peripheral nervous system). The prognosis is relatively good for these injuries, and many patients can regain some useful function in the lower extremities (Fig. 5). The L1 vertebra is involved in the majority of thoracolumbar fractures. At this level, many of the axons for motor neurons to the lower extremities have exited the cord. Permanent impairment is most likely to be seen in the L5 and sacral spinal cord levels, i.e., pelvis instability during gait (glutei), ankle weakness (anterior tibialis, extensor hallius longus, and gastroc), and sphincter dysfunction. Anecdotal data from case series indicate a benefit for early decompression and stabilization of these injuries (30–36).

Figure 3 Sagittal T2-weighted magnetic resonance image of a typical central cord injury in a 67-year-old male. Patient presented with severe symmetric weakness of the deltoids and biceps with preservation of normal intrinsic hand and lower extremity motor function. The patient had brief paraesthsias over the upper portions of the arms, which returned to normal sensory exam shortly after the injury. Note the preexisting spondylosis and high signal within the spinal cord at the C4-5 level.

Cauda Equina Syndrome Although cauda equina syndrome is not a SCI, it is included in this discussion because it is a relatively common

Figure 4 L1 burst fracture with a complete conus medullaris syndrome; 22-year-old male who fell 30 feet from a tree. (A) Plain film of the lumbar spine shows an L1 burst fracture with kyphotic angulation. (B) The sagittal magnetic resonance imaging scan demonstrates compression of the conus and cauda equina with high signal in the distal portion of the spinal cord. (C) Reformated sagittal computed tomography scan shows the decompression of the spinal canal and correction of the kyphotic deformity. (D) The six-month postoperative X-ray shows the final alignment of the repair. The patient underwent early surgery and at six months was ambulatory with bilateral ankle braces.

medwedi.ru

810

Part Five: The Central and Peripheral Nervous System

Figure 5 (A–C) Neurologic grade at presentation and at the final assessment for three case series of conus medullaris injuries. Data from a case series in the mid-1980s. Delayed surgery was considered the standard approach at this time. (B) Data from the mid-1990s in this series surgery was preformed in the first week following the injury. (C) The senior authors series. Surgery was completed within 24 hour of the injury unless contraindicated. (D) Neurologic grade for the authors’ series over time. (E) Description of the Benzel Larson Grading scale.

compression syndrome. The pattern of neurologic deficits is similar to conus medullaris syndrome. Cauda equina syndrome usually occurs due to acute and severe midline compression of spinal nerve roots, i.e., from a massive disc rupture, most commonly at L4-5 (Fig. 6). This is often superimposed on a preexisting spinal stenosis or spondylosis. In contrast to conus medullaris lesions, pain is often the most prominent symptom and is radicular in nature. Motor and sensory deficits tend to be asymmetric. Urinary retention is the most consistent finding, and ‘‘saddle anesthesia’’

is the most common sensory deficit. Studies have shown that early surgical decompression, i.e., within 24 to 48 hours of onset is particularly important in avoiding permanent neurologic deficits (37–39). This syndrome is considered a neurosurgical emergency, and recognition of patients with a possible diagnosis of cauda equina syndrome requires immediate evaluation with magnetic resonance imaging (MRI) or myelogram/computed tomography (CT) of the lumbar spine and possible urgent surgical decompression.

Chapter 41: Spinal Cord Injury

811

Figure 6 Axial T2-weighted magnetic resonance imaging scan in a patient presenting with cauda equina syndrome due to a large L45 herniated disc. Images 31 and 32 show the spinal canal with cerebrospinal fluid and nerve roots in cross section. Images 33 and 34 show the spinal canal completely obstructed with a large free fragment of disc material.

Brown-Sequard Syndrome This syndrome occurs as a result of focal dysfunction in a hemisection of the spinal cord. Classically it was described following penetrating trauma of the cord and is reported to occur in 2% to 4% of traumatic SCIs. Although data for true incidence is lacking, it is more commonly seen in its partial form due to asymmetric distortion of the cord from compression by meningiomas, nerve sheath tumors, and disc herniations. Neurologic symptoms consist of ipsilateral loss of proprioceptive and vibratory sense as well as motor paralysis due to interruption of the posterior column and corticospinal tracts. Contralateral findings are loss of pain and temperature sensation one to two segments below the lesion. Light touch is preserved however, due to redundant ipsilateral and contralateral paths (anterior spinothalamic tracts). The prognosis for this syndrome is the best of any of the incomplete SCIs. The vast majority of patients with this syndrome will regain the ability to ambulate independently, as well as regain anal and urinary sphincter control. Sensory abnormalities are reported to persist in a higher percentage of patients with Brown-Sequard myelopathy, in comparison to other patterns of myelopathy (40–42).

Anterior Cord Syndrome The anterior two-thirds of the spinal cord is affected by this syndrome. The lesion is typically associated with cord infarction in the territory of the anterior spinal artery. This syndrome may occur from occlusion of the anterior spinal

artery or from anterior cord compression, e.g., by a dislocated bone fragment or by traumatic disc herniation. Posterior column function is typically preserved, while spinothalamic and corticospinal tract damage results in loss of pain and temperature sensation as well as paraplegia. Lesions higher than C7 can result in quadriplegia. This syndromes has the worst prognosis of the incomplete injuries. Only 10% to 20% recover functional motor control.

Posterior Cord Syndrome This syndrome is relatively rare and is most frequently associated with isolated damage to the posterior components of the spinal cord. There is usually loss of dorsal column function producing pain and parasthesias in the neck, upper arms, and torso. There also may be mild paresis of the upper extremities.

Posttraumatic Myelopathy Associated with Syringomyelia Posttraumatic syringomyelia is reported to develop in 0.3% to 3.2% of SCIs (43). Typically, the posttraumatic syrinx becomes symptomatic in a delayed and insidious fashion after a few years of stable neurologic functioning. Patients present with signs and symptoms of progressive neurologic dysfunction and pain. The presentation in order of frequency is local pain, loss of motor function, loss of sensory function, increased spasticity, autonomic dysreflexia, hyperhydrosis, increased sphincter dysfunction, increasing

medwedi.ru

812

Part Five: The Central and Peripheral Nervous System

respiratory insufficiency, and Horner’s syndrome. Diagnosis is confirmed by MRI or in rare cases in which an MRI cannot be obtained by delayed (1–2 hour) postmyelogram CT scanning (the delay allows time for the myelogram dye to enter the syrinx cavity). Controversy exists as to optimal management of the syrinx. Hence, many procedures have been used to treat them, including syringosubarachnoid shunting, syringopleural and syringoperitoneal shunting, fenestration of the syrinx, neurolysis of cord with duraplasty, and correction of spinal deformity. Each of these procedures has purported advantages, and specific associated risks and all of them have relatively high reoccurrence rates.

IMAGING The diagnosis and management of SCI will often require a variety of imaging studies. If cervical injury is suspected, anteroposterior, lateral, and open-mouth radiographs can be used to define integrity and alignment of bony structures. Under these circumstances, it is important to adequately visualize the entire cervical spine from occiput to T1. Gentle traction on the patient’s arms or alternatively a ‘‘swimmers view’’ can usually accomplish this. The negative predictive value of a normal three-view cervical spine series has been reported to range from 93% to 98% in several Class I studies (44–46). Dynamic views with flexion/extension can also be helpful and may aid in the diagnosis of ligamentous laxity. However, these views may be contraindicated, if neurologic dysfunction is noted. For suspected injuries in the thoracic or lumbar spine, anteroposterior and lateral films may be obtained. CT is superior to plain radiography and provides better resolution of bony structures. These films may be obtained when a fracture is suggested by plain film or full visualization of the cervical spine to T1 is not attainable. Sagittal and coronal reconstructions may be done if further anatomic information is required or the patient is a surgical candidate. Ideally, scan thickness in the cervical spine is 1.5 mm and 3 mm in the lumbar and thoracic spine. Highquality images can diagnose cord hemorrhages, mass effects, and disc herniations. Although invasive, the combination of myleography and CT remains the gold standard for visualization of cord or nerve root compression. This combination is especially useful when MRI is contraindicated or spinal instrumentation distorts imaging with artifact. If it is crucial to visualize the spinal cord, MRI remains the best available study. MRI would also be indicted, if evidence of SCI is evident without skeletal abnormality. Each examination should include at least one T1-weighted sagittal sequence, a sagittal sequence with water displayed bright (T2 spin echo, fast spin echo, or gradient refocused images), and a series of axial images. There has been a recent interest in diffusion weighted imaging of the spinal cord, given its significant value in detecting early brain injury.

MANAGEMENT OF ACUTE SCI Initial Management The major causes of immediate death in SCI are aspiration and shock (47). Therefore, the basic tenets of advanced trauma life support procedure are critical in the management of SCI. It is also important to be aware that SCI may mask other injuries, i.e., abdominal injuries below the level of the SCI.

Immobilization prior to and during extrication in the fields is important to prevent passive or active movements of the spine. However, if cardiopulmonary resuscitation is necessary, resuscitation takes precedence. The patient should be placed on a backboard with sandbags placed on both sides of the head. A 3-in. strip of adhesives tape from one side of the backboard to the other across the forehead and allows movement of the jaw and provides access to the airway. The backboard may be maintained to facilitate transfer, i.e., to the CT table. However, once urgent studies are completed, the backboard should be removed as soon as possible. Early removal will improve patient comfort and reduce the risk of decubitus ulcers. It is important to avoid hypotension in SCI patients, and systolic blood pressure should be maintained above 90 mmHg. Therapeutic measures may include the use of pressors, fluids, and military antishock trousers (MAST). MAST immbolizes the spine and can also compensate for decreased or lost muscle tone in the patient and prevent venous pooling. Dopamine may be used if necessary and is the pressor of choice. Vasomotor collapse may also contribute loss of temperature control, and the patient should be provided with cooling or warming blankets. Adequate oxygenation is also vital, and oxygen via nasal cannula or face mask should be delivered if intubation is not indicated. If intubation is required, then chin lift (not jaw thrust), without neck extension should be performed. If at all possible, tracheostomy or cricothyroidotomy should be avoided, because it may compromise later anterior cervical surgical approaches. Nasogastric tube suctioning is also often implemented in order to prevent vomiting and aspiration, as well as provide decompression of the stomach. Placement of a Foley catheter is also advised in order to prevent bladder distension from urinary retention.

Critical Care and Management of Complications Assuming survival after initial injury, it was commonly believed that renal failure and urinary tract infections were the leading causes of death in SCI patients. However, more recent studies show that pulmonary complications such as pneumonia are the leading cause of death (48). Cardiac dysfunction is also known to be common sequelae of SCI. These life-threatening events may occur episodically despite early resuscitation and initial restoration of cardiopulmonary function. Early detection through cardiopulmonary monitoring in the intensive care unit (ICU) setting can result in improved neurologic recovery. This is especially true for the patient with cervical cord injury above C5. The muscles of the diaphragm are innervated by the phrenic nerve (C3–C5). Injury at or above this level can thus result in apnea and require ventilator support for the patient. However, even for injuries below C5, respiratory function is often quite compromised. A flaccid paralysis of the intercostal muscles initially occurs—as the diaphragm contracts and descends, the chest wall contracts rather than expands. Forced vital capacity and maximal inspiratory force are reduced by 70%. Eventually, the intercostal muscles become spastic, and respiratory function improves. Approximately five months after injury, the forced vital capacity and the maximal inspiratory force are about 60% of predicted preinjury levels. Perhaps the most significant respiratory complication associated with SCI is ventilator-associated pneumonia. Common organisms include Streptococcus pneumoniae, Haemophilus influenzae, Pseudomanas aeruginosa, and Staphylococcus aureus. Cardiovascular

Chapter 41: Spinal Cord Injury

irregularities such as hypotension, arrhythmias, and even cardiac arrest can also occur. Therapy involves resuscitation with pressors as well as hemodynamic monitoring with a pulmonary artery catheter. Unfortunately, there is no clear consensus on the appropriate end point for volume resuscitation (49). Patients with SCI have a threefold increase in risk for thromboembolic disease (50). Given this risk, it is important to initiate prophylaxis in the ICU setting. Methods available include pneumatic compression devices, stockings, anticoagulants, and inferior vena cava (IVC) filters. Mechanical devices are clearly advisable but insufficient for prophylaxis. Low-molecular-weight-heparin can be added unless contraindicated, in which case an IVC filter may be a consideration. Studies of patients with spinal injuries have shown that the risk of deep venous thrombosis is quite low in the first 72 hours after SCI (51). Anticoagulation may then be held for this initial period. Thereafter it is advisable that anticoagulation be started. Although the optimum length of stay in the ICU is unknown, the available studies show that cardiac and respiratory events often occur within the first week or two after injury. This time frame may be dependent upon the severity of SCI (52).

Management of Instability Clinical stability can be defined as the ability of the spine to resist displacement, under physiologic loads and prevent irritation or injury to the spinal cord or nerve roots. In general, the spine can be viewed as being composed of three columns. Injury to any two of these columns may be regarded as sufficient to raise suspicion for clinical instability. The anterior column is composed of the anterior longitudinal ligament, the anterior half of the vertebral body, and the anterior half of the annulus fibrosis. The middle column includes the posterior half of the vertebral body, the posterior half of the annulus fibrosis, and the posterior longitudinal ligament. The posterior column consists of the spinous processes, laminae, articular processes, and the ligamentum flavum. After SCI, the objective of management is to mechanically limit displacement and pharmacologically prevent the progression of secondary damage. Mechanical stabilization can be provided by bed rest, external orthoses, or immediately through internal fixation. Cervical traction/reduction restores and maintains normal alignment immobilizing the spine to prevent further injury. Reduction may decompress the spinal cord or roots. The timing of reduction is controversial, and it is contraindicated in atlanto-occipital dislocation as well as type IIA or III Hangman’s fractures. A number of cranial tongs are available, and Gardner-Wells tongs are probably the most common tongs in use. The tongs are placed in the temporal ridge (above the temporalis muscle) 3 to 4 cm above the pinna. Traction weight is 5 lbs for the upper C-spine and 10 lbs for lower levels. Halo rings can be used initially for traction or later as a postoperative measure for immobilization. The indications and timing of surgical decompression for acute SCI have been controversial for many years. Considering the steady improvement in surgical technology and widespread capability to quickly complete the trauma evaluation and obtain necessary studies and radiographic evaluations, early surgery for SCI is becoming increasingly feasible. Therefore, we will briefly consider the knowledge base regarding the timing of decompression of acute SCIs.

813

There have been multiple animal studies providing persuasive evidence that SCI has a reversible component. Studies in primates, cats, dogs, and rodents have convincingly shown that early decompressive intervention enhances neurologic recovery in SCI. A study by Dimar et al., using a weight drop model, showed that neurologic recovery in rats was significantly dependent on time to decompression after injury (53). Unfortunately, clinical studies in humans have been less compelling. Basic definitions such as the time frame for ‘‘early surgery’’ have yet to be established. Due to the lack of Class I data, the clinical benefits of surgery for fracture dislocations are difficult to determine. However, there have been several reports of cervical cases receiving significant benefit after decompression with early traction. Overall, the data is lacking and is insufficient to produce practice guidelines or standards.

Posttraumatic Deformity The vast majority of unstable spinal injuries are recognized in the acute setting. However, posttraumatic kyphosis may develop in a delayed fashion. Most cases occur in patients initially managed ‘‘nonoperatively’’ with spinal bracing. Additionally, it is also seen in operatively managed cases that fail to fuse properly or at levels not incorporated into the fusion. The most common presenting symptom is spinal pain, followed by postural changes, increasing neurologic deficits, and, rarely, the development of a syrinx. Treatment is indicated for cases that demonstrate progression over time and for those associated with new or progressive neurologic deficits. A localized kyphotic deformity greater than 30 degrees is associated with an increased risk of chronic pain (54).

Pharmacologic Management There has been a significant evolution of thought in the pathophysiology of SCI within the past two decades. This has led to further progress in the surgical and medical treatment of SCI. The primary strategy has focused on limitation of secondary injury mechanisms. The first positive clinical trial [National Acute Spinal Cord Injury Study (NASCIS II)] for pharmacological treatment for SCI was reported in 1990 (55,56). In a multicenter clinical study, high-dose methylprednisolone was reported to reduce disability when given within eight hours of trauma. Although the mechanism of action has yet to be fully elucidated, it is thought to act in part to reduce swelling, inflammation, glutamate release, and free-radical accumulation. Results of the latest NASCIS III (57,58) showed that high-dose methylprednisolone, started between three and eight hours after injury and continued for 48 hours, was reported to preserve more motor function than treatment for 24 hours. It has become common practice in the United States to administer methylprednisolone (30 mg/ kg) within the first eight hours after injury. Treatment started within the first three hours is continued (5.4 mg/ kg/hr) for 24 hours. Treatment initiated between three and eight hours is continued for 48 hours. However, the use of methylprednisolone remains a topic of heated debate and is a controversial issue in many countries. Treatment with high-dose methylprednisolone is associated with a number of complications, including gastric bleeding and wound infection. The NASCIS studies have opened the door for investigation of other pharmacologic agents such as monosialoganglioside sodium (GM1 ganglioside), naloxone, and tirilazad.

medwedi.ru

814

Part Five: The Central and Peripheral Nervous System

REHABILITATION Early and aggressive rehabilitation is an important key to prevention of medical complications after SCI and for the psychological adjustment of the patient. Following intensive inpatient rehabilitation, most individuals with SCI continue their rehab work in an outpatient setting with physical, occupational, and vocational therapist. However, yearly follow-ups with functional assessments by physiatrists or other specialists with knowledge of SCI are recommended. Urinary and sexual dysfunction are areas of great concern for the SCI patients. Urinary tract infections are common and more often result in serious complications of sepsis and chronic renal insufficiency. Some patients will require chronic suppressive antibiotics. Many males with SCI struggle with erectile and ejaculatory dysfunction. Semen quality and motility can be reduced secondary to recurrent urinary tract infections, drugs, prostatic fluid stasis, retrograde ejaculation, and changes in seminal fluid. Treatment for these issues can be medical or surgical and are beyond the scope of this chapter. However, pregnancy rates for individuals with SCI have improved over the past decade and are between 10% and 60%.

ADVANCED THERAPIES There have been a number of advancements in the management of the very severe disabilities encountered by individuals with SCI. These therapies attempt to limit the effect of SCI on everyday life and maximize existing functional ability. Common options include tendon transfer, functional electrical stimulation, and the use of adaptive equipment and environmental control devices. Tendon transfer is an underused treatment for restoration of limited but useful motor function. Muscle groups that serve redundant roles (e.g., elbow flexion is done by both biceps brachii and brachioradialis) may be used for transfer. The muscles need to be sufficiently strong (at least four out of five) and should be trained to take over lost movements. The most frequent tendon transfers are used for elbow/wrist extension and thumb flexion. Transcutaneous or direct electrical stimulation of muscle can be achieved, but is only useful when lower motor neurons and peripheral nerves are still intact. Denervated muscle cannot be used because the currents necessary would be injurious to the muscle. Transcutaneous electrical activation of leg muscles has been used for strength training and cardiovascular conditioning. Bowel and bladder control is perhaps the function that is the most distressing to individuals with SCI, and functional electrical stimulation is an available therapy for this issue.

RESTORATION OF FUNCTION Fortunately, the damaged spinal cord does not require complete restoration in order to improve quality of life. Small anatomical gains are known to produce a disproportionate improvement in function. Fewer than 10% of functional long-tract connections are required to allow locomotion. This level of connectivity often remains in the doughnut-like outer rim of white matter following trauma. However, axons in this outer rim may be nonfunctional as a result of demyelination. Therefore, remyelination of intact connections is one reasonable approach to improvement of function.

Spinal Cord Regeneration With the increase in understanding of the pathologic processes involved in SCI and neurobiology of the developing spinal cord obtained over the past two decades, research efforts have begun to focus on strategies to promote regeneration of the injured spinal cord. Clinically useful drugs and techniques are still many years into the future, and a complete discussion of the topic is beyond the scope of this chapter. However, we will highlight some of the hurdles to be overcome. Effective neuroprotection to limit the degree of secondary injury, preserve intact axonal fibers crossing the injured segment, and the neuronal cell bodies at the level of the cord injury is a prerequisite for spinal cord regeneration therapies. The NASCIS II and NASCIS III were positive clinical trials for the use of methylprednisolone and tirilazad as neuroprotectants, following SCI (55–58). However, more effective drugs and timing of decompressive surgery have yet to be established. The regenerative capacity of the central nervous system poses additional substantial hurdles: (i) injured neurons have a limited intrinsic ability to regenerate, and (ii) the area of the injury into which they must send axons is not permissive to regeneration. Intense research efforts are underway focusing on the development of neurotrophic agents and delivery mechanisms to enhance the regenerative capacity of the injured neurons. Stem cell, Schwann cell, and olfactory-ensheathing cell transplantation are under investigation as potential means of bridging the gliotic barrier at the site of the injury (59). Complicating the matter further, animal studies demonstrate that the regenerative responses to both neurotrophic factors and tissue grafting decline precipitously within a few weeks to months following the initial injury (11,59–61).

SUMMARY The pathophysiology of SCI involves a sequence of primary and secondary mechanisms. Although the primary injury is fated by the mechanism of the trauma, the progression of secondary injury may be amenable to therapy. Secondary mechanisms of injury encompass an array of interwoven biochemical and cellular processes. Our continued understanding of these mechanisms will provide a framework for future medical and surgical treatment paradigms.

REFERENCES 1. Burke DA, Linden RD, Zhang YP, Maiste AC, Shields CB. Incidence rates and populations at risk for spinal cord injury: a regional study. Spinal Cord 2001:274–278. 2. Kraus JF, Franti CE, Riggins RS, Richards D, Borhani NO. Incidence of traumatic spinal cord lesions. J Chronic Dis 1975:471–492. 3. Griffin MR, O’Fallon WM, Opitz JL, Kurland LT. Mortality, survival and prevalence: traumatic spinal cord injury in Olmsted County, Minnesota, 1935–1981. J Chronic Dis 1985:643–653. 4. Botterell EH, Jousse AT, Kraus AS, Thompson MG, WynneJones M, Geisler WO. A model for the future care of acute spinal cord injuries. Can J Neurol Sci 1975:361–380. 5. Burney RE, Maio RF, Maynard F, Karunas R. Incidence, characteristics, and outcome of spinal cord injury at trauma centers in North America. Arch Surg 1993:596–599. 6. DeVivo MJ. Causes and costs of spinal cord injury in the United States. Spinal Cord 1997:809–813.

Chapter 41: Spinal Cord Injury 7. McDonald JW, Sadowsky C. Spinal-cord injury. Lancet 2002: 417–425. 8. Dumont RJ, Okonkwo DO, Verma S, et al. Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 2001:254–264. 9. Marino RJ, Ditunno JF, Donovan WH, Maynard F. Neurologic recovery after traumatic spinal cord injury: data from the model spinal cord injury systems. Arch Phys Med Rehabil 1999:1391–1396. 10. Tator CH, Koyanagi I. Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg 1997:483–492. 11. Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 2001:S2–S12. 12. Sandler AN, Tator CH. Effect of acute spinal cord compression injury on regional spinal cord blood flow in primates. J Neurosurg 1976:660–676. 13. Rivlin AS, Tator CH. Regional spinal cord blood flow in rats after severe cord trauma. J Neurosurg 1978:844–853. 14. Abe Y, Yamamoto T, Sugiyama Y, et al. Apoptotic cells associated with Wallerian degeneration after experimental spinal cord injury: a possible mechanism of oligodendroglial death. J Neurotrauma 1999:945–952. 15. Shuman SL, Bresnahan JC, Beattie MS. Apoptosis of microglia and oligodendrocytes after spinal cord contusion in rats. J Neurosci Res 1997:798–808. 16. Tator CH. Biology of neurological recovery and functional restoration after spinal cord injury. Neurosurgery 1998: 696–707. 17. Tator CH. Epidemiology and general characteristics of the spinal cord-injured patient. In: Tator C, Benzel EC, eds. Contemporary Management of Spinal Cord Injury: From Impact to Rehabilitation. Park Ridge, IL: American Association of Neurological Surgeons, 2000:9–15. 18. Clinical assessment after acute cervical spinal cord injury. Neurosurgery 2002:S21–S29. 19. Silber JS, Vaccaro AR. Summary statement: the role and timing of decompression in acute spinal cord injury: evidence-based guidelines. Spine 2001:S110. 20. Burns AS, Ditunno JF. Establishing prognosis and maximizing functional outcomes after spinal cord injury: a review of current and future directions in rehabilitation management. Spine 2001:S137–S145. 21. Claxton AR, Wong DT, Chung F, Fehlings MG. Predictors of hospital mortality and mechanical ventilation in patients with cervical spinal cord injury. Can J Anaesth 1998:144–149. 22. Tator CH, Duncan EG, Edmonds VE, Lapczak LI, Andrews DF. Changes in epidemiology of acute spinal cord injury from 1947 to 1981. Surg Neurol 1993:207–25. 23. Tator CH. Spine-spinal cord relationships in spinal cord trauma. Clin Neurosurg 1983:479–494. 24. Guest J, Eleraky MA, Apostolides PJ, Dickman CA, Sonntag VK. Traumatic central cord syndrome: results of surgical management. J Neurosurg 2002:25–32. 25. Newey ML, Sen PK, Fraser RD. The long-term outcome after central cord syndrome: a study of the natural history. J Bone Joint Surg Br 2000:851–855. 26. Tow AM, Kong KH. Central cord syndrome: functional outcome after rehabilitation. Spinal Cord 1998:156–160. 27. Chen TY, Lee ST, Lui TN, et al. Efficacy of surgical treatment in traumatic central cord syndrome. Surg Neurol 1997:435–440. 28. Penrod LE, Hegde SK, Ditunno JF Jr. Age effect on prognosis for functional recovery in acute, traumatic central cord syndrome. Arch Phys Med Rehabil 1990:963–968. 29. Roth EJ, Lawler MH, Yarkony GM. Traumatic central cord syndrome: clinical features and functional outcomes. Arch Phys Med Rehabil 1990:18–23. 30. Aebi M, Mohler J, Zach G, Morscher E. Analysis of 75 operated thoracolumbar fractures and fracture dislocations with and without neurological deficit. Arch Orthop Trauma Surg 1986:100–112. 31. Benzel EC, Larson SJ. Operative stabilization of the posttraumatic thoracic and lumbar a comparative analysis of the

32.

33.

34.

35.

36.

37.

38.

39. 40.

41.

42. 43.

44.

45.

46.

47.

48.

49. 50.

51.

52. 53.

815

Harrington distraction rod and the modified Weiss spring. Neurosurgery 1986:378–385. Jacobs RR, Asher MA, Snider RK. Thoracolumbar spinal injuries. A comparative study of recumbent and operative treatment in 100 patients. Spine 1980:463–477. Jiang JM, Jin DD, Chen JT, et al. Decompression and internal fixation in the treatment of thoracolumbar spine and spinal cord injury: report of 166 cases. Di Yi Jun Yi Da Xue Xue Bao 2002:82–83. McEvoy RD, Bradford DS. The management of burst fractures of the thoracic and lumbar spine. Experience in 53 patients. Spine 1985:631–637. Schnee CL, Ansell LV. Selection criteria and outcome of operative approaches for thoracolumbar burst fractures with and without neurological deficit. J Neurosurg 1997:48–55. Wiberg J, Hauge HN. Neurological outcome after surgery for thoracic and lumbar spine injuries. Acta Neurochir (Wien) 1988:106–112. Kennedy JG, Soffe KE, McGrath A, Stephens MM, Walsh MG, McManus F. Predictors of outcome in cauda equina syndrome. Eur Spine J 1999:317–322. Ahn UM, Ahn NU, Buchowski JM, Garrett ES, Sieber AN, Kostuik JP. Cauda equina syndrome secondary to lumbar disc herniation: a meta-analysis of surgical outcomes. Spine 2000:1515–1522. Shapiro S. Medical realities of cauda equina syndrome secondary to lumbar disc herniation. Spine 2000:348–351. Kobayashi N, Asamoto S, Doi H, Sugiyama H. Brown-Sequard syndrome produced by cervical disc herniation: report of two cases and review of the literature. Spine J 2003:530–533. Kohno M, Takahashi H, Yamakawa K, Ide K, Segawa H. Postoperative prognosis of Brown-Sequard-type myelopathy in patients with cervical lesions. Surg Neurol 1999:241–246. Little JW, Halar E. Temporal course of motor recovery after Brown-Sequard spinal cord injuries. Paraplegia 1985:39–46. Lee TT, Alameda GJ, Camilo E, Green BA. Surgical treatment of post-traumatic myelopathy associated with syringomyelia. Spine 2001:S119–S127. Ajani AE, Cooper DJ, Scheinkestel CD, Laidlaw J, Tuxen DV. Optimal assessment of cervical spine trauma in critically ill patients: a prospective evaluation. Anaesth Intensive Care 1998:487–491. Berne JD, Velmahos GC, El Tawil Q, et al. Value of complete cervical helical computed tomographic scanning in identifying cervical spine injury in the unevaluable blunt trauma patient with multiple injuries: a prospective study. J Trauma 1999: 896–902. MacDonald RL, Schwartz ML, Mirich D, Sharkey PW, Nelson WR. Diagnosis of cervical spine injury in motor vehicle crash victims: how many X-rays are enough? J Trauma 1990:392–397. Chesnut RM. Emergency management of spinal cord injury. In: Narayan RK, Wilberger JE, Povlishock JT, eds. Neurotrauma. New York: McGraw-Hill, 1996:1121–1138. DeVivo MJ, Kartus PL, Stover SL, Rutt RD, Fine PR. Cause of death for patients with spinal cord injuries. Arch Intern Med 1989:1761–1766. Ball PA. Critical care of spinal cord injury. Spine 2001: S27–S30. Velmahos GC, Oh Y, McCombs J, Oder D. An evidence-based cost-effectiveness model on methods of prevention of posttraumatic venous thromboembolism. J Trauma 2000:1059–1064. Green D, Rossi EC, Yao JS, Flinn WR, Spies SM. Deep vein thrombosis in spinal cord injury: effect of prophylaxis with calf compression, aspirin, and dipyridamole. Paraplegia 1982: 227–234. Management of acute spinal cord injuries in an intensive care unit or other monitored setting. Neurosurgery 2002:S51–S57. Dimar JR, Glassman SD, Raque GH, Zhang YP, Shields CB. The influence of spinal canal narrowing and timing of decompression on neurologic recovery after spinal cord contusion in a rat model. Spine 1999:1623–1633.

medwedi.ru

816

Part Five: The Central and Peripheral Nervous System

54. Vaccaro AR, Silber JS. Post-traumatic spinal deformity. Spine 2001:S111–S118. 55. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990:1405–1411. 56. Bracken MB, Shepard MJ, Collins WF Jr, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury: 1year follow-up data. Results of the Second National Acute Spinal Cord Injury Study. J Neurosurg 1992:23–31. 57. Bracken MB, Shepard MJ, Holford TR, et al. Administration Of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury. Randomized

58.

59. 60.

61.

Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997:1597–1604. Bracken MB, Shepard MJ, Holford TR, et al. Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury. Randomized Controlled Trial. J Neurosurg 1998:699–706. Kwon BK, Tetzlaff W. Spinal cord regeneration: from gene to transplants. Spine 2001:S13–S22. Decherchi P, Gauthier P. Regrowth of acute and chronic injured spinal pathways within supra-lesional post-traumatic nerve grafts. Neuroscience 2000:197–210. Houle JD, Ye JH. Changes occur in the ability to promote axonal regeneration as the post-injury period increases. Neuroreport 1997:751–755.

42 Injuries to Peripheral Nerves Irvine G. McQuarrie, Thomas C. Chelimsky, and Karen Bitzer

INTRODUCTION The management of nerve injuries poses special difficulties for the surgeon. Although the majority heal satisfactorily without surgical intervention, a year may pass before it is evident that a particular injured nerve will not heal on its own. By then, it is too late to do a nerve repair (‘‘neurorrhaphy’’) and have this followed by a satisfactory motor recovery. To obtain a good result from neurorrhaphy, it must be performed within six months after injury. On the other hand, the result obtained from carrying out a timely neurorrhaphy is not as good as the result from spontaneous recovery. Neurorrhaphy is to be avoided unless clearly indicated; often this decision must be made before a spontaneous recovery is evident from changes in the neurologic examination. This chapter addresses the pathophysiology of nerve injury and the physiologic basis of nerve repair. It also provides a strategy for the timely identification of nerve lesions that require operative intervention. To accomplish these goals, we only consider mechanical trauma to large mixed (motor and sensory) nerves.

If the ‘‘perineurium’’ enclosing the fascicles has been breached, misdirected axonal sprouts grow for short distances in the ‘‘epineurium’’ (connective tissue that separates fascicles) before rounding up into small neuromas. If the perineurium remains intact, sprouts remain within the fascicle, and there is more than a 90% chance of spontaneous recovery after approximately one year (2). However, there is less than a 60% chance of a good result from excising a neuroma-incontinuity and performing a neurorrhaphy (2) because regenerating axons have a reduced chance of entering the correct fascicle in the distal nerve stump (3–5). When a neuroma-in-continuity contains broken fascicles (perineurial rupture in addition to axonotmesis—an injury termed ‘‘neurotmesis’’), most axon sprouts enter the epineurium and are unable to traverse the lesion. In that event, the only possibility for recovery lies in neurorrhaphy. Because the majority of civilian nerve injuries produce a neuroma-in-continuity that is initially associated with a complete loss of nerve function, the decisions of whether and when to operate assume paramount importance (2).

Homeostasis and Microvasculature ANATOMY AND PHYSIOLOGY Fascicular Anatomy Although physicians agree that the safe and effective treatment of injuries is based on a knowledge of the relevant anatomy and physiology, this is especially true for nerve injuries. Here, the most important consideration is the intraneural anatomy. Each mixed nerve contains 4 to 20 bundles (‘‘fascicles’’) of nerve fibers (axons within myelin sheaths) that combine, divide, and rotate within the nerve while moving distally to assemble into motor and cutaneous branches. As shown in Figure 1, an unbranched 3 cm length of a mixed nerve contains 5 to 10 fascicles that interconnect to such an extent that most axons come to lie in a different quadrant and have different neighbors after traveling that distance (1). Because of this anatomic circumstance, it is impossible for the surgeon who performs a neurorrhaphy to perfectly match the fascicles in a proximal nerve stump to those in a distal nerve stump. Even if neurorrhaphy appears necessary, the surgeon may want to carry out an electrophysiologic investigation at the operating table before deciding to resect an incomplete nerve lesion. The incomplete lesion of greatest concern is the ‘‘neuroma-in-continuity,’’ a fusiform enlargement of the nerve, which often occurs within weeks following a nontransecting nerve injury. Although a variable fraction of axons may have been broken (‘‘axonotmesis’’) at the time of injury, the mass effect is less a result of the axonal sprout formation than of a proliferation of Schwann cells, fibroblasts, and collagen, which has been evoked by the force of injury (Fig. 2).

The special environment of the central nervous system (CNS) tissues is maintained by the blood–brain barrier, which is physically enforced by tight junctions between capillary endothelial cells. Thus, protein is excluded from the extracellular fluid of the CNS. Active transport mechanisms within the endothelial cells permit the transfer of

medwedi.ru 817

Figure 1 Intraneural fascicular anatomy of a 3-cm segment from the musculocutaneous nerve of a human cadaver. Source: From Ref. 1.

818

Part Five: The Central and Peripheral Nervous System

Figure 2 Schematic representation of a neuroma-in-continuity. (A) Intraneural fascicular anatomy is depicted in contrast with a dark background representing the proliferation of Schwann cells, fibroblasts, and collagen, which occurs at any site of nerve contusion; five of the fascicles have sustained perineurial rupture, producing a neurotmesis-type lesion (1). (B) Intrafascicular axonal anatomy is depicted at a site of perineurial rupture (distal fascicle stump is at the top of the figure); a number of ‘‘minifascicles’’ have formed in response to a complete axotomizing lesion, and one of these has found its way to the distal fascicle stump.

specific substances into the extracellular fluid of the brain. Similar mechanisms remove metabolic waste products and toxic substances from the extracellular fluid, because the CNS has no lymphatic vessels. In the peripheral nervous system, each fiber (axon with its supporting Schwann cells) is bathed in endoneurial fluid, which has a composition similar to that of cerebrospinal fluid. As in the CNS, there are no lymphatic vessels, capillaries are nonfenestrated, and endothelial cells are joined by tight junctions (6). The perineurial cells that enclose the endoneurial space are also joined by tight junctions. A breakdown of this ‘‘blood–nerve barrier’’ causes a loss of function in the nerve fibers of the affected fascicle. This pathophysiologic event may not be associated with any change in the ultrastructure of the fibers, and function is restored on restitution of the perineurium (7). The intraneural blood supply is from longitudinally directed arterioles and venules, located in both the epineurium and endoneurium, which connect with intrafascicular capillaries (Fig. 3). These lie between nerve fibers, and the mean distance between capillaries is only 0.15 mm (1). Although the largest nerves (median and sciatic) have nutrient vessels that are larger than arterioles, more than 90% of the intraneural vessels are less than 10 mm in diameter. Because of the length of the arterioles and venules, and the collateralization of intraneural vessels, blood flow rates are little affected by mobilization of the nerve or nerve transection. Experimental studies in cats show that the flow returns to the normal range of 40 to 50 mL/100 g/min in both stumps by one hour after transection (1,8). The surgeon can safely mobilize 20 to 30 cm lengths of nerve without being concerned about blood supply (1), a maneuver that makes it possible to bridge a 5 cm gap if the extremity is splinted in a position of functional flexion.

Impulse Conduction Nerve impulses (action potentials) are conducted over the axon surface to the axon terminal through a propagated reversal of charge that maintains the impulse at a constant

Figure 3 Microradiograph of the rat sciatic nerve (right) and the caudofemoralis muscle (left) after infra-arterial injection of 25% micropaque. The two arrowheads mark the course of the anastomotic artery as it arises in the muscle, emerges from the anterior muscle border, and joins the arteria comitans along the posterior surface of the nerve (9). Source: From Ref. 6.

amplitude and velocity. Although the rate of conduction may exceed 100 m/sec (because of myelin insulation, which forces the impulse to jump from one node of Ranvier to the next), it is much slower than electric conduction over a copper wire. Axons are actually poor electric conductors: a 30 V stimulus could not produce a potential of 1 V at the end of an axon 1 m long without the energy-requiring process that mediates the reversal of charge at the axon surface. Following axonotmesis, the nerve action potential (NAP) cannot propagate across the point of injury. However, the axons of the distal nerve stump retain the ability to propagate an impulse for up to four days after injury. Thereafter, the axon surface loses its functional integrity as a result of the segmentation of the axon into myelin-bound ‘‘ovoids’’ or ‘‘digestion chambers,’’ where the axon is phagocytosed— a process termed ‘‘wallerian degeneration’’ (9).

Nerve Cell Body Reaction to Axonotmesis The possibility of axonal regeneration depends on the survival of the neuron. Because 95% to 99% of the cytoplasm in peripherally projecting neurons is located in the axon and a large fraction of the axonal volume is in the terminal arborization (10,11), axonotmesis removes most of the neuronal cytoplasm. This often results in the death of a small percentage of neurons. The main reason neurons survive the loss of such a large amount of cytoplasm is that the protein synthesis machinery of the neuron is spared (12,13). In response to axonotmesis, the nerve cell body undergoes a series of biochemical, physiologic, and anatomic changes that have been termed ‘‘chromatolysis’’ because of the reduction in cytoplasmic basophilia. This tinctorial change is attributable to the diffusion of cytoplasmic RNA (located mainly within polyribosomes), secondary to the disruption of the rough endoplasmic reticulum and an increase in the cell volume (12). Biochemical changes include an early

Chapter 42: Injuries to Peripheral Nerves

and sharp reduction in the synthesis of proteins used for neurotransmitter production. This decrease is roughly balanced by an increase in the synthesis of proteins used for regrowing an axon, which include tubulin, actin, and ‘‘growth-associated proteins’’ (12–15). Physiologic changes include a prompt internalization and degradation of cellsurface receptors, a marked reduction in the amplitude of excitatory postsynaptic potentials (EPSPs), and a reduction in the velocity of impulse conduction in the surviving or ‘‘parent’’ axon (12). Anatomic changes vary with the type of neuron but commonly include a withdrawal of axon terminals from the cell body and dendrites of the injured neuron (accounting for the reduced amplitude of EPSPs), atrophy of dendrites, enlargement of the nucleolus, eccentric positioning of the nucleus, an increase in perikaryal volume, and a thinning of the parent axon (accounting for the reduced rate of impulse propagation) (12). There is abundant evidence that the nerve cell body reaction plays a prominent role in axonal regeneration (12). In addition, the ‘‘environment’’ of the newly formed ‘‘daughter’’ axon is important to the success of regeneration (13,16). Two recent developments support the primacy of neuronal events. First, studies over the past decade have shown that axonal outgrowth can be accelerated by the use of a conditioning lesion. This axonotmesis initiates a ‘‘crop’’ of regenerating axons, which is removed days later by a second (testing) lesion. The second crop forms sooner and advances faster than the first (13,17,18). This acceleration appears to be based on the increased synthesis and axonal transport of tubulin, actin, and certain growthassociated proteins (13). The environment faced by the second crop of axons, an environment of wallerian degeneration, is not the primary cause for accelerated outgrowth (13,17,18). The neuronal control of outgrowth is also evident from its rapid response to changes in the status of the axon tip. The nerve cell body receives information quickly by means of ‘‘retrograde axonal transport’’ and makes appropriate changes in its protein synthesis and axonal transport priorities (14). It is by this process, for example, that the nerve cell body comes to know within a few hours that it has sustained an axotomy (19).

Axonal Transport During Axonal Regeneration The motive force for axonal outgrowth appears to be the axonal transport system, which is responsible for supplying all the protein needs of the axon (11,13,20). Membranous organelles are carried ‘‘by fast transport;’’ structural proteins and the enzymes of intermediary metabolism are carried by the two subcomponents of ‘‘slow transport’’ (10). The proteins that are used for synaptic transmission and renewal of the axolemma are conveyed in tubulovesicular form by fast transport at approximately 400 mm/day. During regeneration, fast transport provides the glycoproteins that form the new axon membrane. In experimental studies, fast transport is labeled with radioactive glycoproteins (which are enriched fivefold in growth cones) to measure axonal outgrowth distances (17). The principal cytoskeletal proteins are tubulin, actin, and the neurofilament triplet. These are conveyed through the axon by slow transport as both monomers and polymers (microtubules, actin microfilaments, and neurofilaments). The 30 to 40 proteins that associate with actin microfilaments move in a group at 2 to 6 mm/day as slow component b (SCb) of slow transport. The protein triplet composing neurofilaments is transported 1 to 2 mm/day as slow component a,

819

in association with most of the microtubules. During axonal outgrowth, there are changes in the relative amounts of several proteins moving with both fast and slow transport, but proteins are neither added nor deleted (11). However, both the average rate and the overall amount of protein transport via SCb increases (11,13,20). This correlates with the evidence indicating that the rate of outgrowth cannot exceed the rate of SCb (11,13,20). The governing role of SCb may relate to (i) the dependence of growth cone function on the polymerization of actin into microfilaments and (ii) the dependence of axonal elongation on the assembly of tubulin into microtubules (11,13). Examination of these two hypotheses in laboratory animals favors the former: radiolabeling of axonal proteins following nerve injury shows that polymerization of both actin and tubulin upregulates, and radiolabeling prior to injury shows that only actin upregulates (21).

Stages of Axonal Regeneration Four stages of axonal regeneration precede the onset of voluntary motor activity: (i) the ‘‘initial delay,’’ consisting of sprout formation and the advance of sprouts to the lesion site; (ii) the ‘‘scar delay,’’ during which the sprouts cross the lesion; (iii) the ‘‘outgrowth period,’’ during which the axons elongate within fascicles of the distal nerve; and (iv) the ‘‘maturation delay,’’ during which the axons that contact an appropriate end organ initiate a series of recovery events. These include the reversal of end-organ atrophy, radial growth of the axon, and myelination. In experimental studies on sciatic nerves of the rat, sprouts begin to form within a few hours of injury and many acquire a cytoskeleton by 27 hours (18). The zone of ‘‘traumatic degeneration’’ (same pathology as wallerian degeneration but located at the proximal nerve stump) must be traversed before sprouts can attempt to reach the distal nerve stump (22). The average initial delay in rats is 36 hours, and the scar delay at a neurorrhaphy is approximately 48 hours (23). In monkeys, the combined initial and scar delay is one to three weeks (24,25). This is much shorter than the five to seven weeks required by chimpanzees, suggesting that the evolutionary step from monkeys to anthropoid apes involves a major change in neuronal growth potential (24). The outgrowth period terminates with the arrival of axons at an end organ. If an incompatible end organ is encountered, as in the case of a sensory axon reaching a motor end plate, the maturation phase is not initiated, and the axon remains small in caliber (26). If the contact is appropriate, the axon undergoes radial growth (through the addition of neurofilaments), which triggers the formation of myelin by Schwann cells (27,28). The axon initiates myelin formation through both a chemical signal to the Schwann cell and the physical influence of its radial growth (23,28). After the nerve fiber has matured and end-organ atrophy has been reversed through the resumption of neurotrophic activity, function is recovered. The mismatches between motor axons and muscle fibers (e.g., when a motor axon that had originally projected to a flexor muscle reinnervates an extensor muscle) are partially compensated by changes in the sensory connections within the CNS (5) and the neurotrophic induction of changes in muscle fiber type (29). The pathophysiology that we have gleaned from these animal studies can be related to nerve injuries in humans. If the times of onset for voluntary movements (in a proximalto-distal series of muscles served by an injured nerve) and

medwedi.ru

820

Part Five: The Central and Peripheral Nervous System

the distances from the lesion to the motor point (where each muscle is innervated) are noted (1), a regression function of distance on time can be plotted. When this is extrapolated to zero distance, the number of days indicated on the x-axis represents the ‘‘latent period’’ (Fig. 4). This is a combination of the initial delay, the scar delay, and the maturation delay. In a classic study that applies this method to a number of patients following neurorrhaphy, the latent period is estimated to be about 13 weeks (30). These patients were compared to others having closed crush injuries (axonotmesis) and therefore a negligible scar delay, where the latent period is about nine weeks. Thus, the average scar delay is four weeks. Because most of the nerve repairs (in this study of World War II injuries) were carried out more than six months after injury, the maturation delay would not have been the optimal four weeks but rather six to eight weeks (25,31). Subtracting that six- to eight-week interval from the nine-week latent period (seen after axonotmesis) leaves an initial delay of one to three weeks. With the four-week scar delay after neurorrhaphy added, there is a five- to

DISTANCE FUNCTIONALLY REGENERATED (cm)

(A)

60 50 40 30 20 10 0 100

200

300

400

TIME FROM DATE OF LESION (DAYS)

seven-week delay before axons begin to elongate within the distal nerve stump, as in chimpanzees (24). Experience with testing the NAP across the lesion site during surgery has validated this estimate (2). Accordingly, an operation that is partly done for the purpose of recording NAPs from axons that have crossed a suspected neuroma-in-continuity must be delayed until 8 to 10 weeks after injury (2).

PATHOLOGY With acute nerve compression of mild degree and short duration, the local pathology is limited to ‘‘paranodal demyelination’’ (a retraction and thinning of myelin at the nodes of Ranvier) (32). Greater compression causes a loss of myelin between nodes of Ranvier (‘‘segmental demyelination’’). These forms of demyelination block the transmission of action potentials without interrupting the axon, producing a ‘‘neurapraxia’’ (Fig. 5A) (22). Greater compression breaks the axon without disrupting the basement membrane of the Schwann cell (endoneurial tube) or the perineurium (33). This is termed ‘‘axonotmesis,’’ meaning ‘‘a break in the axon’’ (Fig. 5B). Finally, cutting objects, shearing forces, and percussive forces produce additional connective tissue disruption and break the perineurium and/or the nerve. This is termed ‘‘neurotmesis,’’ meaning ‘‘a break in the nerve.’’ Myelin is readily displaced and thinned by pressure, especially at paranodes. When this occurs, impulse transmission is interrupted even though the axon remains intact. The susceptibility of axons to pressure increases with the degree of myelination. This is best illustrated in a pure neurapraxia, such as ‘‘Saturday night palsy,’’ where an intoxicated person develops paralysis and loss of sensation in the upper extremity because of sleeping for prolonged periods in a position that either stretches or compresses a nerve (usually the radial) or the brachial plexus. Examination often shows total paralysis associated with an absence

(B)

DISTANCE FUNCTIONALLY REGENERATED (cm)

40

High lesion

30

Low lesion

20

10

0 0

100

200

300

400

500

600

700

TIME FROM DATE OF SUTURE (DAYS)

Figure 4 Functional motor recovery in patients sustaining radial nerve injuries, illustrating the progress seen after an axonotmesis-type injury within a neuroma-in-continuity (A) versus a neurotmesis-type injury repaired by nerve suture (B). Distances from the lesion site to the muscle nerve entry point are plotted on the ordinate, and the time from injury (or nerve suture) to the onset of recovery (voluntary contractions) is plotted on the abscissa. Latent period is estimated by extrapolating the regression function of distance on time to zero distance. (A) Radial nerve axonotmesis: high lesion; the regression function indicates that the motor axon outgrowth rate is approximately 3 mm/day. (B) Radial nerve sutures: low versus high lesion; regression functions indicate that the axon outgrowth rate is approximately 1 mm/day. Source: From Ref. 30.

Figure 5 Sequence of changes in a myelinated fiber sustaining a neurapraxia-type injury (A) versus an axonotmesis-type injury (B) as a result of nerve compression. (A) Neurapraxia-type injuries produce segmental demyelination and remyelination. A, Normal fiber; B, retraction of paranodal myelin with widening of nodal gap; C, destruction of myelin sheath and Schwann cell mitoses; D and E, remyelination through the intercalation of short internodes. (B) Axonotmesis-type injuries produce axonal degeneration and regeneration. A, Normal fiber; B, by one week after axotomy, Schwann cells containing axon and myelin debris have divided to form ‘‘bands of Bu¨ngner’’; C, during the second week, axon sprouts extend from the enlarged terminus of the proximal axon stump; D, one of the newly formed sprouts becomes myelinated; E, end-organ reconnection occurs. Source: From Ref. 22.

Chapter 42: Injuries to Peripheral Nerves

of proprioception and touch sensation in the distribution of one or more nerves. However, a pin sensation can be perceived as a dull ache, and a normal density of sweat droplets can be discerned (by examining the skin with an ophthalmoscope set at þ20 D). Thus, the functions served by myelinated axons have been lost, but those served by unmyelinated axons have been retained. These patients begin to recover within two weeks and are fully recovered by three months. When the force of compression is greater, there is a break in the axon (axonotmesis). Axonal transport is blocked at the point of breakage, and the axon distal to that point undergoes wallerian degeneration. This process occurs simultaneously at all levels, and all axons show degeneration by the fifth day after injury (9). The most straightforward classification of acute nerve injuries is open versus closed, depending on whether there has been a break in the skin. If closed, the lesion is either an ‘‘acute compression injury’’ (closed crush) or a ‘‘traction injury.’’ Acute compression injuries are usually secondary to fractures, with the radial nerve being involved most often (34). The pathology is paranodal demyelination secondary to increased endoneurial fluid pressure (35). A traction component occurs if the nerve is stretched over a bone fragment. Pure traction injuries because of motorcycle accidents are commonly seen in emergency rooms. In these accidents, the nerve injury occurs because the rider tries to maintain a grip on the handlebars in an attempt to stay with the motorcycle. The upper brachial plexus is involved if the motorcycle stops suddenly, throwing the rider over the handlebars; the lower plexus is involved if the rider is thrown off and dragged while the motorcycle keeps moving. Of the open injuries, there are two types—those caused by bullet wounds and those caused by cutting objects such as glass. A bullet that misses a nerve may still block function. This is because a ‘‘percussion injury’’ is caused as the bullet passes near the nerve and a pressure wave creates a temporary cavity in the tissues. The pathology is usually a combination of segmental demyelination and wallerian degeneration, producing a combination of neurapraxia and axonotmesis (32,36). The extent of nerve damage depends on the proximity of the bullet to the nerve and the amount of kinetic energy that is transferred to the nerve. With a high-velocity bullet (moving at more than 2500 ft/sec), nerve fascicles can be ruptured even though the bullet misses the nerve. This is because the kinetic energy of the bullet is proportional to its weight and the ‘‘square’’ of its velocity. A small bullet moving at several thousand feet per second is going to cause more damage than a large bullet moving at several hundred feet per second. A military assault rifle (e.g., the M-16 used by the U.S. Forces) produces the former condition, whereas a pistol produces the latter condition. A high-velocity bullet causes a prolonged initial delay because the zone of traumatic degeneration is longer than it would be with a simple laceration (the length of this zone being proportional to the kinetic energy of the bullet) (1). For a low-velocity bullet wound, it is appropriate to wait for 8 to 10 weeks before exploring the nerve to test whether a NAP can be transmitted across the lesion, but a wait of 12 to 16 weeks is necessary for a high-velocity bullet wound (1).

ASSESSMENT OF THE DEFICIT Assessment should (i) name the injured nerve, (ii) locate the injury along its course, (iii) differentiate neurapraxia from a

821

complete lesion (axonotmesis or neurotmesis), and (iv) list both negative changes (motor and sensory losses) and positive changes (paresthesias, dysesthesias, pain, and altered autonomic activity). A careful neurologic examination is the most important part of the assessment. In addition, certain neurophysiologic tests are useful. These include nerve conduction studies (NCSs) that are done together with electromyography (EMG). In addition, autonomic testing may be appropriate when pain is present.

Neurologic Examination It is important to assess sensory disturbances, focusing on any loss of sensation that may have occurred in the autonomous cutaneous zone of the injured nerve. Experience has shown that these zones are only innervated by a particular mixed nerve. Neither congenital anomaly nor collateral sprouting from adjacent nerves can provide innervation of these zones; so anesthesia denotes a complete nerve lesion (1). With incomplete nerve lesions, sensation is retained in the autonomous zones, and abnormal spontaneous sensations (paresthesias) or abnormal responses to stimuli (dysesthesias) commonly occur. Dysesthesias can include decreased or increased sensitivity of a normal type (hypoesthesia and hyperesthesia). All sensory changes, including anesthesia, can have a painful component. When a non-noxious stimulus produces pain, the term ‘‘allodynia’’ is used. The pathophysiology of pain after nerve injury has been studied in great detail, and an excellent review has been published by Wall (37). The most important pain syndrome is ‘‘causalgia,’’ which is a severe burning pain that follows nerve injury and may extend beyond the distribution of the injured nerve; both allodynia and abnormalities of autonomic function are typical findings (38,39). It occurs after approximately 2% of incomplete transections (40) but is rarely seen when complete transections are promptly repaired. Causalgia is diagnosed when there is constant burning pain within the distribution of an injured nerve and examination shows allodynia in association with autonomic changes. These changes may include skin that is smooth and glossy, an increase or decrease in the rate of hair growth, tapered digits, thickened nails, periarticular fibrosis, and osteoporosis (41). The pathophysiology of causalgia has been thought to involve an excess of activity in sympathetic motor axons and the transmission of this activity to somatic sensory axons by means of synapse-like connections in the proximal stump neuroma (42,43). Accordingly, there have been many attempts to treat causalgia pharmacologically (by systemic or local administration of agents that block sympathetic activity) and surgically (by sympathectomy) (44). More recently, however, this teaching has come under criticism (39). Following nerve injury, autonomic function is lost in the areas of cutaneous anesthesia. Sweat secretion is undetectable when the skin is examined with the þ20 D lens of an ophthalmoscope. The ninhydrin sweat test can also be used to document both the absence of sweat formation and any recovery caused by collateral sprouting or axonal regeneration. The ‘‘erectores pillae’’ muscles at the base of each hair follicle do not erect the hair in response to cooling, and the skin is warm because of the absence of innervation to arterial smooth muscle. Later, as the b-adrenergic receptors on these muscle cells proliferate in response to the absence of normal innervation, the cells become supersensitive to congeners of the missing neurotransmitter. This may be manifested by the extremity becoming cool in response to

medwedi.ru

822

Part Five: The Central and Peripheral Nervous System

the epinephrine released from the adrenal medulla during environmental or emotional stress. Assessment of the response of muscles to voluntary effort is achieved through manual testing techniques that are specific to the nerve injury in question. For these to be diagnostic, the examiner must be aware of trick movements or substitution patterns. The distribution and extent of muscle atrophy is recorded as mild to severe and is quantified by measuring the circumference of extremities at fixed distances from the bony landmarks. Deformities of posture must be described and interpreted. For example, a ‘‘claw hand’’ deformity denotes an ulnar nerve lesion. The extent of muscle contractures in the hand is determined by applying standard tests for intrinsic and extrinsic tightness (45). Joint contractures are measured with a goniometer and judged to be either reducible or fixed (46). For motor disturbances, the principal problem is muscle atrophy. Both disuse and the lack of neurotrophic influences contribute to this problem. If the muscle is not reinnervated within two to three years, all the muscle cells are replaced by connective tissue. If the muscle is not maintained in dynamic activity (by passive range-of-motion exercises) while it is denervated, much of the rehabilitative potential is lost because of muscle fiber atrophy occurring in concert with endomysial fibrosis. Immobilization and paralysis also cause venous and lymphatic stasis, which further reduce blood flow and cause edema. Finally, joint contractures often occur because of decreased muscular support, edema, fibrosis, and the unopposed action of normally innervated muscles. Although it is clear that passive range-of-motion exercises are worthwhile, the presence of pain may be a limitation. In that event, the regular use of regional anesthesia may be necessary to allow an exercise program to occur.

Examination of Specific Nerves For the ‘‘median nerve,’’ the autonomous zone of skin innervation includes the digital pads of the thumb and index finger, and the dorsum of the terminal phalanx of the index finger. An absence of pin sensation and sweat formation in these areas indicates a complete nerve lesion. The equivalent loss in terms of motor function is an absence of voluntary contraction of the abductor pollicis brevis muscle; without this muscle, it is impossible to elevate the thumb from the palm and rotate it into a position of grasp. If the median nerve injury is near the elbow, other movements are impossible after a complete lesion. These include pronation of the forearm and flexion of the thumb and index finger joints, which results in the ‘‘benediction sign’’ when the patient is asked to make a fist. For the ‘‘radial nerve,’’ there is no autonomous sensory zone. In most individuals, however, a total nerve lesion causes loss of sensation over the radiodorsal forearm and the dorsum of the thumb. On motor examination, the fingers cannot be extended at the metacarpophalangeal joints, the thumb cannot be extended at any joint, and the hand cannot be extended at the wrist. For the ‘‘ulnar nerve,’’ the autonomous zone is over the terminal phalanx of the fifth finger. None of the fingers can be adducted or abducted, and the metacarpophalangeal joints cannot be flexed without first flexing the interphalangeal joints. A claw hand deformity is common. This involves hyperextension of the metacarpophalangeal joints and flexion of the interphalangeal joints. In the lower extremity, the ‘‘common peroneal nerve’’ does not have an autonomous zone of skin sensation.

However, a complete lesion commonly causes a loss of sensation over part of the mid-dorsum of the foot and the web space between the great and second toes. On motor examination, there is an inability to evert the foot, dorsiflex the ankle, or extend the toes. For the ‘‘tibial nerve,’’ the autonomous zone is the entire sole of the foot. The motor deficit is a loss of plantar flexion at the ankle and metatarsophalangeal joints. Complete lesions of the ‘‘sciatic nerve’’ produce combinations of the patterns of loss for the tibial and common peroneal nerves. Nerve blocks may be needed to be certain of which nerves have been injured and whether those injuries are complete or incomplete in terms of the loss in function. After a thorough neurologic examination, it may appear that an incomplete nerve injury has occurred because there are strong voluntary contractions of one or two muscles served by the injured nerve while all others are unresponsive. In that event, it is important to block conduction in the uninjured nerves that could be providing anomalous innervation to the myotome traditionally served by the injured nerve. For example, function can be retained in median-innervated muscles of the hand (abductor pollicis brevis and opponens pollicis) in 15% of patients following a complete transection of the median nerve at the wrist because of the Martin– Gruber anastomosis between the median and ulnar nerves in the forearm (1). A ‘‘procaine block’’ of the ulnar nerve at the wrist would demonstrate this.

Neurophysiologic Tests Electrophysiologic tests (NCS and EMG) are of great value after nerve injuries. There are two types of NCS, motor and sensory. For motor, the stimulus is a supramaximal electric discharge delivered by a surface (skin) electrode to an underlying nerve (e.g., the median nerve at the wrist). The motor response is the electric potential recorded over a muscle subserved by the nerve (e.g., the abductor pollicis brevis). This consists of the summed motor unit action potentials (MUAPs), each of which represents the response of muscle fibers innervated by a single motor axon. These responses act to amplify the NAP. In contrast, detection of the sensory response requires recording a NAP directly (e.g., from the median nerve at the wrist after stimulating the digital nerves of the index finger). Accordingly, MUAPs have a large amplitude, in the range of 3 to 15 mV, whereas sensory NAPs have a small amplitude, in the range of 5 to 50 mV. NCS yields two values: an amplitude of response (in microvolts or millivolts) and a latency of response (in milliseconds). The conduction velocity, normally 40 to 60 m/sec, is calculated by dividing the latency into the length of the nerve segment over which the study is performed. Nerve conduction is readily examined following nerve injuries, usually by stimulating distally with digital cuff electrodes and recording sensory NAPs proximally with needle or skin electrodes. By five days after axonotmesis, motor axons distal to the lesion are unable to conduct NAPs because of wallerian degeneration (9). Thus, motor NCS can be used to differentiate neurapraxia from axonotmesis within a week after injury. In general, the findings on NCS depend on the type of injury (whether a neurapraxia or complete lesion), the interval since injury, the severity of negative neurologic changes (motor and sensory loss), and the severity of positive neurologic changes (paresthesia, pain, and autonomic changes). The most useful information is obtained if electrophysiologic tests are carried out both immediately and at three weeks after the nerve injury. The first study, if done within

Chapter 42: Injuries to Peripheral Nerves

two to three days, localizes the lesion by NCS because conduction is absent across the site of injury but intact above and below. (A slowing of conduction velocity is characteristic of a demyelinating lesion, but a total loss of myelin results in a ‘‘conduction block,’’ which is indistinguishable from a complete lesion.) The second study determines whether there is a complete lesion, in which case conduction is lost below the lesion and fibrillations are present in denervated muscles. In axonal injury, the degeneration of nerve fibers becomes complete in five days for motor responses and in seven days for sensory responses. (The difference is due to the sensitivity of the neuromuscular junction to blocked axonal transport.) With the demyelinating lesion of neurapraxia, the distal response is never affected. By one week after injury, nerve conduction changes reach their nadir and the character of the lesion can be fully discerned. With a pure neurapraxia, only the myelin must be reconstituted, and this usually occurs in three to six weeks. With a pure axonal lesion, the axon must grow back to an end organ similar to the original. This occurs at approximately 1 mm/day, as previously described, and depends on daughter axons entering a vacated endoneurial tube distal to the lesion, which then directs the outgrowing axon to an appropriate end organ. With neurorrhaphy, the choice of endoneurial tube is essentially random. Recovery usually takes many months. Motor recovery sometimes begins in weeks because of collateral sprouting, which provides motor axons from nearby uninjured nerves to reinnervate muscles denervated by the injury. EMG examines the pattern of individual MUAPs seen after inserting a bipolar (concentric) needle electrode into a muscle. Complete lesions produce two types of abnormalities (Fig. 6). First, spontaneous discharges are the most important, including positive deflections that occur

Figure 6 (A) Fibrillation potentials recorded at slow and fast sweep speeds. (B) EMG responses during weak voluntary contractions: normal EMG contrasted with neuropathic EMG seen following axonal regeneration. Abbreviation: EMG, electromyogram. Source: From Refs 47,48.

823

with needle insertion and, later, fibrillation potentials. Both are regular discharges, which represent denervation supersensitivity of the muscle cell. Second, with the onset of motor recovery, there is an alteration in the shape and amplitude of voluntary MUAPs. EMG is of particular value whenever there is a total loss of nerve function as a result of injuries that are unlikely to have divided the nerve. These include nerve compression resulting from a compartment syndrome, nerve traction resulting from a fracture, and nerve percussion resulting from a bullet. The most useful information is obtained when the test is carried out as early as possible after injury and again at three weeks. By this time, wallerian degeneration has eliminated any neurotrophic influence of axonal transport on the denervated muscle, and sufficient time has passed for muscle fibers to become supersensitive to the missing neurotransmitter by producing extrajunctional acetylcholine receptors. Fibrillations depend on these. The EMG method of electrophysiologic testing uses a concentric needle electrode to record from muscles in the distribution of the lesioned nerve. After the needle is placed in a muscle, the patient is asked to attempt a movement using that muscle. If no MUAPs are recorded, the nerve is stimulated by inserting a needle electrode near the nerve between the muscle and the lesion site. When the lesion is a neurapraxia, nerve stimulation elicits MUAPs without difficulty—even though none can be elicited by voluntary effort and the muscle is electrically silent when the nerve is not being stimulated. By one week after axonotmesis or neurotmesis, MUAPs cannot be elicited by stimulation of the distal nerve; by three weeks, the muscle exhibits fibrillations at rest and stimulation does not alter that activity. Fibrillation potentials (Fig. 6A) are never seen in normally innervated muscles and differ from MUAPs by having a regular firing pattern. Fibrillations occur at a frequency of 5 to 15 per second, arise from single muscle fibers, and are thought to be the result of supersensitivity of the muscle fiber membrane to acetylcholine-like molecules that enter extracellular fluid from the blood stream. The EMG is very helpful for detecting axonal reconnection at motor end plates: fibrillations disappear and are replaced by nascent MUAPs that mature into large polyphasic potentials (Fig. 6B). The use of NCS and EMG for differential diagnosis is summarized in Table 1. Imaging techniques have advanced to the point of detecting that a muscle has been denervated. A magnetic resonance imaging technique termed ‘‘short time to inversion recovery’’ reveals a specific increase in signal intensity (49). Further study in a rat model has shown that gadolinium enhancement augments the sensitivity enough to detect denervation 24 to 48 hours after nerve transection (50). Autonomic testing is important when causalgia is suspected. The general principle of testing is to compare the unaffected and affected extremities for measures of autonomic function. Different laboratories may employ different methods. When resting sweat output and axon reflex sweat output are tested, and both results are abnormal, there is a 98% chance of ‘‘reflex sympathetic dystrophy’’ (RSD), a syndrome that differs from causalgia by not requiring a prior nerve injury. RSD and causalgia may or may not be associated with ‘‘sympathetically maintained pain’’ (39). The finding of warmer skin over the affected limb when compared to its normal counterpart suggests a positive response to sympathetic block. If bilateral axon reflex abnormalities are present, the prognosis for response to a sympathetic block is poor. In our laboratory, at this time, we use the combination of six tests of autonomic function: resting and

medwedi.ru

824

Part Five: The Central and Peripheral Nervous System

Table 1 Uses of NCSs and EMG for Differential Diagnosis Axonal injury (axonotmesis) Time 0 days 5 days 7 days 10 days 21 days 6 wks

3 mos 6 mos

1 yr

NCS Amplitudes drop proximal to point of injury Distal motor amplitude reaches nadir Distal sensory amplitude reaches nadir No change No change Slight motor amplitude improvement by collateral sprouting Sensory amplitude may improve Maximal motor improvement; continued sensory amplitude improvement EMG: collateral sprouts are replaced by regenerating axons (‘‘remodeling’’); MUAP amplitudes may drop, and recruitment may be normalized

Demyelinating injury (neurapraxia) EMG

NCS

EMG

Reduced recruitment; no fibrillations; normal MUAPs No change

Amplitudes drop proximal to point Reduced recruitment; no of injury; slowing may be present fibrillations; normal MUAPs No change No change

No change

No change

No change

Insertional activity appears Insertional activity appears

No change Amplitude and slowing begin to improve Further improvement

No change Recruitment may improve

Maximal recovery

Maximal recovery

No change

No change

No change

No change

Polyphasic MUAPs (nascent units); fibrillations decrease Increased ‘‘duration’’ of MUAPs, less polyphasic Increased ‘‘amplitude’’ of MUAPs No change

Further improvement

Abbreviations: NCS, nerve conduction study; EMG, electromyography; MUAP, motor unit action potentials.

axon reflex sweat output (by direct sudorometry), blood flow in both skin (by laser Doppler) and muscle (by plethysmography), limb volume (by water-volume displacement), and skin temperature (by infrared probe). All but sweat output are done both before and after a quantitated exercise load to the extremity. Thus, autonomic testing after nerve injury can determine whether sympathetically maintained pain is present and whether the pain is likely to respond to sympathetic block.

TREATMENT APPROACH Principles of Nonsurgical Treatment Initially, the potential for rehabilitation is evaluated. This must include a careful assessment of the cause for dysfunction. Otherwise, patients may be treated with a pain management program, for example, when partial paralysis is the main obstacle to progress but goes undetected. Dysfunction may arise from any one or combination of the following, and each should be considered by history, examination, and appropriate neurophysiologic tests: (i) loss of nerve function to produce hypoesthesia and weakness; (ii) excess nerve function to produce pain and hypersensitivity to touch, pressure, temperature change, or movement; (iii) tissue changes, such as edema, loss of hair, loss of skin turgor, or loss of joint mobility; (iv) CNS abnormalities, as may occur with sympathetically maintained pain, which create a ‘‘pain cycle’’ and sometimes adventitial movements (spasms and dystonias); (v) psychologic factors, including adjustment abnormalities, anxiety disorders, and even major depression; and (vi) issues of secondary gain, such as litigation, manipulation of family members, or lack of desire to be in the workforce. A psychologist is needed to help in the assessment of the last two factors. The presence of sympathetically maintained pain requires a multidisciplinary rehabilitation approach. The team includes a neurologist who adjusts oral medications

and coordinates treatment, a surgeon who decides on the appropriateness and timing of operative intervention, an anesthesiologist who carries out nerve blocks, a psychologist who evaluates the patient’s motivation and provides treatment with biofeedback and other modalities, and, most importantly, experienced physical and occupational therapists who provide exercise programs and physical treatments designed to improve function. The patient should be told from the outset that the goal is to increase function rather than reduce pain. Medications are selected according to the requirements for treating the patient’s greatest source of limitation. Tricyclic antidepressants have great utility in addressing several frequent problems: loss of sleep, depressed mood, and deep or burning pain. Anticonvulsants and mexiletene are effective with lancinating pain. Baclofen, metho-carbomol, and clonazepam are useful in reducing spontaneous movements and postures, including spasms and dystonias. Capsaicin ointment is helpful for the treatment of superficial burning pain. Nonsteroidal anti-inflammatory drugs help control deep aching pain. The use of narcotics is controversial. These may be safe and beneficial when used in a patient with whom the physician has a solid and long-term relationship, provided that a clear-cut contract is arrived at, giving both an exact duration of the trial and the end point. The selection of a nerve block method depends primarily on what is effective. Bier blocks provide regional anesthesia to the involved limb and are least invasive. Sympathetic blocks are traditionally used in the diagnosis and treatment of sympathetically maintained pain. Longer lasting analgesia may be obtained from epidural, plexus, and axillary blocks. Psychologic techniques include biofeedback, relaxation training, behavior modification, and psychologic investigation of the basic conflicts that may be exacerbating the pain (e.g., reliving an emotionally traumatic event that caused the injury in the first place). Other techniques that may also be useful, but remain unproved, include

Chapter 42: Injuries to Peripheral Nerves

Principles of Surgical Treatment The main goals are to preserve fascicular anatomy (1) and ensure that the end organs become reinnervated within eight months after injury (1,31). To achieve these goals, axonotmesis must be differentiated from neurotmesis with certainty by three months after injury. This is not difficult if there is a skin laceration directly over the course of a nerve that has lost all function below the level of the laceration. The wound should be explored immediately; if the nerve has been transected, it should be repaired. Any delay results in scar formation that necessitates trimming 1 to 2 cm off each nerve stump when the delayed neurorrhaphy is performed. However, if the soft tissues show evidence of contusion (petechial hemorrhages and discoloration) or if a bacterial infection is likely because the wound was not closed within 12 to 24 hours of injury, delayed neurorrhaphy (two to three weeks) is preferable. When there is a highvelocity bullet wound and the initial debridement does not reveal a nerve lesion, any loss of nerve function must be attributed to the percussive force of the bullet. During the Vietnam War, 69% of the casualties recovered spontaneously after three to nine months (51). Nerve injuries caused by acute compression, traction, or the percussive force of a low-velocity bullet often recover spontaneously (34). An element of neurapraxia is usually present, so that NCS is often effective in identifying the patients with a favorable prognosis. When NCS shows no conduction below the level of injury after two to three months and EMG shows only denervation, the nerve should be explored for intraoperative NAP testing (12,25,52). Most patients who are going to recover spontaneously have EMG evidence of recovery in the most proximal denervated muscles within three months. This includes the disappearance of fibrillation potentials and the appearance of nascent MUAPs. These changes occur one to two months before voluntary contractions can be elicited (2,25). Hoffmann’s sign of sensory axon regeneration may mislead the surgeon into delaying the exploration for NAP testing. This crude test was described by military surgeons during World War I. It is elicited by light percussion of the distal nerve stump, beginning distally and proceeding proximally. When the leading sensory axons are percussed, the patient feels a tingling sensation in the normal cutaneous distribution of the injured nerve. There are two possible causes of false-positive findings. One is that percussion of the nerve within 10 cm of the lesion may produce traction on the lesion. This stimulates regenerating sensory axons that are arrested within a neuroma-in-continuity. The other problem is that the sign is positive even if only a few axons have bridged a neurotmesis to enter the distal nerve stump (53). The sign must be easily elicited at progressively more distal points along the nerve before it can be interpreted as presumptive evidence of sensory axon regeneration, and the rate of progression must be appropriate—at least 1.5 mm/day at points proximal to the wrist or ankle (1,54). Following

50 Sensory axon outgrowth

40 DISTANCE FROM SUTURE (cm)

self-hypnosis and acupuncture. The occupational and physical therapists’ roles are most crucial, and the approach depends on the exact type of limitation. All patients require a combination of limb loading and unloading, usually accomplished by the combination of stress loading and water aerobics. For allodynia, desensitization is used with gradually less abrasive materials. Limitations in range-of-motion can be addressed by a continuous passive range-of-motion machine, used during the night, and set at an ever-increasing range.

825

30

20

10 Nerve suture 0

180 240 0 60 120 TIME FROM DATE OF NERVE INJURY (DAYS)

Figure 7 Progress of Hoffmann’s sign of sensory axon outgrowth in a patient sustaining a neurotmesis injury of the ulnar nerve at the elbow. By extrapolating the regression function to zero distance, the latent period can be estimated to be seven to eight weeks after nerve suture. With this test of nerve function, there is no maturation delay; the axon terminal is continuously and exquisitely sensitive to mechanical stimuli (31,55–57). Thus, the latent period simply represents the sum of the initial delay and the scar delay. Source: From Ref. 54.

neurorrhaphy, the sign should be elicited at 10 cm below the repair within 9 to 12 weeks, assuming an initial delay of two weeks and a scar delay of four weeks (Fig. 7) (1).

Treatment of Neuroma-in-Continuity From the point of view of pathology, a neuroma-incontinuity (fusiform enlargement of the nerve) involves a proliferation of connective tissue elements that may, if a fascicle has been ruptured, include thin axons that lack linear organization. Ruptured fascicles must be identified and repaired within three months if the patient is to have a reasonable chance of satisfactory motor recovery (2,31,52). Ruptured fascicles are identified by intraoperative NAP testing (52), done after a period of time that allows the neuroma to be crossed by any axon within the unruptured fascicles. An appropriate interval is two months after injuries caused by acute compression or low-velocity missiles and three months after injuries caused by traction or highvelocity missiles. It is not reasonable to carry out nerve exploration earlier than two months after injury unless there is reason to think that the diagnosis is neurotmesis. Even if all fascicles are intact, one cannot expect to demonstrate NAPs across the lesion site if testing is carried out before seven to eight weeks (2). For high-velocity missile wounds and most traction injuries, there should be a 12-week wait because of the greater extent of traumatic degeneration in the proximal stump. However, delaying definitive diagnosis and treatment any longer only serves to increase the likelihood of a poor result should neurorrhaphy prove necessary.

medwedi.ru

826

Part Five: The Central and Peripheral Nervous System

This is because axonal regeneration proceeds slowly, at an overall rate of 1 mm/day, and distances of over 250 mm often must be overcome before end-organ atrophy can be reversed by the arrival of regenerating axons. After one year, the effects of atrophy and endomysial fibrosis on striated muscle fibers reach a stage that is not compatible with good motor recovery (1,31). When nerve lesions that are caused by a bullet or fracture are explored, a great amount of scarring is encountered in the region. In these cases, the nerve is initially identified in the normal tissues above or below the site of injury. These operations can be facilitated by consulting a useful guide that has been written by Henry (58).

Treatment of Nerve Gap When a nerve gap is discovered at surgery and the nerve stumps have been trimmed back to the point at which endoneurial tissue bulges beyond the cut edge, and microscopic examination shows no endoneurial fibrosis, the gap between stumps can be measured. When the extremity is flexed to a position of function, and the residual gap is more than 3 to 5 cm, it is unreasonable to expect that a tension-free neurorrhaphy can be achieved with extensive mobilization of the nerve. In this situation, it is preferable to reconnect the fascicles with several free autogenous nerve grafts of small caliber taken from a long cutaneous nerve serving a small skin area (59,60). The sural nerve is most commonly used for this purpose. To restore fascicular anatomy most effectively, it is important to make a map of the location and size of fascicles in the proximal and distal stumps (and the position of blood vessels on the surface of the nerve) as a guide for reconnecting appropriate quadrants of the nerve and matching major fascicles (60).

REHABILITATION AFTER NEURORRHAPHY Principles of Rehabilitation Current rehabilitation programs are effective in addressing most of the sensory, autonomic, and motor disturbances that result from denervation (55). Although we recognize that most nerve lesions consist of a neuroma-in-continuity and that many of these have a neurapraxic element that does not involve denervation, we focus here on the rehabilitation of patients after neurorrhaphy. Three phases of rehabilitation can be recognized: the denervation phase that precedes end-organ reconnection, the recovery phase during which end-organ atrophy is reversed, and the adaptation phase during which the CNS makes adjustments to altered connectivity. In each of these phases, rehabilitation methods are aimed at preventing unnecessary disability. This is accomplished by using the existing motor and sensory capability and by preserving denervated structures in a state that is optimal for reinnervation. Throughout the rehabilitation program, the outlook of the injured person is an important element in recovery. Beginning with that first moment of despair, patients see their skills destroyed, their careers ruined, and their family life jeopardized. Self-esteem and identity invariably suffer. During the slow and tedious recovery process, the personality of the patient is truly tested. Some patients devote considerable time and effort to assist in the recovery process, whereas others remain indifferent and apathetic. To some, the injured part remains useless despite reinnervation; to others, a permanently disabled part is seen as serving in a useful capacity. Still other patients exploit their injury for monetary and secondary gains.

The rehabilitation program must respect the importance of human interactions between the patient and the health professional (especially the occupational therapist). These play a vital role in rebuilding the patient’s feelings of confidence and trust, feelings that are indispensable to the success of the rehabilitation program. However, even the most devoted professional attention can be rendered ineffectual if the patient does not receive the interest and support of friends and family. At every stage, both the patient and these key people must be advised together about the problems and expectations of the rehabilitation effort. In the end, however, the success of the rehabilitation outcome largely depends on the trust, courage, and determination of the patient (45). Retraining in the activities of daily living is promoted throughout the rehabilitation program, regardless of the extent of motor and sensory recovery or the degree to which the patient has made a psychologic adjustment to the injury. Emphasis is placed on the patient’s existing strengths, with the use of adaptive techniques and devices that encourage the patient to achieve the highest level of performance possible. The activities that are important for self-care, homemaking, recreation, school, and work are broken down into their key components, and a graded program is created to facilitate maximal independent function at each stage of recovery.

Denervation Phase The denervation phase begins at the onset of injury and continues until there is evidence of reconnection. Emphasis is placed on keeping denervated tissues in optimal condition pending reinnervation. Absence of sensation, decreased sweating and circulation, and the presence of edema are impairments that must be addressed swiftly and aggressively to minimize their negative effects. The first part of the sensory reeducation process, protective sensory reeducation, starts when wound closure has been achieved and dressings are no longer necessary. Patients must be educated to appreciate the degree and extent of their sensory deficit, learn to compensate for it, and adopt appropriate safety precautions. They must learn to rely more heavily on their vision while performing activities, and avoid applying excessive pressure to denervated skin by looking for signs of trauma—redness, edema, and warmth (45). Skin that is dry and smooth because of the absence of sweat formation should be treated to prevent cracking. Daily warm water soaks followed by the application of oils help to retain moisture and improve circulation. Blood flow through denervated muscles can also be improved by actively contracting nonparalyzed muscles, thereby exerting a pull on paralyzed muscles through the interconnecting fascial sheaths. Retrograde massage, avoidance of extremes of temperature, and passive range-of-motion exercises are also helpful in this regard. Scar massage and gentle soft-tissue mobilization techniques are used to minimize scar hypertrophy and to prevent adherence of the skin to underlying tissues. Ultimately, this serves to minimize loss of motion as a result of restricted soft-tissue mobility and assists in managing hyperesthesias, which may develop as sensation returns. Passive range-ofmotion exercises and active use of uninvolved muscles are essential for improving circulation and maintaining musculotendinous excursion, preventing stiffness and adhesion formation, and decreasing edema (45). This program can minimize the trophic changes that otherwise occur in denervated skin by improving blood flow and reducing the frequency and severity of minor trauma.

Chapter 42: Injuries to Peripheral Nerves

Denervated muscles must be maintained with dynamic activity to slow the process of myofibrillar atrophy and endomysial fibrosis. Immobilization (beyond that which is needed to prevent tension on the neurorrhaphy) must be avoided because it promotes tissue edema, reduces blood flow, and encourages the development of muscle contractures. Nonetheless, splinting may be indicated for several purposes: (i) to prevent the overstretching of paralyzed muscles, (ii) to support joints, (iii) to balance the forces on joints and tendons, and (iv) to facilitate the active contraction of uninvolved muscles in a manner that substitutes for paralyzed muscles. The type and design of these splints must be individualized to the patient’s needs, and relief from the splint must be provided several times daily to combat the adverse effects of immobilization once the repair has undergone adequate healing. The application of heat in the form of warm water or oil increases circulation without harming sensitive, denervated tissues. Joint stiffness and ankylosis can occur as a result of decreased muscular support, edema, contractures, and the unopposed action of normally innervated muscles. Joint mobility and the ranges of tendon excursion can be preserved by daily passive exercises. Edema, which is caused largely by the inactivity of muscle masses, is combated by elevation, active contraction of uninvolved muscles, massage, use of Jobst intermittent pressure pump, and the application of compression wraps. The use of electric stimulation to prevent denervation atrophy of affected muscles remains controversial because there are no controlled studies in human subjects (55). Although muscle stimulation cannot prevent denervation atrophy, there is considerable experimental evidence suggesting that its use reduces the rate and degree of atrophy and that the electric properties of the stimulated muscle more closely resemble those of the normal muscle (56). However, there is no benefit in terms of final twitch tension or tetanic tension after reinnervation. To reduce the degree of atrophy, treatment must begin soon after injury. The stimulus strength must be sufficient to cause long contractions without pain or discomfort; 15 to 20 contractions per session, with low-frequency stimulation in the range of 10 to 12 Hz, are applied three to four times a day. Treatment is abandoned in favor of active contraction after reinnervation has been documented (1).

Recovery Phase The recovery phase begins with axonal reconnection at an appropriate end organ. During this phase, the therapist plays an important role, monitoring the progress of nerve regeneration through the use of manual muscle testing, sensibility testing, and clinical observation. At each visit, the therapist carefully observes the posture of the involved limb, looking for subtle changes that may indicate the early return of motor function (61). In addition, specific tests of innervation density and sensory threshold are performed. These test the responses to pinprick, temperature, vibration, moving touch/pressure, and static touch/pressure. The Semmes– Weinstein Monofilament Test (North Coast Medical), a standardized threshold test, provides the therapist with an accurate measure of sensibility to graded point pressures throughout the reinnervation period: from unresponsiveness to the return of deep pressure sensation, to the return of protective sensation, to the return of light touch sensation, and to the return of normal sensation (62). Test results are recorded in a color-coded diagram of the limb, providing a

827

clear, simple visual representation of the reinnervation process, which can be forwarded to the surgeon. Early signs of sensory recovery include feelings that ‘‘something is happening,’’ tenderness to pressure exerted on muscles, and an advancing Hoffmann’s sign (55). The reinnervation of sensory receptors results in altered sensation. Normal tactile stimuli may be perceived as noxious, leading patients to complain of pain, paresthesias, or hyperesthesias. A desensitization program can be quite effective in reducing these symptoms. Patients are taught to expose the sensitive skin to graded textures (e.g., cotton progressing to sandpaper), vibratory stimuli (of increasing frequencies), and solid particles (45). Treatment begins with the exposure to the least aversive stimuli, and the patient is taught to increase the intensity and duration of stimulation each day. This progression continues until normal stimulation is tolerated. The Three-Phase Desensitization Test (originally, the Downey Community Hospital hand sensitivity test) is a readily available (North Coast Medical), standardized test for hypersensitivity that provides a systematic, reliable method for performing and documenting a desensitization protocol with the items described above (62). Other methods of providing sensory input that have been shown to decrease hyperesthesias include massage, application of heat, and percussion or tapping of the sensitive area (62,63). The principles of pain treatment following nerve injury include measures directed at the pain itself and use of the involved part. The latter is of value because pain is largely a result of the combined effects of vasomotor dysfunction, scar tissue near the proximal nerve stump, and traction on this scar from movement of the limb. To address the pain directly, transcutaneous electric nerve stimulation (TENS) provides relief in almost half the patients. TENS uses an electric device to emit a pulsed current to skin electrodes in a biphasic asymmetric wave. TENS is so effective in treating pain from peripheral nerve injuries that mild transcutaneous stimulation using surface electrodes may be sufficient even for the treatment of sympathetically maintained pain (64,57). Different forms of stimulation are achieved by adjusting the amplitude, frequency, and duration of the pulse. Constant stimulation of the large-diameter afferent fibers reduces the perception of pain, which depends on slowly conducting nonmyelinated fibers. TENS is not a cure for pain but rather an adjunct to the specific treatment of the nerve injury. Its purpose is to decrease pain to a degree that allows patients to participate in the rehabilitation program and perform functional activities. The pattern of sensory recovery begins with the return of pain and temperature appreciation. This is followed by awareness of vibration at 30 Hz, moving touch stimuli, and then vibration at 256 Hz. The last modalities to recover are the localization of tactile stimuli and two-point discrimination (65). Modality tests include pinprick, temperature discrimination, vibration, moving touch/pressure, and constant touch/pressure. The return of function is assessed from tests of moving and static two-point discrimination, the response to a ridge-shaped sensitometer, and tactile gnosis (the ability to feel the shape, weight, and texture of objects well enough to identify these) (45). The Moberg pickup test is particularly useful because the ability to pick up a series of 10 to 12 small objects of various sizes and then place them into a small container is readily timed and compared to results for the normal hand (45). Qualitative differences in prehension patterns may also become apparent during testing. An effort must be made to standardize the conditions for these tests at follow-up examination, because

medwedi.ru

828

Part Five: The Central and Peripheral Nervous System

there are many uncontrollable factors affecting the transmission of sensory impulses from the periphery to the CNS. Muscle atrophy is reversed by reinnervation of the motor end plate, provided that endomysial fibrosis is not advanced. Rehabilitative efforts are aimed at maximizing voluntary motion, motor control, and strength. The therapist must be familiar with the expected order of reinnervation following repair of the particular nerve lesion being treated, information that is readily obtained from standard texts (1). Treatment methods during the recovery phase include muscle reeducation, biofeedback, resistive exercises (initially resisting gravity alone), proprioceptive facilitation techniques (to maximize the stimulation of muscle afferents), and the use of patterns of movement that recruit the maximal number of muscle fibers (46).

Adaptive Phase Once end-organ function has been restored, central changes occur, which reflect adaptation to a new pattern of connectivity. An important part of this phase, which can be influenced by the rehabilitation program, is the reeducation of integrative mechanisms in the CNS. This facilitates new patterns for acquiring sensory information and distributing commands to muscle groups. Sensory recovery may slowly progress for more than three years before it is complete. Improvement occurs both through the maturation of reunited axon-receptor systems and the subliminal reeducation of integrative mechanisms. Because the CNS acquires sensory information differently after neurorrhaphy (because end-organ reinnervation is a random event), the sensations that occur early in the recovery phase may be somewhat foreign to those normally perceived in a particular part of the CNS (5,58). Sensory reeducation involves a graded series of specific sensory exercises that are instituted at appropriate times in the recovery process. An attempt is made to facilitate central reorganization so that patients can interpret the altered profile of neural impulses reaching consciousness. In the early stages of recovery, patients relearn modalityspecific perceptions (e.g., moving vs. constant touch). In the later stages, patients progress to the second phase of sensory reeducation: discriminative sensation. Readiness for progression to this phase is determined by the patient’s results on the Semmes–Weinstein monofilament test. The patient must be able to perceive filament number 4.31 (2.35 g) before discriminative training proves useful (66). At that time, various structured activities are performed with the ultimate goal of the return of tactile gnosis (name recognition of objects in the hand; two-point discrimination). Various stimuli are applied to the patient’s hand with the patient’s vision occluded. The patient attempts to identify the stimulus, and if unsuccessful, the stimulus is applied while the patient watches. The patient continues this training method, alternating eye occlusion and then using direct visualization in an effort to reorganize and integrate the cortical processing of sensory information from the altered periphery. The patient is challenged with the task of first identifying specific characteristics of the object (e.g., metallic vs. wooden and round vs. square). Ultimately, the patient attempts to name the object itself (e.g., key, coin, and paperclip). Graphesthesia activities and puzzles or mazes that are performed with vision occluded are higher-level tasks that also facilitate the return of discriminative sensation (66). This program is continued until the patient assumes responsibility for self-education and returns to work, avocations, and self-care. With sensory reeducation, maximal recovery may

occur within two years (65), shortening the adaptive phase by a year or more. Surgical procedures for the relief of pain caused by peripheral nerve injuries include the excision of any neuromas and sympathectomy. However, the former is rarely effective (67) and the latter has largely been replaced by TENS, ganglion blocks, and phenoxybenzamine (57,68). Muscle mass is regained through repeated exercises and the use of the injured part in activities of daily living.

Permanent Denervation Specific adaptive techniques, support personnel, or appliances may be required when functional impairment is substantial and permanent (63). Sufficient time should be allowed to elapse before evaluating the extent and significance of recovery. Although reconstructive procedures may be effective if performed in a timely manner, the patient will realize that the hoped-for recovery cannot occur. These procedures include arthrodesis, tendon transfers, tendon translocation, tenodesis, nerve transfers (69), microsurgical free muscle transplants, muscle transfers using an intact neurovascular island pedicle, and amputation with prosthetic fitting. These procedures require specific rehabilitation methods and goals.

SUMMARY Peripheral nerve injuries are rarely followed by a full recovery of function and often leave patients with a significant disability. Most nerve injuries involve an upper extremity and therefore threaten hand function. To minimize the extent and incidence of permanent disability, it is important to preserve as much of the microanatomy of the injured nerve as possible. This may mean ‘‘leaving well enough alone.’’ To know when to intervene surgically and, more importantly, when not to intervene requires an in-depth understanding of the anatomy and physiology of normal nerves. Diagnostic tools such as NCS and EMG are critical in sorting out the nature of the injury. To maintain what has been obtained by successful initial management requires the use of active rehabilitation measures that take account of any residual limb pain. Therapy must begin soon after injury, continue during the phases of recovery, and maximize the patient’s independence in the performance of daily activities.

REFERENCES 1. Sunderland S. Nerves and Nerve Injuries. Edinburgh: Churchill Livingstone, 1978. 2. Kline DG, Hackett ER. Reappraisal of timing for exploration of civilian peripheral nerve injuries. Surgery 1975; 78:545. 3. Brushart TM, Mesulam MM. Alteration in connections between muscle and anterior horn motoneurons after peripheral nerve repair. Science 1980; 208:603. 4. Lisney SJW. Changes in the somatotopic organization of the cat lumbar spinal cord following peripheral nerve transection and regeneration. Brain Res 1983; 259:31. 5. Wall JT, Felleman DJ, Kaas JH. Recovery of normal topography in the somatosensory cortex of monkeys after nerve crush and regeneration. Science 1983; 221:771. 6. Bell MA, Weddell AGM. A descriptive study of the blood vessels of the sciatic nerve in the rat, man, and other mammals. Brain 1985; 107:871.

Chapter 42: Injuries to Peripheral Nerves 7. Hudson A, Kline D. Progression of partial experimental injury to peripheral nerve. II. Light and electron microscopic studies. J Neurosurg 1975; 42:15. 8. Smith DR, Kobrine AI, Rizzoli HV. Blood flow in peripheral nerves. Normal and post severance rates. J Neurol Sci 1977; 33:341. 9. Donat JR, Wisniewski HM. The spatio-temporal pattern of wallerian degeneration in mammalian peripheral nerves. Brain Res 1973; 53:41. 10. Grafstein B, McQuarrie IG. Role of the nerve cell body in axonal regeneration. In: Cotman CW, ed. Neuronal Plasticity. New York: Raven Press, 1978. 11. McQuarrie IG. Role of the axonal cytoskeleton in the regenerating nervous system. In: Seil FJ, ed. Nerve, Organ, and Tissue Regeneration: Research Perspectives. New York: Academic Press, 1983. 12. Grafitein B, Forman DS. Intracellular transport in neurons. Physiol Rev 1980; 60:1167. 13. McQuarrie IG. Effect of a conditioning lesion on axonal transport during regeneration: the role of slow transport. In: Elam J, Cancalon P, eds. Advances in Neurochemistry. Vol. 6. New York: Plenum Press, 1984. 14. Benowitz LI, Yoon MG, Lewis ER. Transported proteins in the regenerating optic nerve: regulation by interactions with the optic rectum. Science 1983; 222:185. 15. Skene HHP, Willard M. Axonally transported proteins associated with axon growth in rabbit central and peripheral nervous systems. J Cell Biol 1981; 89:96. 16. Bray GM, Rasminsky M, Aguayo AJ. Interactions between axons and their sheath cells. Annu Rev Neurosci 1981; 4:127. 17. McQuarrie IG. Accelerated axonal sprouting after nerve transection. Brain Res 1979; 167:185. 18. McQuarrie IG. Effect-of a conditioning lesion on axonal sprout formation at nodes of Ranvier. J Comp Neurol 1985; 231:239. 19. Singer PA, Mehler S, Fernandez HL. Blockade of retrograde axonal transport delays the onset of metabolic and morphologic changes induced by axotomy. J Neurosci 1982; 2:1299. 20. Wujek JR, Lasek RJ. Correlation of axonal regeneration and slow component B in two branches of a single axon. J Neurosci 1983; 3:243. 21. Lund LM, Machado VM, McQuarrie IG. Increased Beta-actin and tublin polymerization in regrowing axons: relationship to the conditioning lesion effect. Exper Neurol 2002; 178:306. 22. Weller RO, Cervos-Navarro J. Pathology of Peripheral Nerves. London-Boston: Butterworth Publishers, 1977. 23. Forman DS, Wood DK, DeSilva S. Rate of regeneration of sensory axons in transected rat sciatic nerve repaired with epineurial sutures. J Neurol Sci 1979; 44:55. 24. Kline DG, Hayes GJ, Morse AS. A comparative study of response to species to peripheral nerve injury. J Neurosurg 1964; 21:980. 25. Kline DG, Hackett ER, May PR. Evaluation of nerve injuries by evoked potentials and electromyography. J Neurosurg 1969; 31:128. 26. Sanders FK, Young JZ. The influence of peripheral connexion on the diameter of regenerating nerve fibers. J Exp Biol 1946; 22:203. 27. Friede RL. Control of myelin formation by axon caliber (with a model of the control mechanism). J Comp Neurol 1972; 144:233. 28. Politis MJ et al. Studies on the control of myelinogenesis. IV. Neuronal induction of Schwann cell myelin-specific protein synthesis during nerve fiber regeneration. J Neurosci 1982; 2:1252. 29. Gordon T, Stein RB. Reorganization of motor-unit properties in reinnervated muscles of the cat. J Neurophysiol 1982; 48:1175. 30. Bowden REM, Sholl DA. The advance of functional recovery after radial nerve lesions in man. Brain 1950; 73:17. 31. Richter HP. Impairment of motor recovery after late nerve suture: experimental study in the rabbit. I. Functional and electromyographic findings. Neurosurgery 1982; 10:70. 32. Gilliatt RW. Physical injury to peripheral nerves. Physiologic and electrodiagnostic aspects. Mayo Clin Proc 1981; 56:361.

829

33. Dyck PJ et al. Structural alterations of nerve during cuff compression. Proc Nad Acad Sci USA 1990; 87:9828. 34. Pollock FH et al. Treatment of radial neuropathy associated with fractures of the humerus. J Bone Joint Surg 1981; 63A:239. 35. Lundborg G, Myers R, Powell H. Nerve compression injury and increased endoneurial fluid pressure: a ‘‘miniature compartment syndrome.’’ J Neurol Neursurg Psychiatry 1983; 46:1119. 36. Richardson PM, Thomas PK. Percussive injury to peripheral nerve in rats. J Neurosurg 1979; 51:178. 37. Wall PD. The painful consequences of peripheral injury. J Hand Surg 1984; 9B:37. 38. Treede RD et al. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobio 1992; 38:397. 39. Verdugo RJ, Ochoa JL. Sympathetically maintained pain. Neurology 1994; 44:1003. 40. Rothberg JM, Tahmoush AJ, Oldakowski R. The epidemiology of causalgia among soldiers wounded in Vietnam. Milit Med 1983; 148:347. 41. Merskey H. Classification of chronic pain. Pain 1986(suppl 3):1. 42. Devor M, Janig W. Activation of myelinated afferents ending in a neuroma by stimulation of the sympathetic supply in the rat. Neu Rosci Lett 1981; 24:43. 43. Roberts WJ. A hypothesis on the physiological basis for causalgia and related pains. Pain 1986; 24:297. 44. Shir Y, Seltzer Z. Effects of sympathectomy in a model of causalgiform pain produced by partial sciatic nerve injury in rats. Pain 1991; 45:309. 45. Hunter JM et al. Rehabilitation of the Hand: Surgery and Therapy. 3rd ed. St. Louis: Mosby, 1990. 46. Nickel VL. Orthopedic Rehabilitation. Edinburgh: Churchill Livingstone, 1982. 47. Goodgold J, Eberstein A. Electrodiagnosis of Neuromuscular Diseases. Baltimore: Williams & Wilkins, 1978. 48. Bradley WG. Disorders of Peripheral Nerves. Oxford: Blackwell Scientific Publications, 1974. 49. Mcdonald CM et al. Magnetic resonance imaging of denervated muscle: comparison to electromyography. Muscle Nerve 2000; 23:1431. 50. Bendszus M, Koltzenburg M. Visualization of denervated muscle by gadolinium-enhanced MRI. Neurology 2001; 57:1709. 51. Omer GE. Injuries of nerves of the upper extremity. J Bone Joint Surg 1974; 56A:1615. 52. Terzis JK, Dykes RW, Hakstian RW. Electrophysiological recordings in peripheral nerve surgery: a review. J Hand Surg 1976; 1:52. 53. Napier JR. The significance of Tinel’s sign in peripheral nerve in juries. Brain 1949; 72:63. 54. McQuarrie IG. Nerve regeneration and thyroid hormone treat ment. J Neurol Sci 1975; 26:499. 55. Wynn Parry CB. Rehabilitation of the Hand. 3rd ed. London: Butterworth Publishers, 1978. 56. Nix WA. The effect of low-frequency electrical stimulation on the denervated extensor digitorum longus muscle of the rabbit. Acta Neurol Scand 1982; 66:521. 57. Meyer GA, Fields HL. Causalgia treated by selective large fibre stimulation of peripheral nerve. Brain 1972; 95:163. 58. Henry AK. Extensile Exposure. 2nd ed. Edinburgh: Churchill Livingstone, 1973. 59. Haase J, Bjerre P, Simensen K. Median and ulnar nerve transections treated with microsurgical interfascicular cable grafting with auto genoussural nerve. J Neurosurg 1980; 53:73. 60. Millesi H. Interfascicular grafts for repair of peripheral nerves of the upper extremity. Orthop Clin North Am 1977; 8:387. 61. Hallin RG, Wiesenfeld Z, Lindblom U. Neurophysiological studies on patients with sutured median nerves: faulty sensory localization after nerve regeneration and its physiological correlates. Exp Neurol 1981; 73:90. 62. Waylett-Rendall J. Desensitization of the traumatized hand. In: Hunter JM, Mackin EJ, Callahan AD, eds. Rehabilitation of the Hand: Surgery and Therapy. 4th ed. St. Louis: Mosby, 1995:693. 63. Trombly CA, Scott AD. Occupational Therapy for Physical Dysfunction. Baltimore: Williams & Wilkins, 1977.

medwedi.ru

830

Part Five: The Central and Peripheral Nervous System

64. Campbell JN, Long DM. Peripheral nerve stimulation in the treatment of intractable pain. J Neurosurg 1976; 45:692. 65. Dellon AL. Evaluation of Sensibility and Reeducation of Sensation in the Hand. Baltimore: Williams & Wilkins, 1981. 66. Callahan AD. Methods of compensation and reeducation for sensory dysfunction. In: Hunter JM, Mackin EJ, Callahan AD, eds. Rehabilitation of the Hand: Surgery and Therapy. 4th ed. St. Louis: Mosby, 1995:701.

67. Noordenbos W, Wall PD. Implications of the failure of nerve re section and graft to cure chronic pain produced by nerve lesions. J Neurol Neurosurg Psychiatr 1981; 44:1068. 68. Ghostine SY et al. Phenoxybenzamine in the treatment of causalgia: report of 40 cases. J Neurosurg 1984; 60:1263. 69. Chacha PB, Krishnamurti A, Soin K. Experimental sensory reinnervation of the median nerve by nerve transfer in monkeys. J Bone Joint Surg 1977; 59A:386.

PART SIX: The Peripheral Vascular System

43 Physiology of Arterial, Venous, and Lymphatic Flow Dennis F. Bandyk and Paul A. Armstrong

INTRODUCTION Clinical evaluation of patients with vascular disease requires a thorough understanding of the anatomy and hemodynamics of the arterial, venous, and lymphatic circulations. The continued improvement of noninvasive ultrasound techniques that produce high-resolution vascular imaging and depict system hemodynamics has resulted in improved understanding of arterial and venous disease pathophysiology, and has better defined the physiologic significance of anatomic disease. The ability to monitor the hemodynamics of arterial and venous flow and vessel anatomy serially has allowed detection of disease progression, resulting in a more cost-effective and timely intervention. In this chapter, the functional anatomy and hemodynamics of the arterial, venous, and lymphatic components of the circulatory system will be discussed. Special emphasis will be placed on how the biophysical properties of the circulation (e.g., pressure, flow velocity, and turbulence) can be measured in man, and how such measurements are used in the evaluation of patients with vascular disease. The discussion will focus primarily on the principles of arterial, venous, and lymphatic flow in the lower extremity; however, the concepts are equally germane and applicable to the upper extremity and cerebrovascular circulation.

pressure energy produced in the heart, by cushioning vessels that convert the pulsatile flow of the blood into smooth flow, and acting as resistance vessels involved in the microcirculation. Arterial wall structure and neural innervations accordingly reflect the specialized function(s) of the various arterial system elements. As blood proceeds through the arterial system, the network of conducting vessels undergoes repeated branching accompanied by a decrease in caliber, resulting in many parallel distributing vessels that terminate in the capillary beds. In the arterial system of the lower extremity, branching produces potential collateral networks that can bypass blood around a hemodynamically significant, i.e., pressurereducing, obstruction in a conduit artery (Fig. 1). The total cross-sectional area progressively increases each time branching occurs, with a concomitant decrease in mean flow

PERIPHERAL ARTERIAL SYSTEM The purpose of the arterial system is to deliver blood and its various components to tissue capillaries in amounts sufficient to maintain normal cellular function. Metabolic demands of body tissues and organs vary widely, in normal (resting), exercising, and diseased states. The ability of the arterial circulation to respond to a variable demand is reflected in the anatomic and physical properties of the cardiovascular system and is mediated through two regulatory mechanisms: local control of blood flow through the tissue according to its metabolic state (autoregulation) and neural control of peripheral vascular resistance. These factors, acting in concert, control tissue blood flow and consequently regulate cardiac output. Control of blood flow is also strongly influenced by factors such as those involved in the regulation of extracellular fluid volume and urinary output. The functional elements of the arterial system include the ‘‘heart,’’ which generates the energy necessary to maintain arterial pressure and blood flow at an appropriate level, ‘‘arteries,’’ which transport blood to the periphery, ‘‘arterioles,’’ which regulate flow of blood into the microcirculation, and ‘‘capillaries,’’ which are the site of nutrient and metabolic exchange to the tissues. Depending on their position in the arterial system, arteries can act as ‘‘storers’’ of

Figure 1 Diagram of the arterial circulation to the lower extremity, indicating the main conduit arteries and corresponding potential collateral arteries.

medwedi.ru 831

832

Part Six: The Peripheral Vascular System

Table 1 Physical and Hemodynamic Characteristics of the Human Arterial System Mean flow Crossvelocity Pressure Resistance Total blood sectional (cm/s) (mmHg) (%) volume (%) area (cm2) Aorta Branching arteries Arterioles Capillaries

8 5 2 5

2.5 20 40 2500

14–18 12

100 90

4 21

0.07

55 25

41 27

velocity (Table 1). At the capillary level, the cross-sectional area is approximately 1000 times that of the aorta. Each red blood cell remains in the microcirculation for only one to three seconds, an exceedingly short time during which all nutrient diffusion and fluid exchange occur. Approximately 20% of the entire blood volume of the body is in the arterial system, in contrast to the 64% in the venous system. The heart contains 7% of the blood, and the pulmonary vessels 9%. Surprisingly, only 5% of the total blood volume resides in the capillaries. Although total capillary volume is small, surface and cross-sectional areas are immense to facilitate the transfer of oxygen, carbon dioxide, water, nutrients, and electrolytes through the capillary walls. In the resting state, the lower limbs receive about 300 to 400 mL/min, two to three times of that in the upper limbs, primarily because of differences in muscle mass. The heart, through cyclic muscle wall contraction, generates a complex pressure pulse and provides the energy for blood flow. The ability of the heart to vary its output is based on its three fundamental properties: the capacity to vary the rate of contraction (chronotropism), the rate of isometric tension development, which is a function of cardiac muscle fiber length (Frank–Starling mechanism), and the ability to alter the velocity of muscle fiber shortening (inotropism). From these properties, four factors that are independent determinants of cardiac output can be defined. These are commonly referred to as ventricular preload, ventricular contractility, ventricular afterload, and heart rate. The output of the heart mainly reflects the demands of the peripheral circulation. The frequency of contraction is determined by the interplay of neural and humeral adrenergic and neural cholinergic activity on the sinoatrial node. The velocity and force of ventricular– muscular contraction are influenced by both circulating and neuron-released catecholamines acting on the muscle fibers themselves. The work output of the heart is the amount of energy that the heart transfers to the blood. This energy, which is in the form of potential energy of pressure and the kinetic energy of blood flow, is used to accelerate blood to its ejection velocity through the aortic valve. In the distribution of blood to the various capillary beds, the viscoelastic properties of the artery walls and the tapered, converging vessel caliber are important physical characteristics maintaining blood pressure and minimizing pressure and kinetic fluid energy losses.

Arterial Wall: Structural Features The composition and structure of the arterial wall in the different segments of the arterial system reflect the local wall mechanics and its functional role. With the exception of the capillaries, the artery wall consists of three concentric layers: tunica intima, tunica media, and tunica adventitia.

The tunica intima is the innermost layer and consists of monolayer endothelium lining the lumen, a thin basal lamina, and a subendothelial layer (present in the large elastic arteries of the thorax and abdomen), composed of collagenous bundles, elastic fibrils, and smooth cell muscles. The tunica media is in the middle layer and is made up of predominantly smooth muscle cells in a varied number of elastic sheets (laminae), bundles of collagenous fibrils, and a network of elastic fibrils. The tunica adventitia consists of dense fibroelastic tissue without smooth muscle cells. The adventitia also contains the nutrient vessels of the arterial wall (vaso vasorum) and both vasomotor and sensory nerves of the vascular wall. Arteries can be classified by the respective amounts of elastin, smooth muscle, and collagen in their walls. The distensibility of an artery wall generally correlates with the elastin content. The large arteries of the thorax and abdomen, such as the aorta, innominate, iliac, subclavian, and common iliacs, are referred to as elastic or ‘‘pressure storer’’ arteries because their walls contain a predominance of elastin and few smooth muscle cells. The large elastic arteries instantaneously accommodate each stroke volume of the heart, storing a portion during systole and draining this volume during diastole (windkessel effect). This helps to propel the blood toward the periphery during diastole and promotes continuous flow to the capillaries. The internal systole pressure in the large arteries is normally about 120 to 160 mmHg. Proceeding distally, the muscular or branching arteries such as brachial, radial, femoral, and popliteal have a media with a predominance of smooth muscle and collagen, but little elastic tissue. The varying arterial wall properties distant from the heart are related to the proportions of collagen and elastin in the media, the linkage between these two elements, the insertions of elastin and muscle on collagen fibers, and the contractile state of the vascular smooth muscle. Proceeding from the thoracic aorta distally, there is a gradual decline in the elastin–collagen ratio. Thus, the initial segment of the arterial tree has a lower vascular impedance, and oscillatory component of work required distally to maintain cardiac output is reduced. The increased relative stiffness of the distal muscular arteries is important to ensure that undampened transmission of the pressure pulse to the baroreceptors (e.g., at the carotid bifurcation) occurs. At the level of the arterioles, the arterial wall is composed almost entirely of smooth muscle. These vessels provide the major site of resistance to the arterial system, and provide for the regulation of blood flow to the microcirculation (Table 1). Mean pressure in the arterioles ranges from 40 to 60 mmHg. The smooth muscle of the media is well innervated by sympathetic nerves. At the cutaneous level, these nerve fibers are involved with temperature regulation, vasoconstriction in cool weather to conserve heat and vasodilatation in warm conditions to dissipate heat. Exceptions to this can occur in the septic states, severe emotional distress, or profound shock, where vasodilatation predominates secondary to sympathetic innervation. Additionally, metabolites at a local level also cause vasodilatation, as does exercise. This autoregulation disappears at pressures below 30 mmHg, where flow occurs secondary to perfusion pressure alone. The collagen content of the arterial wall correlates with its tensile strength, with the adventitia collagen responsible for the majority of wall stability. This is evident from the maintenance of vessel integrity by the adventitia following surgical endarterectomy, which removes the intima and

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

833

large portion of the media. In naturally occurring aneurysms, the collagen content of the adventitia is decreased and failure of wall integrity occurs. Degradation of collagen results in arterial wall rupture. The circumferential tension (T) in the arterial wall is calculated as the product of the transmural pressure, Pt (inside pressure minus outside pressure), and the radius (R). This relationship, known as the Law of Laplace, can be expanded to include the factor of wall thickness (mm): T ¼ Pt R=mm ðdynes/cmÞ In arteries with a radius and wall thickness of equal proportions, wall tension varies with transmural pressure. For example, the small radius and low pressure of a capillary requires only a thin wall to support the wall tension, whereas the aorta with its greater pressure and radius requires a thicker wall to prevent rupture. The elastic properties of any blood vessel can be described by Young’s modules (E), which is stress divided by strain. Because arteries are subject to pulsatile pressure, measurements of elasticity are determined from the strain that accompanies a period of time in which stress is varied, producing what is called dynamic modules (Edyn). The most important component of stress in arteries is the first harmonic of the pressure pulse, i.e., heart rate. The dynamic elastic modules of an artery are also a determinant of pulse wave velocity. In vivo arterial wall motion occurs predominantly in the circumferential direction. The variation of vessel diameter with each cardiac cycle closely resembles the pressure waveform. Intrathoracic arteries vary 12% to 18% in diameter with each pressure pulse, whereas peripheral arteries change 8% to 10% in diameter. The distensibility characteristic of arteries also depends on the extent of stretch (transmural pressure). At low pressure and small diameters, arteries are very distensible, whereas they become gradually stiffer with increasing pressure and diameter. The viscoelastic properties of arteries are altered not only in diseased states but also change with age. With age, artery diameter and length increase, and so do the wall thickness and collagen-to-elastin ratios. These changes result in tortuosity, increased arterial stiffness, and an increase in vascular impedance. Although an increase in the thickness of the intima, which initially occurs in atherosclerosis, has little effect on the elastic properties of the artery, the accompanying changes within the media and adventitia, particularly if the wall nutrition through vaso vasorum is involved, may have marked effects of hemodynamic characteristics and further disease progression.

Figure 2 Effect of hematocrit on relative velocity of blood. Note that as the hematocrit increases, the relative viscosity increases disproportionately. Source: From Ref. 1.

tubes (less than 200 mm) such as the arterioles, capillaries, and venules. This phenomenon is known as Fahraeus– Lindqvist effect and is related to red cell orientation and lower hematocrit in small vessels. The rheology of blood in the capillary circulation is poorly understood, although the deformability of the red cell membrane and erythrocyte velocity are important factors. Rheologic agents focus on increasing the membrane flexibility of the red blood cells and therefore decrease the overall viscosity of blood. They also promote decreased platelet aggregation. The viscosity of blood is important not only for its effect on the resistance to blood flow, but also in producing impairment of tissue perfusion. Increased blood viscosity can potentiate the low flow states seen in pathologic conditions such as polycythemia, trauma, and other hyperviscosity syndromes. Increased blood viscosity combined with a low flow promotes erythrocytes to aggregate into stocks or ‘‘rouleaux,’’ with resultant tissue ischemia.

Essentials of Arterial Hemodynamics Hemodynamics is a discipline concerned with the interrelationships of the physical characteristics of blood and pulsatile flow conditions in the visoelastic arterial and venous circulations. As a first step toward understanding the complexity of arterial flow, it is useful to discuss the energy principles involved in arterial circulation and the interrelationships between pressure, flow, and resistance under steady flow conditions.

Viscous Properties of Blood Flow Blood is a viscous fluid composed of cells and plasma. When blood flows, frictional forces develop between the cellular components of blood, causing it to exhibit the property of viscosity. Because the red blood cells comprise the majority of the cellular component, the hematocrit is a major determinant of blood viscosity, as illustrated in Figure 2. If measured with reference to water, the relative viscosity of blood having a hematocrit of 40 is approximately 3.6. This means that three to four times as much pressure is required to force blood than water through the same tube. Blood viscosity is not constant in the arterial system but exhibits a nonNewtonian fluid property: the faster it flows, the lower is its viscosity. The chief determinants of this property are the red cell concentrations and plasma concentration of fibrinogen and globulins. Blood viscosity decreases in small caliber

Fluid Energy In general, blood flows from a point of high pressure to one of lower pressure, but the true driving force is the differential in total fluid energy. ‘‘Total fluid energy’’ associated with blood flow is of three types: intravascular pressure, gravitational, and kinetic. The intravascular pressure (P) has three components: (i) the dynamic pressure produced by the contraction of the heart, (ii) the hydrostatic pressure, and (iii) the static filling pressure. Both the gravitational energy and the hydrostatic pressure are determined by the product of the specific gravity of blood (r), the acceleration of gravity (980 cm/sec)(g), and the distance (h) above the right atrium. Gravitational energy (þrgh) is the ability of the blood to do work on the basis of its height and is of the opposite value of the hydrostatic pressure (-rgh). The static filling pressure is

medwedi.ru

834

Part Six: The Peripheral Vascular System

the residual pressure that exists in the absence of arterial flow. This pressure is determined by the volume of blood and the compliance of the arterial system, and is in the range of 5 to 10 mmHg. Because the hydrostatic pressure and the gravitational potential energy cancel each other out and the static filling pressure is relatively low, the dynamic pressure produced by the heart is the major source of potential energy used in moving blood. Kinetic energy (Ek) is the ability of blood to do work on the basis of its motion. It is proportional to the specific gravity of blood (p) and the square of the blood velocity (v): Ek ¼1=2 pv2 Omitting the term for gravitational energy (i.e., þpgh), the total fluid energy per volume of blood (E) can be expressed as: Ek ¼ P þ1=2 pv2 where P is intravascular pressure. In an idealized fluid system of steady flow and/or frictional energy losses, total fluid energy along a streamline remains constant with the relationship between the different energy forms described by Bernoulli’s principle of the conservation of energy:

as a result of an atherosclerotic plaque, the Bernouille effect and the production of turbulence with the associated changes in kinetic energy explain the pressure and flow changes that develop under these conditions. It is important to emphasize that the pressure–flow relationship described in Poiseuille’s law is based on assumptions involving idealized fluid mechanics that significantly underestimate the energy losses present in the viscoelastic pulsatile flow conditions of the human circulation. Poiseuille’s law represents the minimum pressure gradient produced by viscous losses that may be expected in arterial flow. In addition to energy loss caused by friction, inertial energy losses related to changes in the velocity and the direction flow occur. In the arterial system, particularly in the presence of disease, energy losses caused by inertial effects usually exceed viscous energy loss. Energy losses related to inertia are proportional to the specific gravity of blood and the square of the blood velocity. Because the density of blood is constant, inertial losses result when blood accelerates, decelerates, or changes direction. In the arterial system, inertial energy losses occur at points of curvature, variations of lumen diameter, and at bifurcations of the vasculature. Blood velocity usually increases from large luminal size to smaller luminal size. The acceleration and deceleration of blood in pulsatile flow add inertial forces to the constant kinetic energy of steady flow.

P þ1=2 pv1 2 ¼ P2 þ1=2 pv2 2 þ heat In the horizontal diverging tube shown in Figure 3, steady flow between two points is accomplished by an increase in cross-sectional area and a decrease in flow velocity. Although fluid energy moves against a pressure gradient (p2 p1) of 2.4 mmHg and gains potential energy, total fluid energy remains constant because of a lower velocity and a proportional loss of kinetic energy. In the normal arterial system in which ideal flow conditions are absent and vessels change diameter only gradually, the pressure gradients caused by viscous losses as predicted by Poiseuille’s law far outweigh the extremely small interconversions to kinetic energy and pressure. In certain disease states, however, such as sudden vessel widening into an aneurysm or narrowing

Figure 3 Vascular resistance in series and parallel. (Top) Total resistance (Rt) of a conducting system with individual resistances in series is the sum of resistances: Rt ¼ (R1 þ R2 þ R3). (Bottom) When resistance vessels are in parallel, the total resistance is the sum of the reciprocals of the individual resistances: Rt¼1-(R1 þ R2 þR3 þ). Note that in a parallel conducting system, the total resistance is less than any individual resistance level. Q indicates blood flow.

Resistance to Flow The relations between flow and pressure in cylindrical tubes were first accurately described by the French physician, Poiseuille, in 1846. Under the conditions of his experiments, the volume flow (Q) through a vessel is determined by: Q¼

Ppr4 ml=min 8lm

where P is perfusion pressure, or the pressure gradient between the ends of the vessel, r is the vessel radius, l is the vessel length, and m is viscosity of the fluid. Poiseuille’s law describes the viscous energy losses that occur in a steady-flow, idealized fluid model. The theoretic derivation rests in the assumptions that each particle of the fluid moves at a constant velocity parallel to the vessel wall, that the force opposing this motion is proportional to fluid viscosity, and that the velocity gradient is perpendicular to the direction of flow. This means that in a cylindrical tube, the fluid moves in a series of concentric lamina and flow is laminar. Steady laminar flow results in a parabolic velocity profile in the tube. As predicted by this law, the resistance to flow is most dependent on vessel radius. Resistance is proportional to vessel length and viscosity, but inversely proportional to the fourth power of the radius. Assuming a constant blood viscosity, a doubling of conduit length will double the resistance, whereas halving the radius increases the resistance 16 times. In the human peripheral arterial system, flow is primarily determined by active changes in the arteriole, arteries less than 200 mm in diameter, and the capillary. Artery caliber varies according to the state of contraction of the vascular smooth muscle, which depends on perfusion pressure, activity of the sympathetic nervous system, and local mechanisms involving metabolic, humeral, and physiologic factors. In a flow model governed by Poiseuille’s law, the physical properties of the system (tube dimensions and fluid viscosity) determine the magnitude of pressure gradient required to produce a given flow. The ratio of mean pressure gradient

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

835

Laminar and Turbulent Flow As previously discussed, the blood flow follows streamlines or is laminar in the steady flow conditions specified by Poiseuille’s law. The velocity profile is parabolic in shape (Fig. 5). In contrast to the concentric laminae of laminar flow, turbulence is a condition in which the flow velocity vectors are moving in a random fashion with respect to space and time. The point at which flow changes from laminar to turbulent, termed the ‘‘critical velocity,’’ depends on the ratio of inertial forces to viscous forces and is best defined in terms of a dimensionless entity known as Reynolds number:

Figure 4 Effect of increasing cross-sectional area on pressure in frictionless fluid system. Although pressure increases, total fluid energy remains constant because of a decrease in velocity. Abbreviations: A, area; V, velocity; P, pressure. Source: From Ref. 2.

to mean flow is thus a measure of the opposition to flow, commonly termed ‘‘vascular resistance.’’ When Poiseuille’s law is simplified to an expression, pressure ¼ flow times resistance, it is exactly analogous to Ohm’s law of electric circuits, V ¼ 1 Re, when Poiseuille’s equation is rearranged to: 8lm P ¼ Q Q 4 mmHg r Q where the term (8lm)/ r4 expresses electrical resistance (Re), P is voltage (V), and Q is flow of current (I). Vascular and electrical resistances both express the dissipation of energy per unit flow within a system. In the arterial system, resistance is expressed as peripheral resistance units (PRU), where 1 PRU equals the resistance to flow encountered when there is a pressure difference between two points of 1 mmHg and flow is 1 m/sec. The resistance of the entire systemic circulation is approximately 1 PRU, calculated using a 100-mmHg pressure gradient between the left ventricle and the right atrium and an average blood flow of 100 mL/sec. The total resistance of a conducting system depends on whether the vessels are in series or in parallel (Fig. 4). When vessels are in series, total resistance is equal to the sum of the individual resistances. On the other hand, if the conducting vessels are in parallel, total resistance is the reciprocal of the total conductance. This means that in a parallel conducting system, total resistance is less than any of the individual resistance vessels. Also resistance usually tends to increase as velocity increases along a fixed diameter artery.

Re ¼ rdv=m where r is the blood density, d is the vessel diameter, v is the mean velocity, and m is the viscosity. Below a Reynolds number of 2000, flow is laminar because viscous forces predominate and damping of random inertial forces on the flow stream occurs. At a Reynolds number above 2000, the inertial forces may disrupt the laminar flow pattern, the result being increased energy dissipation as sound and heat. Energy dissipation in laminar flow is proportional to flow velocity, whereas losses in turbulent flow occur with the velocity squared. Flow conditions that predispose to the development of turbulence include an increased flow velocity (ascending aorta), a decreased vessel diameter (diseased), or a reduced blood viscosity (anemia, over hydration). An important clinical sign of turbulence is the presence of a bruit. Streamline (laminar) flow is silent, but turbulence produces wall vibrations that can often be heard with a stethoscope, termed a ‘‘bruit.’’ Bruits produced by stenoses are loudest over the stenotic segment and are transmitted in a distal direction. Under conditions of turbulent, viscoeleastic flow, the arterial velocity profile changes from the parabolic shape of laminar flow to a blunt or rectangular shape. Although turbulent flow is uncommon in arteries, a condition of disturbed flow commonly occurs. Disturbed flow is a transient perturbation in the laminar streamlines that disappears with time or as the flow proceeds downstream. Sites of focal disturbed flow can be identified in the thoracic aorta during the flow deceleration phase of each heart cycle, in regions of

Arterial Flow Patterns The combination of viscous (frictional) and inertial forces acting on blood determines whether flow is laminar or turbulent (i.e., disturbed flow). The transition to turbulent flow is physiologically important because a greater pressure gradient is needed to maintain flow. Frictional interactions at the inner wall of an artery can also produce flow pattern variations, referred to as boundary layer separation. The clinical importance of local flow patterns in arteries resides in their role in the pathogenesis of atherosclerosis, and the ability of duplex ultrasound systems to detect and grade the severity of disease through the disturbed flow produced.

Figure 5 Relationship between velocity of flow and turbulence. Source: From Ref. 3.

medwedi.ru

836

Part Six: The Peripheral Vascular System

Figure 6 Center stream flow from a normal artery is laminar and is demonstrated on the spectrum (A) as a narrow band of frequencies during systole, with a clear window beneath the frequency envelope. Disturbed flow caused by mild stenosis appears as spectral broadening on the frequency spectrum (B) without producing changes in the park systolic velocity. Highly disturbed flow (turbulence) is characterized by high peak velocities and spectral broadening throught the cardiac cycle. Also note the increase in end-diastolic velocity associated with severe stenosis (C). Abbreviations: SV, systolic velocity; T, time. Source: From Ref. 4.

arterial branching, and in the carotid bulb. Disturbed flow, however, can represent the initial hemodynamic abnormality produced by atherosclerotic plaque formation seen in occlusive disease. Plaque formation alters wall compliance and reduces cross-sectional lumen area, resulting in disturbed flow and an increase in blood flow velocity. The recognition that the kinetic energy losses associated with disturbed flow conditions helps to explain the gross underestimation of energy loss when Poiseuille’s law is used alone to evaluate flow changes produced by arterial stenosis. The magnitude of disturbed flow can be divided into three categories on the basis of the Doppler velocity spectra pattern: undisturbed (laminar), disturbed, and highly disturbed (turbulent). As shown in Figure 6, the velocity spectra of blood flow through a stenosis demonstrates the focal disruption of laminar flow at and distal to the lesion. Highly disturbed velocity spectra associated with pressure–flow– reducing stenosis exhibit high-frequency Doppler shifts and spectral broadening throughout the pulse cycle. Turbulent flow can initiate platelet aggregation, which may lead to thrombus formation. Disturbed velocity waveforms contain high-frequency components only during peak systole and typically indicate a transitional flow condition detected under normal flow conditions in the ascending aorta and at arterial bifurcations. Undisturbed velocity waveforms exhibit negligible high-frequency content and are representative of laminar flow.

Boundary Layer Separation The outer layer of fluid in a flow stream adjacent to the vessel wall is referred to as the boundary layer. Radial-directed velocity gradients exist as a result of the fractional interactions of fluid with the vessel wall and the more rapidly moving fluid in the center of the vessel. When vessel geometry changes suddenly, such as at points of curvature and

Figure 7 Flow patterns at model carotid bifurcation. Adjacent to the outer wall of the bulb, flow is stagnant (a region of flow separation), may reverse, or may be diverted across the vessel lumen. Rapid flow is associated with high shear stress, whereas the slow flow in the separation zone produces a region of low shear. Source: From Ref. 5.

bifurcations, small pressure gradients are created, causing the boundary layer to stop or reverse direction. This results in a complex, localized flow pattern known as an area of flow separation. Areas of flow separation have been observed in models of arterial anastomoses and the carotid bifurcation depicted in Figure 7; an area of flow separation is seen to have formed along the outer wall as a result of the diverging carotid bulb diameter. The complex flow patterns identified in normal human carotid bifurcation include vortex flow as well as regions of flow separation and reversal along the lateral, posterior wall of the bulb. Shear rate is the variation of velocity of flow changes between concentric laminae of blood. Shear stress at the vessel wall (Dw) can be characterized by the following formula: Dw ¼ 4

V Q ¼4 3 r pr

Gw ¼ 4Z

V Q ¼ 4Z 3 r pr

where Gw is the shear stress at the wall, V, the mean velocity, r, radius, Q, mean flow, and Z, the blood viscosity. Therefore shear rate and stress are directly proportional to mean velocity, turbulence, and viscosity and inversely proportional to the inner radius of the vessel. At bifurcations and vessel curves, shear is highest at the wall where the velocity of flow is also highest. It has been shown that arterial vasoconstriction and vasodilatation occur with shear rate changes, most likely via production of endothelium-derived relaxing factor, now known to be nitric oxide (NO). Production of NO in the wall in response to increased shear causes relaxation of the media smooth muscle, resulting in vasodilatation.

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

837

The disturbed flow and low shear stress in regions of boundary layer separation may contribute to the formation of atherosclerotic plaques. Examination of carotid and iliac bifurcations, both at autopsy and during surgery, indicate that intimal thickening and plaque formation tend to occur in the regions of flow separation. Within these zones, there is an opportunity for a synergistic effect for rheologic and contact activation of blood elements with the intima. The role of localized flow disturbances as an initiator or promoter of atherosclerosis is speculative and awaits further analysis and research.

Principles of Pulsatile Flow In the arterial system, pressure and flow vary continuously with time, and the velocity profile changes throughout the cardiac cycle. The addition of a pulsatile component on steady flow increases fluid energy expenditure. As much as 30% of the energy in cardiac output is dissipated as a result of pulsatile flow. With increasing heart rate, energy losses caused by pulsatile flow decrease exponentially up to a heart rate of approximately 150 beats/min. The remainder of cardiac output energy is used for tissue perfusion, and therefore primarily dissipates in the arteriolar and capillary bed. Although the true nature of pulsatile energy loss remains poorly defined, contributing factors include inertia energy loss with acceleration, geometric vessel tapering, vessel curvature, and bifurcation, production of disturbed flow, and the non-Newtonian character of blood. It is apparent that Poiseuille’s law cannot accurately predict all the hemodynamic characteristics of flow through the artery. Of importance to the surgeon is that, with pulsatile flow, the energy losses produced by arterial reconstructions, which commonly have anatomic and physical characteristics much different from the normal arterial system, are likely to be much greater than predicted by the equations governing steady flow. Although pulsatile flow appears less efficient than steady laminar flow, studies indicate that individual organs require pulsatile flow for optimum function. Perfusion of a kidney with a steady flow instead of pulsatile flow results in a reduction of urine volume and sodium excretion. Pulsatile flow and pressure probably exert their effect at the microvascular level. Although the exact mechanism is unknown, transcapillary exchange, arteriolar and venular tone, and lymphatic flow are all responsive to pulsatile pressure. With each stroke volume of the heart, blood is pumped into the distensible arterial tree, which acts as an elastic reservoir or windkessel absorbing the cardiac energy that is later released during ventricular diastole. The physiologic effect is to damp the flow/no-flow effect of the heart so that the pressure and flow are maintained during diastole. As blood is forced into the aorta, the instantaneous increase in volume is transmitted along the artery as a pressure and flow wave. As shown in Figure 8, the increase in flow starts almost synchronously with the rise in pressure, but the peak flow velocity precedes peak pressure. The instantaneous flow rate is not determined by the magnitude of the pressure pulse but by the pressure gradient developed along the artery. The pressure gradient is determined by recording the pressure at two points, a short distance apart, and subtracting the downstream pressure from the upstream pressure during the cardiac cycle. The effect of the traveling pressure wave is to produce a oscillatory pressure gradient. The magnitude of the pressure gradient determines both instantaneous flow velocity and the

Figure 8 Generation of flow velocity waveform by traveling pressure pulse wave. Simultaneous pressure pulse and flow velocity pulse recordings from an arterial segment. Although similar in configuration, peak flow occurs before the systolic pressure peak, indicating a complex relationship between these hemodynamic parameters. Flow is determined by the pressure gradient that develops along the arterial segment.

direction of flow. Unless there is a marked decrease in the mean pressure along the artery, there will always be a period during the pulse cycle when the pressure gradient is reversed. This reversal of gradient causes a rapid deceleration of flow, and, if it continues after the forward flow has been brought to a halt, flow reversal can occur. Indeed, flow reversal during diastole is a normal pattern of blood flow in peripheral limb arteries. As the pressure-pulse wave travels from the aorta to the periphery, its speed, magnitude, and configuration are altered. The pressure wave is produced by the sudden ejection of blood into the aorta. The pressure wave velocity increases from 4 to 6 cm/sec to approximately 13 cm/sec in the muscular arteries of the lower limb. The velocity of the pressure wave is 20 times greater than the mean velocity imparted to the blood in the aorta (20–40 cm/sec), illustrating that the pressure wave has no direct relationship to flow and can be recorded under ‘‘no flow’’ conditions of acute arterial occlusion. The acceleration of the pressure wave in the peripheral arteries is caused primarily by increasing wall stiffness. Because of this relationship, the transmission velocity of the pressure wave has been used as an index of arterial distensibility. The amplitude of the pressure wave, otherwise known as the pulse pressure, increases, as wave configuration changes with propagation to the periphery (Fig. 9). With increasing distance from the heart, the rate of systolic pressure rise increases, and the sharp inflection of the downslope known as the ‘‘dicrotic notch’’ becomes rounded and disappears in the abdominal aorta, where dicrotic waves appear. In the arteries of the lower limb, systolic pressure is higher, and diastolic pressure is lower than that in the aorta. This is the result of the viscoelastic characteristics of the arterial conduits, the effect of pressure waves being reflected from sites of increased peripheral resistance (i.e., from sites of tapering and branching), and the abrupt increase in resistance at the level of the arterioles.

medwedi.ru

838

Part Six: The Peripheral Vascular System

Figure 9 Pressure waves at different sites in the arterial tress. With pressure wave transmission into the distal aorta and large arteries, the systolic pressure increases, and the diastolic pressure decreases with a resultant increase in pulse pressure. Note that mean arterial pressure declines steadily.

It is important to note that the mean pressure decreases with the distance from the heart, but the pressure loss in the large arteries of the thorax and abdomen is small because of their large radius. As shown in Table 2, systolic and diastolic pressures recorded from large arteries are influenced by various hemodynamic factors. Careful analysis of the pressure wave configuration and its transmission can provide useful clues to important cardiac and peripheral arterial physiology. The pulsatile characteristics of the pressure wave are dampened considerably at the level of arterioles at which mean pressure reaches values up to 40 to 60 mmHg. In general, perfusion pressure in the capillaries is nonpulsatile, and pressure waves in the venous system are caused primarily by pressure changes in the right heart and not the left. Exercise increases total leg blood flow 5X to 10X in the normal patient. In the diseased extremity seen during treadmill duplex evaluation, ankle pressure drops severely and requires prolonged periods of time to recover.

Measurement of Arterial Pressure A major advance in the understanding of and approach to patients with arterial occlusive disease came with the recognition that the physiologic disturbance responsible for symptoms is predominantly related to development of a pressure gradient in the proximal arterial segment. Pressure measurement is a more sensitive index of an occlusive process than is the measurement of flow, because in the presence of moderate arterial disease blood flow is essentially normal, Table 2 Main Determinants of Aortic Systolic and Diastolic Pressures Systolic pressure Stroke volume Aortic distensibility Ejection velocity

Diastolic pressure Systolic pressure Aortic distensibility Heart rate Peripheral resistance

owing to the reduction of resting arteriolar resistance compensating for the increased resistance of the proximal arterial system. Although flow measurement techniques (i.e., indicator dilution methods and impedance flowmeter) have clinical value in the determination of cardiac output, flow volume measurement in the limbs is of limited value as a clinical or diagnostic tool. For these reasons, a variety of direct and indirect arterial pressure measurement techniques are available using noninvasive instrumentation. Direct pressure measurement involves placing a needle or catheter into the artery and recording the pressure waveform with the aid of manometer or strain-gauge transducers. From a continuous recording of the pressure waveform, systolic pressure is the peak pressure during the pulse cycle, and diastolic pressure is the lowest pressure. The difference between these two pressures is the pulse pressure. Mean pressure, the force responsible for the mean flow of blood to an organ, can be determined electronically by calculating the area of the pulsatile waveform or estimated from systolic and diastolic pressure measurements (mean pressure ¼ diastolic pressure þ 1/3 pulse pressure). Although direct pressure measurements provide the most accurate data, their routine clinical use is not warranted, because the technique is invasive and requires sterile conditions, and pressure data obtained indirectly are sufficiently accurate for diagnostic purposes. Indirect pressure measurements depend on (i) the production of Korotkoff sounds, which are the result of turbulence in the flow stream, (ii) the appearance and disappearance of the pressure pulse, or (iii) the reappearance of flow when a proximally located pneumatic cuff has been inflated and slowly deflated above the regional perfusion pressure. Auscultatory (Riva–Ricci method) and palpatory techniques to measure upper limb arterial pressure are the most common hemodynamic assessments of the arterial circulation. To avoid measurement errors, the occluding cuff should be 20% wider than the limb diameter. If it is too narrow, the pressure will be erroneously high; if it is too wide, the reading may be erroneously low. Several techniques are used clinically to measure systolic pressure in the limbs, including plethysmography (mercury strain gauge, air, and photocell) and the ultrasonic velocity detector (continuous-wave Doppler). These instruments are used as sensors to indicate return of flow with cuff deflation. Plethysmography operates on the principle that changes in the circulation of the blood to a body part (e.g., leg) will result in corresponding changes in the size of that part that are measurable. Such changes in size can be measured by displacement of air or mercury in a strain gauge or emission of light in a photoelectric cell, as is done in photoplethysmography. In general, devices with ultrasound are most commonly used because instruments are inexpensive and simple to use, and the Doppler-derived pressure measurements have been thoroughly evaluated and have been noted to be as accurate as plethysmographic measurements. Even when an ultrasonic signal is difficult to obtain, it is almost always possible to record a pressure with the photoplethysmograph. Digital volume changes are then amplified and can be recorded. This allows pressures to be recorded in digits in the presence of severe obstructive arterial disease, when flow velocities are too low to be picked up by a Doppler transducer. The assessment of arterial flow with ultrasound is made on the basis of the Doppler effect, which refers to the shift in frequency that occurs when sound is reflected from a moving object. Moving red blood cells reflect the

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

ultrasound beam and shift the frequency proportional to the flow velocity. The Doppler signal can be (i) amplified to provide an audible sound, with the pitch directly proportional to blood velocity, (ii) converted into an analog waveform using a zero-crossing frequency meter, or (iii) analyzed for its frequency–amplitude content. Failure to obtain a Doppler signal from an artery usually indicates occlusion; however, an extremely low flow rate (under 2 cm/sec) may not produce detectable Doppler frequency shift. The systolic pressure at any level of an extremity can be measured by applying a pneumatic cuff and positioning the Doppler probe over a patent artery distal to the cuff (Fig. 10). The arterial signal is distinguished from the adjacent venous signal by its characteristic high pitch that corresponds to the cardiac cycle. When the cuff is inflated above systolic pressure, the arterial flow signal disappears. As cuff pressure is gradually lowered, the point at which flow resumes is recorded as the systolic pressure. In the lower limb, the use of multiple cuffs placed at the high-thigh, above and below the knee, ankle, and digital levels permits the measurement of segmental pressures. The level of pressure measurement is determined by cuff placement and not the site of Doppler flow detection. The difference in systolic pressure between any two adjacent cuffs or between corresponding segments in the opposite limb is less than 20 mmHg in normal individuals. Because of cuff artifact, proximal thigh systolic pressure normally exceeds brachial pressure by 30 to 40 mmHg. As the distance increases from the heart, an amplification of the pressure wave produces a higher systolic pressure to be measured at the ankle than in the brachial artery, which, in the absence of disease, is nearly equal to central aortic pressure. To compensate for variation in central perfusion pressure and to permit comparisons of serial measurements, the ankle systolic pressure is expressed as a

Figure 10 Measurement of ankle systolic pressure. Doppler probe is positioned over the posterior tibial artery.

839

ratio of brachial pressure, termed the ankle-brachial systolic pressure index (ABI). The normal ABI is equal or greater than 1 (mean value of 1.1 0.1), and reductions correlate with the degree of arterial insufficiency. In limbs with intermittent claudication, the ABI (mean þ S.D.) is 0.58 0.15, in limbs with ischemic rest pain, 0.26 0.13, and in limbs with gangrene, 0.05 0.08. The measure of toe pressures can be used to identify obstructive disease distal to the ankle and to measure pressure in diabetic patients in whom ankle pressure measurement by the cuff method is artifactually high because of the incompressibility of calcified arteries. Normal systolic toe pressure is approximately 80% of the brachial systolic pressure. Photoplethysmographic techniques are better suited than the ultrasonic methods of flow determination at the digital level, because of vessel caliber and a low flow velocity in the digital arteries.

Real-Time Ultrasound Arterial Imaging and Flow Analysis Since the 1970s, ultrasound technology has developed instrumentation to both image vascular anatomy and display blood flow patterns within the lumen in real time. The technique referred to as color duplex ultrasonography, which combines real-time imaging (B-mode) with pulsed Doppler flow detection, is most versatile and permits the arterial and venous circulations to be mapped analogous to arteriography or venography in body regions accessible to interrogation by ultrasonic energy. Duplex scanning can be used to address specific queries concerning location and extent of vascular disease and disease morphology (stenosis, occlusion, or aneurysm), to measure vessel diameter and grade stenosis severity, and to measure occlusion length based on visualization or exit and reentry collateral vessels. In atherosclerotic lesions, B-mode imaging with high (10–15 MHz) frequency transducers can demonstrate features such as ulceration, calcification, acoustic heterogeneity, and intraplaque hemorrhage. Blood flow velocity within visualized vessels is characterized with the use of a Doppler velocity detector. Accurate characterization of blood flow patterns requires the use of a pulsed Doppler whose sample volume (the point in space from which blood flow is detected) is small in relation to the vessel diameter. The Doppler signal is processed by a real-time spectrum analyzer to determine the velocity of blood, the direction of flow, and the velocity distribution of the RBCs in the sample volume. When the pulsed Doppler sample volume is positioned in the midstream of nondisturbed (laminar) arterial flow, the Doppler signal will contain a narrow range of frequencies (spectral width) of similar amplitude corresponding to streamline movement of RBCs during the pulse cycle. Undisturbed flow produces a ‘‘clear window’’ in the spectra beneath the frequency envelope and is characteristic of normal peripheral arterial hemodynamics. Calculation of blood flow velocity requires estimation and assignment of the angle between the incident Doppler beam and the blood velocity vector. An operator-controlled line on the B-mode image indicates the direction of the sound beam from the pulsed Doppler probe. In general, the Doppler beam is adjusted to intersect the flow stream at an angle of approximately 60. A ‘‘cursor’’ on the Doppler beam indicator locates the position of the sample volume and can be placed at any point in the vessel. The Doppler angle is calculated electronically by the operator positioning

medwedi.ru

840

Part Six: The Peripheral Vascular System

a cursor parallel to the longitudinal axis of the vessel. Blood flow velocity is calculated from the frequency spectra waveform measurements using the Doppler equation: Flow velocity ¼

C Fs cos Yðcm=secÞ 2 Fo

where C is the average speed of sound in tissue [1.54 106 cm/sec], Fs is the shift in frequency between the transmitted and reflected Doppler beam, Fo is the frequency of the transmitted Doppler beam, and Y is the Doppler beam angle. If the mean frequency shift can be electronically extracted from the Doppler spectrum, the spatial average velocity (Vsa) as a function of time can be calculated. Volumetric blood flow (Q) can then be determined from a measurement of lumen diameter (D) by the equation: Q¼

Vsa

Q 4

D2

ðmL=minÞ

Although the determination of volumetric flow is attractive, the accurate calculation of Vsa can be quite difficult, because it requires complete insonation of the flow stream across the vessel lumen, knowledge of the velocity profile configuration, and a correction for both the forward and reverse components of pulsatile flow. Duplex scanning provides both anatomic and physiologic informations regarding arterial flow. Tables 3 and 4 provide normal arterial lower limb mean and peak velocities and velocity waveform configurations seen with duplex scanning. This information has been applied clinically to the evaluation and classification of the atherosclerotic occlusive disease involving the carotid bifurcation, visceral arteries (renal, celiac, and superior mesenteric), the abdominal aorta, and the arteries of the lower limb. Under normal conditions, the flow in peripheral and carotid arteries is undisturbed (Figs. 11 and 12). As discussed previously, turbulence is responsible for most of the fluid energy loss associated with arterial disease. Because turbulence occurs at lesser degrees of stenosis than that causing detectable changes in mean flow and pressure, assessment of arterial flow by duplex scanning permits a more accurate diagnosis of altered hemodynamics than is possible by using techniques that monitor pressure and flow. Distal to a site of stenosis, turbulence is evident in the Doppler signal by an increase in peak systolic velocity, an alteration in the velocity waveform, and the presence of spectral broadening corresponding to the disordered, random movement of red blood cells in the flow stream. Accurate characterization of vessel anatomy and

Table 4 Normal Blood Flow Velocity Waveform Configurations in Peripheral Arteries Arterial location Cerebrovascular Internal, common carotid External carotid Vertebral Visceral Celiac Superior mesenteric Fasting Post-prandial Renal Peripheral (upper/lower limbs) Resting After exercise

Biphasic

Triphasic

X X X X X X X X X

flow in both normal and diseased states is possible by duplex mapping of the peripheral arterial system. Accuracy approximates that of contrast and magnetic resonance imaging and can also estimate whether lesions seen on angiogram are hemodynamically significant. Risks, cost, and discomfort are less than that of contrast and magnetic resonance imaging studies, although it is operator dependent and well-trained experienced technologists are required. Natural history studies of atherosclerosis using duplex scanning have demonstrated anatomic and hemodynamic features associated the initiation and progression of vascular disease. Compared with arteriography, diagnostic accuracy of duplex scanning is in excess of 80% in detection of greater than 50% diameter–reduction arterial stenosis or occlusion. Clinical applications include preintervention testing of peripheral, cerebrovascular, and visceral arterial disease, venous testing for acute/chronic venous thrombosis and venous insufficiency, intraoperative assessment of surgical and endovascular therapies, and postoperative graft surveillance and vascular disease.

Table 3 Duplex-Derived Flow, Diameter, and Mean/Peak Systolic Flow Velocity Measurements from Lower Limb Artery Segments Artery segment Duplex Flow (mL/min) Diameter (mm) Mean velocity (cm/s) Peak velocity (cm/s)

Common femoral

Popliteal

Anterior tibial

Posterior tibial

371 8.6 11

140 6.6 7

11 2.2 4

16 2.3 5

89

66

58

57

Figure 11 Color duplex scan imaging of the internal carotid artery. Sample volume of the pulsed Doppler probe is positioned in the proximal internal carotid artery. Narrow band of frequencies during the pulse cycle and the clear area beneath the waveform are characteristics of laminar flow in a normal carotid artery.

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

Figure 12 Color duplex examination of normal superficial femoral artery flow. Velocity spectra and waveform configuration are typical of normal flow in a limb artery.

THE VENOUS SYSTEM The most important role of the venous system is probably that of a return conduit for blood from the peripheral tissues back to the heart and lungs for oxygenation. Veins also serve as a fluid reservoir for the vascular system, with up to 75% of the circulating blood volume being found in the venous system at any one time. In addition to these functions, the venous system is capable of augmenting ventricular filling pressure, thereby increasing cardiac output and stroke volume by sympathetic stimulated vasoconstriction. The mechanisms responsible are best addressed by considering first the anatomic configuration and unique structure of the venous channels, and then the interaction of the structural characteristics with the forces responsible for normal venous return.

841

fascia (Fig. 13). The veins are usually three times the size of their accompanying arteries and are composed of intima, media, and adventitia layers. Generally as one proceeds down the lower extremity, they encounter more valves. These superficial channels are responsible for collection of venous blood from the skin and subcutaneous tissues, and terminate by penetrating the deep fascia at the groin and popliteal fossa, respectively, to enter the deep venous channels. The superficial veins are subject to increased hydrostatic pressure and are therefore relatively thick walled. The superficial veins contain numerous bicuspid valves that facilitate flow from the periphery of the limb to the central portion of the limb and prevent flow in a retrograde direction. Competency of the valves in the lower extremities is more critical as compared to the upper extremity, where a malfunction more often leads to deep vein thrombosis, venous insufficiency, and venous stasis ulcers. The deep system veins accompany the major muscular arteries and are similarly named. In the periphery of the limb, these channels are frequently present in duplicate and, because they are protected from the force of gravity by the muscles in the lower extremity, are relatively thin walled. Bicuspid valves are also present in these veins, with the greatest density occurring peripherally, and relatively few valves being located in the more central larger channels. For example, the superior and inferior vena cava, as well as the common iliac veins are devoid of valves, whereas the external iliac vein infrequently has a single bicuspid valve present. The popliteal vein has one to two valves, while the greater and lesser saphenous systems have about 8 to 10 valves each.

Venous Anatomy The venous system of the lower extremities is divided into superficial and deep systems. There is great variability in the anatomy of the deep and superficial veins, including segmental and complete duplicated systems. In the lower limbs, the common femoral vein is medial to the common femoral artery. The greater saphenous vein joins the common femoral vein at the saphenofemoral junction. The deep and superficial femoral veins generally join 3 to 5 cm cephalad to this point. The greater saphenous venous system begins anterior to the medial malleolus and travels subcutaneously on the anteriomedial aspect of the lower leg, 1 to 2 cm posterior to the tibia. It joins the femoral vein 2 to 4 cm lateral to the pubic tubercle and inferior to the inguinal ligament in the fossa ovalis. The superficial circumflex iliac vein and superficial inferior epigastric vein join the greater saphenous vein also in this area. The venous system is more complex than the arterial system because veins are collapsible, affected by gravity and a low pressure system, contain valves, and are affected by the right side of the heart. The superficial system of the legs consists of the greater and lesser saphenous veins that are located in the subcutaneous tissue superficial to the deep

Figure 13 Diagrammatic representation of the major anatomic features of the greater and lesser saphenous veins and their tributaries.

medwedi.ru

842

Part Six: The Peripheral Vascular System

Figure 15 Schematic representation of the valvular relationships in the superficial veins, the connecting veins or perforators, and the deep venous system. It can be seen that under normal circumstances flow only occurs from the superficial to deep channels.

Figure 14 Schematic representation of the soleal sinuses and their relationship to the calf muscles and deep venous system. It should be noted that these empty directly into the deep venous system and also on occasion receive communications from the superficial system.

A second major component of the deep venous system is the soleal sinuses, a group of endothelium-lined venous reservoirs or ‘‘lakes’’ located within the substance of the gastrocnemius and soleus muscles (Fig. 14). These venous lakes are compressed by the calf muscles and are emptied during contraction, thereby facilitating venous emptying of the lower limb. These vein segments are also devoid of valves, and are a common site of early thrombus formation. Distally, they coalesce to join the peroneal and posterior tibial vessels. The superficial and deep venous systems of the lower extremity are united by a series of perforating veins that pass from the superficial venous system through the deep fascia to the deep venous channels. These perforators range in number from 100 to 200, and are also most frequently located below the level of the knee. Bicuspid valves are also located in these channels so that, under normal circumstances, the flow occurs only from the superficial to the deep venous system (Fig. 15). Venous flow in the lower extremity, therefore, always travels in centripetal direction from peripheral to central channels. The presence of valves prevents reflux in the superficial, deep, and connecting systems. The necessity for valves is greatest at the most peripheral locations, where the gravitational force is greatest, and is least important in the central venous channels, where the pressure changes generated by respiration are sufficient to overcome the effects of gravity. In addition to blood traveling from the peripheral to central regions, it also moves preferentially from the superficial to the deep system, with only 10% of the venous outflow being conducted by the superficial veins and 90% by the deep veins.

Venous Structural Features Vein wall thickness varies from one-third to one-tenth the thickness of the artery wall. Elastin wall content is

considerably less than in the arterial wall, but like arteries, the amount of smooth muscle in the media is variable. The major factor influencing the smooth muscle content is not the necessity for control of regional blood flow as in arteries, but rather the gravitational force from blood the wall must withstand. The great saphenous vein has the highest percentage of smooth muscle, because it is located in the subcutaneous tissue in the lower limbs where it is exposed to maximum gravitational force with standing. At the foot and ankle, the smooth muscle may account for as much as 80% of the total wall thickness, whereas in the axillary vein, it composes only 5% of the vein wall. The smooth muscle fibers are arranged in helical bundles united by strands of connective tissue, with a tough outer layer of predominately collagen fibers constituting the adventitia. Luminal to the smooth muscle layer is the intima, the most important component of which is the single layer of endothelial cells responsible for the blood and vessel wall interface. Perhaps because of the relatively low velocity in the venous system, these cells contain abundant quantities of fibrinolytic agents, with the veins in the lower extremity having higher concentrations than the intimal cells of the upper extremity. The lowest concentration of fibrinolytic active substances is found in the deep veins of the calf region and may in part explain the predisposition for thrombi to form in this location. Because the deep veins are surrounded by skeletal muscles, which protect them from the adverse effects of gravity, they contain smaller amounts of smooth muscle and larger amounts of collagen. Increased collagen is the major factor responsible for the relative stiffness of these veins. In the large central veins such as the vena cava and iliac veins, this property is of major importance in determining shape changes induced by alterations in pressure–volume characteristics. Reductions in the volume of blood in these vessels result in collapse of the wall and assumption of an elliptical shape (Fig. 16). Restoration of volume to normal is associated with a resumption of the normal resting circular cross section. This shape change can also be demonstrated with more minimal external forces such as that generated by the respiratory cycle. However, the most common factor influencing the central veins is the overall circulatory blood volume. These changes in the venous volume are accomplished with minimal changes in pressure because most

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

843

Pressure–Flow Relationships In contrast to the arterial system, blood flow throughout the venous system is not mediated by a central pumping mechanism. The forces affecting pressure and therefore flow in the venous system are generated by respiration and exercise. The relative importance and interaction of these forces is best understood by considering the independent effects of each one and how they impact on the gravitational forces that must be overcome in the erect position. Figure 16 Capacitance of collapsible tubes. Effect of volume change on the cross-sectional area of veins showing the small cross-sectional ellipsoid state and the significant increase in cross-sectional area associated with filling. This change occurs without a change in circumference; because the wall is not stretched, the change can occur with the application of relatively minor force.

veins are partially collapsed during resting conditions. The importance of this is appreciated when it is realized that 40% of the total blood volume may be found in these large central veins at a pressure of 5 mmHg, whereas a reduction to 5% is accompanied by a fall in pressure of only a few millimeters of mercury. This is an example of how the central veins are able to collapse and auto-transfuse their volume into the arterial system, in order to maintain adequate blood flow. Thus the central venous system may be classified as a high-compliance, high-capacitance system as compared to the low-compliance, low-capacitance arterial system. Then, of practical clinical importance is the fact that the pressure measured in the central veins may be used as an index of the moment-to-moment blood volume, i.e., high pressure represents an expanded blood volume, and low pressure represents a volume deficiency. Unlike arterioles, which are very sensitive to local mediators, veins and venules are controlled exclusively by sympathetic adrenergic activity except for the vein in skeletal muscle, which are without sympathetic influence, and the cutaneous veins, which are primarily thermoregulatory. Venous constriction may occur secondary to Valsalva maneuvers, muscular exercise, pain, hyperventilation, emotional stress, or with vasconstrictive medications. Venous dilation can occur in conditions of shock, general anesthesia, or with vasodilator medications.

Gravitational Effects Gravitational forces have a negative effect on venous flow from the lower extremity, and are best appreciated by considering the pressure relationships first in the supine position when gravity is not a factor. In the supine position, the venular end of the capillaries has a pressure of approximately 15 mmHg, and the pressure in the right atrium is 5 mmHg. There is a point in the venous system located in the inferior vena cave close to the diaphragm, termed the hydrostatic indifference point where the pressure is always zero, regardless of attitude (Fig. 17). These pressure gradients are adequate to sustain normal venous return in the supine position, but are augmented by respiratory-induced pressure changes. Assumption of the erect position results in profound changes in these pressure relationships. The system can then be likened to a vertical column of fluid, approximately 180 cm in height, in a hypothetic six-foot ‘‘dead man,’’ although certain modifications of this model are required to parallel the real circumstances (Fig. 17). As noted earlier, the pressure at the hydrostatic indifference point is unchanged by the erect position, and right atrial pressure is normally 0 mmHg. The veins above this point will either fill or collapse, depending on the degree of filling in the system and the effects of respiration. This is best seen in the external jugular vein clinically, where intermittent filling and decompression are readily apparent. The skull acts as a protective barrier against these collapsing forces and maintains the intracerebral venous channels distended even in the erect position. Below the hydrostatic indifference point, the pressure gradually increases so that at the foot level a hydrostatic pressure of 80 mmHg is produced. This has two profound effects, the first of which is cessation of flow from the lower extremities and progressive pooling

Figure 17 Pressure relationships in the various levels of the arterial and venous system shown in the supine (A) and the erect positions (B). HIP is located just below the diaphragam. Abbreviation: HIP, hydrostatic indifference point.

medwedi.ru

844

Part Six: The Peripheral Vascular System

in the leg veins. This associated reduction in venous return secondarily produces a major decrease in cardiac output and, if the stimulus is long enough, may activate the syncope reflex. This pressure is also apparent in a change of the fluid dynamics at the tissue level, and, again, if it persists for any prolonged period, massive extravascular fluid extravasation may occur, further depleting venous return. This negative effort on venous circulation by gravity is overcome by the combined effects of respiration and exercise.

Effects of Respiration The effects of respiration on venous flow are, again, most easily understood by first considering the pressure characteristics and changes that occur with the subjects in the supine position. During inspiration, negative pressure is generated in the thoracic cavity, which facilitates flow into the superior mediastinum from the venous channels in the head, neck, and upper extremity. Descent of the diaphragm produces an increase in intra-abdominal pressure that compresses the inferior vena cava and is associated with a marked reduction in flow from the lower extremities. The pressure changes produced by respiration are insufficient to overcome the gradient that exists between the peripheral venules and the right atrium, and therefore, even during inspiration, there is some venous outflow from the lower extremities. However, cessation of flow may be produced by increasing the pressure a few millimeters of mercury, as occurs with a Valsalva maneuver. Conversely, during expiration, venous return from the upper extremities and head and neck is interrupted, and flow from the lower extremities is augmented (Fig. 18). Assumption of the erect position, however, introduces the force of gravity that drastically alters the pressure–flow relationships. Without the pulsatile pump of the arterial system, the venous circulation does not contain an intrinsic mechanism capable of overcoming this effect. Clearly the relatively small changes induced by respiration are inadequate for normal venous return, and additional forces must be activated. Prolonged assumption of the erect position without activation of other mechanisms results in a serious disturbance of the hydrostatic forces at the tissue level, with

the development of both peripheral edema and venous pooling in the lower extremities. A major force responsible for maintenance of normal venous return in the erect position is contraction of the calf muscles of the lower extremities.

Pressure Changes with Exercise The calf muscle pump is to the venous system what the left ventricle is to the arterial system. The changes produced by calf muscle contraction are best considered by reviewing (i) the overall net effect after multiple muscle contractions and (ii) the step-by-step pressure relationships. Calf muscle contractions exert a force in excess of 80 mmHg on the walls of the calf veins, thus exceeding that exerted by gravity and resulting in a net efflux of blood out of the limb. With each contraction, the venous pressure is progressively lowered until the mean pressure at the ankle level falls to approximately 15 mmHg, similar to that in the resting supine state. These pressure changes are responsible for an overall reduction in the resistance of the peripheral vascular system and an associated increase in arterial inflow to the extremity, as required with exercise. Although this is the mean effect of exercise, the moment-to-moment pressure changes are more complex. During the phase of calf muscle relaxation or diastole, the large venous channels are distended, and the pressure in the deep veins falls below that in the superficial veins. During calf muscle contraction, however, the pressure in the deep veins increases dramatically to exceed the pressure in the superficial veins, with a pumping effect being generated and forcing venous blood out of the extremities in an antegrade direction. During calf muscle relaxation, therefore, flow occurs from the superficial venous system to the deep venous system through the perforating veins; this flow is facilitated by the unidirectional valves contained in the perforating veins. During calf muscle contraction, the unidirectional valves in the deep venous system lead to the blood being forced to flow in a centripetal direction, with the valves in the perforating veins preventing reflux of blood into the superficial system. At the completion of calf muscle contraction, the cycle is again repeated (Fig. 19). Therefore, peripheral muscle pump resembles the working heart as it promotes the circulation of blood out of the lower extremities and empties the deep vein system, decreasing edema and venous congestion in the extremities, both of which result in an increased central blood volume. The increase in frequency and depth of respiration associated with exercise acts to facilitate overall venous return as well, although to a somewhat smaller degree.

Venous Endothelium

Figure 18 Relationship between respiration and flow in the femoral and subclavian veins in the supine (A) and in the erect positions (B). Abbreviations: Ins, inspiration; Exp, expiration.

The endothelium is involved in the apperception of changes in blood flow and can influence vessel luminal size by changing the degree of contraction of the smooth muscle present in the vessel wall. Both natural and pharmaceutical grade compounds have been shown to alter vessel size by either vasodilatation or vasoconstriction, depending on the presence of an intact endothelium. Vessels devoid of endothelium, however, most often react with vasoconstriction alone. The endothelial cell–dependant dilation is related to the production of a nonprostanoid endothelial factor that results in a rise in cyclic guanosine monophosphate. NO, which is derived from L-arginine present in high concentrations in small resistant vessels also promotes vasodilatation. Intact endothelium has been shown to reduce platelet-induced spasms of the vessel wall. If the endothelial lining is

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

Figure 19 Pressure relationship between the superficial and deep venous system during walking. It should be noted that during calf muscle contraction or systole, the pressure in the deep system exceeds that in the superficial; whereas during calf muscle relaxation, pressure in the deep system is less than in the superficial. Filling of the calf muscle pump therefore occurs as with the heart during diastole. Posterior tibial veins are deep veins and great saphenous veins are superficial veins.

undiminished, the complete absence of blood flow for a prolonged period of time does not result in clotting. Furthermore, the endothelium produces several antithrombotic substances as well as a number of procoagulants such as heparin sulfate and thrombomodulin prostaglandin I2 (prostacyclin), Factor 8, and von Willebrand Factor (vWF).

Changes Induced by Disease Acute Venous Thrombosis The development of deep venous thrombosis (DVT) in the major axial veins of the venous system will obviously have an effect of preventing normal venous outflow from the extremities (Fig. 20). This effect can be used as a diagnostic test with plethysmographic methods, to identify this condition. In veins with acute thrombosis, the venous pressure initially stays the same, but as obstruction increases, there is steady rise in the venous pressure as well. This results in accompanying increased edema and inflammation seen in this condition. This effect, however, can be quite variable and depends not only on the location and extent of the venous thrombosis, but also on the availability of collateral venous channels to compensate for the obstruction. It is, therefore, not infrequent to observe that venous thrombosis may not be associated with significant edema, especially in the setting of a well-functioning collateral venous network. A secondary effect of an occlusive thrombus and the development of peripheral venous hypertension is that the minor pressure changes produced by respiration are not transmitted beyond the area of obstruction. Duplex venous ultrasound is now the gold standard for the diagnosis of this condition and demonstrates nicely the flow disturbances associated with DVT. With acute DVT, the flow distal to the obstruction loses its normal phasic relationship to respiration and becomes continuous (Fig. 21). Flow now does not augment well with manual compression distal to the obstruction. Visualizing thrombus is possible with duplex, which carries a 96% specificity and a 94% sensitivity with an overall accuracy of 96%. Air plethysmography has been used to quantitate venous reflux and calf muscle pump ejection volume

845

Figure 20 Plethysmographic recordings from a 60-year-old man four months after left iliofemoral deep vein thrombasis. Recordings were obtained from the right leg with no deep vein thrombosis and left leg with superficial femoral vein thrombosis. Recordings are obtained by inflating a pressure cuff above venous pressure followed by instantaneous release of the pressure. Rate of emptying is significantly less in right leg compared to left leg, a fact that can be used in a diagnostic investigation. Abbreviations: I, inflate; D, deflate; VC, venous capacitance; VO, venous exit flow.

(Fig. 22). The instrument uses an air-filled chamber wrapped around the lower leg to determine absolute volume changes in the leg as a result of exercise. Baseline limb volume is measured with the patient supine and the leg elevated 45 , to empty the veins. Volume measurements are then made during non–weight-bearing standing, and with single and repetitive calf muscle contractions. Calculations are then made to determine venous filling index, ejection fraction, and residual volume fraction. Plethysmography is usually used to evaluate the venous system in preparation for venous surgery, to correct severe venous valve reflux.

Chronic Post-thrombotic Venous Insufficiency The adverse long-term sequelae of venous thrombosis are produced by the residual venous obstruction and the destruction of valves in both the deep axial veins and the perforating

Figure 21 Venous flow patterns in the normal state (A) and in the presence of venous obstruction (B). It should be noted that in the latter there is a loss of the oscillatory pattern produced by respiration. Abbreviations: Exp, expiration; Ins, inspiration.

medwedi.ru

846

Part Six: The Peripheral Vascular System

are small aggregates of lymph tissue that filter the lymph circulation as it moves more centrally; and (iii) lymphoid tissues, which are responsible for fat absorption in the form of chylomicrons, when found in the gastrointestinal tract (e.g., lactiles), and are involved in the humeral mechanism of the immune reaction, when found elsewhere (e.g., spleen, tonsils, and thymus). Although the lymphatic system is involved with gastrointestinal and immune function, it is its role in protein and interstitial fluid reabsorption that is of significant importance to circulatory pathophysiology. Disruption of the balance of arteriovenous hydrostatic or oncotic pressures can produce an imbalance in lymphatic transport capacity and lead to the development of lymphedema. Figure 22 Methods of deriving air plethysmography values. Abbreviations: EV, evoked potential; RV, residual volume; RVF, residual volume fraction; VFI, venous filling index; VFT, venous filling time; VV, venous volume. Source: From Ref. 6.

veins. This latter effect, in particular, produces profound changes in the dynamics of the venous circulation during exercise, which at least, in part, is responsible for the clinical changes of edema, hyperpigmentation, and ulceration. The most significant changes are demonstrated during exercise. Valve destruction adversely affects the flow patterns produced by the pressure changes seen with exercise, and, instead of flowing in a centripetal direction and from superficial to deep, blood may be forced under high pressure from the deep system, during calf muscle contraction, through incompetent perforating veins, into the superficial system producing severe superficial hypertension. In the deep system, the normal antegrade flow pattern is completely interrupted and venous return from the leg is significantly reduced. Instead of a gradual reduction in venous pressure in the lower extremity produced by exercise, in severe cases, exercise may actually be associated with an increase in the venous pressure in both the deep and superficial systems, as depicted in Figure 23. The likelihood of developing severe complications such as venous ulceration is closely related to the degree of ambulatory venous hypertension that occurs in such patients as shown in Table 5.

LYMPHATIC SYSTEM The lymphatic system consists of: (i) lymphatic vessels or plexuses, which consist of a network of closed endothelial tubes that function to recover fluid and macromolecules (e.g., albumin and other proteins) that have diffused into the interstitium at the capillary level; (ii) lymph nodes, which Table 5 Relation of Ambulatory Venous Hypertension to Incidence of Ulceration Ambulatory venous pressure (mmHg) 45 45–50 50–59 60–69 70–79 80

Incidence of ulceration (%) 0 5 15 50 75 80

Anatomy Similar to the venous system of the extremities, the lymphatic system is composed of superficial and deep lymphatic systems. The basic unit of the superficial lymphatic vasculature is an initial lymphatic sinus. These terminal sinuses are lined by a single layer of lymphoid endothelial cells. They coalesce to form lymphphatic aerola, which serve as collection stations for lymph drainage from the skin and subcutaneous tissues. Lymphatic aerola are connected by precollector lymph channels and eventually empty into larger collector lymph channels. One way valves are spaced every several millimeters (mm) throughout the precollector and collector lymph channels and provide with one way lymph flow. The superficial lymphatics are estimated to handle 90% to 95% of the lymphatic effluent from the extremities. The deeper system of the lymphatic vasculature serves to drain the subfascial structures of the musculoskeletal system and the deep circulatory vessels. These two systems seem to run parallel in the extremities, joining in the regions of the pelvis or axilla. In the lower extremities, the lymphatic channels approximate 1 to 2 mm in diameter. The major superficial lymph channels begin in the dorsum of the foot and course primarily along the medial aspect of the leg in the distribution of the saphenous vein. In the upper thigh, these channels terminate in the superficial inguinal lymph nodes and in turn empty into the deep nodal basins. Usually five to eight major lymphatic channels are located at this level. The deep lymphatic channels are less numerous and course in close proximity to the deep muscular arteries of the extremities. In the high thigh, they empty into the deep inguinal lymph nodes as well. In the lower extremities, the lymph circulation then flows from the deep nodal basins into the lymph nodes/channels along the pelvic brim. Again these channels course intimately with the major pelvic vessels. At the level of the lumbosacral joints, these channels form the para-aortic lymph channels that course along the aorta and through the central retroperitoneum. At this level, the lymph from the lower extremities now joins chyle from the intestinal lymphatics in the cisterna chyle, which is eventually transported via the thoracic duct through the thorax, terminating in the posterior triangle on the left side at the junction of the internal jugular and subclavian veins. In the upper extremities, the superficial and deep systems coalesce in the axillary regions and the travel in larger lymph channel to the venous circulation. The thoracic duct drains lymph from the entire body except that of the right arm, neck, head, and thorax. The lymphatics on this side of the body use a lymphatic pathway that empties lymph into the right lymphatic duct that in turn empties in the junction of the right subclavian and internal jugular veins.

Chapter 43: Physiology of Arterial, Venous, and Lymphatic Flow

Physiology Bicuspid valves are located every few centimeters along the course of the lymphatic channels and enable lymph flow to occur from peripheral to more central regions. The lymphatic adventitia contains smooth muscle fibers and is capable of exhibiting vasomotion and self-propagation of fluid. Independent contractions, also called propulsor lymphaticum, can produce pressures in the vicinity of 50 mmHg every four to five minutes. These contractions mimic venous and arterial vasomotion and are mediated by sympathomimetic agents (alpha- and beta-adrenergic agents), arachidonic acid metabolism (thromboxanes and prostaglandins), and neurogenic stimuli. Contraction of adjacent muscle groups as well as the respiratory cycle also serves to assist in the return of lymph flow to the venous system. Intrinsic lymphatic contractility increases in response to tissue edema, temperature change, exercise, and hydrostatic pressure. The understanding of the exchange dynamics at the capillary level is paramount in defining the role of the lymphatics in recovering interstitial proteins and fluids. Capillary filtration and diffusion are the two main processes that drive this exchange and recovery process. The movement of fluid across the capillary membrane is known as filtration. This process is governed by the principles of the Starling hypothesis. Basically, intravascular hydrostatic pressure and osmotic pressure oppose interstitial hydrostatic and osmotic pressure at the capillary level (Fig. 23). A relative increase in the intravascular hydrostatic pressure or a decrease in oncotic pressure favors an increased filtration of fluid out of the capillary membrane. Under normal circumstances, there is a slight excess of fluid filtered at the arterial capillary end over that reabsorbed at the venous end. It is this excess fluid, which approximates 0.003 mL/min/g of tissue in the moving lower limb, that is transported in the lymphatics. Diffusion also plays a major role in the exchange of molecules across the capillary membrane. The semipermeable capillary membrane and the size of the pores govern the diffusion process of micro- and macroprotiens. The lymphatic sinuses of the terminal lymphatics are highly permeable to these proteins and act as suction pumps to facilitate the recovery of these lost proteins. Contraction of the lymphatic wall may result in the generation of a positive

847

pressure proximal to the area of contraction and a negative pressure at the bulbous terminal portion of the lymphatic that facilitates entry of the protein rich interstitial fluid. As much as 50% (150–200 g) of circulating albumin is lost into the interstitial space every 24 hours. The lymphatic system allows for the return of two to four liters of this protein-rich lymph to the venous circulation.

Lymphatics in Disease Disruption in lymphatic flow from occlusion, trauma, infection, or other illness can interfere with the lymphatic system’s role in fluid dynamics, homeostasis, and immune function, termed as secondary lymphedema. Primary lymphedema reflects heritable defects in lymphatic development and function and is classified by the age of onset. Congenital lymphedema is apparent within the first two years of life, represents 15% of clinical cases, and is caused by aplasia or hypoplasia of lymphatic channels. Lymphedema prascox comprises 75% of clinical cases and is first detected at puberty. Lymphedema tarda, which typically appears after the age of 35, can result from either hypoor hyperplastic lymphatic vasculature. Skin and limb changes with lymphatic obstruction or inefficient lymphatic outflow are different from those seen with arterial or venous obstruction. Obstructed lymphatic vessels have been known to have pressures as high as 50 to 60 mmHg, and unlike the vascular system, a collateral network does not exist. If flow in the vascular system becomes impaired or obstructed, the supply of essential nutrients to tissues is impaired and tissue ischemia results. Because valves are absent in the terminal sinuses of the minute lymphatic capillaries of the dermal plexuses, disruption or obstruction in the larger lymph channels results in a significant increase in extracellular fluid retention and resultant edema. This edema, also called ‘‘lymphedema,’’ appears gradually with lymphatic obstruction. An accumulation of large protein molecules in the tissue results in increased oncotic pressure and a net accumulation of extracellular fluid. The delivery of nutrients is typically only minimally impaired, and tissue viability is generally maintained. Eventually a steady state will be reached at which the hydrostatic pressure exerted by the fluid in the tissues will balance that of the oncotic pressure, and essentially normal fluid exchange will continue. Despite what seems like a restoration of fluid homeostasis, the edema will remain, unless additional therapy is instituted. Treatment programs, also known as lymphedema clinics, institute a multidiscipline team approach toward dealing with this condition. Medical management and dietary counseling is undertaken. Physical therapy and exercise programs are initiated. These programs typically use a combination of compression garments and massage therapies to reduce the peripheral edema. Occasionally, lymphatic pumps can also be employed. The role of surgery for the condition of lymphedema continues to decline due in part to the success of these programs.

SUMMARY

Figure 23 Effect of calf muscle exercise on ankle pressure in patients with the postthrombotic syndrome. There is no significant decrease in venous pressure associated with exercise as is seen in the normal state.

The circulatory system as a whole serves to maintain normal tissue nutrition under conditions of rest and exercise, with both the arterial and venous systems, like many other body systems, having a sizeable functional reserve capacity. The arterial and venous systems are primarily involved in the maintenance of a favorable tissue milieu for normal

medwedi.ru

848

Part Six: The Peripheral Vascular System

metabolism, with the lymphatics functioning as a scavenger system to remove macromolecules and any excess of fluid that is extravasated from the capillary mechanism. Whereas the arterial system is dynamic with the energy being provided intrinsically by contraction of the left ventricle, both the venous and lymphatic systems are uniquely designed to facilitate movement of fluid under relatively low pressures and rely predominately on extrinsic forces such as respiration and skeletal muscle contraction to offset the ‘‘edema-producing’’ effects of gravity.

Diagnosis of Vascular Disease. Pasadena, Calif: AppeletonDavies, 1984. 5. Summer DS. Pitfalls on noninvasive cerebrovascular testing and angiography. In: Bernhard VM, Towne JB, eds. Complications in Vascular Surgery. 2d ed. New York: Grune & Stratton, 1985. 6. Belcaro G, Laurora G, Christopoulos S, et al. Noninvasive tests in venous insufficiency. J Cardiovasc Surg 34; 3:1993. Reprinted with permission.

FURTHER READINGS REFERENCES 1. Smith JJ, Kampine JP. Circulatory Physiology. 2nd ed. Baltimore: Williams & Wilkins, 1984. 2. Zierler RE, Strandness DE. In: Moore WS, ed. Vascular Surgery–A Comprehensive Review. New York: Grune & Stratton, 1983. 3. Ruch TC, Patton HD. Physiology and Biophysics. Philadelphia: WB Saunders, 1974. 4. Roederer G, Langlois Y, Strandness DE Jr, et al. Comprehensive noninvasive evaluation of extracranial cerebrovascular disease. In: Hershey FB, Barnes RW, Sumner DS, eds. Noninvasive

Burton AC. Physiology and Biophysics of the Circulation. Chicago: Year Book Medical Publishers, 1972. Cockett FB, Dodd H, eds. The Pathology and Surgery of the Veins of the Lower Limb. Edinburgh: Churchill Livingstone, 1976. Folkow B, Neil E. Circulation. Oxford: Oxford University Press, 1971. Guyton AC. Human Physiology and Mechanism of Disease. 2d ed. Phildelphia: WB Saunders, 1982. Milnor WR. Hemodynamics. Baltimore: Williams & Wilkins, 1982. Strandness DE, Sumner DS. Hemodynamics for Surgeons. New York: Grune & Stratton, 1975. Szuba A, Rockson S. Lymphedema anatomy, physiology, and pathogenesis. Vasc Med 1977; 2:321–326.

44 Aorta and Arterial Disease of the Lower Extremity Christopher K. Zarins and Sheila M. Coogan

INTRODUCTION Degenerative changes in the aorta and atherosclerosis of lower extremity arteries account for the majority of vascular complications in elderly patients (1). Aging of the baby boom population will result in rapid growth of the elderly population. By the year 2040, people older than 65 will comprise 22% of the U.S. population, or 67 million people. The most striking aspect of this trend is the increased rate of survival of those older than 75 (2). Obviously, the management of atherosclerotic complications of the aorta and its branches will play an increasingly significant role in the primary health care of a major portion of the adult American population. Atherosclerotic arterial disease is characterized by the formation of intimal plaques. These plaques may obstruct the lumen, ulcerate and embolize, cause thrombosis, or contribute to aneurysmal degeneration of the arterial wall. Each of these processes may result in a spectrum of clinical presentations requiring different diagnostic and therapeutic approaches. In this chapter, we consider some of the general features of the atherosclerosis, along with its pathologic and clinical manifestations in the lower extremity, and discuss diagnostic methods and current treatment alternatives.

ATHEROSCLEROSIS Risk Factors The risk factors for atherosclerosis may be divided into two major categories, reversible and irreversible. Major reversible factors include cigarette smoking, diabetes mellitus, hyperglycemia, hypertension, abnormalities of lipid metabolism, obesity, and low levels of physical activity. Nonreversible factors are primarily sex, age, and genetic influences of family history. It has been generally assumed that the factors associated with plaque formation and development in the extracoronary arteries are the same as those in the coronary arteries (2). However, there have been few population-based studies of risk factors associated with atherosclerosis of the aorta or the lower extremity branches. Several early studies considered only the symptomatic form of the disease (3,4). More recently, noninvasive methods have been used to identify and include asymptomatic subjects in these investigations (5,6). These findings are summarized in Table 1. The most significant risk factors apparently have independent effects (i.e., not cumulative) on the vasculature of the abdomen, pelvis, and lower extremity. Control of certain risk factors may have a beneficial effect on the expression, of the disease. Cessation of tobacco use has a beneficial effect on peripheral occlusive disease, and limb loss rates and arterial graft patency rates are

improved in patients who can successfully abstain from tobacco (7,8). Optimization of serum lipid profiles and control of hypertension have less certain impact on the progression of lower extremity arterial disease, but are known to be beneficial in preventing progression of coronary atherosclerosis (2). Physical exercise may ameliorate the symptoms, of aortic and peripheral occlusive disease, and may play a role in preventing progression of disease. Weight reduction and control of environmental stress also play important roles. Recent data from the Diabetes Control and Complication Trial suggest that close control of serum glucose does not prevent progression or complications of peripheral vascular occlusive disease as measured by limb salvage in the setting of insulin-dependent diabetes mellitus (9).

Configuration and Composition of Atherosclerotic Plaque Although atherosclerotic plaques contain varying amounts of lipids, it is unclear whether all lesions containing lipids are necessarily precursors of clinically significant atherosclerotic plaques. A prime example of this uncertainty is demonstrated by the questionable significance of the socalled fatty streak lesion. This term describes a flat, yellow, focal luminal patch or streak, representing an accumulation of lipid-laden foam cells in the intima, evident in most people older than three years. They are identified with increasing frequency between the ages of 8 and 18, after which many apparently resolve. Fatty streaks exist at any age, often adjacent to or even superimposed on advanced atherosclerotic plaques. Fatty streaks and atheromata, however, do not have identical patterns of localization, and fatty streaks do not compromise the lumen or ulcerate (10). Although this subject remains controversial, the link and

Table 1 Risk Factors Associated with the Development of Lower Extremity Arterial Disease, Disease Progression, and Mortality Risk factor Smoking Diabetes Hyperlipidemia Hypertension Physical activity Hemorheologic factors Obesity

Genetic factors

Development of disease

Progression

Mortality

Yes Yes Yes Yes Yes NAI

Yes NAI NAI NAI NAI NAI

Yes Yes NAI Yes Yes NAI

No; however, may be a weak risk factor in men NAI

NAI

NAI

NAI

Yes

Abbreviation: NAI, not adequately investigated.

medwedi.ru 849

850

Part Six: The Peripheral Vascular System

transition between fatty streak and fibrous plaque formation remain to be clarified. The term fibrous plaque identifies the characteristic and unequivocal atherosclerotic lesion. These intimal deposits appear in the second decade of life, becoming predominant or clinically significant only during or after the fourth decade. Fibrous plaques usually are eccentric and are covered by an intact endothelial surface. Although considerable variation exists in plaque composition and configuration, a characteristic architecture prevails. The immediate subendothelial region of the plaque consists of a compact and well-organized stratified layer of smooth muscle cells and connective tissue fibers known as the fibrous cap. This structure may mimic medial architecture, including the formation of a subendothelial elastic lamina, which may function to sequester the underlying necrotic and thrombogenic plaque core from the luminal surface. This surface usually is regular, with a concave contour corresponding to the circular or oval cross-sectional lumen of the uninvolved vessel wall segment. The stable necrotic core occupies the deeper plaque (Fig. 1). The core contains amorphous, crystalline, and droplet forms of lipid. Cells of undetermined origin, with morphologic, functional, and cell surface receptor characteristics of smooth muscles or macrophages are noted beneath the core. These cells also may contain lipid vacuoles. Calcium and myxoid deposits, collagen and elastin matrix fibers, basal lamina, and amorphous ground substance are also evident. Atherosclerotic plaques grow in an episodic fashion, demonstrating dense fibrocellular regions adjacent to organizing thrombus and atheromatous debris. Intermittent ulceration and healing occur, with thrombi being incorporated into the lesion. Vasa vasorum may nourish the plaque, facilitating the organization of thrombotic deposits and the remodeling of

Figure 1 Atherosclerotic plaque demonstrating the fibrous cap over a necrotic center. Note the oval external contour with the round lumen typical of these plaques.

the plaque and artery wall (11). Attenuation of the subadjacent media promotes outward bulging of the plaque toward the adventitia. Although this attenuation sequesters plaque, enlarges the artery, and stabilizes the wall, a predominant lytic reaction may result in excessive arterial dilation or aneurysmal degeneration. Experimental evidence suggesting such a mechanism for aneurysm formation has been obtained in nonhuman primates in our laboratory (12) and by other investigators (13). Tissues between the necrotic core and the media, however, usually are densely fibrotic. Arterial wall support may thus be maintained by the integrity of the fibrous cap or thickened adventitia. Advanced lesions, particularly those associated with aneurysms, may appear to be atrophic and relatively acellular, consisting of dense fibrous tissue and a minimal necrotic center. Calcification is a prominent feature, involving the superficial and deeper layers. Terms such as fibrocalcific, lipid-rich, necrotic, and myxomatous describe various predominant aspects of advanced plaques. Calcific deposits are most prominent in plaques in older people and in the abdominal aorta or coronary arteries, where the earliest plaques form in animal models and in humans (14). The usual eccentric plaque bulges outward from the lumen; the external cross-sectional contour of an atherosclerotic artery becomes oval while retaining a circular lumen (Fig. 1) (15,16).

Localizing Factors in the Development of Atherosclerotic Lesions Adaptive changes in arterial luminal diameter are determined by changes in blood flow. During embryologic growth and development, lumen diameter is determined by the volume of blood flow. After birth, increases in artery diameter continue as a response to increases in blood flow (17). This phenomenon is also demonstrated in mature arteries after cessation of growth, with enlargement of arteries proximal to arteriovenous fistulas and a decrease in the size of arteries proximal to amputated limbs (18). Luminal diameter adaptation is responsive to wall shear stress, as determined by the effective velocity gradient at the endothelial-blood interface (19). In mammals, wall shear stress normally ranges between 10 and 20 dynes/cm2 at all locations throughout the arterial vasculature. In arteriovenous fistulas, the afferent artery enlarges enough to restore shear stress to this physiologic range (20). This response depends on the presence of an intact endothelial surface (21) and may be mediated by the release of endothelium-derived relaxant factors, including nitric oxide or other vasoactive agents (22). Near-wall properties of arterial flow fields and the distribution of mural wall shear stress correspond closely to atherosclerotic plaque localization (23–30). Plaques develop where shear stress is reduced (25,26), not elevated, with an intact endothelial surface, even in the absence of platelet deposition (31). The revised response to injury hypothesis now stresses on metabolic or functional changes sustained by intact endothelial cells that alter binding or metabolism of lipid molecules or modify transendothelial transport, rather than denudation of the endothelium itself (32). Atherosclerosis tends to occur principally in three locations within the arterial vasculature: the carotid-cerebral, coronary, and aortic-peripheral system. Within these predisposed regions, lesions form in predictable geometric configurations, demonstrating the influence of shear stress and flow patterns. Size as well as localization closely correlates with low wall shear stress and departures from unidirectional

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

flow (25,26). Plaque initiation and localization are the result of low rather than high shear stress, low flow velocity, flow separation, and oscillation in wall shear direction (33). Regions of increased mural tensile stress about branches (23), pulsatile wall motion (34), and wall thickness and density (35,36) are also associated with selective plaque localization. Conversely, regions of relatively elevated wall shear stress or reduced tensile stress, at flow dividers and along the outer or convex aspects of curved arterial segments, generally are spared (37). Hemodynamics and tensile influences are also important in plaque progression and evolution (38,39) and influence potential plaque regression (40). As an example of this influence on regression, hypertension was found to sustain experimental plaque progression in a hypercholesterolemic cynomolgus monkey model, despite a reduction in serum cholesterol level (41). Reduced flow and consequent reduction in wall shear stress also tend to induce intimal thickening. An increase in wall volume, including cell enlargement, cell proliferation, and net matrix accumulation, is demonstrated in long-term reactions (42). A sieving effect related to these changes in wall composition (43,44) and porosity (35) has been proposed. Wall thickening, including intimal thickening, may retard transmural mass transport, providing the basis for intimal lipid deposition (45). The accumulation of matrix fibers with affinity for lipid molecules (46–50) and the fusion or accretion of lipid particles on these components may also be responsible.

851

vessels are naturally existing branches of large- and mediumsized arteries that enlarge to carry blood flow around an obstruction. They do not represent neovascularization but adaptation of existing vessels to an increased demand of blood flow. The collateral blood flow that develops in the face of a developing, progressive obstruction usually can supply the demands of resting tissue. However, it often is unable to supply the flow necessary for an exercising muscle group. There are a number of well-recognized collateral beds that develop in the presence of atherosclerosis of the aorta and distal tree: 1. 2. 3. 4. 5.

Intercostal and lumbar arteries Superior and inferior mesenteric arteries Hypogastric artery Profunda-genicular arteries Peroneal-tibial arteries

Patients may have a totally occluded abdominal aorta for several years, with relatively mild symptoms of hip and buttock claudication. Under these circumstances, the intercostal arteries, superior epigastric arteries, and visceral arteries become important sources of collateral flow to the lower extremity (Fig. 2). For example, blood supply to the distal aorta may be through the inferior mesenteric artery, which derives collateral supply from the superior mesenteric artery. In addition, the inferior mesenteric artery

PATHOPHYSIOLOGIC PROCESSES AFFECTING THE AORTA AND LOWER EXTREMITY ARTERIES The processes affecting the arteries to the lower extremity include plaque formation with obstruction of the lumen and subsequent limitation of flow, thrombosis resulting in acute ischemia, ulceration of the plaque with distal embolization, and weakening of the arterial wall with aneurysmal formation resulting in rupture or thrombosis.

Stenosis Progressive intimal plaque deposition may result in narrowing of the lumen, or stenosis. Mild degrees of stenosis producing less than 50% reduction in lumen diameter usually do not obstruct blood flow. It is not until lumen diameter falls below a critical point that resistance to blood flow increases. This is referred to as critical arterial stenosis, or the percentage by which the lumen diameter must be reduced to produce a measurable drop in blood flow. Under experimental conditions, there is no significant pressure drop and no reduction in flow until there is more than 80% reduction in lumen cross-sectional area (equivalent to 55% diameter reduction) (51). However, pressure drops across stenoses are critically dependent on flow, and noncritical stenoses at rest may develop significant pressure gradients when flow is increased with exercise. This can account for the clinical observation of disappearing pedal pulses after exercise and symptoms of claudication in patients with palpable pedal pulses. The extent of disability from an obstruction is related to the location of the lesion, the degree of obstruction, the length and number of obstructions, the metabolic needs of the tissues distal to the obstruction, and the ability of collateral vessels to provide the necessary flow. Collateral blood flow may be quite extensive in occlusive disease. Collateral

Figure 2 Angiogram revealing severe aortoiliac disease. Note the large collateral vessels (arrows) that have developed in response to occlusion of the left iliac artery.

medwedi.ru

852

Part Six: The Peripheral Vascular System

can be an important source of collateral flow to the lower extremity through the superior hemorrhoidal network.

Thrombosis The causes of acute arterial obstruction can be divided into two categories: embolism and thrombosis. Emboli arise from a proximal source, either the heart or proximal great vessels, and obstruct the tapering arterial tree at a branch point or at the point where the embolus is larger than the lumen diameter. Mural thrombus that forms in a fibrillating atrium is the most common source of arterial emboli (52), but emboli can also arise from areas of recent transmural infarction, ventricular aneurysms, and diseased valves. Spontaneous thrombosis usually occurs in arteriosclerotic arteries as a result of slow flow caused by severe stenotic lesions or as a result of sudden dissection or hemorrhage under a previously nonstenotic plaque. Acute thrombosis usually results in very sudden and severe symptoms of arterial ischemia. The severity of clinical symptoms is related to the site of the obstruction, the size and extent of the thrombus, and the adequacy of the collateral vessels. In severe ischemia, one or more of the often-described five Ps may be present: pulselessness, pallor, paresthesia, pain, and paralysis. The loss of motor power and sensation in the toes and foot indicates very severe ischemia and limb loss unless the ischemia is relieved promptly. Acute thrombosis of a previously stenosed artery that has excellent collateral vessels about it may occur with only mild symptoms and little risk of limb loss.

This explains why larger aneurysms have a greater tendency to expand and rupture than do smaller aneurysms. Blood flow in the dilated aneurysmal sac is slower than normal, producing an increased tendency to thrombosis. Most large abdominal aortic aneurysms are lined by laminated mural thrombus. Mural thrombus may be so thick that the lumen caliber on angiography does not appear enlarged. However, mural thrombus provides little, if any, support for the artery wall and no protection from aneurysm rupture.

ARTERIAL OCCLUSIVE DISEASE OF THE AORTA AND PERIPHERAL ARTERIES The manifestations of atherosclerosis in the aorta and peripheral arteries are either occlusive disease or aneurysm formation. The arteries of importance in the circulation to the lower extremities are diagrammed on Figure 3. Obstructive plaques may occur in each of the vessels shown but are most common in the infrarenal abdominal aorta, iliac arteries, and superficial femoral arteries. The profunda femoris artery is relatively spared, and diabetic patients are more prone to develop lesions in the tibial arteries.

Ulceration Ulceration occurs when breakdown of the fibrous cap over a lesion exposes the necrotic core of the plaque to the circulation. This may be the site for platelet deposition (1) and thrombus formation or may result in embolization of the plaque contents itself, producing cholesterol emboli in the distal arterial tree. The most common clinical syndrome in the peripheral circulation associated with distal embolization from a proximal ulcerated plaque is the blue toe syndrome. Patients may have normal pedal pulses but suddenly develop one or more cold, blue, painful toes—a condition that resolves in three to four days. These symptoms may be caused by cholesterol emboli in the digital arteries of the feet. The source of the emboli usually is a proximal ulcerated lesion in the aorta, iliac, or femoral vessels. Unrecognized and untreated repeated embolization to the foot results in obstruction of the small arteries of the foot, gangrene, and limb loss.

Aneurysm Formation An aneurysm is a localized arterial dilation. A true aneurysm is one in which there is thinning or atrophy of all layers of the artery wall, with enlargement of the lumen. This should be distinguished from a false aneurysm, which results from a rupture of the artery wall, usually caused by trauma, with containment of the blood stream by fibrous tissue surrounding the vessel. Thus in a true aneurysm there is an inadequate artery wall, whereas in a false aneurysm there is absence of the artery wall. As the lumen radius of an aneurysm enlarges, there is an increase in tension on the vessel wall (T), according to the law of Laplace (T ¼ Pr), where P is pressure and r is radius. The larger the radius, the greater is the tension and the greater is the tendency for further enlargement of the lumen.

Figure 3 Arterial supply to the viscera and lower extremity. Obstructive or aneurysmal changes can occur in each of these vessels. The clinical signs and symptoms vary depending on the location and blood supply distribution of a given artery. Full angiographic evaluation of the aorta and lower extremity vessels should demonstrate flow through each of these arteries.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

Clinical Manifestations of Peripheral Occlusive Disease The clinical manifestations and physical findings of peripheral occlusive disease are as follows: Clinical manifestation Claudication Rest pain Ulceration Gangrene Impotence

Physical findings Absent or diminished pulses Bruits Skin pallor Hair loss Dependent rubor Skin and muscle atrophy Trophic changes of the nails Tissue necrosis

Claudication Claudication arises from the term claudicatio, which means to limp. It is a clinical syndrome of pain on exercise, which is relieved by rest and results from a fixed obstruction or stenosis in arteries to the lower extremity. Although circulation may be adequate at rest, with exercise there is an increasing demand for flow. When such flow is obstructed by a stenosis, the muscle served by that vessel becomes ischemic and begins to function with anaerobic metabolism. This results in pain and symptoms of fatigue, causing the patient to stop and rest. Typically, the patient rests for one to two minutes, allowing the circulation to again restore aerobic conditions, after which the patient can again exercise. Patients with aortoiliac occlusive disease have symptoms of claudication in the hips and buttocks, whereas patients with superficial femoral artery obstruction have symptoms of claudication in the calf. The level of claudication is always below the level of the arterial obstruction. Most patients with claudication, although symptomatic, are at low risk for developing gangrene. Only 33% of patients with proven arterial stenosis report symptoms of claudication. It is a stable disease in 70% to 80% of patients, and it is generally clinically accepted that only 25% of claudicants deteriorate (53–57). Thus patients with stable, nonlimiting claudication may be safely followed, and revascularization should be reserved for those with disabling symptoms. Reconstructive surgery to improve blood flow is done in less than 10% of all patients with claudication. Amputation may be required in 1% to 5% (58). The benign nature of this symptom should be carefully considered when planning any type of intervention, either catheter based or via traditional open arterial surgery.

Rest Pain Patients with worsening ischemia develop a clinical syndrome called rest pain. The condition of rest pain indicates a much more severe degree of ischemia than claudication and, unlike claudication, indicates that the patient is at high risk for developing gangrene and limb loss. Typically, the patient experiences pain in the toes and forefoot during the night, which causes him or her to awaken from sleep. The patient usually sits up in bed, dangles the legs over the side of the bed, and frequently relieves the symptoms by getting up and walking. After a short period of time, the patient’s symptoms have disappeared and the patient can return to sleep. The symptoms of rest pain occur because of severe ischemia in the forefoot and toes, brought about by two conditions: (i) the patient is recumbent and thereby eliminates the hydrostatic pressure gradient that assists

853

the arteriolar perfusion pressure when erect; and (ii) during sleep there is a diminution of cardiac output that correspondingly diminishes the volume of peripheral blood flow. When the patient dangles the feet, he or she restores the hydrostatic gradient; when the patient gets up to walk, he or she increases cardiac output and thereby improves the perfusion of the lower extremities. Sometimes patients complain of nocturnal cramps in the calf muscles. Such cramps are usually not related to vascular ischemia and should be differentiated from nocturnal rest pain, which typically is in the toes and forefoot rather than in the calf.

Ulceration Cutaneous ulcers may be the first evidence of peripheral vascular disease. These ulcers are caused by severe ischemia from proximal arterial occlusions and often are initiated by minor skin trauma. However, there are many causes of skin ulceration, which must be differentiated from ischemic ulcers: & & & & & & & &

Venous stasis Infection Neoplasm Neurotropism Hematologic abnormalities Allergic reactions Insect bites Injections

Each type of ulcer has certain clinical and physical characteristics. The ischemic ulcer is most commonly found on the toes, heel, dorsum of the foot, or lower third of the leg. The pain is usually severe and persistent, and worsens at night. The ulcer itself is generally irregular, with a pale or necrotic base. At times, patients have ulcerations that are attributed to venous disease that may in fact be the result of a combination of arterial ischemia and venous stasis. Ulcerations not in the classic position for venous disease (at the medial malleolus) should be considered as potentially being of an arterial origin. Even if a component of venous disease is present, the arterial component must be evaluated if effective therapy is to be instituted.

Gangrene Progressive ischemia caused by atherosclerosis can result in gangrenous changes of the tissues. Most commonly the digits are affected initially, but progression to the forefoot is not unusual. Small amounts of infection superimposed on a severe chronic ischemic state can progress very rapidly to gangrene. Clinically, dry and wet gangrene should be differentiated. Dry gangrene represents mummification of tissue, and active purulent tissue and cellulitis are absent. Wet gangrene is characterized by active infection with cellulitis and purulent tissue planes and is an indication for urgent amputation to prevent ascending infection.

Impotence Penile erection requires a threefold increase in blood flow through the penile arteries, which is shunted into the vascular spaces of the corpora cavernosa. Arterial obstruction that prevents this increase in blood flow can result in erectile impotence in much the same way that symptoms of claudication are brought about by exercise when there is an unmet demand for increased blood flow. Rene Leriche in 1923 first noted the association among atherosclerotic occlusion of the

medwedi.ru

854

Part Six: The Peripheral Vascular System

aorta, hip claudication, buttock atrophy, and erectile impotence. This is now known as the Leriche syndrome. Obstruction can occur at any level from the abdominal aorta, the common iliac arteries, the internal iliac arteries, the internal pudendal arteries, or the penile arteries, resulting in erectile impotence. Although the majority of cases of impotence have psychogenic or urologic causes or are the result of the side effects of medication, the importance of an adequate vascular supply is becoming increasingly recognized and can be objectively assessed, as is discussed below.

EVALUATION OF PERIPHERAL VASCULAR OCCLUSIVE DISEASE Peripheral vascular occlusive disease is evaluated on the basis of a thorough medical history and clinical examination, noninvasive vascular testing, continuous acquisition (‘‘spiral’’) computed tomography (CT) scanning, magnetic resonance (MR) angiography, and intra-arterial contrast angiography.

Clinical Examination Peripheral oscular occlusive disease may be accurately diagnosed with a careful history and thorough physical examination of the patient. In addition to the important determination of symptoms of claudication or rest pain, the patient’s level of activity and walking distance should be noted. Often patients with very severe disease do not walk enough to develop symptoms. A careful evaluation of all pulses should be made, although the presence of a palpable pulse does not rule out the possibility of significant arterial occlusive disease. A bruit may be appreciated during the physical examination. Bruits are produced by the turbulence of blood just distal to a stenosis but may also be produced by angulations and bends in arteries. Bruits may be audible with a stethoscope over and distal to an area of stenosis. A high-pitched bruit may be indicative of a severe stenosis. Finally, the temperature, quality, and color of the skin, hair, and nails should be noted, including the presence of skin ulcerations or gangrenous changes. Noninvasive tests are used after the clinical examination to confirm the presence of occlusive disease, identify the level and severity of the disease, and assess whether angiography is required to further evaluate these patients.

Objective Assessment with Vascular Laboratory Techniques Doppler Ankle Pressure The ready availability of the handheld Doppler ultrasound has made measurement of lower extremity blood pressure simple and convenient and has permitted the development of objective means of assessing lower extremity perfusion. The Doppler ultrasound probe emits high-frequency sound waves in the range of 2 to 10 MHz. The sound is reflected by the movement of red blood cells in the vessel, which produces a frequency shift that is picked up by the receiving crystal of the Doppler probe. This frequency shift is proportional to the blood flow velocity. This Doppler shift can be expressed by the following formula: Df ¼

2fVcosy C

where V is velocity, f is frequency of the incident sound beam, C is velocity of sound in tissue, and y is the angle

of the incident sound beam to the vessel examined. Because V, C, and y can be constant, the shift in frequency is proportional to the velocity of the blood flow. To measure the blood pressure in the legs, a blood pressure cuff is placed at the ankle just above the malleoli and inflated while a handheld Doppler is used to listen to the flow in the dorsalis pedis and posterior tibial artery. Inflation of the cuff above systolic pressure causes obliteration of the Doppler signal, and systolic blood pressure can be recorded as the cuff is deflated and flow resumes in the measured vessel. Because a patient’s blood pressure may fluctuate, more precision can be gained by comparing the ankle pressure to the brachial pressure. Usually, the ankle systolic pressure is divided by the brachial systolic pressure to produce an ankle-brachial index (ABI). Such an index is quite useful in assessing the severity of peripheral occlusive disease. Patients without occlusive disease have an ABI of 1, whereas patients with claudication have an ABI of 0.5 to 0.6. Patients with rest pain, gangrene, and ulceration have an ABI of 0.4 and less (Fig. 4). Despite these ranges, considerable overlap can be present, especially around an ABI of 0.5. This measurement is useful for differentiating patients with lower extremity pain caused by spinal stenosis, arthritis, or other nonvascular conditions. Patients with diabetes frequently have calcified vessels that cannot be compressed by the blood pressure cuff. This may lead to a false elevation of the ABI. In the setting of incompressible ankle vessels, toe pressure or waveforms may be more accurate. It is important to note that the pressure measured is determined by the location of the cuff rather than the location of the listening probe. Thus an ankle pressure can be recorded by placing a cuff at the level of the malleoli, and a below-knee or above-knee pressure can be recorded by appropriate blood pressure cuff placement. Patients with superficial femoral artery occlusion have a normal pressure reading in the upper thigh but an abnormal pressure reading below the knee and at the level of the ankle. The resting ankle index is the most accurate of the noninvasive techniques for objectively assessing the presence or absence of occlusive disease. It is reproducible, and hence the index can be followed to identify the progression of disease. It should also be recognized that listening for and hearing flow in the dorsalis pedis and posterior tibial arteries does not represent a pulse. A pulse is palpated with the fingers. Flow can be heard at very low levels of circulation in the dorsalis pedis and the posterior tibial arteries, and patients may have frank gangrene of their foot even though audible Doppler signals are heard. One should not be lulled into a false sense of security of good perfusion of the foot if Doppler flow signals in the foot are heard but pulses cannot be palpated.

Figure 4 Ankle-brachial index is used to determine severity of lower extremity ischemia. Circles denote range consistent with claudication; Xs denote area of limb-threatening ischemia. Note area of considerable overlap around 0.5.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

855

Stress Testing Because patients with claudication develop their symptoms only with exercise, stress testing is a useful means for documenting the degree of walking impairment. Treadmill exercise can be performed at a standard pace of 1.5 miles/hr at a 7-degree grade. Normally, one has no diminution of the ankle pressure following exercise. On walking to the point of claudication, there is a substantial drop in ABI because blood flow is shunted to the proximal thigh muscle and cannot pass through the obstruction to the distal vascular bed. There is return of ankle pressure to normal with rest. The symptom of reduction in ankle pressure is similar to the finding of disappearing pulses with exercise, seen on clinical examination.

Doppler Waveform Analysis Doppler detectors can provide an analog signal that is proportional to the velocity of the blood in vessels studied. The shape of the waveform reflects the status of the vessel. Normally, a triphasic waveform is seen, indicative of reversal of flow in early diastole. Stenosis proximal to the vessel examined first eliminates this reversed flow. As the stenosis becomes more severe, the peak of the waveform is blunted, and the waveform widens (Fig. 5). Qualitative analysis of these waveforms at different levels of the extremity can identify the level and severity of occlusive lesions. Analysis of the Doppler waveforms in conjunction with systolic pressures at several levels in the leg can allow the clinician to make an accurate diagnosis of the location and extent of peripheral vascular occlusive disease. For example, Figure 6 illustrates the decrease in the waveform and systolic pressures across an obstructed superficial femoral artery. A decrease in systolic blood pressure of 30 mmHg or more between any two levels in the leg usually indicates total occlusion of the intervening artery.

Doppler Ultrasound Imaging and Duplex Scanning B-mode ultrasound imaging of arteries and plaques combined with pulsed Doppler ultrasound flow determination and sound spectral analysis is now a routine method evaluating the common femoral, superficial femoral, and popliteal arteries. This technique provides the ability to noninvasively image arteries and to assess flow. This technology has also been used to image autogenous vein grafts to prevent vein graft thrombosis and failure. Routine postoperative vein graft surveillance using duplex ultrasound imaging every six months can detect elevated flow velocities (peak systolic velocity >200 cm/sec) within the vein graft or at the anastomotic sites (59,60). Early detection

Figure 6 Doppler flow velocity waveforms recorded at four places in an extremity with SFA occlusion demonstrated by angiography. Recordings were made at the CFA, SFA, DP artery, and PT artery. Associated systolic blood pressures were measured to be 140 mmHg in the thigh and 106 mmHg below the knee. This 34 mmHg drop in pressure indicates occlusion of the intervening artery (in this case, the SFA). Distal arteries fill through collateral vessels. Note the change in Doppler velocity waveforms. Abbreviations: CFA, common femoral artery; SFA, superficial femoral artery; DP, dorsalis pedis; PT, posterior tibial.

of vein graft stenoses allows localized treatment with surgical revision or endovascular treatment and thus may prevent graft occlusion and prolong graft patency (61,62). Duplex ultrasound scanning may also be used to identify aneurysms and stenotic and ulcerated lesions in the aortoiliac and femoropopliteal arteries, which may be potential sources for distal emboli.

Penile Brachial Pressure Index

Figure 5 Doppler ultrasound velocity waveforms indicating the normal triphasic waveform, the loss of the reverse flow component seen in moderately stenotic vessels, and the blunted waveform of a severely stenotic vessel.

The simplest and most reliable assessment of the adequacy of penile perfusion is the measurement of arterial pressure in the corpora cavernosa supplied by the penile arteries. A Doppler velocity probe is positioned directly over one of the six penile arteries, and a small pneumatic cuff is placed around the penis proximal to the probe. The cuff is inflated until arterial flow is abolished and is then allowed to slowly deflate until flow returns, which indicates the systolic blood pressure. The penile systolic pressure is divided by the brachial systolic pressure to provide a penile-brachial index (PBI). A PBI greater than 0.9 is normal. A PBI less than 0.7 is consistent with a vascular occlusive cause of impotence.

medwedi.ru

856

Part Six: The Peripheral Vascular System

Catheter-Based Angiography Catheter-based angiography provides the most definitive anatomic assessment of obstructing vascular lesions and is performed before vascular reconstruction. This includes visualization of the abdominal and infrarenal aorta, the iliac arteries, and the femoral, popliteal, tibial, and pedal vessels throughout their length (Fig. 3). Angiography is usually performed through a transfemoral approach, which has the advantage of allowing selective catheterization and the study of individual arteries as needed. Transbrachial and translumbar aortography can also be used successfully. Newer techniques of digital subtraction and computer enhancement of images permit the use of smaller volumes of iodinated contrast materials. Patients should be well hydrated before and after angiography to minimize the possibility of renal failure caused by the osmotic diuresis produced by the hypertonic contrast medium (63).

CT and MR Angiography Advances in computer technology have resulted in significant advances in CT and MR imaging. Timed bolus injection of a contrast agent allows vascular imaging, which rivals the resolution that can be obtained with contrast arteriography. Continuous acquisition of data using helical or spiral CT techniques allows three-dimensional (3-D) image reconstruction with image rotation, shaded-surface display, and curved planar reformation of images. CT angiographic techniques allow imaging not only of the lumen contour but also of the artery wall and extravascular structures. Thus CT angiographic imaging is the imaging procedure of choice for thoracic and abdominal aortic aneurysms and is used to plan endovascular treatments, as well as to follow patients who have undergone treatment of aneurysms (64,65). CT angiography can also be used to study the carotid artery (66) and peripheral vessels. Multislice spiral CT scans with 16-row detectors can precisely image the aortoiliac and femoral vessels as well as infrageniculate arteries in 13 seconds using as little as 130 mL of iodinated contrast (67). MR angiography using gadolinium contrast agent, which is not nephrotoxic, is currently being used to supplant catheter-based, contrast angiography in some centers (68): In addition to anatomic data, however, MR sequences can encode for flow volume (69) and the oxygen saturation of hemoglobin (70,71). Although still limited in quality and the field of view available compared to a traditional aortogram with bilateral runoff, MR anatomic and flow imaging may ultimately replace catheter-based, invasive arterial diagnostic methods.

TREATMENT OF PERIPHERAL VASCULAR OCCLUSIVE DISEASE The treatment of peripheral vascular occlusive disease is determined by the severity of the patient’s symptoms and the anatomic location and extent of obstructing lesions. Treatment options include nonoperative measures, minimally invasive procedures such as transluminal angioplasty and stenting, and operative revascularization.

Nonoperative Measures Patients with peripheral occlusive disease usually have one or several risk factors for the development of vascular disease, including cigarette smoking, hyperlipidemia, hypertension, and diabetes mellitus. Every effort should be

made to control these factors to prevent progression of obstructive disease. Patients with symptoms of claudication, which are not physically limiting have a low risk for limb loss (72) and usually respond well to a program of cessation of smoking and walking exercise to stimulate enlargement of collateral circulation and to condition the muscles to function at a higher level with the available blood supply. Exercise programs are effective in improving walking distance. In a meta-analysis of randomized trials of supervised exercise trials for intermittent claudication, exercise therapy improved pain-free walking time by 180% and maximal walking time by 150% at six months. However, exercise programs must be maintained in order to remain effective. Cessation of the exercise program usually returns the patient to the same level of claudication as present originally. Patients often adjust their levels of activity and coexist well with occlusive disease for many years. Those who continue to smoke have the poorest outlook.

Risk Factor Modification A comprehensive program of risk factor modification should be undertaken in patients with peripheral artery disease, including smoking cessation, increased physical activity, blood pressure control, reduction of elevated total and low-density lipoprotein (LDL) cholesterol levels, antiplatelet therapy, angiotensin-converting enzyme–inhibitor therapy, weight reduction, and glycemic control in patients with diabetes mellitus. Tobacco use is the single most important modifiable risk factor for peripheral occlusive disease. Smoking increased the risk of intermittent claudication by a factor of 8 to 10 and smoking cessation resulted in a 50% reduction in intermittent claudication over a 20-year period among Icelandic men (73). Rest pain developed in 16% of smokers, with intermittent claudication, but there was no disease progression in nonsmoking patients, with intermittent claudication (74). Long-term graft patency is significantly better in patients who quit smoking than in those who continue to smoke (75). Lowering of cholesterol with statin drugs has been shown to reduce the incidence of new or worsening intermittent claudication by 38% (76). Several studies have confirmed an increase in pain-free and total walking distances, as well as improvement in overall physical function in patients treated with statin drugs. Dietary modifications to reduce cholesterol and statin therapy with a target LDL of less than 100 mg/dL is recommended. Antiplatelet therapy with aspirin has been shown to reduce overall cardiovascular morbidity and mortality in patients with peripheral occlusive disease. Ticlid has benefits similar to aspirin but is associated with a risk of thrombocytopenia and neutropenia and is therefore not routinely recommended. Clopidogrel has been shown to be superior to aspirin but is considerably more expensive than aspirin. There is evidence to suggest that the combined use of clopidogrel and aspirin may provide added benefit. Strict glycemic control with a target hemoglobin A1c of less than 7.0 is recommended for diabetic patients with peripheral occlusive disease (77). Reduction in hemoglobin A1c by 1% has been shown to result in an 18% reduction in myocardial infarction, a 15% reduction in stroke and, a 42% reduction in symptomatic peripheral occlusive disease in the prospective U.K. diabetes study (78).

Medical Therapy A number of vasodilating drugs have been used in an attempt to diminish vasospasm and improve peripheral

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

perfusion in patients with peripheral occlusive disease. These, in general, have been found to be ineffective and most have been removed from the market. Nifedipine has been found to be useful in the treatment of vasospasm as seen in Raynaud’s disease (79), but has no beneficial effect in peripheral occlusive disease. Pentoxifylline was the first medication approved by the Food and Drug Administration (FDA) for the treatment of intermittent claudication. Pentoxyfylline is a xanthine derivative that is believed to exert its effect by decreasing the rigidity of erythrocytes so that they can more readily deform and pass through the small capillary beds, thereby increasing tissue perfusion. A multicenter trial of patients with claudication demonstrated a 30% increase in walking distance in patients treated with pentoxyfylline as compared to placebo (80). However, more recent studies suggest that improvement in walking distance with pentoxyfylline is unpredictable and may offer little benefit over placebo. There is no evidence for a beneficial effect from pentoxyfylline for patients with rest pain, ulceration, or gangrene. Cilostazol is a phosphodiesterase inhibitor with antiplatelet and antiproliferative activity. It is the second FDAapproved drug for the treatment of intermittent claudication and appears to provide significant benefit compared to placebo. In a meta-analysis of eight randomized, placebocontrolled trials of cilostazol in patients with intermittent claudication, after 12 to 24 weeks of therapy, patients on cilostazol had an increase in pain-free walking of 40% to 70% and an increase in maximum walking distance of 65% to 83% compared to placebo controls (81). Cilostazol is contraindicated in patients with congestive heart failure because of a proarrhythmic effect. However, it may be considered as initial medical therapy in addition to smoking cessation and walking exercise in patients with mild-tomoderate claudication. Although metabolism-enhancing drugs such as 6-proprionyl carnitine, agents such as L-arginine, dietary supplements such as gingko biloba, and pneumatic compression stockings may hold promise for patients with intermittent claudication, they have yet to demonstrate clinical efficacy in prospective, controlled clinical trials. Intravenous prostaglandin infusion, which has a significant vasodilator and platelet inhibitory effect, has been proposed for the treatment of ischemic ulcers, but no significant improvement in rest pain of ischemic ulcer healing has been demonstrated in controlled clinical trials.

857

Transluminal Angioplasty Transluminal balloon angioplasty is accomplished by first performing a diagnostic arteriogram to localize the occlusive lesion. A catheter with a balloon that has a predetermined maximal diameter at its tip is then passed over a guide wire under X-ray control through the obstructing lesion. Inflation of the balloon disrupts the plaque and stretches the arterial wall, resulting in enlargement of the lumen. This enlargement of the lumen cross-sectional area occurs by separating the plaque from the underlying tunica media and stretching the artery wall (Fig. 7). At times, the media is stretched and thinned to the point of media rupture, in which case vessel integrity is maintained by the adventitia (82). There is no plaque compression or removal of the lesion, and long-term patency depends on the vessel wall remaining in the overstretched state. When the vessel contracts to its predilated state, restenosis occurs. This occurs in a substantial number of patients and is a significant limitation of the procedure. Intra-arterial stents have been introduced as a method, of maintaining lumenal patency after angioplasty. Stents have improved the longterm effectiveness of angioplasty by preventing recoil, intimal flaps, and dissections, such as seen in Figure 8.

Intraluminal Stenting Stenting of recanalized or dilated arterial segments prevents lumen collapse and recoil and maintains lumen caliber. Stents also tack down dissected and separated intimal flaps, preventing lumen obstruction and occlusion (Fig. 8A–C). Stents are either balloon expandable or self-expanding and are widely used for coronary artery stenoses and occlusions. They are FDA approved for use in iliac artery lesions and recently have been approved for high-risk patients with carotid stenosis. Balloon-expandable stents provide maximal radial strength and allow precise positioning. They, however,

Endovascular Treatment Endovascular catheter-based therapy of stenotic lesions and short-segment occlusions has gained acceptance as an effective treatment modality for peripheral occlusive disease. While the overall long-term results are not as durable as surgical reconstruction and bypass procedures, the procedures are minimally invasive and well tolerated by patients. Endovascular treatment is usually percutaneous and is performed in the angiography suite under fluoroscopic image guidance. Proper patient selection is important and clinical criteria for treatment, similar to those used to select patients for surgical treatment, should be used. Treatment consists of transluminal balloon dilation of lesions with or without stenting. Dilation of lesions that appear to be significant on angiographic images but, which produce minimal or no symptoms, should be avoided. The best candidate for transluminal angioplasty is a patient with severe claudication, with an isolated hemodynamically significant common iliac artery stenosis.

Figure 7 Mechanism of balloon dilation of arteries. (A) Human superficial femoral artery that has been fixed with an intraluminal pressure of 100 mmHg and cut in cross section. Note the eccentric plaque and round lumen. (B) Segment of the same artery after balloon dilation. Note the separation of plaque from the media and protrusion of the plaque into the lumen. The media is thinner and has ruptured, and lumen integrity is maintained by the adventitia. Disruption and stretching of the artery wall results in a larger lumen area. There is no plaque compression. Source: From Ref. 82.

medwedi.ru

858

Part Six: The Peripheral Vascular System

Figure 8 Endovascular treatment of bilateral common iliac stenoses: (A) following balloon angioplasty, dissection flaps and residual stenoses are seen; (B) Balloon expandible stents are deployed in the common iliac arteries; (C) completion angiogram demonstrating no residual stenosis and smooth lumen caliber.

may be compressed by extrinsic force. Self-expending stents are commonly oversized to create a continual outward force resisting recoil. The hoop strength of self-expanding stents is less than for balloon-expandable stents but they are useful in vessels at risk for external compression, such as the carotid artery or the superficial femoral artery. While stenting has largely eliminated intimal flaps and early recoil following balloon angioplasty, restenosis and intimal hyperplasia remain a problem, particularly for smaller-caliber arteries. Promising results in controlling restensosis of the coronary circulation has been achieved with drug-eluting stents. Drug-eluting stents are bare-metal stents that are coated with a drug that acts locally to inhibit or prevent cellular proliferation and restenosis. Restenosis is a significant problem for superficial femoral artery stenting as well as popliteal and tibial artery stenting, and drugeluting stents are not yet available for these vessels.

Adjunctive Endovascular Treatments Laser angioplasty of peripheral artery lesions has fallen into disfavor because of high restenosis and recurrence rates. Transcatheter atherectomy devices that shave or debulk plaque are currently being investigated but there is no evidence that these will be more successful in avoiding restenosis. Secondary treatments of restenotic lesions can be carried out with cutting balloon techniques and cold thermal energy application, but the effectiveness of these therapies are unproved. Medical therapy aimed at inhibiting platelet aggregation with glycoprotein IIb/IIIa complex inhibition has been shown to decrease in-stent restenosis (83) and treatment with the antiplatelet agent cilostazol has been

shown to have a beneficial effect in preventing coronary stent restenosis (84). New and improved methods to control and treat in-stent restenosis can be expected to expand the role of endovascular therapy in the near future.

Results of Endovascular Therapy The results of transluminal balloon angioplasty and stenting are to a large degree determined by the location and character of the lesion being treated. The predictors of success include the location and length of the target lesion, whether the lesion is a stenosis or an occlusion, and the adequacy of the outflow vascular bed. In general, the larger the artery being treated and the shorter the lesion being treated, the better the results. Thus, in the lower extremity vessels, the best results are achieved with short-segment stenoses in the common iliac artery. Long-term patency of angioplasty of selected common iliac lesions is comparable to open surgical bypass. The long-term patency of common iliac balloon angioplasty of common iliac stenoses at one year is 90%, at three years is 80%, and at five years is 70% (85). The results for iliac occlusions with stenting is somewhat less favorable, but considering the minimally invasive nature of the endovascular treatment, iliac angioplasty and stenting should be considered for isolated iliac artery lesions. Results for external iliac stenoses are not as favorable as for common iliac lesions and surgical bypass should probably be considered for patients with diffuse aortoiliac disease, which involves the external iliac artery. Results for angioplasty and stenting below the inguinal ligament are distinctly inferior to those for iliac stenting. Bypass surgery for superficial femoral artery occlusions, particularly

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

with autogenous saphenous vein bypass, is the procedure of choice for such patients. However, even though long-term patency rates may not be high, significant benefit can be achieved in some patients who are facing limb loss and who have no satisfactory options for bypass. An example is shown in Figure 9. This elderly diabetic patient with gangrene of the toes had occlusion of anterior tibial, posterior tibial, and peroneal arteries and no saphenous or upper extremity veins. A balloon angioplasty of the diffusely diseased and occluded anterior tibial artery was successful in restoring flow to the foot and allowed a transmetatarsal amputation to heal. Even though the anterior tibial artery restenosed eight months later, the transmetatarsal amputation remained fully healed and the patient was able to ambulate. The recent codification of reporting standards for endovascular procedures including angioplasty should facilitate future comparisons with existing surgical standards, and help clarify the relative indications for angioplasty (86). Despite technical issues, cost, and ongoing problems with restenosis, interest in non–angioplastyrelated endovascular procedures such as rotational arthrectomy, laser-mediated plaque obligation, and thermal- or laser-assisted angioplasty continues (87).

Surgical Revascularization Endarterectomy Endarterectomy is a surgical procedure in which the obstructing intimal plaque is removed from an artery to restore flow. The cleavage plane for endarterectomy is usually just below the internal elastic lamina, although the media below extensive plaque is often degenerated and is removed along with the intimal plaque. In these circumstances, the cleavage plane is at the external elastic lamina, and thus only the adventitial layer contains the blood stream. The adventitial layer alone provides sufficient structural support, and aneurysmal dilation of endarterectomized arterial segments does not occur. Although endarterectomy is the standard mode of treatment for carotid bifurcation atherosclerosis, it has a more limited usefulness in the treatment of peripheral vascular occlusive disease. This is because carotid plaques are

Figure 9 Angiogram of infrapopliteal arteries in a diabetic patient with gangrene of toe. (A) The posterior tibial and peroneal arteries are occluded in mid calf and the anterior tibial artery is diffusely narrowed with a focal occlusion. The distal anterior tibial artery reconstitutes by a large collateral vessel. (B) Following balloon angioplasty, the anterior tibial artery is patent with restoration of a normal dorsalis pedis pulse. The patient successfully healed a toe amputation.

859

localized in the carotid bifurcation, whereas lower extremity atherosclerosis usually is extensive, with no discrete starting or end points. Some patients with localized aortoiliac disease and no distal occlusive disease are candidates for local aortoiliac endarterectomy, but bypass procedures are more commonly performed. If a local endarterectomy is to be considered, these patients must not have aneurysmal disease or fibrotic small-caliber vessels. Results of local aortoiliac endarterectomy compare favorably to aortobifemoral bypass grafts. Most surgeons occasionally use local endarterectomy as an adjunctive procedure to aortobifemoral bypass grafting. Such local endarterectomies are frequently performed in the common and profunda femoris arteries at the time of anastomosis of bypass grafts; but primary endarterectomies have limited usefulness in the peripheral circulation.

Bypass Procedures Procedures to bypass occlusive lesions are the standard surgical methods for treatment of lower extremity peripheral occlusive disease. Procedures are usually considered as inflow or outflow procedures, depending on the level of obstruction. Inflow procedures refer to those used for aortoiliac obstructions, and outflow procedures are those used for superficial femoral and popliteal artery obstructions, with the level of the inguinal ligament usually being the dividing line. Angiographic, vascular, laboratory, and clinical criteria are used to determine the primary level of obstruction. If a patient has both inflow and outflow disease, the proximal, or inflow, obstruction is treated first and usually is sufficient to relieve symptoms.

Aortofemoral Bypass The indications for surgical intervention in patients with aortoiliac occlusive lesions are severe claudication and limb-threatening ischemia as defined by rest pain, ulcerations, and gangrene. The standard surgical treatment for bypass of aortoiliac obstructions is the aortofemoral bypass graft (88). In this procedure, a knitted or woven Dacron bifurcation graft is sutured from the infrarenal aorta, which is usually free of disease, to the common femoral arteries. This graft bypasses the entire aortoiliac segment, which includes the inferior mesenteric artery and internal iliac arteries. The proximal anastomosis is placed just below the level of the renal arteries and may be performed in either an end-to-end or an end-to-side fashion (Fig. 10). When an end-to-end anastomosis is used, the distal aorta is ligated, and the entire aortic outflow passes through the graft. Blood is supplied to the distal aorta and the inferior mesenteric and internal iliac arteries by retrograde flow from the common femoral artery through the external iliac artery. With an end-to-side proximal anastomosis, blood flows in parallel in the bypass graft and in the distal aorta. This anastomosis is preferred when the external iliac arteries are occluded and would prevent retrograde fill of the aorta from the groin. The distal anastomosis is usually placed on the common femoral artery, with outflow through the superficial femoral and profunda femoris vessels. If there is associated superficial femoral artery occlusion, the profunda femoris artery alone can serve as the outflow bed, with relief of symptoms. Concomitant endarterectomy of the orifices of the superficial femoral and profunda femoris arteries can be undertaken to improve the distal anastomosis. Profundaplasty is performed by extending the opening of the common femoral artery onto the profunda femoris artery and suturing the Dacron graft onto the profunda femoris

medwedi.ru

860

Part Six: The Peripheral Vascular System

Figure 10 Aortofemoral bypass for aortoiliac obstruction. Proximal anastomosis may be performed end-to-end (A) or end-to-side of the aorta (B). With an end-to-end anastomosis, perfusion of the internal iliac arteries and distal aorta is retrograde from the common femoral artery in the groin.

artery. This results in enlargement of the lumen of the proximal profunda femoris artery and is useful when there is a stenosis at that site. Aortofemoral bypass graft is a stable and durable operation that effectively eliminates the inflow obstruction. Surgical mortality rate is less than 2%, and the five-year graft patency rate is greater than 90% (89). Should these operations fail, they generally do so because of progression of disease in the arteries at or distal to the groin anastomosis rather than because of failure of the Dacron graft itself. Early complications of aortobifemoral grafts are caused mainly by technical misadventures. These include postoperative hemorrhage, early graft thrombosis, distal embolization, groin hematomas, and lymph leaks. Longterm complications include graft infection, pseudoaneurysm formation, and aortoduodenal fistula. Details of these problems are expanded on below.

Extra-Anatomic Bypass Patients who require bypass of aortoiliac lesions but are too ill to withstand an intra-abdominal operation for placement of an aortobifemoral graft may be revascularized with an axillofemoral or femorofemoral bypass graft (Fig. 11). These operations are effective in relieving aortoiliac, or inflow, obstruction but do not require that the abdominal cavity be entered. The bypass is tunneled in the subcutaneous space, and incisions to expose the axillary and femoral vessels can be performed while the patient is under local anesthesia. Thus they are safer and more amenable to use in high-risk patients. Axillofemoral bypass grafts are also useful to bypass the aorta in situations of infection within the abdominal cavity. There is no steal of blood from the upper extremity when an axillofemoral bypass is placed because there is an increase in flow in the feeding subclavian artery. This increase is sufficient to supply the arm and both legs. However, the great length of the axillofemoral graft makes it prone to thrombosis. Recent reports suggest that the long-term patency of axillofemoral bypass grafting supports its use in highly selected cases when in-line anatomic reconstruction is less desirable (90). However, proximal anastomotic disruption remains a serious though infrequent complication (91). Afemorofemoml bypass graft can be used to bypass an iliac artery occlusion if the opposite patent iliac artery is

Figure 11 Illustration of extra-anatomic bypasses for aortoiliac obstruction. Axillofemoral bypass graft courses in the subcutaneous space in the midaxillary line and brings blood from the subclavian artery to the femoral artery to bypass an aortic obstruction. Femorofemoral bypass graft brings blood from one femoral artery across to the other. ‘‘Steal’’ phenomenon does not occur if there is no obstruction to the inflow of the donor artery.

disease free. In this situation, one iliac artery is able to deliver enough flow to supply both legs. Five-year patency rates for femorofemoral grafts vary from 44% to 74%. Axillofemoral bypass grafts have a poorer patency rate than aortofemoral grafts, with five-year patency rates reported near 75% (92). These grafts fail more commonly than an aortobifemoral graft because of their longer course and the risk of external compression in the subcutaneous tunnel. Thus extra-anatomic grafts should be considered only when endovascular treatments, aortobifemoral grafts, or local aortoiliac endarterectomies are not feasible.

Femoropopliteal and Femoral Distal Bypass Grafts Claudication or severe ischemia of the legs despite a good aortoiliac segment is usually the result of obstruction of the superficial femoral or popliteal artery and its branches. A preoperative angiogram demonstrates which distal vessels are patent and of adequate caliber to accept a bypass graft. If the popliteal artery is patent with runoff through at least one of the tibial vessels, a femoropopliteal bypass graft is the procedure of choice. If the popliteal artery is occluded, bypass should be performed to the tibial artery that best fills the plantar arch. The saphenous vein is the most suitable conduit for bypasses below the inguinal ligament. It may be used as a reversed or in situ vein bypass (Fig. 12). In a reversed saphenous vein femoropopliteal bypass graft, the saphenous vein is excised, and all branches are ligated and divided. The vein position is reversed so that the distal end of the vein is sewn to the common femoral artery, whereas the proximal portion of the vein is sewn to the popliteal artery. This permits arterial flow to course in the vein in the direction of the valves. An in situ vein bypass graft is left in its normal position (93). The proximal vein is sewn to the common femoral artery, and the distal portion is sewn to the popliteal (or

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

861

sympathectomy was the chief surgical therapeutic approach for peripheral occlusive disease. With progressive improvement in the ability to directly revascularize ischemic tissue, lumbar sympathectomy has fallen into disfavor. It has no beneficial effect in the treatment of claudication but has been reported to improve rest pain in approximately 50% of patients. It has been shown to increase cutaneous, but not muscle, blood flow and thus has been recommended for the treatment of ischemic ulcers. Some surgeons use sympathectomy as an adjunct to arterial reconstruction, believing that sympathectomy adds to the total improvement of blood flow to the extremity by causing vasodilation in the small vessels of the foot. However, there is little evidence that there is improved flow over and above the benefit derived from arterial reconstruction alone. In addition, there are potential complications of lumbar sympathectomy, including postsympathectomy neuralgia and failure of ejaculation. Although sympathectomy has limited usefulness in the treatment of arteriosclerosis obliterans, it is effective in the treatment of causalgia and hyperhidrosis.

Embolectomy/Thrombectomy

Figure 12 Saphenous vein bypass grafts in the lower extremity for treatment of femoropopliteal occlusions. These may be performed as a reversed saphenous vein bypass graft (A) or an in situ saphenous vein bypass graft (B). In the in situ bypass graft, the saphenous vein valves must be cut to render them incompetent. Selection of the site of distal anastomosis depends on angiographic demonstration of the patency of distal arteries.

tibial) artery. To permit blood to flow in the vein against the direction of the valves, the valve leaflets must be cut to render them incompetent. The in situ graft avoids extensive dissection of the vein, provides a better size match between the smaller distal artery and vein, and allows the use of smaller veins that might not be suitable for reversed vein bypass. Autogenous vein is far superior to prosthetic materials in all infrainguinal positions, and every effort should be made to use the vein, even if the arm veins or lesser saphenous veins are employed. Limb salvage rate for patients undergoing femoropopliteal bypass grafting with autogenous tissue is 73% at four years; for femoral distal bypass grafts, limb salvage is 80% at four years (94). The limb salvage rates are usually 15% higher than the actual graft patency rates. The patency of each individual graft depends on the adequacy of inflow, the type of graft material used, the quality of the outflow vessels, and the technical aspects of the procedure (94). The complications of femoropopliteal and femoral distal bypass grafts are similar to those associated with an aortobifemoral procedure. Early thrombosis is the most serious early problem and usually represents technical error or inadequate runoff vessels. Prompt thrombectomy and recognition of the technical problem returns function to the graft but usually results in reduction of long-term patency (95).

Sympathectomy Lumbar sympathectomy produces vasomotor paralysis, which increases blood flow by decreasing peripheral resistance. Before the advent of direct arterial surgery,

Acute arterial occlusion with severe ischemia may be caused by emboli, which usually arise from the heart, or by thrombosis of a diseased artery. In addition to the ischemia caused by the embolus, the limb is threatened by propagation of thrombus in the arteries distal to the embolus where blood flow is slow. Therefore patients with acute arterial occlusion should be immediately anticoagulated with heparin. In addition to preventing clot propagation, anticoagulation helps prevent recurrent embolization from the heart. Removal of the obstructing embolus is readily accomplished using the Fogarty balloon catheter (Fig. 13). An incision is made in the femoral artery, and the catheter with the balloon deflated is passed through the thrombus. The balloon is then inflated, and the clot extracted. This procedure is very effective in removing fresh thrombus and restoring blood flow in patients with embolism. However, bypass may be required to restore flow in patients who have thrombosis induced by severe stenotic plaques.

Figure 13 Fogarty balloon catheter embolectomy. Deflated balloon is passed through the thromboembolus. Balloon is inflated and withdrawn, and the embolus is extracted from the artery.

medwedi.ru

862

Part Six: The Peripheral Vascular System

Percutaneous catheter-directed thrombolysis may be used as initial therapy for patients with acute arterial ischemia due to embolization or thrombosis and intact neuromuscular function. Thrombolytic agents such as streptokinase, urokinase, and recombinant tissue plasminogen activators (alteplase and recombinant plasminogen activatorreteplase) induce a systemic fibrinolytic state and carry a risk of inducing hemorrhage. However, the risk of hemorrhage may be reduced by direct infusion of the thrombolytic agent into the clot, using an infusion catheter. Such catheterdirected thrombolysis has been shown to be effective in removing thrombus, reducing the need for subsequent surgery and improving limb salvage in three prospective randomized clinical trials (96).

ANEURYSMAL DISEASE OF THE AORTA The abdominal aorta is particularly vulnerable to aneurysm formation and contains 90% of all aneurysms. Aneurysms are usually located in the infrarenal abdominal aortic segment, with sparing of the first 1 to 2 cm below the level of the renal arteries. Aneurysms are usually clinically silent but may enlarge, cause symptoms, and rupture.

Cause of Aortic Aneurysms Special anatomic features of the infrarenal abdominal aorta may make it vulnerable to the development of aneurysms. The aortic media is composed of groups of smooth muscle cells surrounded by layers of elastin in a network of collagen fibers. The elastin layers serve to allow distensibility of the aortic wall in pulse propagation, whereas the collagen fibers provide tensile strength and prevent overdistention and rupture. The number of medial lamellar units increases proportionally with the aortic diameter to support the tensile stress. The aortic media is nourished by diffusion from the lumen to a depth of approximately 29 medial lamellar units (97). However, if the aorta is thicker than 29 layers, adventitial vasa vasorum penetrate the media to supply nutrition. The relationship between the number of medial layers and the depth of penetration of vasa vasorum in the aortic media applies to both the thoracic aorta and abdominal aortic segment in most mammals. However, the human abdominal aorta is a noticeable exception in that it contains fewer lamellar units than would be expected for its diameter and the media is devoid of vasa vasorum (98). Thus each layer is thicker than expected and sustains an increased tension per lamellar unit. This may make the aorta vulnerable to relative ischemic injury of the medial smooth muscle cells, leading to medial atrophy in aneurysm formation (99). Atherosclerotic plaques are also prone to develop in the infrarenal abdominal aorta and may be a factor in aneurysm formation. Intimal plaques may obstruct diffusion of nutrients from the lumen to the media. Usually there is ingrowth of new medial vasa vasorum to supply the media and plaque under these circumstances. When this does not occur, aneurysmal degeneration may take place because of inadequate medial nutrition. Vasa vasorum usually arise from the renal arteries, and the immediate infrarenal aortic segment may have a better vasa vasorum supply than the rest of the aorta. This may explain the relative protection from aneurysm formation in this area. Other etiologic factors in aneurysm formation have been proposed, including increased elastase or collagenase activity, hemodynamic factors in the infrarenal aorta, and genetic predisposition.

Aneurysms are also found in the femoral and popliteal arteries, although much less commonly. Patients with peripheral aneurysms usually have coexistent abdominal aortic aneurysms, suggesting a more general aneurysmal diathesis.

Clinical Manifestations The biologic fate of an aneurysm of the abdominal aorta is to increase in size with eventual rupture. When first detected in a patient, aneurysms may be asymptomatic, symptomatic, or ruptured. In addition, slow flow within the dilated aneurysm may result in thrombus formation along the wall, which occasionally may totally occlude the lumen, causing acute ischemia, or may embolize to the distal arterial vasculature. The prevalence of aneurysms increases with age. Aneurysms are more common in men than in women and approximately 1 in 10 men over the age of 75 will have an aneurysm.

Asymptomatic Aneurysms Aneurysms are remarkable by their clinical silence in the majority of cases. Asymptomatic aneurysms are frequently discovered by palpating a pulsatile mass during physical examination of the abdomen. Because the aortic bifurcation is located at the level of the umbilicus, the pulsatile mass is usually in the epigastrium. However, aneurysms less than 5 cm in diameter are difficult to palpate, especially in corpulent people; most aneurysms are discovered incidentally during ultrasound X ray or CT examination for gastrointestinal, genitourinary, orthopedic, or other lesions. The best screening test for abdominal aortic aneurysms is an abdominal ultrasound examination (100). The single most important prognostic feature of asymptomatic abdominal aortic aneurysms is the size, or transverse diameter. The absolute risk of rupture related to size is unknown. Best estimates suggest that small abdominal aortic aneurysms less than 4 cm in diameter have a low risk of rupture whereas aneurysms greater than 8 cm in diameter have a 75% risk of rupture within five years (Fig. 14).

Figure 14 Relationship between the five-year risk of rupture and the diameter of infrarenal abdominal aortic aneurysms. A 6-cm abdominal aneurysm has a 30% risk of rupturing within five years.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

Enlarging and Symptomatic Aneurysms Aneurysms tend to progressively enlarge because of the increased tension on and thinning of the artery wall. If this process is slow, symptoms do not appear or are very late in appearing. If, however, enlargement is relatively rapid, symptoms of pain may arise as a result of pressure on the somatic sensory nerve elements of the retroperitoneal soft tissue in the vicinity of the aneurysmal sac. The pain is usually severe, constant, unrelated to posture, and boring in character; it is most commonly located in the lumbar spine region, in the midabdomen, or in the pelvis. Such symptoms indicate the impending rupture of the aneurysm and require immediate clinical attention. Serial follow-up examinations using clinical and radiologic methods identify the patient with an aneurysm that is expanding and yet asymptomatic. The rate of enlargement can be variable and unpredictable. The mean rate of expansion of infrarenal abdominal aortic aneurysms is 0.4 cm/yr (101); however, some do not change at all, whereas others enlarge at twice that rate.

Ruptured Aneurysms Aneurysms may rupture into the retroperitoneal space, with the development of severe back pain and sudden hypotension. If the rupture occurs anteriorly, free intraperitoneal hemorrhage results, with rapid exsanguination and death. Rupture can also occur into the inferior vena cava, resulting in the development of an aortocaval fistula with hypotension and an elevated central venous pressure. Approximately 50% of patients who sustain aneurysm rupture die suddenly, before medical help can arrive. Of those who survive to reach the hospital, mortality rates range from 50% to 80%. For patients who are stable with normal blood pressure, operative mortality may be as low as 10%. However, patients who are in shock and have required cardiopulmonary resuscitation have mortality rates approaching 90%. Thus, overall mortality rates for ruptured aortic aneurysms are in the range of 80% to 90%. On physical examination, ruptured aneurysms, even large ones, may be difficult to palpate because of hypotension and because the aortic aneurysm is often diffuse and ill defined as a result of obliteration of the margins of the aneurysm by retroperitoneal hematoma.

Diagnosis The diagnosis of abdominal aortic aneurysm may be made on physical examination. However, physical examination commonly overestimates the true size of the aneurysm by 1 to 2 cm when compared to ultrasound or CT examination. A cross table lateral X-ray may demonstrate a rim of calcium outlining the anterior wall of the abdominal aorta and indicate the presence of an aneurysm. This X-ray film is taken with the patient lying supine, with the X-ray beam running horizontally, allowing intestinal gas to rise superiorly and the retroperitoneum to be visualized. Physical examination and a lateral X-ray film were in the past the predominant methods of evaluation for an abdominal aortic aneurysm. However, in view of the new development of ultrasound, the lateral abdominal X-ray film is currently used infrequently. B-mode ultrasound is the most commonly used method of diagnosing an abdominal aortic aneurysm. It is simple, safe, noninvasive, and accurate and can be readily repeated for serial evaluation of aneurysms. It provides information on the presence or absence of an aneurysm and on the transverse diameter, length, and presence or absence of mural

863

thrombus. It is the procedure of choice for routine evaluation for aneurysm. CT scan provides better resolution and imaging of aneurysms than does ultrasound, especially when intravenous contrast enhancement is used. It provides the most detailed evaluation of the aortic wall and mural thrombus and the most accurate assessment of aneurysm size and characteristics of the infrarenal aortic neck. It also allows the evaluation of retroperitoneal extravasation and rupture. The CT scan offers significant advantages over ultrasound in assessing the thoracoabdominal aorta, because ultrasound does not pass through the air in the lung and cannot visualize the thoracic aorta. Thus it is particularly helpful in assessing thoracoabdominal aneurysms. In addition, CT is very useful in evaluating the pelvis for the presence of internal iliac aneurysms. CT scanning is essential for preoperative planning for endovascular aneurysm repair. Angiography is useful in the evaluation of abdominal aortic aneurysms but provides little information on aneurysm size because only the aortic lumen is visualized. Aneurysms frequently contain mural thrombus, which may result in a normal or relatively normal lumen contour and diameter. This mural thrombus provides no structural strength to the aortic wall, and such aneurysms are just as likely to rupture as those without extensive mural thrombosis. CT scanning has largely replaced angiography in the evaluation of aortic aneurysms and provides, other important information regarding (i) accurate assessment of the proximal extent of the aneurysm in relation to the renal arteries, (ii) the status of the renal arteries and the presence of accessory renal arteries arising from the aneurysm itself, (iii) the inferior mesenteric artery and its collateral blood supply to the left colon, (iv) coexistent occlusive disease of the iliac and femoral vessels, and (v) identification of congenital abnormalities of the kidneys such as horseshoe kidney.

Treatment Indications for Surgery Indications for surgical repair of abdominal aortic aneurysms depend on the presence or absence of symptoms, the size of the aneurysm, and the general medical condition of the patient. If a patient has a ruptured aortic aneurysm, immediate surgical treatment is imperative. No diagnostic tests should be performed, and resuscitation should be carried out in the operating room. Fluid resuscitation may be useful during transport. Patients with symptoms attributable to an aneurysm but without hypotension or signs of rupture should undergo confirmatory CT examination and urgent operative repair of the aneurysm. Similarly, if there is evidence of rapid enlargement of the aneurysm on routine physical examination or imaging follow-up such as B-mode ultrasound, urgent repair of the aneurysm is advised. The absolute size of the aneurysm also determines whether repair should be undertaken. Studies of the natural history of aneurysms reveal that the risk of rupture of untreated aneurysms is directly proportional to their size (102,103). Aneurysms greater than 5 cm in transverse diameter as measured by ultrasound or CT scan or aneurysms that have more than twice the diameter of the adjacent, nonaneurysmal aorta should be surgically repaired if the patient has no medical contraindications to surgery, such as severe cardiac, pulmonary, renal, or neoplastic disease. However, it must be realized that aneurysms smaller than 5 cm can also rupture and must be carefully observed.

medwedi.ru

864

Part Six: The Peripheral Vascular System

Surgical Repair The surgical treatment of an abdominal aortic aneurysm consists of excluding the aneurysm from the circulation and replacing it with a Dacron prosthetic bypass graft. The aorta is clamped proximal to the aneurysm, below the level of the renal arteries, and distal to the aneurysm. The aneurysm sac is opened, and the graft is sutured to the normal, nonaneurysmal aorta from within the aneurysm. The graft may be a straight ‘‘tube’’ graft confined to the abdominal aorta or a bifurcation graft to the iliac arteries if the aortic bifurcation and iliac arteries are involved (Fig. 15). The aneurysm sac is not excised but closed over the graft after it is in place to isolate the graft from the bowel. This prevents possible erosion of the bowel, aortoduodenal fistula formation, and graft infection. The inferior mesenteric artery, which always arises from the aneurysm, is usually ligated. Collateral circulation from the celiac and superior mesenteric arteries and internal iliac arteries maintains flow to the sigmoid colon. Occasionally, when collateral flow is insufficient, the inferior mesenteric artery must be reimplanted into the bypass graft to avoid colonic ischemia.

Endovascular Aneurysm Repair During the past decade a new less invasive strategy for treating aortic aneurysms has been introduced. This strategy involves the transfemoral placement of self-expanding endoluminal devices to exclude the aneurysm from the circulation. The first FDA-approved devices appeared in 1999 and favorable long-term results extending to six years and longer have been reported (104). All current FDA-approved devices are self-expanding, bifurcated, modular stent grafts that are introduced through the femoral arteries and deployed under fluoroscopic image guidance. Endovascular aneurysm repair requires a suitable infrarenal aortic neck and iliac arteries to allow secure fixation and sealing of the endovascular device (Fig. 16). Precise preoperative imaging with high-quality CT scanning and 3-D image reconstruction is required to select appropriate candidates for endovascular repair. Because endovascular aneurysm repair requires only groin exposure of the femoral arteries, the procedure can be performed in elderly, high-risk patients who are not suitable candidates for open surgical repair. However, not all patients with infrarenal aortic aneurysms are suitable candidates for endovascular repair because of adverse morphologic features such as a short (<15 mm long) or severely angulated infrarenal aortic neck, absent infrarenal aortic neck, large diameter (>28 mm) aortic neck, iliac aneurysms, or iliac stenosis. Thus, careful preoperative

Figure 15 Repair of abdominal aortic aneurysm. Aneurysm sac is opened, and a Dacron graft is sutured to the normal, nonaneurysmal artery. Aneurysm is not excised, but it is excluded from the circulation.

Figure 16 (A) Three-dimensional reconstruction of spiral computed tomography (CT) scan demonstrating a 5.8 cm-abdominal aortic aneurysm. (B) CT scan following endovascular aneurysm repair using a stent graft.

patient evaluation and planning are required to obtain satisfactory results.

Results: Open vs. Endovascular Repair Both open and endovascular aneurysm repair are highly effective in achieving the primary objective of aneurysm repair, namely prevention of aneurysm rupture. Operative mortality for elective open surgical repair is approximately 5% to 6% (105,106) although elective operative mortality rates of less than 2% are reported from high-volume specialized centers (107–109). Operative mortality for endovascular aneurysm repair is 1% to 2% even though most series include high-risk patients who would not be candidates for open surgical repair (106). Two recent prospective randomized trials comparing open to endovascular repair in good-risk patients revealed a statistically significant reduction in operative mortality in patients undergoing endovascular repair (1–2%) compared to patients undergoing elective open repair (4–5%) (110,111). In addition to reduced operative mortality, there is a significant reduction in morbidity following endovascular repair, with a reduction in blood loss and transfusion requirements, shorter intensive care unit and hospital stay, and earlier return to function. Thus, endovascular repair has significant shortterm advantages over open surgical repair and is favored for most patients who have suitable anatomy (112). However, the long-term outcome of endovascular repair is uncertain, because long-term outcome data is limited. Adverse outcomes of endovascular aneurysm repair include continued blood flow in the aneurysm sac (endoleak), device migration over time, aneurysm enlargement, and possible late rupture. These adverse events may require secondary procedures, including possible conversion to standard open repair in the future. Although open surgical repair appears to be needed in no more than 5% of patients at five years, more complete long-term outcome analysis will be required to fully define the role of endovascular aneurysm repair.

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

Regardless of the mode of therapy, elective aortic aneurysm repair has far better results than emergent repair of ruptured aortic aneurysms. Operations for ruptured abdominal aortic aneurysms have a mortality rate of 50% to 80% or higher (105,109,113). Thus, every effort should be made to repair abdominal aortic aneurysms before rupture. Improved operative techniques with better preoperative and perioperative care, including central hemodynamic monitoring, earlier diagnosis, improvements in fluid management, and refinements in anesthesia techniques, have allowed elective aneurysm repair to be carried out with a similar low mortality rate even in octogenarians (114). Thus, age alone is not a contraindication to aneurysm repair. The long-term survival of patients who have undergone abdominal aortic aneurysm repair is approximately 60% at five years (106). Associated coronary artery disease is responsible for the majority of deaths in the long-term follow-up of these patients. In a matched group, the expected five-year survival is 80% (108). It is possible that with more aggressive treatment of coexistent coronary disease this mortality rate can be decreased. The overall survival and long-term outlook with elective repair of abdominal aortic aneurysms is significantly better than that for nonsurgical treatment.

PERIPHERAL ARTERY ANEURYSMS Although it is not common, aneurysms can form in arteries other than the aorta. The most commonly involved peripheral arteries are the common femoral and popliteal arteries, which together account for 90% of all peripheral aneurysms. The popliteal artery accounts for 70% of these aneurysms. Popliteal aneurysms are unique in that they are found almost exclusively in males, and the vast majority are atherosclerotic in origin. Approximately two-thirds of the patients have bilateral aneurysms, with one-half of these patients having associated abdominal aortic aneurysms. Popliteal aneurysms are usually symptomatic when discovered, and over 50% have complications at the first medical visit (114). The most common complication is thrombosis of the aneurysm, which is associated with a 33% amputation rate. Embolization of mural thrombus from within the aneurysm to the distal arterial tree also occurs and is associated with a high amputation rate. Rupture of popliteal aneurysms is unusual but can occur. Compression of the popliteal vein with lower extremity edema and neurologic pain syndromes from nerve compression are also possible. Treatment of popliteal aneurysms consists of ligation of the aneurysm to exclude it from the circulation, followed by bypass grafting from the femoral artery to either the popliteal or tibial vessels. Results of surgery are influenced by the status of the leg at the time of presentation and the extent of coexistent occlusive disease in the tibial vessels and vessels of the foot. If these are obstructed because of prior and repeated embolization from the aneurysm, prospects for revascularization are poor. There is minimal risk for limb loss in patients with asymptomatic aneurysms, but 34% of limbs are lost if the patient initially has symptoms (114). Therefore, popliteal aneurysms should be repaired electively when found, before symptoms of embolization or thrombosis occur. Femoral artery aneurysms are similarly found in elderly men and are caused by atherosclerosis. Associated hypertension is extremely common. Associated abdominal aortic aneurysms are present in 51% to 85% of patients (115,116) and associated popliteal aneurysmare present in 17% to 44%

865

of patients (116,117), suggesting an aneurysmal diathesis. As in the popliteal artery, symptoms may be caused by local pressure from the expanding aneurysm on the adjacent femoral vein or nerve, distal embolization, acute or chronic thrombosis, or rupture of the aneurysm. Because of the risk for limb loss from acute thrombosis and distal embolization, surgical management of these aneurysms is advised in all patients who are reasonable medical risks. Surgical techniques include replacement of the aneurysm with an interposition graft (118).

COMPLICATIONS OF VASCULAR PROCEDURES Complications following vascular procedures fall into two categories: those involving the generalized disease process of atherosclerosis and those involving local factors related to the vascular procedure or bypass graft. The generalized process of atherosclerosis involves not only the peripheral arteries but also the carotid and coronary arteries. The risk factors of hypertension, hyperlipidemia, diabetes mellitus, and cigarette smoking are important in determining whether there is disease progression, stabilization, or regression, and control of these factors is important. The major cause of morbidity and mortality in the vascular surgical patient is disease progression in the coronary arteries, with myocardial infarctions accounting for the majority of deaths in these patients despite successful peripheral vascular procedures. Stroke from progression of cerebrovascular disease is also a major problem. These same risk factors play a major role in the progression of distal disease following bypass grafts and are a common reason for restenosis and subsequent graft occlusion and its related morbidity. Local factors related to vascular procedures may produce a number of complications following vascular procedures. Graft thrombosis in the early postoperative period may be the result of a technical error in the graft-to-artery anastomosis or caused by an obstructed outflow bed with slow flow in the graft. Late graft occlusion is usually caused by progression of atherosclerotic occlusive disease in the inflow or outflow vessels or by a hypertrophic proliferative response of intima at the anastomosis and can usually be corrected by reoperation. Pseudoaneurysms may form at the sites of vascular anastomoses and must be distinguished from true aneurysms that involve dilation of all layers of the artery wall. In a pseudoaneurysm, there is separation of the vascular graft from the artery wall, and the blood stream is contained by surrounding fibrous tissue. The integrity of an anastomosis of prosthetic graft to artery is forever dependent on the integrity of the suture line. Failure of the suture or excess tension on the suture line can result in the disruption of the anastomosis with pseudoaneurysm formation. In addition, anastomotic breakdown with pseudoaneurysm formation may be a harbinger or sign that infection of the prosthetic bypass graft has occurred. Treatment of a pseudoaneurysm mandates replacement of that segment with a prosthetic graft if it is not infected. However, infected grafts must be totally removed because prosthetic grafts are foreign bodies and infection cannot be eradicated until all foreign material is excised. Revascularization under these circumstances is complex and usually involves the use of an ‘‘extra-anatomic’’ bypass in a clean, noninfected area. An example of such a bypass is an axillofemoral bypass to bypass an infected intra-abdominal aortoiliac bypass graft.

medwedi.ru

866

Part Six: The Peripheral Vascular System

SUMMARY Atherosclerosis is a degenerative disease process that affects the aorta and peripheral arteries, as well as coronary and carotid arteries. It can result in occlusive disease, obstructing the lumen, or aneurysmal disease, with dilation of the lumen. Occlusive disease can result in stenosis and diminished blood flow or embolization with occlusion of distal arteries. Obstruction of blood flow can result in ischemia of the lower extremities, producing symptoms of claudication, rest pain, ulceration, or gangrene. Obstructions can be detected with the use of clinical, noninvasive, and angiographic diagnostic techniques. Revascularization of the lower extremities with a bypass or with transluminal balloon angioplasty can restore circulation and help avoid limb loss. Aneurysmal disease results in progressive arterial enlargement and weakening of the aortic wall, with eventual rupture unless the patient dies of intercurrent disease. The larger the aneurysm, the higher the risk of rupture. Most aneurysms are asymptomatic and are detectable by noninvasive techniques. Operative replacement of aneurysmal segments of artery with a Dacron graft or endovascular aneurysm repair prevents further degeneration and aneurysm rupture.

REFERENCES 1. Fann JI, Dalman RL. Genetic and metabolic causes of arterial disease. Ann Vasc Surg 1993; 7:594. 2. Vogt MT, Wolfion SK, Kullen LN. Lower extremity arterial disease and the aging process. J Clin Epidemiol 1992; 45:529. 3. Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Med Scand 1982; 211:249. 4. Kannel WB, Mcbee DL. Update on some epidemiological features of intermittent claudication. The Framingham Study. J Am Geriatr Soc 1985; 33:13. 5. Scheoll M, Murck O. Estimation of peripheral arteriosclerotic disease by ankle pressure measurements in a population study of 60 year old men and women. J Chron Dis 1981; 34:261. 6. Criqui MH, Browner D, Fronek A, et al. Peripheral arterial disease in large vessels is epidemiologically distinct from small vessel disease. An analysis of risk factors. Am J Epidemiol 1989; 129:1110. 7. Knipski WC. The peripheral vascular consequences of smoking. Ann Vasc Surg 1991; 5:291. 8. Powell JT, Greenhalgh RM. Arterial bypass surgery and smokers. Br Med J 1994; 308:607. 9. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993; 329:977. 10. Wissler RW, Hiltscher l, Oinuma T, et al. Pathogenesis of atherosclerosis—the lesions of atherosclerosis in the young: from fatty streaks to intermediate lesions. In: Fuster V, Ross R, Topol E, eds. Atherosclerosis and Coronary Artery Disease. New York: Lippincott-Raven Press, 1995:475–489. 11. Paterson JC. Vascularization and haemorrhage of the intima of arteriosclerotic arteries. Arch Pathol 1936; 22:312. 12. Zarins CK, Glagov S, Vesselinovitch D, Wissler RW. Aneurysm formation in experimental atherosclerosis: relationship to plaque formation. J Vasc Surg 1990; 12(3):246–256. 13. Strickland HL, Bond MG. Aneurysms in a large colony of squirrel monkeys (Saimiri sriures). Lab Anim Sci 1983; 33:589. 14. Rifltin RD, Parisis HF, Follard E. Coronary calcification in the diagnosis of coronary artery disease. Am J Cardiol 1979; 44:141. 15. Glagov S, Eckner FAO, Lev M. Controlled pressure fixation apparatus for hearts. Arch Pathol 1963; 76:640.

16. Zarins CK, Zatina MA, Glagov S. Correlation of postmortem angiography with pathologic anatomy: quantitation of atherosclerotic lesions. In: Bond MG, et al., ed. Clinical Diagnosis of Atherosclerosis. New York: Springer-Verlag, 1983:283. 17. Mulvihill DA, Harvey SC. The mechanism of the development of collateral circulation. N Engl J Med 1931; 104:1032. 18. Holman E. Problems in the dynamics of blood flow. I. Condition controlling collateral circulation in the presence of an ateriovenous fistula following ligation of an artery. Surgery 1949; 26:889. 19. Kamiya A, Tbgawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol 1980; 239:H14. 20. Furchgott RF. Role of endothelium in responses of vascular smooth muscle. Circ Res 1983; 53:557. 21. Langille BL, O’Donnel F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium dependent. Science 1986; 231:405. 22. Ying H, Harris EJ, Dalman RL. Unpublished observations, 1992–1993. 23. Thubrikar M, Maker J, Nolan S. Inhibition of atherosclerosis associated with reduction of arterial intramural stenosis in rabbits. Arteriosclerosis 1988; 8:410. 24. Friedman MH. Some atherosclerosis may be a consequence of the normal adaptive vascular response to shear. Atherosclerosis 1990; 82:193. 25. Zarins CK, et al. Carotid bifurcation atherosclerosis: quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ Res 1983; 53:502. 26. Ku DN, et al. Pulsatile flow and atherosclerosis in the human carotid bifurcation: positive correlation between plaque localization and low oscillating shear stress. Arteriosclerosis 1985; 5:292. 27. Karino T. Microscopic structure of disturbed flows in the arterial and venous systems and its implication in the localization of vascular disease. Int Angiol 1986; 5:297. 28. Glagov S, Rowley DA, Kohut R. Atherosclerosis of human aorta and its coronary and renal arteries. Arch Pathol 1961; 72:558. 29. Svindland A. The localization of sudanophilic and fibrous plaques in the main left coronary arteries. Atherosclerosis 1983; 48:139. 30. Giddens DP, Zarins CK, Glagov S. The role of fluid mechanics in the localization and detection of atherosclerosis. J Biomech Eng 1993; 115:588. 31. Fingerle J, Johnson R, Clowes AW. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci USA 1989; 86:8412. 32. Falcone DJ, Haijar DP, Minick CR. Lipoprotein and albumin accumulation in re-endothelialized and de-endothelialized aorta. Am J Pathol 1984; 114:112. 33. Bassinouny HS, et al. Quantitative inverse correlation of wall shear stress with experimental intima thickening. Surg Forum 1988; 39:328. 34. Lyon RT, Hass A, Davis HR. Protection from atherosclerotic lesion formation by reduction of artery wall motion. J Vasc Surg 1987; 5:59. 35. Caro GG, et al. Influence of vasoreactive agents on arterial hemodynamics: possible relevance to atherogenesis. Biorheology 1986; 23:197. 36. Glagov S. Microarchitecture of arteries and veins. In: Abrahson D, Dobrin P, eds. Blood Vessels and Lymphatics. Orlando, Florida: Academic Press, 1984:3. 37. Glagov S, et al. Hemodynamics and atherosclerosis: insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988; 112:1018. 38. Glagov S, et al. Establishing the hemodynamic determinants of human plaque configuration, composition and complication. In: Yoshida Y, et al., ed. Role of Blood Flow in Atherogenesis. New York: Springer-Verlag, 1988:3. 39. Born VRG, Richardson PD. Mechanical properties of human atherosclerotic lesions. In: Glagov S, Newman WP, Schaffer SA,

Chapter 44: Aorta and Arterial Disease of the Lower Extremity

40. 41.

42. 43.

44.

45.

46.

47.

48.

49.

50.

51. 52. 53. 54. 55. 56.

57. 58. 59. 60.

61.

62.

63. 64.

eds. Pathobiology of the Human Atherosclerotic Plaque. New York: Springer-Verlag, 1990:413. Zarins CK, et al. Artery stenosis inhibits regression of dietinduced atherosclerosis. Surgery 1980; 88:86. Xu Chengpei, Glagov S, Zatina M. Hypertension sustains plaque progression despite reduction of hypercholesterolemia. Hypertension 1991; 18:123. Zarins CK, et al. Shear stress regulation of artery lumen diameter in experimental atherogenesis. J Vasc Surg 1987; 5:413. Fry DL. Problems and progress in understanding ‘‘endothelial permeability’’ and mass transport in human arteries. In: Glagov S, Newman WP, Schaffer SA, eds. Pathobiology of the Human Atherosclerotic Plaque. New York: Springer-Verlag, 1990:271. Smith EB. Accumulating evidence from human artery studies of what is transported and what accumulates relative to atherogenesis. In: Glagov S, Newman WP, Schaffer SA, eds. Pathobiology of the Human Atherosclerotic Plaque. New York: Springer-Verlag, 1990. Tracy RE, Kissling GE. Comparisons of human populations for histologic features of atherosclerosis. Arch Pathol Lab Med 1988; 112:156. Frank JS, Fogelman AM. Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultrarapid freezing and freeze-etching. J Lipid Res 1989; 30:967. Berenson GS, et al. In: Glagov S, Newman WP, Schaffer SA, eds. Pathobiology of the Human Atherosclerotic Plaque. New York: Springer-Verlag, 1990:189. Kramsh DM, Hollander W. The interaction of serum and arterial lipoproteins with elastin of the arterial intima and its role in the Kpid accumulation in atherosclerotic plaque. J Clin Invest 1973; 52:236. Wagner WD, et al. Low density lipoprotein interaction with artery derived proteoglycan: the influence of LDL particle size and the relationship to atherosclerosis susceptibility. Atherosclerosis 1989; 75:49. Grande J, et al. Effect of an elastin growth substrate on cholesteryl ester synthesis and foam cell formation by cultured aortic smooth muscle cells. Atherosclerosis 1987; 68:87. May AG, De Weese JA, Rob CG. Hemodynamic effects of arterial stenosis. Surgery 1963; 53:513. Thompson JE, et al. Arterial embolectomy: a 20 year experience with 163 cases. Surgery 1970; 67:212. Coffinan JD. Intermittent claudication-be conservative. N Engl J Med 1991; 325:557. Jelnes R, et al. Fate in intermittent claudication: outcome and risk factors. Br Med J 1986; 293:1137. Sibert S, Zazeela H. Prognosis in arteriosclerotic peripheral vascular disease. JAMA 1958; 156:1816. Kallero KS. Mortality and morbidity in patients with intermittent claudication as defined by venous occlusion plethysonography. A ten year follow-up study. J Chron Dis 1981; 34:455. Croneneitt JL, et al. Intermittent claudication. Current results at non-operative management. Arch Surg 1984; 119:430. Dormandy J, et al. Fate of the patient with chronic leg ischemia. J Cardiovasc Surg 1989; 30:50. Bandyk DF. Essentials of graft surveillance. Semin Vasc Surg 1993; 6:92. Mills JL, et al. The origin of infrainguinal vein graft stenosis. A prospective study based on duplex surveillance. J Vasc Surg 1995; 21:16. Bandyk DF, et al. Intraoperative duplex scanning of arterial reconstructions: rate of repaired and unrepaired defects. J Vasc Surg 1994; 20:426. Ferris BL, Mills JL Sr, Hughes JD, Durrani T, Knox R. Is early postoperative duplex scan surveillance of leg bypass grafts clinically important? J Vasc Surg 2003; 37(3):495–500. Shehadi WH, Tbnielo G. Adverse reactions to contrast media. Radiology 1980; 137:299. Rubin GD, et al. Three dimensional spiral computed tomographic angiography: an alternative imaging modality for the abdominal aorta and its branches. J Vasc Surg 1993; 18:656.

867

65. Napel S, Rubin GD, Jeffiey RB Jr. STS-MIP: a new reconstruction technique for CT of the chest. J Comput Assist Tomogr 1993; 17:832. 66. Marks MP, et al. Diagnosis of carotid artery diseases: preliminary experience with maximum intensity projection spiral CT angiography. Am J Roentgenol 1993; 160:1267. 67. Boll DT, Lewin JS, Fleiter TR, Duerk JL, Merkle EM. Multidetector CTangiography of arterial inflow and runoff in the lower extremities: a challenge in data acquisition and evaluation. J Endovasc Ther: Official J Int Soc Endovasc Specialists 2004; 11(2):144–151. 68. Carpenter JP, et al. Peripheral vascular surgery with magnetic resonance angiography as the sole preoperative imaging modality. J Vasc Surg 1994; 20:861. 69. Debatin JE, et al. Phase contrast MRI assessment of pedal blood flow. Eur Radiol 1995; 194:321. 70. Li KCP, et al. Oxygen saturation of blood in the superior mesenteric vein: in vivo verification of MR imaging measurements in a canine model. Radiology 1995; 194:321. 71. Li KCP, et al. Simultaneous measurement of flow in the superior mesenteric vein and artery with cine phase-contrast MR imaging: value in diagnosis of chronic mesenteric ischemia. Radiology 1995; 194:327. 72. Peabody CN, Kannel WB, McNamara PM. Intermittent claudication: surgical significance. Arch Surg 1974; 109:693. 73. Ingolfsson IO, Sigurdsson G, Sigvaldason H, Thorgeirsson G, Sigfusson N. A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968–1986: a strong relationship to smoking and serum cholesterol—the Reykjavik Study. J Clin Epidemiol 1994; 47(11):1237–1243. 74. Jonason T, Bergstrom R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand 1987; 221(3):253–260. 75. Ameli FM, Stein M, Provan JL, Prosser R. The effect of postoperative smoking on femoropopliteal bypass grafts. Ann Vasc Surg 1989; 3(1):20–25. 76. Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiol 1998; 81(3):333–335. 77. Stoyioglou A, Jaff MR. Medical treatment of peripheral arterial disease: a comprehensive review. J Vasc Interv Radiol 2004; 15(11):1197–1207. 78. Group UPDSU. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [see comment] [erratum appears in Lancet 1999 Aug 14; 354(9178):602]. Lancet 1998; 352(9131):837–853. 79. Smith CD, McKendry RJ. Controlled trial of nifedipine in the treatment of Raynaud’s phenomenon. Lancet 1982; 2:1299. 80. Porter JM, et al. Pentoxifylline efficacy in the treatment of intermittent claudication. Am Heart J 1982; 104:66. 81. Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol 2002; 90(12):1314–1319. 82. Zarins CK, et al. Arterial disruption and remodeling following dilatation. Surgery 1982; 92:1086. 83. Yalcin R, Erkan A, Ergun MA, Yurtcu E. The effect of clopidogrel on apoptosis an in vivo study. Cell Biol Int 2004; 28(6):477–481. 84. Douglas JS, Weintraub WS, Holmes D. Rationale and design f the randomized, multicenter, cilostazol for RESTenosis (CREST) trial. Clin Cardiol 2003; 26(10):451–454. 85. (TASC) TI-SC. Treatment of intermittent claudication in Management of Peripheral Arterial Disease (PAD). J Vasc Surg 2000; 31(1):S77. 86. Ahn SS, et al. Reporting standards for lower extremity arterial endovascular procedures. J Vasc Surg 1993; 17:1103. 87. Dalman RL, Taylor LM, Porter JM. Current status of extracoronary endovascular procedures. Ann Vasc Surg 1990; 3:1. 88. Rutherford RB. Aortofemoral bypass: the gold standard. Technical considerations. Semin Vasc Surg 1994; 7:11.

medwedi.ru

868

Part Six: The Peripheral Vascular System

89. Brewster DC, Darling RC. Optimal methods of aortoiliac reconstruction. Surgery 1978; 84:739. 90. Taylor CM, et al. Axillofemoral grafting with externally supported PTFE. Arch Surg 1994; 129:588. 91. Taylor CM, et al. Acute disruption of polytetrafluoroethylene grafts adjacent to axillary anastomosis: A complication of axillofemoral grafting. J Vasc Surg 1994; 20:520. 92. Farm JI, Harris EJ, Dalman RL. Extra-anatomic bypass. Ann Vasc Surg 1993; 7:378. 93. Corson JD, et al. In situ vein bypasses to distal tibial and limited outflow tracts for limb salvage. Surgery 1984; 96:756. 94. Dalman RL, Taylor CM. Basic data regarding intrainguinal revascularization procedures. Ann Vasc Surg 1990; 4:309. 95. Craver JM, et al. Hemorrage and thrombosis as early complications of femoropopliteal bypass grafts: causes, treatment, and prognostic implications. Surgery 1971; 74:839. 96. Giannini D, Balbarini A. Thrombolytic therapy in peripheral arterial disease. Curr Drug Targets Cardiovasc Haematol Disord 2004; 4(3):249–258. 97. Wolinsky H, Glagov S. Nature of species differences in the medial—distribution of aortic vasa vasorum in mammals. Circ Res 1967; 20:409. 98. Wolinsky H, Glagov S. Comparison of abdominal and thoracic aortic medial structure in mammals: deviation of man from the usual pattern. Circ Res 1969; 25:677. 99. Zarins CK, Glagov S. Aneurysms and obstructive plaques: differing local response to atherosclerosis. In: Bergan JJ, Yao JST, eds. Aneurysms: Diagnosis and Treatment. New York: Grune & Stratton, 1982. 100. Lederle FA. Ultrasonographic screening for abdominal aortic aneurysms.[see comment][erratum appears in Ann Intern Med. 2003 Nov 18;139(10):873]. Ann Intern Med 2003; 139(6): 516–522. 101. Bernstein EF, et al Growth rates of small abdominal aortic aneurysms. Surgery 1976; 80:765. 102. Bernstein EF. The natural history of abdominal aortic aneurysms. In: Najarian JS, Delaney JP, eds. Vascular Surgery. Miami, Florida: Symposia Specialists, 1978. 103. Szilagyi DE, Elliott JP, Smith RE. Clinical fate of patients with asymptomatic abdominal aortic aneurysm and unfit for special treatment. Arch Surg 1972; 104:600. 104. Zarins CK. Aneu Rx Clinical I. The US AneuRx Clinical Trial: 6-year clinical update 2002. J Vasc Surg 2003; 37(4):904–908. 105. Zarins CK, Harris EJ Jr. Operative repair for aortic aneurysms: the gold standard. J Endovasc Surg 1997; 4(3):232–241.

106. Zarins CK, Heikkinen MA, Lee ES, Alsac JM, Arko FR. Shortand long-term outcome following endovascular aneurysm repair. How does it compare to open surgery? J Cardiovasc Surg (Torino) 2004; 45(4):321–333. 107. DeBakcy MD, et al. Aneurysms of the abdominal aorta: analysis of results of graft replacement therapy one to eleven years after operation. Ann Surg 1964; 160:622. 108. Thompson JE, et al. Surgical management of abdominal aortic aneurysms: factors influencing mortality and morbidity—a 20 year experience. Ann Surg 1975; 188:654. 109. Brewster DC, Cronenwett JL, Hallett JW Jr, Johnston KW, Krupski WC, Matsumura JS, Joint Council of the American Association for Vascular S, and Society for Vascular S. Guidelines for the treatment of abdominal aortic aneurysms. Report of a subcommittee of the Joint Council of the American Association for Vascular Surgery and Society for Vascular Surgery. J Vasc Surg 2003; 37(5):1106–1117. 110. Prinssen M, Verhoeven EL, Buth J, et al. Dutch Randomized Endovascular Aneurysm Management Trial G. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. [see comment]. N Eng J Med 2004; 351(16):1607–1618. 111. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG, participants Et. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. [see comment]. Lancet 2004; 364(9437):843–848. 112. Lee WA, Carter JW, Upchurch G, Seeger JM, Huber TS. Perioperative outcomes after open and endovascular repair of intact abdominal aortic aneurysms in the United States during 2001. J Vasc Surg 2004; 39(3):491–496. 113. Garrett HE, Ilabaca PA. The ruptured abdominal aortic aneurysm. In: Bergan JJ, Yao JST, eds. Aneurysms: Diagnosis and Treatment. New York: Grune & Stratton, 1982. 114. Evans WE, Conley JE, Bernhard V. Popliteal aneurysms. Surgery 1971; 70:762. 115. O’Donnel TF Jr, Darling RC, Linton RR. Is 80 years too old for aneurysmectomy? Arch Surg 1976; 111:1250. 116. Cutler BS, Darling RC. Surgical management of arteriosclerotic femoral aneurysms. Surgery 1973; 74:764. 117. Graham L, et al. Clinical significance of arteriosclerotic femoral artery aneurysms. Arch Surg 1973; 115:502. 118. Baud RJ, et al. Arteriosclerotic femoral artery aneurysms. Can Med Assoc J 1977; 117:1306.

45 Cerebrovascular Disease and Upper-Extremity Vascular Disease Bruce L. Gewertz and James F. McKinsey

INTRODUCTION In each calendar year, nearly 500,000 people in the United States suffer cerebral infarctions; in 175,000 patients, the strokes are fatal, and the remaining patients experience variable disability. The emotional and economic consequences of advanced cerebrovascular disease are staggering; the cost of care and loss of earnings secondary to permanent disability or death have been estimated at more than $10 billion annually. In contrast to these depressing statistics, there has been a persistent 10-year decline in the death rate from stroke, which has exceeded the general decline in cardiovascular mortality observed over the same time period (1). It is difficult to explain this phenomenon. Although surgery for extracranial occlusive disease has become much more common in the last 15 years, improved medical and surgical care can account for only a small fraction of the change in death rate. It is most likely that the decline in cardiovascular mortality reflects better control of arterial hypertension, changes in lifestyle, and the general reduction in cigarette smoking (2,3). Although the natural history of stroke in the United States was defined in an earlier era, studies performed from 1950 to 1975 provide useful information regarding the indications and timing of cerebrovascular surgery (4,5). The following are now accepted facts. 1. 2.

3.

Patients who have survived one cerebral infarction have a high incidence of recurrent strokes (approximately 25%). More than half of these recurrent strokes are fatal. Prodromal symptoms of stroke, such as transient cerebral ischemic attacks, identify the patients at greatest risk of suffering later completed strokes. The cumulative stroke rate approaches 50% at five years and is highest in the first year after the transient ischemic episode (6,7). Patients suffering transient ischemic attacks (TIA) or strokes from atheromatous stenotic lesions of the carotid bifurcation are significantly benefited by carotid endarterectomy if the complications of the procedure are equal to or less than current norms.

In this chapter, the anatomy and physiology of cerebral blood flow will be reviewed, the variable clinical presentations of cerebral ischemia characterized, and the diagnostic and therapeutic options considered. In addition, clinically relevant upper-extremity vascular disease will also be reviewed. It has become clear that only through better understanding of cerebrovascular physiology and upperextremity vascular pathology can the care of patients with advanced vascular disease be improved.

CEREBRAL BLOOD FLOW Anatomy The brain is perfused by paired carotid and vertebral arteries that communicate with each other through the circle of Willis at the base of the skull. Although there is substantial variation in the effectiveness of this collateral network (less than 20% of patients have ‘‘complete’’ circles), occlusion of one vessel is frequently compensated for without neurologic deficit. In general terms a carotid artery supplies only the ipsilateral cerebral hemisphere through the middle, anterior, and posterior cerebral vessels. The vertebral arteries join to form a single basilar artery that supplies the brainstem and cerebellum with additional contributions to the posterior aspect of the circle of Willis (Fig. 1). Boundary zones or ‘‘watershed’’ areas between the primary perfusion territories of the middle, anterior, and posterior cerebral arteries can be demonstrated by anatomic studies. These areas are most at risk for ischemia and infarction during hypotension or vascular occlusion. Perhaps because of the lower basal vascular tone of these vessels, boundary zones are frequently the site of intracerebral hemorrhages associated with acute hypertension. The subclavian origin of both vertebral arteries makes possible the unique subclavian steal syndrome that will be discussed in greater detail in the section on ‘‘Vertebrobasilar Disease’’ (Fig. 2). This syndrome occurs when an occlusive lesion proximal to the origin of the vertebral vessels decreases perfusion pressure in the distal subclavian artery. The vertebral artery then functions as a collateral pathway for the arm, and reversal of flow (away from the cranium) can be demonstrated angiographically. This flow pattern ‘‘steals’’ blood from the basilar system and may result in cerebellar ischemia or infarction.

Characteristics of Flow The cerebral circulation is supplied with nearly 15% of cardiac output. Resting total blood flows range from 50 to 60 mL/min/ 100 g of tissue, with higher values in the cellular gray matter (100 mL/min/100 g) and lower flows in the cell-poor white matter (20 mL/min/100 g) (8,9). Cerebral blood flow is regulated by both metabolic and myogenic mechanisms that tend to maintain or ‘‘autoregulate’’ perfusion to avoid cerebral infarction during hypotension and cerebral hemorrhage during hypertension (10,11). Cerebral infarcts may result when regional blood flows decline below 15 mL/min/100 g, although the metabolic state of the brain strongly influences the likelihood of cell death (12). Barbiturate coma has been shown to decrease the ischemic limit to as low as 5 mL/min/100 g (13). The cerebral circulation is further distinguished by a blood–brain barrier that effectively isolates brain tissue from

medwedi.ru 869

870

Part Six: The Peripheral Vascular System

Figure 2 Subclavian origin of vertebral arteries allows these vessels to function as collateral pathways for upper extremity. Cerebellar ischemia may result from the ‘‘steal’’ of blood flow.

Figure 1 (A) Carotid artery supplies middle cerebral and anterior cerebral arteries predominantly, with major contributions to posterior cerebral artery. (B) Vertebral arteries form the basilar artery that supplies cerebellar vessels and posterior cerebral arteries.

serum ionic changes and humoral factors (14). The barrier is both a physical and biochemical impediment to the transport of protein and polar substances into cerebral extracellular fluid. Anatomic features include very tight junctions between endothelial cells, with only a few scattered pores and minimal transport by pinocytotic vesicles. A membranebound enzyme system, primarily composed of monoamine oxidase, effectively degrades circulating catecholamines and limits cerebral extraction to less than 5%. It is noteworthy that the areas of the brain responsible for hormone regulation, such as the hypothalamus, pituitary gland, and pineal gland, do not demonstrate the anatomic or functional characteristics of the blood–brain barrier. The blood–brain barrier is disrupted in areas of tissue infarction and during periods of severe hypertension (15). These observations are clinically important because breakdown of the blood–brain barrier (i) facilitates the diagnosis of cerebral infarcts by radionuclide scanning, and (ii) explains the occurrence of late hemorrhage in previously ‘‘bland’’ infarcts when patients become severely hypertensive.

Measurement Techniques Diverse methods have been used to measure cerebral blood flow in experimental settings, including venous outflow

collections, radioactive microspheres, autoradiography, and heat or hydrogen clearance (16). In clinical practice, most measurements of total and regional cerebral blood flow are made on the basis of the clearance of inhaled inert gases including xenon-133. Using the modified Kety–Schmidt technique, xenon-133 washout is monitored by external gamma scintillation counters and subjected to ‘‘curve stripping’’ to remove any component of extracranial blood flow (17). This technique is most accurate in the middle cerebral distribution and least helpful in evaluating the posterior cerebral or cerebellar circulations. The recent introduction of positron emission tomography allows repeated imaging of radionuclide concentration in any transverse section of the brain (18). Depending on the labeled element, regional blood flow H215O or substrate use (C11-glucose) can be measured (19). Although this technology was once only regarded as a research tool, now it provides the most precise metabolic and flow data available in a wide range of clinical settings.

Flow Regulatory Mechanisms Pressure-flow autoregulation is the ability of an organ to maintain normal blood flow despite variations in blood pressure. This protective mechanism is well documented in the cerebral circulation. Most physiologists agree that the process is an intrinsic property of blood vessels, involving a continuous readjustment of the myogenic activity of vascular smooth muscle, which depends on changes in transmural pressure and the local (extracellular) chemical environment. Increased intravascular pressure (hypertension) predictably results in compensatory vasoconstriction, whereas decreased pressure (hypotension) elicits vasodilation (20). Although early experiments suggested that pCO2 was the primary chemical regulator of vascular tone, it has become well accepted that the hydrogen ion concentration in the extracellular space provides the vasodilatory influence (21,22). Decreasing pCO2 results in lower hydrogen ion concentration and vasoconstriction. An elevated pCO2 leads to

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease

higher hydrogen ion concentration and vasodilation. This relationship is applied clinically in the management of severe head injuries; hyperventilation with resultant hypocarbia and decreased hydrogen ion concentration decreases cerebral blood flow and attenuates posttraumatic cerebral edema. Responses to changes in pCO2 are less vigorous, although hypoxia does result in moderate cerebral vasodilation. Sympathetic stimulation and other neural stimuli have only a small influence on cerebrovascular resistance and blood flow autoregulation (23). In fact, there is minimal histologic evidence of adrenergic vasoconstrictive fibers on cortical vessels (18). Neurally mediated vasoconstriction is limited to large vessels outside the brain proper and, as such, does not represent a primary regulatory mechanism (24).

CLINICAL PRESENTATION OF CEREBROVASCULAR DISEASE Definitions For purposes of discussion, clinicians have grouped neurologic deficits into four categories. TIA are classically defined as short-lived, often repetitive alterations of mentation, vision, motor, or sensory function that are completely reversed within 24 hours. Although TIA often involve the middle cerebral artery distribution and present with contralateral arm, leg, and facial weakness, perhaps the most well-recognized episodes involve transient monocular blindness (amaurosis fugax or ‘‘fleeting blindness’’). TIA that last only a few minutes may be prognostically different from those deficits that persist for longer than two hours. For this reason, longerlasting episodes (2–72 hours) that still result in no permanent neurologic deficit or radiologic evidence of brain infarction are usually designated reversible ischemic neurologic deficits. A documented cerebral infarction (stroke or cerebrovascular accident) implies a permanent neurologic deficit that is usually associated with computed tomography scan evidence. Neurologic recovery is quite variable and may be complete, but the time course of recovery (weeks or months) clearly distinguishes infarcts from TIA or reversible ischemic neurologic deficits. A ‘‘stuttering stroke’’ in which the neurologic deficit ‘‘waxes and wanes’’ has been termed stroke-in-evolution. This type of presentation is not as common but has received much recent attention because of the potential that therapeutic maneuvers could improve the eventual outcome (25,26). Although the above definitions have aided communication, they can be criticized for arbitrarily grouping diverse mechanisms with quite variable prognoses. For example, TIA can be caused by migraines, seizure disorders, and intracranial aneurysms, as well as carotid artery lesions. This ‘‘lumping’’ phenomenon is most confusing when large multicenter studies attempt to characterize the natural history of a clinical presentation without rigorous preselection on the basis of cause.

Mechanisms Symptoms of cerebrovascular disease reflect both the mechanism of ischemia and the specific areas affected. In general, ischemia and infarction result from either low flow in largeor medium-sized vessels associated with obstructive lesions or hypotension, or emboli in smaller vessels from proximal ulcerative lesions or turbulent flow. Hemodynamic derangements predisposing to the low flow are manifest clinically by neurologic deficits corresponding to the ‘‘watershed areas’’ between the main cerebral artery perfusion territories.

871

Symptoms of embolic occlusion depend on the site of distal impaction. Predictably, the size of the embolus determines the vessel it will occlude. Both mechanisms can result in permanent and reversible deficits (27). In particular, repetitive short-lived neurologic deficits (i.e., TIA) are compatible with either (i) recurrent ischemia of watershed areas, or (ii) impaction and lysis of intermittent platelet emboli following a consistent route mandated by hemodynamics and anatomy.

Arterial Pathology The most common disease process involving the cerebral and extracranial vessels is atherosclerosis (28). Although the disease is most prevalent in patients over the age of 50, presentations of younger patients are not rare. In roughly half of the cases, the atheroma is localized to the extracranial bifurcation of the common carotid into the internal and external carotid arteries. Such atherosclerotic plaques may slowly encroach on the arterial lumen or suddenly occlude following intraplaque hemorrhage (29). Other pathologic processes are less common and may more frequently involve younger patients. These include spontaneous subintimal dissections of the internal carotid and fibromuscular dysplasia. Although it is generally accepted that the majority of emboli arise from ulcerated atherosclerotic lesions in the common or internal carotid artery, the intracranial carotid siphon near the origin of the ophthalmic artery can also harbor symptomatic ulcerative lesions. Stenoses and occlusions can involve either the extracranial or the intracranial carotid arteries, both areas simultaneously (tandem lesions), or any portion of a specific cerebral artery (30,31). The mechanisms that underlie plaque instability may involve biologic factors that are intrinsic to plaque structure and biomechanical factors that induce structural breakdown or specific cellular responses. Ongoing histopathologic studies at the University of Chicago have found that large symptomatic and asymptomatic plaques, often highly stenotic, possess remarkably similar histopathologic features with regard to the presence of necrosis, calcification, fibrous-cap ulceration, hemorrhage, and surface thrombosis (32,33). Although intraplaque hemorrhage, hematoma, and surface thrombosis have been regarded by other investigators as cardinal features of symptomatic plaques, such a finding was not substantiated in these studies. It was consistently observed, however, that proximity of the necrotic core to the overlying fibrous cap and lumen was associated with embolic symptoms. In symptomatic plaques, the necrotic core was twice as close to the lumen when compared with asymptomatic plaques, whereas the degree or location of calcification had little effect. Symptomatic plaques also exhibited a greater degree of macrophage infiltration in and about the fibrous cap and were associated with fibrous-cap thinning and erosion. This implicated an ongoing inflammatory or immune-mediated response as a factor in plaque instability. The potential role of biomechanical forces in inducing structural fatigue of plaque constituents and the localization of plaque neoformation and inflammatory cell response is also of interest. Marked elevation of wall shear stress occurs within stenoses that are associated with large plaques. Although high shear may inhibit plaque formation (34), changes in flow dynamics associated with marked stenoses, including wall vibration, flutter, and cyclical collapse (35), could induce disruptions within plaques, lumen ulcer formation, and associated surface irregularities.

medwedi.ru

872

Part Six: The Peripheral Vascular System

TYPES OF CEREBROVASCULAR DISEASE Extracranial Carotid Artery Disease Clinical Presentation The symptoms of extracranial carotid disease can be described by the timing of impairment (permanent, transient, or relapsing) and the type of neurologic deficit (motor, sensory, cognitive, or communicative). As discussed earlier in this chapter, both decreases in cerebral blood flow and embolic occlusions can produce the entire clinical spectrum. The persistence of any neurologic deficit is synonymous with death of brain tissue. Transient and relapsing episodes unassociated with infarctions are distinguished by the return of the neurologic examination to normal. The exact nature of a deficit can be directly correlated with the area of brain rendered ischemic. The most commonly involved area is the perfusion territory of the middle cerebral artery (the parietal lobe), which is the main outflow vessel of the carotid artery. The patient with middle cerebral ischemia presents with contralateral hemiparesis or hemiplegia, usually more severe in the arm, and paralysis of the contralateral lower part of the face (‘‘central seventh nerve paralysis’’). Associated findings include some degree of hypesthesia (decreased sensation) on the paralyzed side and a contralateral homonymous hemianopsia (visual-field deficit). Aphasia (difficulty with speech) is noted if the dominant hemisphere is involved. The left hemisphere is dominant in nearly all right-handed people and roughly 50% of left-handed people. Such defects can be expressive (Broca’s aphasia), receptive (Wernicke’s aphasia), or complete. If the nondominant hemisphere is affected, a curious ‘‘neglect response’’ is noted in which the paralyzed extremity is essentially ignored by the patient. Ischemia of the anterior cerebral artery most commonly presents with contralateral monoplegia involving only the lower extremity; visual–spatial problems and cortical sensory loss are also common. Posterior cerebral artery ischemia may result from carotid occlusive disease, but is also closely related to vertebral– basilar lesions. Presentations often include visual-field defects and may overlap with symptoms of ischemia of the posterior portion of the middle cerebral distribution, such as language disturbances and contralateral hemiparesis. Other neurologic signs consistent with posterior cerebral artery ischemia include ipsilateral third–cranial nerve palsy and contralateral complete sensory loss (thalamic syndrome).

Diagnosis Symptomatic carotid artery disease is commonly associated with the above neurologic presentations. However, it is essential to exclude other causes for such syndromes, including migraines, brain tumors, intracranial hemorrhage, and vascular malformations. The physical finding most consistent with extracranial carotid disease is a demonstration of a bruit on auscultation of the upper cervical region, reflecting turbulent blood flow at a stenosis. Classic carotid bruits have the following characteristics: they are (i) high pitched and fade into diastole, (ii) localized to the angle of the jaw, and (iii) best heard with the bell rather than the diaphragm of the stethoscope. Unfortunately, even experienced examiners frequently cannot distinguish internal or common carotid bruits from clinically irrelevant turbulence in the distal external carotid artery or other cervical blood vessels. As many as 50% of symptomatic ulcerations may be unassociated with stenoses and hence may not present with bruits. Finally, when a

stenosis exceeds 90% of vascular cross-sectional area, the intensity of the bruit often decreases because of lower volume flow. This lack of specificity of cervical bruits is most disturbing in asymptomatic patients with bruits, because physical examination alone does not allow assessment of the degree, or even the presence, of carotid disease. Many noninvasive tests have been developed to better characterize extracranial carotid disease without the risk of angiographic procedures. They are most widely used in asymptomatic patients with cervical bruits and in the long-term follow-up of patients already treated with carotid endarterectomy.

Imaging Techniques Direct noninvasive tests using ultrasound techniques to visualize the extracranial vessels have largely replaced the indirect methods previously used to detect and quantitate disease (e.g., oculoplethysmography). When combined with sophisticated range-gated pulsed Doppler instruments (duplex scanning), the velocity and volume flow can be determined (1). The resolution of duplex scanning has improved recently such that ulcerative nonstenotic lesions can be detected in most patients. Arteriography for cerebrovascular disease commonly includes imaging of the aortic arch and selective injections of the common carotid arteries, with delineation of the carotid siphon and intracranial vessels (Figs. 3 and 4). The common carotid artery and its bifurcation are readily visualized along with any associated stenoses or ulcerated plaques. Perhaps the most significant advantage of cerebral arteriograms is their ability to demonstrate intracranial lesions and aortic arch disease. Relevant intracranial lesions include tumors, aneurysms, arteriovenous malformations, and arterial occlusive disease, particularly of the carotid siphon. Indeed, ulcerative or occlusive lesions of the aortic arch or intracranial vessels may produce symptoms identical to those associated with carotid artery disease such as TIA or amaurosis fugax. When associated with carotid bifurcation disease, such proximal or distal occlusive lesions are termed ‘‘tandem’’ lesions. Due to its invasive nature, contrast angiography has associated morbidity and mortality (36). These adverse reactions can be grouped into three major categories: local, systemic, and neurologic. Local complication rates (ranging from 5% to 15%) include hemorrhage, hematomas, pseudoaneurysms, and formation of thrombi or emboli at the arterial puncture site. Systemic complications include allergic reactions to the contrast agent, as well as renal and cardiovascular manifestations. While the incidence of serious allergic reactions to radiographic contrast agents is less than 2% in most reported series, in patients with a history of contrast allergy, the incidence of anaphylactic reactions may be as high as 20% (37). Allergic reactions range from minor sequelae such as nausea, vomiting, hives, and chills, to major lifethreatening reactions such as hypotension, bronchospasm, laryngospasm, and pulmonary edema. Radiographic contrast agents can also produce a deterioration in renal function, especially in patients with preexisting kidney disease. One series reported that nonazotemic patients experienced a 2% incidence of acute renal failure following all types of angiography, while patients with chronic azotemia suffered a 33% incidence (38). However, the same study revealed that the occurrence of acute renal failure was less in patients undergoing carotid–vertebral studies than in patients undergoing visceral angiograms with more direct delivery of dye to the kidneys. Cardiac complications of cerebral

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease

873

Figure 4 Operative specimen (bivalved) reveals narrow lumen (L) with fresh hemorrhage (H) within atherosclerotic plaque. Extensive ulcerations are noted.

Operative Indications

Figure 3 Preoperative angiogram of patient presenting with repeated episodes of contralateral hemiparesis demonstrates severe stenosis of both internal (arrow) and external carotid arteries.

angiography include hypotension, arrhythmias, myocardial ischemia or infarction, and even cardiac arrest. Neurologic complications are the most important risk of cerebral angiography (39). Events range from TIA (lasting less than 24 hours) to completed strokes. Hankey et al. reviewed eight prospective studies consisting of 2227 patients with mild ischemic cerebrovascular disease (40). A 4% incidence of postangiographic neurologic complications was observed, of which 1% were permanent. As would be expected, the incidence was higher in patients with active symptoms or bilateral severe carotid artery stenoses. Magnetic resonance arteriography (MRA) is another noninvasive method of imaging the extracranial carotid arteries. It has an advantage over conventional angiography in that there is no risk of stroke, arterial injury, or systemic complications such as contrast reactions. Rigorous correlation between magnetic resonance angiography and carotid endarterectomy specimens has yet to be reported. In our early experience with this technique, the degree of stenosis is often factitiously overestimated. Even modest degrees of turbulence at the carotid bifurcation or siphon (such as 50% stenoses) may appear to be critical lesions.

The indications for carotid endarterectomy are constantly being reevaluated and redefined. In a recent multicenter randomized trial, it has been shown that carotid endarterectomy will significantly decrease the risk of stroke in symptomatic patients with carotid stenoses of 70% to 99% of diameter (41). Symptoms referable to carotid stenosis included hemispheric TIA with resultant loss of motor and/or sensory function on one side of the body, monocular ipsilateral blindness (amaurosis fugax), or a nondisabling stroke. In this study, there was a reduction in risk of major or fatal stroke from 13.1% in the medical therapy group to 2.5% in the surgical group over two years. The timing of carotid endarterectomy after a completed stroke due to an ipsilateral carotid lesion is somewhat controversial. Most would agree that endarterectomy should be considered unless the patient has sustained a severely disabling stroke such that there is minimal salvageable function in the affected carotid artery distribution. The procedure should be delayed until the patient’s neurologic status has stabilized, usually three to six weeks after the stroke (42). The risk of recurrent stroke after carotid endarterectomy is approximately 1.6% per year (15% at nine years), as compared to a recurrent stroke rate of 50% at five years in those patients not undergoing carotid endarterectomy (9). Nevertheless, many surgeons will not operate if severe intracranial disease or cardiac risk factors would decrease the effectiveness or increase the morbidity of the procedure. The prognosis of asymptomatic patients with highly stenotic carotid lesions remains difficult to characterize (25,43). Long-term follow-up of patients with persistent disease of the contralateral carotid artery following unilateral carotid endarterectomy documents a 20% incidence of

medwedi.ru

874

Part Six: The Peripheral Vascular System

cerebrovascular symptoms; the incidence of stroke without antecedent TIA is approximately 3% to 5% (44). The recent Veterans Affairs Cooperative Study found a benefit for endarterectomy if the stenosis was greater than 50%, but the endpoints included all neurologic events, not just stroke (45). Because experienced surgeons document a perioperative stroke rate of less than 2%, operative intervention may be appropriate in asymptomatic patients with limited anesthetic risk factors and those undergoing major surgical procedures that may predispose to hypotension (36).

Nonoperative Treatment The most significant risk factor for stroke is hypertension. Hence, the control of hypertension is most important in the medical management of patients with cerebrovascular disease (46). Evaluation of serum lipoproteins will likely assume a greater role in the prevention and retardation of atherosclerosis as dietary and drug therapies for specific abnormalities become more clear. Direct medical therapy for cerebrovascular disease has focused on anticoagulation (heparin and warfarin) and antiplatelet drugs (aspirin, dipyridamole, and sulfinpyrazone) (47,48). Mechanisms of action differ considerably, but the common rationale includes prevention of sudden thrombosis of stenotic lesions and inhibition of platelet activation on ulcerative lesions. Although many studies have suggested a benefit of long-term anticoagulation, the methodologies of these investigations have been seriously questioned, especially regarding their lack of randomization and precise patient selection. Furthermore, the statistically significant reduction in stroke rate (from 19% to 12% in one series) does not compare to better results achieved by carotid endarterectomy (49,50). Many clinicians believe that antiplatelet agents are most appropriate in patients with minimal ulcerative nonstenotic lesions and only one episode or one closely spaced series of TIA (7). If symptoms recur in such patients, endarterectomy remains an option. Other candidates for anticoagulation include patients with very high operative risk or those with severe associated intracranial disease.

Operative Techniques and Results Carotid endarterectomy is the surgical procedure of choice for disease of the common carotid artery or the extracranial portion of the internal carotid artery (51). The procedure can be performed under general or local anesthesia. Patients at greatest risk for a perioperative ischemic stroke include patients with previous infarcts, those with contralateral carotid occlusions, and those with unstable neurologic deficits (52). Some surgeons routinely use an indwelling vascular shunt to maintain carotid cerebral perfusion during endarterectomy, whereas others use shunts selectively or not at all. Intraoperative monitoring of electroencephalograms or retrograde carotid perfusion pressure (‘‘stump pressure’’) has been used to assess the need for shunt placement. Because it is likely that embolic events account for the majority of perioperative strokes, precise dissection technique is crucial in patients with thrombotic or ulcerative plaques (53). Exposure of the vessels must be carried out in an unhurried and gentle manner, mindful of surrounding cranial nerves, especially the vagus, hypoglossal, superior laryngeal, and glossopharyngeal nerves. We administer heparin and clamp the distal internal carotid prior to any manipulation of the bifurcation. Only then is the lateral

carotid bulb sharply dissected free and rotated anteromedially. The arteriotomy is made in this lateral aspect and usually extended past the distal edge of the plaque. Unhindered visualization of the end point is essential. It is also important that the proximal extent of the endarterectomy achieves a suitable nondiseased segment of the vessel. If there is any question of the distal ‘‘feather’’ of the endarterectomy, fine tacking sutures are placed; such sutures should not be tied too tightly or puckering of the luminal surface may result. It has also been our practice to tack the edges of the proximal end point if a thickened intimal layer has separated from the medial layer. Intraoperatively, Doppler signals are evaluated in both the internal and the external carotid arteries. Completion duplex ultrasonography or arteriography is not used routinely; however, both are employed if deemed necessary. Recently we have applied more liberal indications for placement of prosthetic or vein patch (extensive arteriotomy into the internal carotid artery, vessels smaller than 3 mm, female sex, or active smoking). For example, patching was performed in about 10% of our patients during 1981 through 1987, and nearly half of patients in the more recent period. The type of patch does not seem to strongly influence early or late outcomes, but care must be taken to avoid excessively enlarging the artery and altering flow dynamics. The incidence of perioperative stroke varies with operative indication. Most large series report stroke rates of 1% to 2% in patients with TIA and 3% to 5% in patients with previous strokes or contralateral carotid occlusion (54). Other postoperative complications include cranial nerve injury (especially the hypoglossal and recurrent laryngeal nerves) and myocardial infarction. Because the carotid sinus regulates blood pressure homeostasis, postoperative hypotension or hypertension is noted in many patients during the 24 hours required for baroreceptor reacclimation (55). Death following carotid endarterectomy is infrequent and is more commonly due to myocardial infarction than stroke. In our series of 367 consecutive carotid endarterectomies, two of the three deaths were attributable to acute myocardial infarction, while none of the four patients suffering perioperative neurologic deficits died (56). This experience is not unique. In 1981, Lees and Hertzer (57) reported a total of 10 postoperative deaths in 335 patients, many of whom underwent other major surgical procedures during the same hospitalization. Myocardial infarction was the cause of 6 of the 10 deaths, and only two deaths were due to stroke. In the multicenter Asymptomatic Carotid Atherosclerosis Study (58), only one patient in the 825-patient surgical group died following surgery; the cause of death was myocardial infarction. In the North American Symptomatic Carotid Endarterectomy Trial report (41) in 1991, of the 328 patients undergoing surgical treatment of severe carotid stenoses, two deaths were noted (0.7%), one from stroke and one from myocardial infarction or arrhythmia. In the multicenter Veterans Medical Centers study of asymptomatic stenoses described by Hobson et al. (45), all four surgical deaths (1.9%) resulted from myocardial infarction. The occurrence of myocardial ischemia and infarction has been linked to hypertension. Riles et al. (59) specifically linked the overzealous use of a-adrenergic agents to increase carotid artery ‘‘stump’’ pressure intraoperatively with both myocardial ischemia and infarction. In their view, the incidence of myocardial infarction was 4.9% in 284 patients with hypertension as compared with zero in 207 normotensive patients. The well-described fluctuations in

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease

875

systemic blood pressure in the postoperative period (including hypertension and hypotension) also contribute to cardiac morbidity (55,60). The risk for myocardial complications and death appears to increase slightly with age. Meyer et al. (61) reported an overall mortality of 1.3% in 749 carotid endarterectomies performed on patients 70 years of age or older, between 1971 and 1989; 6 of 10 deaths were due to myocardial infarction. A more recent series of 63 endarterectomies in patients 75 years or older, from Perler and Williams (62), included five major cardiac complications but no deaths. It has been well accepted that the indications for surgery and the neurologic status strongly influence outcome. For example, in a large series of more than 1700 carotid endarterectomies, Thompson (63) reported an operative mortality rate of 3.4% for patients with previous stroke, 1.1% for patients with TIA, and 0% for asymptomatic patients. Taken as a whole, it seems clear that mortality reflects cardiac status and management, while neurologic morbidity reflects patient selection and technical aspects of the operation. Recurrent stenoses occur in approximately 8% to 10% of patients, if followed closely, although the incidence of symptomatic recurrence is much lower (3%). Restenosis within 24 months usually represents exuberant intimal regeneration, whereas later presentations reflect recurrent atherosclerosis (64).

ischemic symptoms are generally mild, true posterior fossa infarction can be progressive and lethal, as a result of extensive edema and midbrain compression. Emboli can contribute to posterior cerebral and cerebellar ischemia, but occlusive disease of the vertebral arteries or the basilar artery is the most common mechanism. The thrombotic process may involve the basilar artery proper or the basilar branch vessels that penetrate into the brain stem (49). A classic syndrome of vertebrobasilar insufficiency (subclavian steal syndrome) is associated with subclavian or innominate arterial occlusive disease (71). The subclavian origins of the vertebral arteries allow the vessels to function as collaterals for the upper extremity. During arm exercise, flow is reversed in the vertebral artery, and basilar arterial blood flow and perfusion pressure are decreased. Symptoms of posterior cerebral and cerebellar ischemia can result, especially if any flow-limiting carotid lesions are present. The anatomic relationship favors left-sided involvement, approximately in the ratio of 4:1 (72). The diagnosis of subclavian steal syndrome is supported by complaints of intermittent vertigo, lightheadedness, and nausea and vomiting intensified by arm exercise. Physical findings include supraclavicular bruits and 40- to 60-mmHg blood pressure discrepancies between the arms.

Carotid Angioplasty and Stenting

Diagnosis

The recent and remarkable improvements in interventional devices and skills offer nonsurgical options for treatment of carotid and vertebral lesions. The advantages of angioplasty and stenting include extending the definitive treatment of carotid lesions to higher-risk patients as well as those with special considerations mitigating against operative repair. This population would include patients with previous endarterectomies, in whom cranial nerve injury might be a concern, and patients with cervical radiation (65,66). Initial experience in angioplasty and stenting was limited to patients with severe comorbidities, which precluded safe operative repair (67). Technical success was observed in more than 95% of patients treated in a number of recognized centers, although the incidence of neurologic complications exceeded the best operative endarterectomy series (68). Increasing experience in endovascular techniques and the introduction of various types of ‘‘cerebral protection devices’’ (which filter or trap atheroembolic debris downstream from the dilated lesion) have both contributed to lower complication rates in the current literature (69). More widespread use of this endovascular approach is occurring, although the proper assessments of the safety and durability of these procedures await the completion of a number of ongoing randomized clinical trials.

Measuring blood pressure in both upper extremities is essential in any patient with cerebral symptoms. More sophisticated tests include B-mode imaging of the subclavian and vertebral vessels and the use of directional dopplers to document reversal of vertebral-artery blood flow. The primary diagnostic test remains arteriography (70). It is important to obtain delayed films to adequately demonstrate retrograde flow through the vertebral into the distal subclavian (Figs. 5 and 6). The origin of the contralateral vertebral artery and the status of the basilar artery should also be evaluated with oblique films if necessary. The incidental demonstration of subclavian steal during arteriography for some other reasons is, in itself, not cause for concern or surgical therapy.

Vertebrobasilar Disease Clinical Presentation As noted earlier, the paired vertebral vessels join to form the basilar artery. For this reason, proximal occlusion or ligation of only one vertebral vessel will not cause symptoms unless the contralateral vessel is diseased or hypoplastic. More distal disease of one vertebral vessel with occlusion of the small branches supplying the lateral medulla can result in neurologic deficits. The most frequent symptoms of basilar insufficiency include nausea, vertigo, ipsilateral facial numbness, ipsilateral Horner’s syndrome, and limb ataxia (70). Although

Operative Indications and Techniques Symptomatic patients with multiple vertebral occlusive lesions or subclavian steal syndrome should be considered for elective surgery. Procedures include endarterectomy of the proximal vertebral artery or carotid subclavian bypass to restore antegrade vertebral flow (73). The latter can be accomplished by bypass graft or division of the cervical subclavian artery with reimplantation into the common carotid artery. These procedures can be performed through a cervical incision (Figs. 7 and 8). In patients with associated carotid artery disease, carotid endarterectomy alone may relieve symptoms of vertebrobasilar insufficieny, by increasing collateral flow to the posterior cerebral artery and cerebellum (28). This is most appropriate in symptomatic patients with severe carotid stenoses and those with more distal vertebral or basilar occlusion.

Results and Complications Patency of vertebral endarterectomies and carotid subclavian bypass grafts exceeds 90%. In most cases, symptoms are completely relieved by successful bypass. Failure to

medwedi.ru

876

Part Six: The Peripheral Vascular System

Figure 5 Preoperative angiogram in patient presenting with stroke in basilar distribution (superior cerebellar) demonstrates complete occlusion of left subclavian artery (arrow).

achieve symptomatic improvement may be caused by continued carotid disease or intracranial lesions (75). Perioperative complications include injuries to the phrenic nerve, cervical sympathetic ganglia (with Horner’s

Figure 7 Postoperative intravenous digital angiogram demonstrates patent carotid–subclavian bypass (arrow) with return of cephalad flow in left vertebral artery.

syndrome), or the thoracic duct. Basilar territory infarction after carotid subclavian bypass is very rare; even early graft failure should not further compromise vertebral flow.

UPPER-EXTREMITY VASCULAR DISEASE Symptomatic arterial insufficiency of the upper extremity is relatively uncommon, accounting for approximately 2% of all peripheral vascular reconstructive procedures. Although atherosclerosis is the predominant cause of arterial ischemia of the upper extremity, there are other etiologies including extrinsic compression, vasospasm, arteritis, connective tissue disorders, trauma, Buerger’s disease, previous radiation therapy, and occupational injury.

Nonatherosclerotic Disease

Figure 6 Delayed films document reversed flow in large left vertebral artery (arrow) with reconstitution of distal subclavian artery (subclavian steal syndrome).

Extrinsic compression of the subclavian artery usually occurs at the thoracic outlet and may result in distal extremity ischemia or emboli. While impingement on the subclavian artery is commonly positional and temporary, long-standing external compression can lead to fibrosis and permanent arterial stenoses. If arteriography with positional maneuvers confirms a persistent and significant stenotic or ulcerative lesion, simple excision of the local soft tissue, primarily the medial scalene muscle and first rib, will not be sufficient treatment. Exclusion and bypass of the involved portion of the subclavian artery should be performed. In some patients, upper-extremity arterioles are exceptionally sensitive to sympathetic stimuli, resulting in vasospasm with intermittent ischemia and even gangrene. Vasospasm of the hands presents with a characteristic progression of color changes in the fingers: digits first become pallorous, secondary to decreases in the flow of oxygenated blood, then cyanotic, and finally ruborous as the vasospasm decreases and reperfusion occurs. This clinical syndrome is

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease

Figure 8 Aneurysms of palmar vessels secondary to repetitive hand trauma in a meat packer.

termed ‘‘Raynaud’s phenomenon,’’ after the French physician who first described it. Patients with Raynaud’s phenomenon should be screened for collagen-vascular diseases such as lupus erythematosis, rheumatoid arthritis, and scleroderma. In approximately 50% of patients with manifestations of severe digital ischemia, the phenomenon predates or is associated with these disorders. The most critical therapy of Raynaud’s phenomenon is avoidance of the cold, wind, and moisture, which classically trigger each episode; in some patients, stress also is a major factor. Vasoactive drugs including sympatholytics, which reduce the uptake and subsequent release of local norepinephrine, and calcium-channel blocking agents can be helpful. Finally, cervical dorsal sympathectomy can be employed if tissue loss is threatened or if symptoms are intolerable; unfortunately, the benefits of this procedure are not uniform or particularly durable. Two other causes for digital ischemia are vibratory injury to the palmar and digital vessels and Buerger’s disease. Vibratory injury results from repetitive blunt trauma to the hands, which are associated with certain occupations (construction work, especially with jack-hammers, meat packing, etc.) (76). The cumulative force of the injuries results in medium-vessel occlusions as well as true aneurysms due to medial and adventitial necrosis (Fig. 9). Patients may present with distal ulcers from ischemia and embolization. If aneurysms are demonstrated, direct microvascular

877

repair is indicated to prevent enlargement and continued embolization. Buerger’s disease is a progressive medium- and smallvessel obliterative disease associated with nicotine abuse. Patients present with distal ischemia of both upper and lower extremities; recurrent venous thrombophlebitis is a frequent comorbidity. Local treatments of ischemic lesions and sympathectomy may be successful, but only if smoking cessation is complete. Unfortunately, this goal is almost never attained at this level of addiction to smoking. Takayasu’s Disease is an example of an inflammatory large vessel arteritis resulting in fibrosis and scarring of the aorta and its primary branches. Symptoms start as fever, myalgias, and anorexia, but then progress to upperextremity arterial insufficiency (77). The progression of arterial stenosis leads to the loss of the upper-extremity pulses, hence the name ‘‘pulseless disease.’’ Takayasu’s disease primarily affects people of Asian descent, with a strong predominance for females (8:1) less than 40 years of age. The etiology is still uncertain, although infection and autoimmune processes have been implicated; the disease is associated with rheumatoid arthritis, ankylosing spondylitis, and ulcerative colitis. Laboratory evaluation may reflect a generalized inflammatory process with an elevation of the erythrocyte sedimentation rate and a mild hypochromic anemia. Takayasu’s arteritis can be divided into four types based on the distribution of lesions (77,78). Type I is limited to the aortic arch and its primary branches, Type II includes lesions of the descending thoracic and abdominal aorta, Type III extends from the aortic valve to the abdominal aorta, and Type IV includes pulmonary artery involvement and/or associated aneurysms (77,78). The majority of patients present during the ‘‘pulseless’’ stage, and symptoms reflect the organ or extremity that is rendered ischemic. Complaints can include headache, light-headedness, hemiparesis, blurring of vision, diplopia, and blindness. The classic ocular findings include optic atrophy and retinal vein or artery thrombosis (79). Extremity symptoms can be limited to exercise-related complaints or progress to rest pain and tissue loss. Initial therapy, especially in the prepulseless stage, is centered upon the administration of corticosteroids. If a patient with symptomatic lesions has failed corticosteroid therapy, operative therapy is directed toward bypass of the involved or occluded vessels (80). If at all possible, operative intervention should be delayed until the acute phase of the disease has resolved. This may not be possible in patients presenting with active cerebrovascular symptoms. Endarterectomy has not proven effective, due to the transmural inflammatory response and the tendency toward aneurysmal degeneration. Bypass grafts are the preferred treatment and should originate and terminate in arteries known to be free of disease by both angiography and inspection (81); often, grafts must originate from the ascending aorta. Distal anastomotic stenoses occur in 20% to 30% of cases and may require reoperation.

Atherosclerotic Upper-Extremity Arterial Disease Clinical Presentation Atherosclerosis of the subclavian or innominate arteries is the most common cause of upper-extremity ischemia; symptoms may be due to low flow or emboli. Lesions involving the innominate artery can result in thrombotic atherosclerotic emboli to either the right vertebral artery or the right

medwedi.ru

878

Part Six: The Peripheral Vascular System

Figure 9 (A) Classic lesion at origin of innominate artery presented with right hemispheric transient ischemia attacks. Proximity of left carotid artery origin mandated ascending aorta to innominate bypass graft. (B) Complete occlusion due to radiation injury required bypass to relieve right upper extremity ischemia.

common carotid artery, with resulting TIA or strokes (Fig. 10). Emboli to the left cerebral hemisphere can also originate from the innominate artery lesions, due to the proximity of the origin of the left common carotid artery to the innominate artery. In one large series, 77% of the patients with symptomatic innominate artery lesions presented with neurologic symptoms, not upper-extremity problems (82). Stenosis or occlusion of the subclavian artery occurs three to four times more commonly on the left than the right subclavian artery. As noted earlier, a proximal subclavian artery occlusion or stenosis can result in reversal of flow in the left vertebral artery. The clinical presentation of unilateral upper-extremity weakness or coolness, vertigo with upper-extremity exercise (subclavian ‘‘steal’’ syndrome), or ischemic lesions of the hand should raise a suspicion of subclavian artery stenosis or occlusion. The diagnosis is suspected by comparing upper-extremity arterial pressures, and is confirmed by arteriography. Arteriograms will not only define the extent of disease of the subclavian artery, but will also evaluate the thoracic aorta, carotid arteries, and the vertebral arteries.

Treatment Symptomatic patients should be considered for arterial revascularization (83). Innominate lesions are usually approached directly through a median sternotomy (Fig. 11) (74). Both endarterectomy and bypass from the aortic arch are durable procedures. The selection of the specific procedure is based on the nature of the lesion and the location of origin of the left carotid artery. If it originates close to the innominate, clamping of the latter vessel for endarterectomy is inadvisable and bypass is preferred (82).

Bypass procedures for subclavian disease include transposition of the subclavian artery to the adjacent nondiseased carotid artery or carotid artery to subclavian artery bypass with a prosthetic graft (Fig. 8) (74). Transposition entails the complete mobilization of the subclavian artery proximal to the origin of the vertebral artery. The subclavian artery is divided and the proximal arterial stump oversewn. An anastomosis is created between the side of the proximal carotid artery and the end of the subclavian artery. If the subclavian cannot be mobilized enough for a tension-free apposition to the proximal carotid artery, a carotid– subclavian bypass can be performed. In these instances, the preferred bypass graft conduit is a synthetic graft, due to its decreased tendency to kink. Both subclavian artery transposition and carotid–subclavian artery bypass have similar long-term patencies of greater than 95% (84).

Thoracic Outlet Syndrome Clinical Presentation Thoracic outlet syndrome is best described as an intermittent but reproducible compression irritation of the brachial plexus caused by congenital fibromuscular bands, cervical ribs, or the anterior scalene muscle (Fig. 12) (85,86). Classic symptoms include shoulder pain with radiation to the occiput and down the arm along the C8 to T1 distribution. Numbness and tingling frequently accompany the pain. In advanced cases, weakness of the hands and forearm may be noted. Although the subclavian artery may also be compressed by the same anatomic configuration, most symptoms of thoracic outlet syndrome relate directly to neurologic rather than vascular compromise.

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease

879

Figure 12 Brachial plexus compression occurs at triangular outlet between scalene muscles and first rib.

cause-and-effect relationship is nearly impossible. The differential diagnosis includes carpal tunnel syndrome, cervical disk compression, arthritis, tendonitis, and angina pectoris.

Diagnosis

Figure 10 Innominate endarterectomy can be performed if a vascular clamp can be applied proximal to the lesion without also obstructing the left carotid artery origin. Source: From Ref. 74.

A history of neck or shoulder trauma can be elicited in many patients, which some clinicians consider to be suggestive of scalene muscle spasm being an initiating event. Whiplash injuries are frequently implicated, but documentation of a

The chronicity and lack of specificity of the clinical presentation is paralleled by a lack of definitive diagnostic tests other than chest x-ray film demonstration of an abnormal cervical rib. The Adson maneuver is a positional test long associated with thoracic outlet syndrome. The test is considered positive if the radial pulse disappears during abduction and external rotation of the arm. Unfortunately, the Adson maneuver is frequently positive in asymptomatic patients and negative in patients with classic symptoms of thoracic outlet syndrome, again emphasizing the neurologic as opposed to vascular origin of the pain syndrome. Angiographic demonstration of subclavian artery compression in extreme abduction also does not contribute significantly to the diagnosis unless there is evidence of a persistent blood pressure gradient in the involved arm (5). Electromyograms and nerve conduction velocities have been suggested as objective measures of thoracic outlet nerve compression. Unfortunately, enthusiasm for these studies has decreased recently because of the difficulty of electrically stimulating nerves proximal to the presumed site of compression and the intermittent nature of the syndrome. Furthermore, clinical correlations between positive nerve conduction studies and symptomatic relief following surgery have not been very convincing.

Operative Indications and Techniques

Figure 11 Subclavian reconstructions include both carotid–subclavian bypass and transposition of the distal subclavian into the carotid artery (illustrated here). Source: From Ref. 74.

Initial therapy should include shoulder girdle exercises and avoidance of extreme posturing. If pain remains and symptoms are fully consistent and reproducible, surgical therapy is appropriate. Unfortunately, even experienced surgeons report complete relief in only 80% to 85% of patients. The most common operation is transcervical or transaxillary resection of the first rib or a cervical rib, if present. In some patients, merely transecting the insertion of the anterior scalene muscle onto the first rib may suffice (87). Although there has been some enthusiasm for concurrent cervical sympathectomy, this is usually unnecessary unless symptoms of posttraumatic sympathetic dystrophy (causalgia) are evident.

medwedi.ru

880

Part Six: The Peripheral Vascular System

Complications The failure rate from all procedures remains relatively high in thoracic outlet syndrome (88). Complications of surgery include Horner’s syndrome, direct injury to the brachial plexus, lymphatic leaks, and pneumothorax.

SUMMARY Although cerebrovascular disease remains a major cause of morbidity and mortality in our population, improved understanding of the mechanisms and pathologic processes involved has allowed a wider application of preventive medical and surgical therapies. Appropriate selection of noninvasive tests to evaluate asymptomatic patients with signs of extracranial cerebrovascular disease has further characterized the natural history of these disorders. Although specific recommendations for medical or surgical therapy will continually be modified, it is generally accepted that patients with repetitive neurologic deficits (TIA) associated with extracranial atherosclerotic disease benefit significantly from surgical intervention. In patients with upper-extremity ischemia, extensive medical evaluation and careful assessments of the brachial–cephalic arterial system are mandatory.

REFERENCES 1. Lees RS, Kistler JP, Sanders D. Duplex Doppler scanning and spectral bruit analysis for diagnosing carotid stenosis. Circulation 1982; 66(2 Pt 2):I102–I105. 2. Levy RI. Stroke decline: implications and prospects. N Engl J Med 1979; 300(9):490–491. 3. Whisnant JP. Epidemiology of stroke: emphasis on transient cerebral ischemia attacks and hypertension. Stroke 1974; 5(1): 68–70. 4. Wolf PA, Kannel WB, Sorlie P, McNamara P. Asymptomatic carotid bruit and risk of stroke. The Framingham study. JAMA 1981; 245(14):1442–1445. 5. Judy KL, Heymann RL. Vascular complications of thoracic outlet syndrome. Am J Surg 1972; 123(5):521–531. 6. West H, Burton R, Roon AJ, Malone JM, Goldstone J, Moore WS. Comparative risk of operation and expectant management for carotid artery disease. Stroke 1979; 10(2):117–121. 7. Goldner J, Wisnant JP, Taylor WF. Long-term prognosis of transient cerebral ischemic attacks. Stroke 1971; 2(2):160–167. 8. Diaz FG, Ausman JI, de los Reyes RA, et al. Combined reconstruction of the vertebral and carotid artery in one single procedure. Neurosurgery 1983; 12(6):629–635. 9. Mani RL, Eisenberg RL. Complications of catheter cerebral arteriography: analysis of 5,000 procedures. III. Assessment of arteries injected, contrast medium used, duration of procedure, and age of patient. Am J Roentgenol 1978; 131(5):871–874. 10. Dinsdale HB, Robertson DM, Haas RA. Cerebral blood flow in acute hypertension. Arch Neurol 1974; 31(2):80–87. 11. Gregory PC, McGeorge AP, Fitch W, Graham DI, MacKenzie ET, Harper AM. Effects of hemorrhagic hypotension on the cerebral circulation. II. Electrocortical function. Stroke 1979; 10(6): 719–723. 12. Lassen NA, Henriksen L, Paulson O. Regional cerebral blood flow in stroke by 133Xenon inhalation and emission tomography. Stroke 1981; 12(3):284–288. 13. Wechsler RL, Drips PO, Kety SS. Blood flow and oxygen consumption of the human brain during anesthesia produced by thiopental. Anesthesia 1951; 12:308. 14. Abboud FM. Special characteristics of the cerebral circulation. Fed Proc 1981; 40(8):2296–2300.

15. Johansson B, Li CL, Olsson Y, Klatzo I. The effect of acute arterial hypertension on the blood-brain barrier to protein tracers. Acta Neuropathol (Berl) 1970; 16(2):117–124. 16. Busija DW, Heistad DD, Marcus ML. Continuous measurement of cerebral blood flow in anesthetized cats and dogs. Am J Physiol 1981; 241(2):H228–H234. 17. Marcus ML, Bischof CJ, Heistad DD. Comparison of microsphere and Xenon-133 clearance method in measuring skeletal muscle and cerebral blood flow. Circ Res 1981; 48(5):748–761. 18. Raichle ME, Hartman BK, Eichling JO, Sharpe LG. Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc Natl Acad Sci USA 1975; 72(9):3726–3730. 19. Raichle ME, Welch MJ, Grubb RL Jr, Higgins CS, Ter-Pogossian MM, Larson KB. Measurement of regional substrate utilization rates by emission tomography. Science 1978; 199(4332):986–987. 20. Ekstrom-Jodal B. On the relation between blood pressure and blood flow in the canine brain with particular regard to the mechanism responsible for cerebral blood flow autoregulation. Acta Physiol Scand Suppl 1970; 350:1–61. 21. Borgstrom L, Johannsson H, Siesjo BK. The relationship between arterial po2 and cerebral blood flow in hypoxic hypoxia. Acta Physiol Scand 1975; 93(3):423–432. 22. Greenberg JH, Alavi A, Reivich M, Kuhl D, Uzzell B. Local cerebral blood volume response to carbon dioxide in man. Circ Res 1978; 43(2):324–331. 23. D’Alecy LG, Feigl EO. Sympathetic control of cerebral blood flow in dogs. Circ Res 1972; 31(2):267–283. 24. Heistad DD, Marcus ML. Evidence that neural mechanisms do not have important effects on cerebral blood flow. Circ Res 1978; 42(3):295–302. 25. Humphries AW, Young JR, Santilli PH, Beven EG, deWolfe VG. Unoperated, asymptomatic significant internal carotid artery stenosis: a review of 182 instances. Surgery 1976; 80(6):695–698. 26. Mentzer RM Jr, Finkelmeier BA, Crosby IK, Wellons HA Jr. Emergency carotid endarterectomy for fluctuating neurologic deficits. Surgery 1981; 89(1):60–66. 27. Pessin MS, Hinton RC, Davis KR, et al. Mechanisms of acute carotid stroke. Ann Neurol 1979; 6(3):245–252. 28. Solberg LA, Eggen DA. Localization and sequence of development of atherosclerotic lesions in the carotid and vertebral arteries. Circulation 1971; 43(5):711–724. 29. Javid H, Ostermiller WE Jr, Hengesh JW, Dye WS, Najafi H, Julian OC. Natural history of carotid bifurcation atheroma. Surgery 1970; 67(1):80–86. 30. Craig DR, Meguro K, Watridge C, Robertson JT, Barnett HJ, Fox AJ. Intracranial internal carotid artery stenosis. Stroke 1982; 13(6):825–828. 31. Eisenberg RL, Nemzek WR, Moore WS, Mani RL. Relationship of transient ischemic attacks and angiographically demonstrable lesions of carotid artery. Stroke 1977; 8(4):483–486. 32. Bassiouny HS, Davis H, Massawa N, Gewertz BL, Glagov S, Zarins CK. Critical carotid stenoses: morphologic and chemical similarity between symptomatic and asymptomatic plaques. J Vasc Surg 1989; 9(2):202–212. 33. Bassiouny HS, Sakaguchi Y, Mikucki SA, et al. Juxtalumenal location of plaque necrosis and neoformation in symptomatic carotid stenosis. J Vasc Surg 1997; 26(4):585–594. 34. Zarins CK, Bomberger RA, Glagov S. Local effects of stenoses: increased flow velocity inhibits atherogenesis. Circulation 1981; 64(2 Pt 2):221–227. 35. Cancelli C, Pedley TJ. A separated flow model for collapsible rube oscillations. J Fluid Mech 1985; 157:375–404. 36. Makhoul RG, Moore WS, Colburn MD, Quinones-Baldrich WJ, Vescera CL. Benefit of carotid endarterectomy after prior stroke. J Vasc Surg 1993; 18(4):666–670; discussion 670–671. 37. Witten DM, Hirsch FD, Hartman GW. Acute reactions to urographic contrast medium: incidence, clinical characteristics and relationship to history of hypersensitivity states. Am J Roentgenol Radium Ther Nucl Med 1973; 119(4):832–840. 38. D’Elia JA, Gleason RE, Alday M, et al. Nephrotoxicity from angiographic contrast material. A prospective study. Am J Med 1982; 72(5):719–725.

Chapter 45: Cerebrovascular Disease and Upper-Extremity Vascular Disease 39. Faught E, Trader SD, Hanna GR. Cerebral complications of angiography for transient ischemia and stroke: prediction of risk. Neurology 1979; 29(1):4–15. 40. Hankey GJ, Warlow CP, Sellar RJ. Cerebral angiographic risk in mild cerebrovascular disease. Stroke 1990; 21(2):209–222. 41. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325(7):445–453. 42. Whittemore AD, Mannick JA. Surgical treatment of carotid disease in patients with neurologic deficits. J Vasc Surg 1987; 5(6):910–913. 43. Busuttil RW, Baker JD, Davidson RK, Machleder HI. Carotid artery stenosis—hemodynamic significance and clinical course. JAMA 1981; 245(14):1438–1441. 44. Podore PC, DeWeese JA, May AG, Rob CG. Asymptomatic contralateral carotid artery stenosis: a five-year follow-up study following carotid endarterectomy. Surgery 1980; 88(6): 748–752. 45. Hobson RW II, Weiss DG, Fields WS. The Veterans Affairs Cooperative Study Group. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med 1993; 328(4):221–227. 46. Kannel WB, Dawber TR, Sorlie P, Wolf PA. Components of blood pressure and risk of atherothrombotic brain infarction: the Framingham study. Stroke 1976; 7(4):327–331. 47. Brust JC. Transient ischemic attacks: natural history and anticoagulation. Neurology 1977; 27(8):701–707. 48. Olsson JE, Brechter C, Backlund H, et al. Anticoagulant versus anti-platelet therapy as prophylactic against cerebral infarction in transient ischemic attacks. Stroke 1980; 11(1):4–9. 49. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. The Canadian Cooperative Study Group. N Engl J Med 1978; 299(2):53–59. 50. Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Stroke 1977; 8(3):301–314. 51. Thompson JE, Talkington CM. Carotid surgery for cerebral ischemia. Surg Clin North Am 1979; 59(4):539–553. 52. Goldstone J, Moore WS. A new look at emergency carotid artery operations for the treatment of cerebrovascular insufficiency. Stroke 1978; 9:599. 53. Steed DL, Peitzman AB, Grundy BL, Webster MW. Causes of stroke in carotid endarterectomy. Surgery 1982; 92(4): 634–641. 54. DeWeese JA, Rob CG, Satran R, et al. Results of carotid endarterectomies for transient ischemic attacks-five years later. Ann Surg 1973; 178(3):258–264. 55. Bove EL, Fry WJ, Gross WS, Stanley JC. Hypotension and hypertension as consequences of baroreceptor dysfunction following carotid endarterectomy. Surgery 1979; 85(6):633–637. 56. McKinsey JF, Desai TR, Bassiouny HS, et al. Mechanisms of neurologic deficits and mortality with carotid endarterectomy. Arch Surg 1996; 131(5):526–531; discussion 531–532. 57. Lees CD, Hertzer NR. Postoperative stroke and late neurologic complications after carotid endarterectomy. Arch Surg 1981; 116(12):1561–1568. 58. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273(18):1421–1428. 59. Riles TS, Kopelman I, Imparato AM. Myocardial infarction following carotid endarterectomy: a review of 683 operations. Surgery 1979; 85(3):249–252. 60. Towne JB, Bernhard VM. The relationship of postoperative hypertension to complications following carotid endarterectomy. Surgery 1980; 88(4):575–580. 61. Meyer FB, Meissner I, Fode NC, Losasso TJ. Carotid endarterectomy in elderly patients. Mayo Clin Proc 1991; 66(5): 464–469. 62. Perler BA, Williams GM. Carotid endarterectomy in the very elderly: Is it worthwhile? Surgery 1994; 116(3):479–483. 63. Thompson JE. Carotid endarterectomy, 1982—the state of the art. Br J Surg 1983; 70(6):371–376.

881

64. Cossman D, Callow AD, Stein A, Matsumoto G. Early restenosis after carotid endarterectomy. Arch Surg 1978; 113(3):275–278. 65. Jordan WD Jr, Voellinger DC, Fisher WS, Redden D, McDowell HA. A comparison of carotid angioplasty with stenting versus endarterectomy with regional anesthesia. J Vasc Surg 1998; 28(3):397–402; discussion 402–403. 66. New G, Roubin GS, Iyer SS, et al. Safety, efficacy, and durability of carotid artery stenting for restenosis following carotid endarterectomy: a multicenter study. J Endovasc Ther 2000; 7(5):345–352. 67. Roubin GS, New G, Iyer SS, et al. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001; 103(4):532–537. 68. Hertzer NR, Ouriel K. Results of carotid endarterectomy: the gold standard for carotid repair. Semin Vasc Surg 2000; 13(2): 95–102. 69. Al-Mubarak N, Colombo A, Gaines PA, et al. Multicenter evaluation of carotid artery stenting with a filter protection system. J Am Coll Cardiol 2002; 39(5):841–846. 70. Caplan LR, Rosenbaum AE. Role of cerebral angiography in vertebrobasilar occlusive disease. J Neurol Neurosurg Psychiatry 1975; 38(6):601–612. 71. Fisher CM. A new vascular syndrome: ‘‘the subclavian steal’’. N Engl J Med 1961; 265:912. 72. Fields WS, Lemak NA. Joint Study of extracranial arterial occlusion. VII. Subclavian steal—a review of 168 cases. JAMA 1972; 222(9):1139–1143. 73. Clark K, Perry MO. Carotid vertebral anastomosis: an alternate technic for repair of the subclavian steal syndrome. Ann Surg 1966; 163(3):414–416. 74. Zarins CK, Gewertz BL. Atlas of Vascular Surgery. New York: Churchill Livingstone, Inc., 1989. 75. Allen GS, Cohen RJ, Preziosi TJ. Microsurgical endarterectomy of the intracranial vertebral artery for vertebrobasilar transient ischemic attacks. Neurosurgery 1981; 8(1):56–59. 76. Clark ET, Mass DP, Bassiouny HS, Zarins CK, Gewertz BL. True aneurysmal disease in the hand and upper extremity. Ann Vasc Surg 1991; 5(3):276–281. 77. Ishikawa K. Natural history and classification of occlusive thromboaortopathy (Takayasu’s disease). Circulation 1978; 57(1):27–35. 78. Lupi E, Sanchez G, Horwitz S, Gutierrez E. Pulmonary artery involvement in Takayasu’s arteritis. Chest 1975; 67(1):69–74. 79. Takayasu M. Case with unusual change of the vessels in the retina. Acta Soc Ophthalmol 1908; 12:554. 80. Alpert HJ. The use of immunosuppressive agents in Takayasu’s arteritis. Med Ann Dist Columbia 1974; 43(2):69–71. 81. Weaver FA, Yellin AE, Campen DH, et al. Surgical procedures in the management of Takayasu’s arteritis. J Vasc Surg 1990; 12(4):429–437; discussion 438–439. 82. Cherry KJ Jr, McCullough JL, Hallett JW Jr, Pairolero PC, Gloviczki P. Technical principles of direct innominate artery revascularization: a comparison of endarterectomy and bypass grafts. J Vasc Surg 1989; 9(5):718–723; discussion 723–724. 83. Whitehouse WM Jr, Zelenock GB, Wakefield TW, Graham LM, Lindenauer SM, Stanley JC. Arterial bypass grafts for upper extremity ischemia. J Vasc Surg 1986; 3(3):569–573. 84. Salam TA, Lumsden AB, Smith RB III. Subclavian artery revascularization: a decade of experience with extrathoracic bypass procedures. J Surg Res 1994; 56(5):387–392. 85. Kirgis HD, Reed AF. Significant anatomic relations in the syndrome of the scalene muscles. Ann Surg 1948; 127:1182. 86. Roos DB. Congenital anomalies associated with thoracic outlet syndrome. Anatomy, symptoms, diagnosis, and treatment. Am J Surg 1976; 132(6):771–778. 87. Sanders RJ, Monsour JW, Gerber WF, Adams WR, Thompson N. Scalenectomy versus first rib resection for treatment of the thoracic outlet syndrome. Surgery 1979; 85(1):109–121. 88. Urschel HC Jr, Razzuk MA, Albers JE, Wood RE, Paulson DL. Reoperation for recurrent thoracic outlet syndrome. Ann Thorac Surg 1976; 21(1):19–25.

medwedi.ru

46 Venous and Lymphatic Abnormalities of the Limbs Jose R. Parra and Julie A. Freischlag

INTRODUCTION William Harvey’s monumental work nearly four centuries ago on the circulation of blood first emphasized the important role that the extremity veins play in this process. The impact of derangements in venous and lymphatic function of the limbs is staggering and contributes substantially to human disease. This chapter discusses our current understanding of these disorders and the physiologic rationale underlying their management.

ANATOMY Veins of the lower extremity can be classified as deep, superficial, or perforating venous systems. The superficial veins run in the subcutaneous tissue external to the deep fascia. The two major tributaries in the superficial venous system are the greater and lesser saphenous veins. The greater saphenous vein, formed by the confluence of the medial veins of the dorsum and plantar aspect of the foot, is found anterior to the medial malleolus and travels along the medial aspect of the leg until it crosses laterally at the proximal thigh to join the common femoral vein (Fig. 1). This junction is commonly 2 to 4 cm lateral to the pubic tubercle and inferior to the inguinal ligament. Cutaneous sensation to the medial aspect of the lower leg is provided by the saphenous branch of the femoral nerve, which runs adjacent to or crosses the greater saphenous vein in the lower leg. This is an important anatomic finding in that saphenous nerve injury can result in a troublesome neuropathy. The lesser saphenous vein, arising behind the lateral malleolus, takes its origin from the veins draining the lateral aspect of the foot and travels through the midline of the posterior calf to join the popliteal vein behind the knee (Fig. 1). Both of these major veins are commonly used as bypass conduits and are also the main sites of superficial venous reflux. The deep veins of the calf include the peroneal, posterior tibial, and anterior tibial vein, which ascend along the course of their corresponding artery (Fig. 2). In addition, there is a complex of veins within the soleal and gastrocnemius muscles often referred to as venous lakes, which are important physiologically because of their propensity to generate thrombus. These venous lakes coalesce and join the posterior tibial and peroneal veins. The aforementioned veins then merge with the anterior tibial vein to form the popliteal vein at the knee. This vein continues proximally as the superficial femoral vein and joins the deep femoral vein below the inguinal ligament to become the common femoral vein. The common femoral vein, traveling medial to the femoral artery, passes beneath the inguinal ligament

and continues as the external iliac vein. As a rule, deep veins are duplicated below the knee and are the first structures identified when dissecting out the arteries. Perforating veins traverse the deep fascia and connect the superficial and deep venous systems. These veins play a critical role in the pathophysiology of chronic venous insufficiency insofar as they can transmit elevated pressures from the deep venous system into the superficial system. Superficial and deep venous systems are present within the upper extremity (Fig. 3). The major superficial veins are the cephalic vein, which runs from the anatomic snuffbox along the lateral aspect of the arm to empty into the axillary vein at the deltopectoral groove, and the basilic vein, which travels along the medial aspect to empty into the brachial vein in the upper arm. These veins are commonly used as outflow tracts for arteriovenous fistulas created for hemodialysis. The deep veins parallel the radial

Figure 1 Diagram depicting the two main superficial tributaries of the venous system: the greater saphenous vein and lesser saphenous vein.

medwedi.ru 883

884

Part Six: The Peripheral Vascular System

Figure 2 Diagram depicting the deep venous system of the lower extremity.

and ulnar arteries below the elbow and then coalescence to form the brachial vein. The brachial vein merges with the basilic vein to become the axillary vein followed by the subclavian vein at the lateral border of the first rib. The subclavian vein then drains into the innominate vein ultimately ending up in the superior vena cava.

Figure 3 Diagram depicting the upper-extremity venous anatomy.

pressure. With competent valves and a functioning calf pump during exercise, venous blood in these capacitance vessels is returned to the heart. A clinical application of this action is the use of pneumatic compression devices in patients at bed rest. These devices rhythmically inflate to mimic the function of the calf muscles and reduce stasis and the risk for venous thrombosis.

VENOUS PHYSIOLOGY The venous system is a low-pressure capacitance system with significant redundancy, which depends upon external compression and compartmentalization to return blood to the heart. The veins have an intima, media, and adventitia but lack a significant muscular and elastic layer in all but the most central veins. A feature unique to the venous circulation is the presence of bicuspid valves in all veins distal to the common iliac vein. These one-way valves are oriented so to maintain a unidirectional flow of blood toward the heart. Upon standing, the column of venous blood is arrested as the valves slam shut and reflux is prevented. The valves of the perforating veins are crucial in preventing reflux of blood from the deep to the superficial systems, which prevents superficial venous hypertension. In the supine position at rest, the foot vein has a pressure of approximately 15 mmHg. On standing, the gravitational hydrostatic forces are added increasing the measured foot vein pressure to approximately 115 mmHg. Assuming the standing position also increases venous volume with an increase in the capacitance by about 500 cm3. Ambulation produces contraction of the calf muscles that serve as an external ‘‘pump’’ to squeeze the venous blood in a cephalad direction and lower the venous

VENOUS DISORDERS OF THE LOWER EXTREMITY Deep Venous Thrombosis Deep venous thrombosis (DVT) is the most serious and potentially life-threatening disorder of the venous system. The most lethal complication, pulmonary embolism (PE), is the cause of approximately 200,000 deaths each year in the United States (1). More than half of the patients surviving DVT suffer from the postphlebitic syndrome notable for disabling edema and potential stasis ulcers. Much of the pathophysiology of DVTs was first postulated by Virchow. He described three conditions (Virchow’s triad) that permit the development of a venous thrombus: stasis, hypercoagulability, and vessel wall damage. Stasis is the most important predisposing factor in the surgical patient. With the induction of general anesthesia, there is a considerable reduction in the venous flow because of the loss of the ability to contract the muscles of the lower extremity and a generalized peripheral dilation that is present throughout the procedure. Furthermore, a hospitalized patient frequently remains at bed rest, which also induces stasis and subsequent DVT. It is this consequence that provides the stimulus for early ambulation in most surgical patients. Other risk factors for DVT include age, obesity, malignancy, oral

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

contraceptive use, hypercoagulability syndromes, and pregnancy (2). Each of these factors alters venous stasis or coagulopathy.

Clinical Presentation Clinical signs of venous thrombosis are found in only 40% of the patients. When symptoms are present, they initially include edema and calf pain. The level at which swelling occurs is determined by the site of venous obstruction. If the swelling is confined to the calf or foot, obstruction is at the femoropopliteal level, whereas swelling at the thigh level implies iliofemoral obstruction. Physical examination reveals calf tenderness on palpation and occasionally a palpable cord representing the thrombosed vein. Homans’ sign, tenderness or tightness in the back of the calf with forcible dorsiflexion of the foot, may be present but is nonspecific and unreliable. There is a higher incidence of DVTs in the left leg compared to the right. Most DVTs involve the popliteal vein and its tributaries. However, if the thrombus extends proximally to involve the iliofemoral system, there may be massive swelling from the toes to the inguinal ligament. The clinical picture of pain, extensive pitting edema, and blanching is referred to as phlegmasia alba dolens or ‘‘milk leg.’’ With the progression of the thrombus, venous return becomes compromised and produces a painful, cyanotic leg known as phlegmasia cerulea dolens (3). If left unchecked, venous congestion and swelling can eventually limit arterial flow leading to gangrene of the extremity (Fig. 4). However, as previously mentioned, most patients are asymptomatic, and these dramatic presentations represent a very small percentage of the patients with venous thrombosis.

Diagnosis Diagnostic tests are critical in establishing the diagnosis because false-positive clinical signs have been found to occur in up to 45% of the patients evaluated (4). Duplex ultrasonography scanning is noninvasive and can be conveniently used at the bedside to detect venous thrombi with an accuracy of approximately 90%. Flow abnormalities such as a loss of phasicity or augmentation with distal compression are suggestive of thrombi. The most sensitive test, however,

Figure 4 Venous gangrene following iliofemoral deep venous thrombosis associated with malignancy.

885

is a loss of compressibility of the normally compliant vein (Fig. 5). In the femoral vein, duplex scanning has a specificity of 100% and sensitivity of 95% (5). Diagnostic accuracy is lower in the calf. Nevertheless, it has been suggested that duplex scanning replaces venography as the standard method of diagnosing femoropopliteal DVT. Venography is the most accurate means of establishing the diagnosis of venous thrombosis and its extent of involvement. This test requires injection of a contrast medium into a foot vein while the superficial veins are occluded by a tourniquet to promote filling of the deep venous system. Filling defects and nonvisualization of the deep veins identify the thrombus. This invasive test carries the risk of producing venous thrombosis secondary to the thrombogenicity of the injected contrast medium. Other rare complications include cellulitis or skin necrosis secondary to extravasation of contrast and gangrene (6). This test remains the gold standard. Venography can also be performed with isotope injection and thus eliminate some of these complications. A gamma scintillation counter is then used to record the flow of the isotope. The image with this technique is not as well defined, but this method may be valuable for the sequential study of patients. A similar technique involves radioactivelabeled fibrinogen scanning. This technique involves intravenous injection of 125I-labeled fibrinogen. A developing thrombus incorporates fibrinogen with an increase in radioactivity that represents an organizing thrombus. This test is primarily used in clinical research studies given its oversensitivity to clot formation. Impedance plethysmography is another alternative to venography. This method measures the rate of volume changes in the extremity following rapid deflation of a blood pressure cuff. A prolongation of the outflow following deflation is indicative of occlusive thrombus. This technique has largely been supplanted by duplex ultrasonography.

Prophylaxis Several prophylactic measures can be used in the hospitalized patient. The goals of these measures are to reduce stasis or alter blood coagulability. Early ambulation has become a routine part of a patient’s postoperative course in an attempt to prevent stasis. Other options to reduce stasis include graded compression stockings and intermittent pneumatic compression devices, both of which augment venous flow. These devices are placed on the patient just prior to surgery and remain in place until the patient is actively ambulating. Anticoagulation therapy using heparinoids is commonplace. Heparin and its derivative low-molecular-weight heparin (LMWH) bind to anti–thrombin III, which causes an increased inhibition of factors IIa, Xa, IXa, XIIa, and thrombin. Unfractionated heparin (5000 U subcutaneously) can be given two hours preoperatively and then every 8 to 12 hours postoperatively until the patient is ambulating. Although controversy exists over its efficacy, a large randomized series of surgical patients showed protection against DVT and a markedly decreased incidence of PE (7). LMWH is composed entirely of lower-molecular-weight heparin moieties and has the benefit of lowering the risk of bleeding complications. Other advantages include a lower incidence of the heparin-induced thrombocytopenia (HIT) syndrome and lower risks of osteopenia with long-term use. Several different brands of LMWH are available and the dosing for prophylaxis varies among the brands (8).

medwedi.ru

886

Part Six: The Peripheral Vascular System

Figure 5 (A) Longitudinal view using the duplex scan to identify normal flow in the superficial femoral artery (SFA) and superficial femoral vein (SFV). (B) Longitudinal view using the duplex scan demonstrating normal SFA and loss of venous flow in the SFV caused by thrombus. (C) Duplex scan of the greater saphenous vein showing nonoccluding thrombus identified by arrows. (D) Transverse view of the SFA and SFV demonstrating no flow in a completely thrombosed SFV.

Colditz et al. (9) evaluated general surgery patients using a variety of different types of prophylaxis. The incidence of DVT using the fibrinogen uptake test or venography was estimated to be 27% without any therapy, while those treated with subcutaneous heparin had an incidence of 9.6%, those with compression stockings 6.3%, and those with pneumatic compression devices 17.6%. A combination of heparin and stockings revealed an incidence of DVT of 6.3%, and stockings with intermittent pneumatic compression revealed an incidence of 4.5% (9). Indications for prophylaxis depend upon the type of surgery as well as associated risk factors. There are three levels of risk ranging from negligible risk not warranting treatment to high risk requiring multi-modality treatment. Patients undergoing outpatient surgery with no risk factors do not require prophylaxis, while patients undergoing major general surgery and/or having multiple risk factors need one of the prophylactic measures described above. Trauma, orthopedic and neurosurgical procedures, and/or

several risk factors require therapy with two of the above measures (e.g., compression devices and LMWH).

Treatment The goal of DVT management is to halt the propagation of thrombus, prevent PE, and promote resolution of existing clot to minimize the risk for postphlebitic syndrome. The mainstay of initial therapy for DVT is anticoagulation with heparin. This can take the form of an adjusted dose heparin drip or LMWH. Traditional dosing of a heparin drip consists of a 80 U/kg intravenous bolus followed by 18 U/kg/hr as a continuous infusion. The adequacy of anticoagulation is monitored by serial partial thromboplastin time levels, which are maintained between 60 and 80 seconds. Adjusted dose heparin therapy requires inpatient treatment. In contradistinction, LMWH is administered as subcutaneous injections and can be given in the outpatient setting. Treatment with LMWH has been shown to have a lower rate of major and minor bleeding as well as lower rates of PE than

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

adjusted dose heparin (10). A predictable pharmacokinetic profile obviates the need for any type of monitoring except in obese and renal failure patients. However, an anti-Xa assay can be obtained to verify efficacy with a target goal of between 0.6 and 1.0 IU/mL (11). Heparin limits any further propagation of the thrombus and prevents the formation of new thrombi. It does not break up the original thrombus. The affected extremity should be elevated when the patient is not ambulatory to reduce swelling and tenderness. Compression stockings should be used to prevent edema formation. Once the patient is anticoagulated, oral warfarin (Coumadin) therapy is begun. Warfarin acts by inhibiting the synthesis of the vitamin K–dependent clotting factors, II, VII, IX, and X. The prothrombin time (PT) or international normalized ratio (INR) is used to monitor warfarin therapy. The PT is brought to within 1.3 to 1.5 times the control value or an INR of 2 to 3 to maintain sufficient anticoagulation. Warfarin therapy should be continued for at least three months when identifiable risk factors are present, six months for an idiopathic thromboembolism, and 12 months to lifetime in patients with a hypercoagulable condition (12). Recently, a randomized trial demonstrated that lower INRs in the 1.5 to 2.0 range were as efficacious as higher doses with lower bleeding complications (13). Both heparin and warfarin therapy have serious potential side effects. Side effects associated with heparin treatment include bleeding, thrombocytopenia, hypersensitivity reaction, arterial thromboembolism, and osteoporosis in patients receiving long-term therapy (14). HIT syndrome is an antibody-mediated reaction to heparin leading to venous and arterial thromboses (15). A drop in the platelet count by 50% or skin lesions at the site of injection are highly suggestive of HIT syndrome. Laboratory assays that can detect HIT antibodies exist. Treatment of this syndrome involves cessation of heparin use and administration of direct thrombin inhibitors such as lepirudin or argatroban. Coumadin should be avoided in these patients because there are multiple reports of warfarin-induced venous limb gangrene. Arterial thromboembolism caused by HIT is the most severe complication. Complications associated with warfarin therapy include bleeding, skin necrosis, dermatitis, and a painful blue toe syndrome. Skin necrosis occurs in areas with significant adipose tissue such as thighs, breasts, and buttocks. It has been found that thrombosis of venules and capillaries supplying this region occurs as a result of an underlying protein C deficiency. Protein C and protein S are the first factors to decrease following the administration of Coumadin, which results in a transient hypercoagulable state amplified in patients with a preexisting protein C deficiency. A blue toe syndrome can occur secondary to bleeding into an arterial plaque, which results in distal embolization and ischemia. Warfarin is also teratogenic and should not be used during pregnancy. Heparin is the drug of choice during pregnancy and is given subcutaneously for long-term treatment. Fibrinolytic therapy for the management of DVT has been an area of great interest. Bleeding is the major complication associated with this course of treatment and is therefore contraindicated in patients who have had recent surgery, trauma, or hemorrhagic stroke. This technique is most effective when performed within 72 hours of the event and involves placement of a catheter directly into the thrombus and providing a local infusion of the lytic agent. Urokinase has been found to be more effective than streptokinase with fewer hemorrhagic and allergic complications (16).

887

Objectives of this form of therapy include reduction of lower-extremity edema and pain and preservation of venous valve function. The presence of an iliofemoral DVT resulting in phlegmasia cerulea dolens or venous gangrene is a situation where thrombolysis or surgical thrombectomy is indicated to prevent limb loss. A more controversial indication for thrombolysis has been to preserve venous valve integrity by rapid resolution of the thrombus so as to protect against the development of valvular incompetence and subsequent postphlebitic syndrome (17). Early recanalization is important in preserving valve integrity; however, it is not clear that postphlebitic syndrome can be prevented by early lytic therapy (18,19). Quality-of-life assessments have shown a benefit to the use of lysis in patients with iliofemoral DVTs (20).

Complications of DVT Pulmonary Embolism The most fatal complication of DVT is a PE. PEs occur most frequently between 7 and 10 days postoperatively; if the symptoms remain unrecognized and untreated, the mortality is approximately 30%. Pathophysiology. A patient with a DVT of the lower extremity has a 50% chance of PE if the thrombus reaches the iliofemoral system. Even though thrombi may develop in the smaller veins of the calf, the risk of PE is less until the thrombus extends to the level of the femoral and iliac veins. Once embolization occurs and pulmonary blood flow is interrupted, a regional ventilation–perfusion mismatch and a bronchoconstrictive response are produced. Occlusion of more than 30% of the pulmonary vascular bed leads to a rise in pulmonary artery pressures, while a 50% occlusion leads to a fall in systemic pressures. The classic presentation is that of sudden pleuritic chest pain, dyspnea, and tachypnea. Other findings can include cough, tachycardia, and hemoptysis; hemoptysis is an uncommon finding indicative of pulmonary infarction. Physical examination reveals tachycardia, a prominent second heart sound, and cyanosis. Diagnosis. The clinical presentation of a PE mimics several other life-threatening conditions. An electrocardiogram is essential to exclude a myocardial infarction. Nonspecific ST and T wave changes are a nonspecific finding with PE. Chest X rays demonstrate enlargement of the central vasculature, a lack of the vascular markings with segmental or lobar ischemia (Westermark’s sign), or pleural effusion. A wedge-shaped infiltrate is occasionally seen. Arterial blood gas analysis shows hypoxemia coupled with alkalosis. Central venous pressure is elevated or normal if hemodynamic compensation has occurred, with a low central venous pressure essentially excluding PE. Definitive diagnosis of PE requires a computed tomography (CT) scan, ventilation–perfusion scan, or pulmonary arteriography. The ventilation–perfusion scan involves intravenous infusion of labeled albumin, to demonstrate perfusion abnormalities, combined with xenon gas inhalation, to demonstrate ventilation abnormalities. The combination of a poorly perfused area that shows excellent ventilation has the highest probability of representing a PE. Lesser concordances are given lower probabilities. With this technique, there is a high false-positive rate, because other diseases such as pneumonia or atelectasis can lead to similar results. Spiral CT scans of the chest with intravenous contrast have sufficient resolution to allow discrimination of thrombosis

medwedi.ru

888

Part Six: The Peripheral Vascular System

in the segmental pulmonary arteries (21). The sensitivity of this test varies widely (63–94%), but it has a high specificity (22). Pulmonary angiography remains the gold standard for identification of PE, but it is best reserved for situations where there is disagreement or uncertainty with the other imaging techniques. Treatment. Anticoagulation with heparin is the mainstay of treatment, and the technique of administration is the same as that described for DVT. Again, heparin therapy is initiated and is converted to oral anticoagulation for three to six months. Those patients in whom anticoagulation is contraindicated are candidates for inferior vena caval interruption to prevent further DVTs. Surgical thrombectomy is another procedure for treating iliofemoral DVTs. The indications for this treatment include phlegmasia, venous gangrene, and the inability of patients to be treated by anticoagulation or thrombolysis. A longitudinal venotomy is made in the distal common femoral vein and an Esmarch bandage (i.e., a wide, thick rubber band) is used to squeeze thrombus from the distal veins, while balloon catheters are used to extract clot from the proximal veins. A temporary arteriovenous fistula is often created to increase venous patency. This procedure is associated with an early patency rate of 87% and a significant decrease in the incidence of reflux following treatment (23). This procedure is somewhat morbid with potential for significant intraoperative blood loss and high rates of postoperative hematomas and groin infections. Although anticoagulation remains the mainstay of treatment for DVT, this therapy is contraindicated in some patients leaving them at high risk for the development of pulmonary emboli. To treat patients in this situation, several techniques to ‘‘filter’’ the vena cava have been explored. Inferior vena cava filters are made by several manufacturers but basically consist of a metallic screen that filters the vena cava of thrombi. These filters can be placed percutaneously and are usually deployed in the vena cava between the caval bifurcation and the lowest renal vein. Complications of inferior vena cava filters include misplacement, insertion-site DVT, migration of the filter, erosion of the device into the inferior vena cava wall and inferior vena cava obstruction, and PE (24,25). Although this procedure has a relatively low morbidity and mortality, the complications can be severe, and placement should be reserved for those patients who have absolute contraindications to traditional anticoagulation. Temporary filters are currently under investigation. For patients with a massive PE with refractory hypotension, an emergent pulmonary embolectomy may be required. A thoracotomy is performed to surgically remove the thrombus. Given the high mortality rate associated with this procedure, alternative approaches using interventional techniques have been developed although the only Food and Drug Administration–improved device is the Greenfield aspiration (26). Other devices and techniques use mechanical means to break up the thrombus. Thrombolytic therapy has also been used as an alternative treatment for those patients not in shock. Urokinase and tissue plasminogen activator are available lytic agents proven to be effective. The patient’s symptoms often improve quickly with the dissolution of the clot; however, no improvement has been seen in early mortality in patients with pulmonary emboli, who have been treated with thrombolytic therapy (27). In addition, there are significant complications secondary to bleeding, which have limited the use of this therapy.

Postphlebitic Syndrome Chronic venous insufficiency is a disabling venous disorder characterized by chronic lower-extremity edema, skin changes, and a propensity for ischemic ulcer formation. Postphlebitic syndrome is the chronic venous insufficiency that occurs following a DVT; 74% of patients with DVTs involving the femoral or iliac vein develop this condition (28). Clinical Presentation. Hyperpigmentation and edema of the lower extremity are the earliest signs of chronic venous insufficiency (Fig. 6). The swelling has been described as brawny and nonpitting. The hyperpigmentation is associated with a dermatitis (venous eczema) that leads to severe pruritus, frequently the initial complaint. In addition to the skin changes, the patient experiences an aching discomfort or night cramps that are aggravated by dependency and relieved with elevation. Venous claudication or a throbbing pain throughout the leg may occur with ambulation. These changes occur because valves in the deep venous system are compromised by the inflammation associated with a DVT. Blood is diverted into the communicating veins and into the superficial venous system with the development of venous hypertension and varicosities. Chronic venous hypertension leads to increased hydrostatic pressure at the capillary level, causing transudation of fluid and proteins as well as hemosiderin-laden red blood cells. The latter is responsible for the typical brownish skin pigmentation seen in these patients. From a histologic perspective, there is fat necrosis and fibrosis of the skin and subcutaneous tissue, a condition commonly referred to as lipodermatosclerosis. All these factors promote an inflammatory reaction conducive to skin breakdown and ulceration (29). Ultimately, patients can develop ulcerations in the region of the medial or lateral malleolus (Fig. 7). Diagnosis. The diagnosis is generally made on history and physical examination alone. In an attempt to distinguish chronic venous insufficiency from lymphedema, one can focus on the extent of edema. Edema secondary to venous insufficiency begins at the ankle and extends to involve primarily the lower leg, whereas lymphedema begins in the toes and foot and involves the entire extremity. Also, those patients with lymphedema do not have pigmentation of the skin. Diagnostic studies such as duplex scanning or

Figure 6 Chronic venous insufficiency with a small amount of stasis dermatitis around the right toes.

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

889

Varicose Veins

Figure 7 Venous stasis ulcer in a patient with chronic venous insufficiency.

venography are infrequently performed. However, these tests can be used to locate areas of valvular incompetence if surgery is contemplated. Treatment. Ideally, the best treatment is prevention, and this is accomplished by applying the prophylactic measures against DVT previously described. Unfortunately, those who develop postphlebitic syndrome often require a lengthy and frustrating treatment course. It is essential that patients avoid prolonged standing and elevate their legs when sitting and sleeping. Graded compression stockings are also required to increase venous return. The skin is extremely fragile, and all efforts must be taken to avoid trauma. The skin is frequently dry, flaky, and itchy; therefore liberal use of skin emollients to prevent cracking and subsequent ulceration is necessary. When venous ulcers are present, an occlusive protective paste dressing such as Unna’s boot is used. This dressing allows for ambulation while providing compression and protection from trauma. Healing of venous ulcers is slow, and it is not uncommon to require many months of vigilant wound care. Erickson et al. examined 99 limbs with venous stasis ulcers. They found that those patients with low venous refill times (10 seconds), indicative of severe venous insufficiency, took significantly longer to completely heal. Although 91% of the ulcers healed at a median of three months, 56% of the healed ulcers recurred (20). Antibiotics should be reserved for the presence of frank cellulitis. If the ulcer is slow to heal, split thickness skin grafting can be employed if there is a viable granulation bed. A plethora of other wound care treatments have been suggested for use in venous stasis ulcers. Incompetent perforating veins contribute to elevated lower-extremity pressures and are often associated with recalcitrant ulcer healing. Ligation of these veins can be performed via an open approach or an endoscopic approach. Endoscopic perforating vein ligation results in healing of 88% of ulcers at one year, although approximately 28% of the ulcers will reoccur after two years (30). Overall, 50% of patients with postthrombotic deep venous involvement will remain ulcer-free at three years. Transplantation of competent valves from the axillary vein to the popliteal vein has also been employed to assist in the healing of ulcers. This technique results in ulcer healing rates of 79% with 50% to 65% remaining ulcer-free at six years (31). Other procedures that attempt to reduce reflux by surgically reconstructing incompetent valves have been investigated.

Varicose veins are superficial veins that have become dilated and tortuous (Fig. 8). The development of varicose veins is thought to result from venous valve incompetence and defects in the elastic properties of the vein wall. This venous valve incompetence can arise secondary to local trauma, thrombophlebitis, familial weakness in the valve structure, increased blood volume as seen after DVT, and hormonal changes especially during pregnancy (32–34). Incompetence leads to the unimpeded reflux of blood into the lower veins, which results in a significant rise in resting venous pressure. This chronic elevation of pressure contributes to the dilation and elongation of the veins and formation of varicosities. In addition, enzymatic abnormalities in the vein segments distant from the varicosities have been identified suggesting that additional biochemical defects may be present as well (35). Varicosities of the lower extremity can be classified as primary varicose veins or secondary varicose veins depending on the cause. Primary varicose veins have an unclear etiology and occur in individuals with no previous history of DVT. Studies of select populations have found that 20% to 40% of patients with primary varicosities have a family history of this disease (36). Women have a threefold greater risk of developing varicose veins compared to men. Female hormones are thought to contribute to this increased risk. Specifically, progesterone, a hormone whose levels are elevated during the second phase of the menstrual cycle and during pregnancy, causes passive dilation of varicosities (37). This distention renders the valves incompetent and initiates the formation of varicose veins or makes existing varicosities more symptomatic. Advancing age, obesity, and increased intra-abdominal pressure are other factors associated with primary varicose veins. Secondary varicose veins arise subsequent to the consequences of DVTs or as a result of venous obstruction. Venous obstruction may be caused by compression of the proximal venous system or by an intra-abdominal or pelvic tumor. The underlying increased venous pressure and vascular incompetence caused by these conditions result in reflux of blood from the deep to the superficial veins and the development of varicosities.

Clinical Presentation Varicose veins may or may not produce symptoms. In fact, many women have asymptomatic varicosities; however, they seek medical attention because of the unsightly blue, dilated, and tortuous veins. Those with symptoms usually complain of pain, fatigue, and aching, most noticeable in the calves

medwedi.ru

Figure 8 Varicose veins marked prior to vein stripping.

890

Part Six: The Peripheral Vascular System

and ankles especially at the end of the day. A feeling of heaviness is often described by the patient, particularly if the day has been spent standing or sitting without much walking. These symptoms are relieved by lying down, elevating the leg, or wearing elastic support stockings. The symptoms are exacerbated in women during their menstrual cycle because of venous valve dilation and worsening incompetence. Physical examination must include the abdomen and pelvis to access the possibility of venous obstruction secondary to a tumor. Examination of the legs should be performed in the standing and supine position. Varicose veins should be examined and palpated. Palpation can detect hidden varicosities in obese legs where they may not be visualized. Arterial pulses should be palpated as well.

Preoperative Testing There are several clinical tests that are applied to evaluate deep venous patency and valvular competence. The Perthes test is performed by placing a tourniquet around the proximal thigh snug enough to compress the superficial veins. The patient is then asked to walk, and attention is paid to the superficial ankle veins. If the veins become less prominent, the perforator and deep vein valves are intact; however, if the veins remain the same size, the perforator valves are incompetent. If the veins should become more prominent with exercise and the patient complains of pain, it can be assumed that there is significant deep venous insufficiency along with incompetent perforators. The retrograde filling test or Trendelenburg test aids in distinguishing between superficial valvular incompetence and perforator valvular incompetence. This procedure is done by elevating the leg initially to empty the veins and then placing a tourniquet over the saphenofemoral junction. The patient is then asked to stand, and the pattern of superficial venous refill is noted. If the varicosities do not fill on standing but do so immediately after releasing the tourniquet, the perforating veins are competent and the varicosities are secondary to superficial venous valve incompetence. If the patient stands and there is rapid filling of the varicosities with the tourniquet still in place, the perforator veins are incompetent secondary to deep venous disease. Duplex scanning can be performed to document venous valvular reflux as well. The test is important if there are clinical findings or a history suggestive of DVT. A handheld Doppler probe can also give the information needed to demonstrate deep venous patency and venous reflux especially at the saphenofemoral junction and at the level of the perforators (38). With the patient sitting on the examining table with the legs hanging over the edge of the table, the popliteal and posterior tibial veins can be examined for venous valvular insufficiency using compression above and below the Doppler probe. A delayed response with augmentation can indicate poor outflow secondary to obstruction. This is quite rare unless the patient has a history of DVT. Reflux heard during proximal compression confirms the diagnosis of venous valvular insufficiency. Venous reflux can be determined in a similar manner in the perforator veins. Saphenofemoral junction incompetence can be ascertained with the Doppler probe by placing it over the site and having the patient perform a Valsalva maneuver. This should be repeated with a tourniquet placed around the proximal thigh area. The reflux should disappear when the Valsalva maneuver is performed again with the tourniquet in place.

Treatment Conservative therapy is recommended for those with minimal varicosities or for those who desire to avoid invasive measures to cure the disease. Graded compression stockings can relieve the symptoms. The stockings are put on in the morning and removed at night. Patients are encouraged to avoid long periods of standing and to elevate the legs while sitting. Patients are also encouraged to walk as much as possible, which helps facilitate venous outflow by using the calf muscle pump. For those patients with symptomatic varicosities or for those who do not like the unsightly nature of their varicose veins, there are several treatment options for cure. Sclerotherapy has become a popular treatment option given its success and availability in an outpatient setting. Venous sclerotherapy is an ablative procedure that actually causes thrombosis in the affected vein, preferably without blood in the lumen (27). The procedure is performed by having the patient stand to mark the varicose veins and perforating veins. With the patient remaining standing, 23-gauge butterfly needles are placed approximately 1 cm apart along the course of the varicose veins (Fig. 9). One proceeds from distal to proximal until all veins have been cannulated. The patient is then placed in the supine position, and each site is injected with 0.5% to 1% of the sclerosing agent. The preferred sclerosing agent is sodium tetradecyl sulfate. Up to 60 sites and 30 mL of this solution can be used during venous sclerotherapy of one limb without sequelae. Immediately after the injection, the butterfly needle is removed, and a gauze and foam rubber pad are placed over the injection site. A stockinette and compression stocking are then placed over the gauze and pad. These should remain in place for

Figure 9 Multiple butterfly needles seen placed along the course of symptomatic varicose veins prior to injection of a sclerosing agent.

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

three weeks without being removed. The patient is encouraged to walk and remain active. When stocking, gauze, and pad are removed after three weeks, inspection and palpation can document the obliteration of the varicose vein. Those patients with saphenofemoral junction incompetence have high recurrence rates with venous sclerotherapy alone; therefore high ligation of the saphenofemoral junction should be performed in these patients either prior to or in conjunction with venous sclerotherapy. The main complication resulting after venous sclerotherapy is localized phlebitis, which occurs approximately 10% of the time (39,40). It is usually self-limiting and requires little intervention. Other uncommon complications include skin necrosis and ulceration secondary to extravasation of the sclerosing agent, intraluminal hematomas, and pigmentation of the surrounding skin. Vein stripping is an alternative method of treating varicose veins. This procedure requires a general or regional anesthetic and potential overnight stay in the hospital, even though most patients do go home the same day of the procedure. After marking all varicosities, the patient is given a general anesthetic, and attention is given to ligation of the saphenous vein and all other tributaries at the saphenofemoral junction. The vein stripper, a flexible rod, is then passed up the length of the vein from a distal venotomy at the level of the medial malleolus. The divided vein at the saphenofemoral junction is tied to the stripper, and the vein is removed with the instrument. Prior to stripping the vein, the other varicosities that are located away from the course of the stripper are treated. This is accomplished by making very small incisions by stabbing the skin over the vein with a No. 11 blade scalpel. The vein is grasped with fine forceps and divided. Each end is then avulsed by direct traction and removed through the incision. Bleeding is controlled with pressure; no ligatures are used. After removal of the stripper and therefore avulsion of the main venous channel from the perforators, the leg is wrapped firmly from the toes to the groin to allow the perforators to thrombose. The patient may resume daily activities but is encouraged to sit with the leg elevated and avoid prolonged standing. Complications after vein stripping are infrequent. They may include bleeding, with ecchymosis being the most common complication appearing three to five days postoperatively. This usually resolves within three to four weeks. Leg edema is common but is relieved by the use of the elastic support stockings. Hypoesthesia of the skin particularly at the level of the ankle may occur because of trauma to the saphenous and sural nerves (39). Other options for the treatment of varicosities include radio frequency and laser ablation of the saphenous vein. These techniques can be performed as outpatient procedures and, when combined with high ligation techniques, have reasonable success rates.

Superficial Thrombophlebitis Thrombophlebitis is a local inflammatory process that is restricted to the superficial veins. This condition most commonly occurs in varicose veins of the lower extremity below the level of the knee. Thrombophlebitis can also occur in association with intravenous cannulation, local trauma, and parenteral drug abuse. The typical clinical finding is an indurated, painful, and erythematous venous cord as a result of the thrombosed superficial vein. When thrombophlebitis involves the distal aspect of the greater saphenous venous system, therapy is managed

891

in the outpatient setting. Treatment consists of symptomatic relief with bed rest, leg elevation, and warm compresses to the affected vein. Anticoagulation therapy is not warranted, because embolization virtually never occurs. However, if the thrombophlebitis extends above the knee, the risk of embolization exists. These patients require close observation in the hospital setting; if they remain refractory to symptomatic therapy, anticoagulation is initiated. If the thrombophlebitis worsens despite these interventions, excision of the affected vein may become necessary. Formation of an abscess in the thrombosed segment—septic thrombophlebitis—also mandates surgical excision.

VENOUS DISORDERS OF THE UPPER EXTREMITY Axillary/Subclavian Vein Thrombosis DVT of the upper extremity is now more common than previously reported. Earlier studies have cited a 1% to 2% incidence; however, with the increasing use of subclavian venous access, the incidence has risen (41). In fact, subclavian catheters are the number one cause of axillary and subclavian venous thrombosis (42,43). The presence of an upper-extremity DVT is not an innocuous event. Studies indicate that 12% of patients with an upper-extremity DVT have had a documented pulmonary embolization (43). The most common causes of axillary/subclavian vein thrombosis are (i) central venous lines or pacemakers; (ii) malignancy secondary to tumor compression of the vein or the hypercoagulable state associated with the malignancy; (iii) effort thrombosis or primary thrombosis, frequently referred to as Paget–Schroetter syndrome (42). Several factors are involved in the pathophysiology of effort thrombosis. First, there is compression of the axillary/ subclavian vein resulting in stasis. This may be due to an anomalous subclavius or anterior scalene muscle or the presence of a cervical rib. Second, repetitive movement at the level of the arm and shoulder may cause intimal tears in the vessel. Third, the stress of exercise may temporarily produce a hypercoagulable state. All these factors are conductive to the development of a thrombus. Primary or effort thrombosis develops clinically as an acute swelling of the involved extremity. It is frequently found in young otherwise healthy men with a recent history of trauma or heavy exertion. It is often noted after activities requiring the arm to be hyperabducted and externally rotated such as painting, throwing a baseball or football, or chopping wood. The involved extremity is usually the patient’s dominant arm.

Clinical Presentation The diagnosis of an upper-extremity DVT can be clinically difficult, especially in the case of iatrogenic injury from a central venous catheter. Often, it has a relatively indolent course that is infrequently associated with symptoms. The subtlety of this injury may be a result of the well-developed venous collateral system of the upper extremity and its ability to compensate in the case of obstruction of a major vein (44). With increased activity of the involved arm, arterial flow increases in the face of venous outflow obstruction resulting in venous hypertension. This promotes effusion of edema fluid into the tissues and distention of the superficial veins. This venous congestion may make the arm feel heavy or achy. In addition, a dusky cyanosis may develop especially with exertion and dependency of the arm. Physical examination discloses an obvious size and color discrepancy in the upper extremity. Frequently, the superficial veins of the hand and forearm are distended. This can be

medwedi.ru

892

Part Six: The Peripheral Vascular System

accentuated with the arm in the dependent position; the veins remain paradoxically distended when the arm is elevated.

Diagnosis Duplex scanning can often diagnose the problem by revealing the presence of the thrombus in the subclavian or axillary vein. Venography is used to locate the thrombus anatomically and provide access for thrombolytic therapy. Venographic demonstration of prominent collateral veins bypassing an obstructed axillary/subclavian vein provides the definitive diagnosis of thrombotic obstruction (Fig. 10).

Treatment The traditional treatment of axillary/subclavian vein thrombosis has been bed rest with limb elevation and anticoagulation. With this conservative approach, resolution without recurrence of symptoms has been reported in only 25% of patients (45). Other studies have shown that 50% to 70% of those with an upper-extremity DVT proceed to develop significant postphlebitic sequelae. The recent development of thrombolytic therapy has improved results dramatically. Most patients with primary or effort thrombosis are young and healthy and excellent candidates for thrombolysis. A successful protocol for effort thrombosis described by Machleder (46) recommends continuing the anticoagulation for three months. This is followed by transaxillary first rib resection and decompression with subsequent balloon angioplasty in cases of residual stenosis. Surgical decompression by first rib resection is advocated to correct the anatomic abnormality that caused the thrombosis and prevent recurrent thrombosis. Subsequent angioplasty or stenting of residual venous stenoses may be required. In cases of secondary thrombosis or catheter-related thrombosis, removal or correction of the offending cause is important. Thrombolytics and anticoagulation are the mainstay of therapy, and surgical intervention is usually not warranted. The most significant complication of upper-extremity DVT is pulmonary embolization. This was formerly thought to be almost nonexistent; however, rising numbers of upperextremity thrombosis studies have found a 12% incidence of pulmonary embolization (43). Other complications include postphlebitic changes and long-term disability, septic

thrombophlebitis, and loss of central venous access. A rare but morbid complication is venous gangrene. Severe edema of the fingers from venous hypertension can occlude arterial inflow and produce ischemia. This rare condition is best treated with thrombectomy or thrombolysis.

Superficial Thrombophlebitis The cause of superficial thrombophlebitis of the upper extremity is usually secondary to prolonged intravenous cannulation or infusion of an acidic fluid. The incidence has risen in the recent years, secondary to intravenous drug abuse. Treatment involves elevation, warm compresses, and pain control with nonsteroidal anti-inflammatory drugs. Surgical excision is reserved for septic thrombophlebitis.

LYMPHEDEMA Clinical Presentation The embryonic development of the lymphatic system begins with paired jugular and iliac sacs, the cisterna chyli, and a second retroperitoneal sac. It is from these sacs that the lymph vessels sprout and course throughout the body following the major venous pathways (Fig. 11). The cisterna chyli within the abdomen communicates with the paired jugular sacs by two lymphatic channels. The more predominant channel connecting the cisterna chyli to the left jugular bud is known as the thoracic duct. The elaborate network of lymphatic channels and regional nodes of the upper and lower extremities drain lymph into the thoracic duct and cisterna chyli, respectively, which then return the lymph to the venous system. The lymphatics are formed by a layer of endothelial cells with a discontinuous basement membrane in contrast to the continuous basement membrane found in blood capillaries (47). The lymphatic capillaries are a valved system that allows for unidirectional flow of lymph back to the venous system. The functions of the lymphatic system include resorption of interstitial fluid, particularly macromolecular proteins such as albumin; lymph node filtering of bacteria and other antigenic particles; and transport of certain substances (vitamin K and long-chain fatty acids) from the gastrointestinal tract to the venous system (48). During a 24-hour period, approximately 4 L of lymph flow containing 100 g of plasma protein is returned to the venous circulation.

Figure 10 (A) Venogram revealing a thrombosed right subclavian vein in a patient with effort thrombosis. (B) Following urokinase infusion, venous outflow is restored. However, an irregular proximal subclavian vein remains.

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs

Figure 11 Normal anatomy of the lymphatic system.

893

unilateral extremity swelling is venous disease, one must be able to distinguish between this and lymphedema. Edema secondary to venous disease presents with decreased capillary perfusion, a brawny discoloration of the involved skin, and ulceration. These findings are not indicative of lymphedema. Venous edema also improves after several hours of limb elevation, whereas lymphedema may require several days of extremity elevation to see a decrease in swelling. If there is any question in the differentiation, noninvasive evaluation is required. Duplex examination is the preferred test to rule out DVT. Lymphangiography is rarely used, because it is invasive and hazardous. Complications include dye allergy, oil embolism, and worsening lymphedema. Lymphoscintigraphy is now becoming the diagnostic procedure of choice for lymphedema. This test is noninvasive, without side effects, and has an overall diagnostic accuracy of 93% (50). The procedure involves a subcutaneous injection of a radiolabeled tracer particle specific for the lymphatics. The diagnosis of lymphedema is made when no radioactivity can be detected in the regional lymph nodes one hour after injection. A CT scan of the pelvis should also be considered in those patients with lymphatic obstruction to rule out malignancy.

Treatment

If the lymphatics fail to return this considerable volume of protein-rich fluid, lymphedema results. Lymphedema can be categorized as either primary (congenital) or secondary depending on its cause. Primary lymphedema is subdivided according to the age of onset; however, all forms are a result of the congenial abnormalities in the development of the lymphatic system. Congenital lymphedema is present from birth. Milroy’s disease is a hereditary form of congenital lymphedema with a sex-linked dominant pattern and characteristic hypoplasia of the lymphatic trunks. Lymphedema praecox becomes apparent from the adolescent years to age 35 and accounts for approximately 80% of the patients with congenital lymphedema. Lymphedema tarda occurs after age 35. The anatomic anomalies seen in these three forms of primary lymphedema include hypoplasia (the most common), aplasia, and hyperplasia (varicose pattern) of the lymphatic system. Primary lymphedema is found to affect women three times more frequently than it is found to affect men. The left leg is more often involved than the right, and the upper extremity is rarely involved. There is no single identifiable precipitating factor that can account for these findings. Secondary or acquired lymphedema is the most common form of lymphedema. Worldwide, the most common cause is filariasis, resulting in the obstruction of lymph nodes by the parasite Filaria bancrofti. In the United States, a common cause is surgical excision of lymph nodes and irradiation for malignant disease. For those who undergo mastectomy with axillary node dissection and radiation therapy, the incidence of lymphedema in the ipsilateral arm can be as high as 38% (49). Prostate carcinoma or other pelvic carcinomas can also cause lymphatic obstruction. Other causes of secondary lymphedema include trauma or infection.

Diagnosis The diagnosis of lymphedema can frequently be made on clinical grounds alone. Because the most common cause of

Palliative therapy is the only treatment option for lymphedema, because there is no medical or surgical cure. The goal of therapy is to reduce the limb volume and prevent infectious complications. Medical treatment begins with the treatment of the inciting event if the lymphedema is acquired as in the case of filariasis. Concomitantly, all patients must be fitted with compressive stockings. For those who are refractory to stocking compression, the use of pneumatic compression has been shown to be effective in reducing the swelling. Compression therapy and skin care alone has resulted in an 80% improvement rate in patients with lymphedema of the lower extremity (51). It is imperative that patients understand the chronicity of this disease and the need to maintain the use of compressive stockings. In addition, it must be stressed to these individuals that meticulous foot care is also necessary to avoid fungal infections. Pharmacotherapy has consisted of diuretics and benzopyrones. Diuretics are not recommended for routine use. They do remove excess fluid but do not change the high interstitial protein concentration and therefore do not alter the underlying pathology. Diuretics can provide short-term relief of the painfully swollen limb, when used on an intermittent basis. Benzopyrones have been demonstrated to reduce lymphedema by enhancing proteolysis via increased macrophage phagocytic activity (52). These drugs are used to provide slow relief of chronic lymphedema but have yet to be approved for use in the United States. Only a small percentage of the patients with lymphedema require surgical intervention. Indications for operation include an extremely edematous limb, resulting in loss of function, and recurrent infections that are refractory to medical management. The operations for lymphedema are divided into two categories—excisional and physiologic procedures. Excisional operations remove the lymphedematous subcutaneous tissue and skin. This is preferably accomplished by staged subcutaneous excisions with preservation of a viable skin flap for primary closure. If this is not possible, the wound can be covered with splitthickness skin grafts; however, breakdown and ulceration of the skin graft is common, and therefore primary closure is preferred.

medwedi.ru

894

Part Six: The Peripheral Vascular System

Physiologic procedures are geared toward reconstruction of lymphatic drainage. Microlymphatic venous anastomosis has been used for the treatment of obstructive lymphedema. This procedure is not applicable to those with primary lymphedema caused by hypoplastic lymphatics. The patient must have patent lymphatic vessels distal to the site of obstruction. The microsurgical lymph vessel-tovein anastomosis is constructed to bypass the obstructed lymphatics. Long-term subjective improvement and limb volume reduction have been reported (53).

Complications Episodes of lymphangitis occur several times a year in patients with lymphedema. This accounts for a significant amount of morbidity and accelerates the process of fibrosis. When infection occurs, systemic antibiotics and bed rest with leg elevation are required. Streptococcus is the most common inciting organism. In patients with recurrent infections, prophylactic antibiotic therapy is recommended. A rare but deadly complication of lymphedema is lymphangiosarcoma. This malignant lesion is most frequently associated with postmastectomy lymphedema. It presents as a reddish purple lesion of the skin and subcutaneous tissue, usually appearing approximately 10 years after the onset of lymphedema. Treatment consists of radical amputation; however, prognosis remains dismal with an average survival of less than two years.

SUMMARY Of all the venous disorders, DVT is the most serious and potentially life threatening. More than 50% of those with DVT progress to develop postphlebitic syndrome with its disabling consequences. Prophylactic measures in the hospitalized surgical patient are essential. Heparin therapy remains the mainstay of care for the patient diagnosed with DVT, and the inferior vena cava filter is an effective alternative for those with contraindications to anticoagulation. Of the lymphatic disorders, lymphedema is the most important. This disorder may result from a congenital cause or may be the result of lymphatic obstruction from malignancy and radiation therapy. Therapy is based on external compression and avoidance of infection. A select group of patients with severe disease may benefit from operative intervention. All treatment is palliative, because there is no known cure for lymphedema.

REFERENCES 1. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975; 17:259–270. 2. Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999; 82:610–619. 3. Bertelsen S, Anker W. Phlegmasia cerulea dolens: pathophysiology, clinical features, treatment, and prognosis. Acta Chir Scand 1968; 134:107–114. 4. Haeger K. Problems of acute deep venous thrombosis. I. The interpretation of signs and symptoms. Angiology 1969; 20:219–223. 5. Mitchell DC, Grasty MS, Stebbings WS, et al. Comparison of duplex ultrasonography and venography in the diagnosis of deep venous thrombosis. Br J Surg 1991; 78:611–613. 6. Thomas LM, MacDonald LM. Complications of phlebography of the leg. Br Med J 1978; 2:317–318.

7. Kakkar VV, Corrigan T, Spindler J, et al. Efficacy of low doses of heparin in prevention of deep vein thrombosis after major surgery: a double-blind, randomised trial. Lancet 1972; 2(7768):101–106. 8. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin. Chest 2001; 119:64S–94S. 9. Colditz GA, Tuden RL, Oster G. Rates of venous thrombosis after general surgery: combined results of randomized clinical trials. Lancet 1986; 2(8499):143–146. 10. Anderson DR, O’Brien BJ, Levine MN, et al. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med 1993; 119:1105–1112. 11. Abbate R, Gori AM, Fari A, et al. Monitoring of low-molecular weight heparins. Am J Cardiol 1998; 82:33L–36L. 12. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001; 119:176S–193S. 13. Ridker PM, Goldhaber SZ, Danielson E, et al. Low-intensity warfarin for prevention of venous thromboembolism. NEJM 2003; 348:1425–1434. 14. Greenfield LJ. Deep vein thrombosis: prevention and management. In: Veith FJ, et al., eds. Vascular Surgery. Principles and Practice. 2d ed. New York: McGraw-Hill, 1994. 15. Warkentin TE. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost 1999; 82(suppl):439–447. 16. Semba C, Dake M. Iliofemoral deep venous thrombosis: aggressive therapy with catheter-directed thrombolysis. Radiology 1994; 191:487. 17. Killewich LA, et al. Spontaneous lysis of deep venous thrombi: rate and outcome. J Vasc Surg 1989; 9:89. 18. Kakkar VV, Lawrence D. Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis. A prospective study. Am J Surg 1985; 150:54–63. 19. Meissner MH, et al. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg 1993; 18: 596–605. 20. Comerota AJ, Throm RC, Mathias SD, Haughton S, Mewissen M. J Vasc Surg 2000; 32:130–137. 21. Drucker EA, Rivitz SM, Shepard JA, et al. Acute pulmonary embolism: assessment of helical CT for diagnosis. Radiology 1998; 209:235–241. 22. Mullins MD, Becker DM, Hagspiel KD, Philbrick JT. The role of spiral volumetric computed tomography in the diagnosis of pulmonary embolism. Arch Intern Med 2000; 160:293–298. 23. Plate G, Einarsson E, Ohlin P, Jensen R, Qvarfordt P, Eklof B. Thrombectomy with temporary arteriovenous fistula: the treatment of choice in acute iliofemoral venous thrombosis. J Vasc Surg 1984; 1:867–876. 24. Greenfield LJ, Michna BA. Twelve-year experience with the Greenfield vena cava filter. Surgery 1988; 104:706–712. 25. Becker DM, Philbrick JT, Selby BJ. Inferior vena cava filters. Indications, safety, effectiveness. Arch Intern Med 1992; 152:1985–1994. 26. Greenfield LJ et al. Transvenous management of pulmonary embolic disease. Ann Surg 1974; 180:461–468. 27. Urokinase Pulmonary Embolism Trial Study Group. Urokinase pulmonary embolism trial. Phase I results. A cooperative study. JAMA 1970; 214:2163–2172. 28. Browse NL, Clemenson G, Thomas MI. Is the postphlebitic leg always postphlebitic? Relation between phlebographic appearances of deep-vein thrombosis and late sequelae. Br Med J 1980; 281:1167–1170. 29. Pappas PJ, Duran WN, Hobson RW. The pathology and cellular physiology of chronic venous insufficiency. In: Gloviczki P, Yao J, eds. Handbook of Venous Disorders. 2d ed. New York: Oxford University Press, Inc., 2001:58–67. 30. Gloviczki P, Bergan JJ, Rhodes JM, Canton LG, Harmsen S, Ilstrup DM, and the North American Study Group. Mid-term results of endoscopic perforator vein interruption for chronic venous insufficiency: lessons learned from the North American Subfascial Endoscopic Perforator Surgery (NASEPS) registry. J Vasc Surg 1999; 29:489–502.

Chapter 46: Venous and Lymphatic Abnormalities of the Limbs 31. O’Donnell TF. Venous valve transplantation and vein transposition for valvular incompetence of deep veins. In: Gloviczki P, Yao J, eds. Handbook of Venous Disorders. 2d ed. New York: Oxford University Press, Inc., 2001:336–346. 32. Burnand KG, Whimster I, Clemenson G, Thomas ML, Browse NL. The relationship between the number of capillaries in the skin of the venous ulcer-bearing area of the lower leg and the fall in foot vein pressure during exercise. Br J Surg 1981; 68:297. 33. Duffy DM. Small vessel sclerotherapy: an overview. Adv Dermatol 1988; 3:221–242. 34. Greene GL. Estrogen and progesterone receptor measurements with monoclonal antibodies. Int J Biol Markers 1988; 3:57–59. 35. Parra JR, Cambria RA, Hower CD, et al. Tissue inhibitor of metalloproteinase-1 is increased in the saphenofemoral junction of patients with varices in the leg. J Vasc Surg 1998; 28:669–675. 36. Hobbs JJ, ed. The Treatment of Venous Disorders. Philadelphia: JB Lippincott, 1977. 37. Bergan JJ. Varicose veins: chronic venous insufficiency. In: Moore WS, ed. Vascular Surgery. A Comprehensive Review. 3d ed. Philadelphia: WB Saunders, 1991. 38. O’Donnell TF Jr, et al. Doppler examination vs clinical and phlebographic detection of the location of incompetent perforating veins—a prospective study. Arch Surg 1977; 112:31. 39. Keith LM Jr, Smead WI. Saphenous vein stripping and its complications. Surg Clin North Am 1983; 63:1303–1312. 40. Sadick NS. Treatment of varicose and telangiectatic leg veins with hypertonic saline: a comparative study of heparin and saline. J Dermatol Surg Oncol 1990; 16:24–28. 41. Monreal M, Lafoz E, Ruiz J, Valls R, Alastrue A. Upper extremity deep venous thrombosis and pulmonary embolism: a prospective study. Chest 1991; 99:280–283. 42. Aburahma AF, Sadler DL, Robinson PA. Axillary-subclavian vein thrombosis. Changing patterns of etiology, diagnostic, and therapeutic modalities. Am Surg 1991; 57:101–107.

895

43. Horattas MC, Wright DJ, Fenton AH, et al. Changing concepts of deep venous thrombosis of the upper extremity—report of a series and review of the literature. Surgery 1988; 104: 561–567. 44. Erickson CA, Lanza DJ, Karp DL, et al. Healing of venous ulcers in an ambulatory care program: the roles of chronic venous insufficiency and patient compliance. J Vasc Surg 1995; 22(5):629–636. 45. Tilney NL, Griffiths HJG, Edwards EA. Natural history of major venous thrombosis of the upper extremity. Arch Surg 1970; 101:792–796. 46. Machleder HI. Evaluation of a new treatment strategy for Paget-Schroetter syndrome: spontaneous thrombosis of the axillary-subclavian vein. J Vasc Surg 1993; 17:305–315. 47. Leak LV. Electron microscopic observations on lymphatic capillaries and the structural components of the connective tissue-lymph interface. Microvasc Res 1970; 2:361–391. 48. Turk AE, Miller TA. Lymphedema and tumors of the lymphatics. In: Moore WS, ed. Vascular Surgery. A Comprehensive Review. 3d ed. Philadelphia: WB Saunders, 1991. 49. Kissin MW, Querci della Rovere G, Easton D, Westbury G. Risk of lymphoedema following the treatment of breast cancer. Br J Surg 1986; 73:580–584. 50. Gloviczki P, Calcagno D, Schirger A, et al. Noninvasive evaluation of the swollen extremity: experiences with 190 lymphoscintigraphic examinations. J Vasc Surg 1989; 9:683–689. 51. Pappas CJ, O’Donnell TF. Long-term results of compression treatment for lymphedema. J Vasc Surg 1992; 16:555–562. 52. Piller NB. Lymphedema, macrophages, and benzopyrones. Lymphology 1980; 13:109–119. 53. O’Brien BM, Mellow CG, Khazanchi RK, Dvir E, Kumar V, Pederson WC. Long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema. Plast Reconstr Surg 1990; 85:562–572. 54. Sladen JG. Compression sclerotherapy: preparation, technique, complications, and results. Am J Surg 1983; 146:228–232.

medwedi.ru

47 Diseases of the Thoracic Aorta Michael P. Macris and O. Howard Frazier

INTRODUCTION With the advent of cardiopulmonary bypass, improved anesthetic techniques, and synthetic grafts, diseases of the thoracic aorta have become amenable to surgical treatment. However, despite these advances, surgical repair of aortic lesions remains one of the greatest challenges in cardiovascular surgery. These procedures are associated with substantial postoperative morbidity; for example, patients undergoing surgical repair of descending or thoracoabdominal aortic aneurysms have a 3.6% to 16% rate of postoperative paraplegia or paraparesis (1,2). Therefore, many surgeons do not perform thoracic aortic repairs, and others will do so only as a last resort. Lesions of the thoracic aorta that may necessitate surgery include aneurysms, dissections, and traumatic pseudoaneurysms. In the past, syphilitic aneurysms were common; now, however, most thoracic aortic diseases result from atherosclerotic and degenerative processes. Early recognition and diagnosis, along with timely surgical intervention and improved preoperative and postoperative care, have resulted in long-term survival for patients with these lesions. This chapter discusses the factors responsible for the development of thoracic aneurysms, aortic dissections, and traumatic pseudoaneurysms. It also discusses the physiologic principles that underlie the management of these conditions.

Aneurysms involving the aortic arch are classified into four categories, according to their location (4). Type A lesions are localized and saccular, involving only the transverse arch. Type B lesions are fusiform and involve the ascending aorta and arch. Type C lesions extend into the proximal descending aorta, and type D lesions are more extensive, involving the entire descending aorta (Fig. 1). Although type D lesions are the least common of the four types, they are the most challenging in terms of surgical therapy. Aneurysmal disease of the aorta is often multifocal. In a review of 1510 patients with aortic aneurysms, Crawford and Cohen (5) found 191 patients (12.6%) with multifocal disease. Abdominal aortic aneurysms commonly accompany thoracic aneurysms. For this reason, the entire aorta should be evaluated when a patient is being considered for surgical treatment of an aortic aneurysm, because better results are obtained when both lesions are corrected at the same time. Traumatic rupture of the aorta produces a false aneurysm, usually distal to the left subclavian artery at the level of the ligamentum arteriosum. This type of lesion is generally saccular and constitutes a surgical emergency, so it is most commonly seen in major trauma centers. These aneurysms are discussed below in the section on Traumatic Pseudoaneurysms.

Pathophysiology

INTRINSIC THORACIC AORTIC DISEASE Thoracic Aneurysms Classification Aneurysms of the thoracic aorta are classified according to type, shape, and location. Classification allows the surgeon to use a systematic approach in the treatment of these challenging vascular lesions. Thoracic aortic aneurysms involving all three layers of the arterial wall are called true aneurysms, whereas those involving only the tunica adventitia are called false aneurysms or pulsating hematomas. False aneurysms usually result from traumatic rupture, most commonly seen in decelerating blunt chest trauma. Fusiform aneurysms, in which the vessel assumes a spindle shape, result in circumferential dilation of all layers of the aorta. These aneurysms may affect a localized portion or an extensive segment of the aorta, and they are usually related to degenerative diseases such as arteriosclerosis and cystic medial necrosis (3). Saccular aneurysms are localized spherical dilations that affect one segment of the vessel wall and are connected to the lumen by a mouth. The aneurysmal sac is usually filled with thrombus. These lesions typically form after an episode of bacterial endocarditis.

Saccular and fusiform aneurysms of the aorta result from loss of structural integrity of the aortic wall and its individual components (6). Alterations in the tunica adventitia (7) and loss of lamellar units in the tunica media (8) have been cited as the major causes of aneurysmal dilation of the aorta. Unusual hemodynamic stresses and impaired blood flow may cause these pathologic changes as a result of deficient delivery of nutrients and ischemia of the vessel wall related to involvement of vasa vasorum by various degenerative, inflammatory, and infectious disease states. This assumption is supported by the following facts: (i) aneurysms are more common in the abdominal aorta than in the thoracic aorta and (ii) compared with the abdominal aorta, which has single lumbar vessels, the thoracic aorta has more vasa vasorum originating from a system of paired intercostal arteries (9). Currently, most aneurysms of the ascending aorta exhibit the histologic characteristics of cystic medial necrosis (10), as originally described by Erdhiem (11). This type of pathologic lesion is found in patients with Marfan’s syndrome (MFS) (12,13) and usually affects the aortic root, which is subject to high stress because of the velocity and

medwedi.ru 897

898

Part Six: The Peripheral Vascular System

Figure 1 Cooley classification of aortic arch aneurysms. (A) Type A lesions are saccular lesions, confined to the arch. (B) Type B lesions are fusiform, involving the ascending aorta and proximal arch. (C) Type C lesions extend into the proximal descending aorta. (D) Type D lesions involve the entire descending aorta. Source: From Ref. 4.

turbulence of blood flow in this region.a The histologic pattern reveals necrosis and disappearance of muscle cells in the middle third of the tunica media, with disintegration of elastic laminae and collagen. A mucinoid material fills the cystic spaces. The primary lesion is accompanied by secondary tears caused by the underlying focal weakness (12–14). Annuloaortic ectasia represents a severe form of cystic medial necrosis in which electron-microscopic changes occur that are similar to those found in patients with MFS or forme fruste annuloaortic ectasia (15). This ectatic condition affects the entire ascending aorta, extending from the aortic annulus to the innominate artery. It may cause severe congestive heart failure related to aortic insufficiency, with a high risk of aortic rupture or dissection (16). The concept of cystic medial necrosis as an intrinsic disease of the tunica media that causes aneurysms of the aorta has been challenged by Schlatmann and Becker (17). In histologic studies of the aortic media in 100 patients of different ages with normal aortas, these investigators found changes attributable to cystic medial necrosis, the frequency of which increased with age. They proposed that these changes result from hemodynamic stress on the vessel wall and represent a process of injury and repair in the normal aging aorta. Therefore, the ascending aorta, which is subject to relatively high hemodynamic stress, is the most common site of histologic changes caused by cystic medial necrosis. Because of a steady increase in both the elderly population and clinicians’ ability to control the late complications of syphilis, arteriosclerosis has become a more common cause of aortic aneurysmal disease. Arteriosclerotic aneurysms, which are confined mainly to the descending and distal thoracic aorta, are fusiform. Once the tunica media and tunica adventitia have been weakened by arteriosclerosis, the disease progresses steadily. It is aggravated by hypertension, progression of the dilation, and further ischemia of the aneurysmal wall. The primary factors that contribute to the formation of arteriosclerotic aneurysms are alterations in flow to the vasa vasorum of the vessel wall and disturbances in intraluminal flow patterns (7). Moreover, flow across stenotic plaques creates high lateral pressures, and turbulent,

a

These conditions make aneurysms of the ascending aorta particularly dangerous to repair. Surgeons at Grady Hospital in Atlanta in the 1940s sometimes referred to these lesions as ‘‘four-poster’’ aneurysms; patients afflicted with them would be placed in fourposter beds with sheets hung over the posts to protect the ceiling from being spattered with blood when the aneurysm ruptured.

reversed flow likewise strikes against the vessel wall. These stresses, which result in structural fatigue and subsequent dilation (18), may be of etiologic importance. Through suppurative or granulomatous processes, infections of the vessel wall cause the formation of mycotic aneurysms (19). These aneurysms are usually saccular and can develop in any part of the aorta. Previously damaged vessels are most likely to be affected, and the resultant symptoms depend on the size and location of the lesion. Aortitis of unknown cause or associated with different autoimmune disorders is also characterized by aortic dilation and the formation of aneurysms. The exception is Takayasu’s arteritis, which is primarily an inflammatory disease associated with severe stenotic lesions of the aorta and other largeand medium-sized vessels (19). Nonspecific aortitis may also result in multiple saccular aneurysms of the aorta, leading to death attributed to rupture (20). Inflammatory aneurysms of the aorta are usually located in the terminal aorta and are accompanied by a severe retroperitoneal inflammatory process that encases the ureters and, sometimes, the vena cava. Histologic analysis reveals destruction of both the tunica media and the tunica adventitia, with replacement of these structures by a thick, fibrotic wall. Both layers are infiltrated with lymphocytes, plasma cells, lymphoid follicles, and multinucleated giant cells (21). When these aneurysms occur in the thoracic aorta, however, they usually do not involve the surrounding mediastinum and pleura.

Diagnosis Clinical Presentation The clinical presentation and symptomatology of thoracic aneurysms are related to the location of the lesion and the compression of adjacent structures. Erosion of large masses through the ribs and sternum is a late finding that is, fortunately, rarely seen these days. Symptoms include pain, stridor, and coughing caused by aneurysmal compression of the vagus nerves, trachea, and bronchi. With ascending aortic aneurysms that involve the aortic annulus, congestive heart failure commonly occurs as a result of aortic insufficiency. Free rupture into the pericardial sac or pleura is catastrophic and is usually diagnosed postmortem. Occasionally, the diagnosis is suspected in a patient without symptoms, in whom routine chest roentgenography shows an upper mediastinal mass contiguous with the aortic shadow. In such cases, further studies are indicated to confirm the diagnosis.

Chapter 47:

Special Diagnostic Techniques The patient with thoracic aortic aneurysmal disease requires a thorough multidisciplinary evaluation to provide the surgeon with all the information necessary to plan the surgical procedure. Routine chest roentgenography and arteriography remain the standard evaluative techniques to which newer ones are compared. However, because the invasiveness of arteriography entails specific risks for critically ill patients, there is a trend toward use of less invasive diagnostic techniques. In particular, computed axial tomography is useful in clarifying certain characteristics of thoracic aneurysms, including their configuration and location, the extent of the disease process, and tissue modifications (Fig. 2). Another method, magnetic resonance imaging (MRI), can produce images of mediastinal vessels along their axes and create sagittal and coronal views without degradation of spatial resolution (22). This technique is especially helpful in the recognition of annuloaortic ectasia and the serial evaluation of postoperative results or disease progression. Furthermore, recent advances in cardiovascular MRI technology allow the detection and even quantification of aortic valve insufficiency (23). Although MRI is not currently a primary method of assessing the condition of the coronary arteries, advances are being made in this area (24,25). Since the early 1980s, two-dimensional (2-D) transesophageal echocardiography (TEE) has emerged as an important technique for visualizing the thoracic aorta (26–29). This method is highly sensitive and specific, particularly in the diagnosis of aortic dissection (30). It also seems well suited to detecting thoracic aortic aneurysms, especially in patients with unstable hemodynamics and a risk of aneurysmal rupture (26). Major advantages include safety, reproducibility, cost-effectiveness, and portability (because TEE can be performed at any location). Although these newer techniques are attractive in the diagnosis of aneurysmal disease of the thoracic aorta, aortography is still usually preferred, because it provides a detailed image of the aortic lesion, the coronary arteries, and the branches of the aortic arch (27). Nevertheless, the newer techniques provide important information that, combined with the aortographic results, gives the surgeon a more complete anatomic picture of the diseased aorta and its branches.

Figure 2 Computed axial tomogram showing an aneurysm of the ascending aorta (arrow).

Diseases of the Thoracic Aorta

899

Treatment With the introduction of cardiopulmonary bypass, modern techniques of hypothermic circulatory arrest, and improved synthetic vascular grafts, surgical treatment of thoracic aortic aneurysms has become the standard approach to these difficult lesions. Most patients who do not undergo surgery for the treatment of these aneurysms die of rupture. Overall survival after emergency surgery is also dismal. Elective intervention, on the other hand, clearly results in lower mortality and morbidity rates (31). For these reasons, elective surgical repair is recommended if the patient has symptoms related to the aneurysm, if the diameter of the lesion is greater than 10 cm, or, in cases involving smaller lesions, if enlargement has been documented (32). Elective repair is also recommended for the patient with MFS, whose ascending aorta is more than 5.5 to 6.0 cm in diameter (32). Early and late risks of death are related to advanced age, the need for emergency surgery, and the presence of congestive heart failure and arterial hypertension. The best surgical approach varies according to the aneurysm’s location and specific anatomic characteristics. Unique surgical techniques and complications associated with aneurysms of the different segments of the thoracic aorta are discussed below. Ascending Aorta The treatment of choice for most ascending aortic aneurysms is surgical resection and graft replacement. Cardiopulmonary bypass with cannulation of the right atrium and femoral artery is instituted, when cannulation of the ascending aorta or proximal transverse aorta is not possible; otherwise, the ascending aorta is the preferred site. Once full cardiopulmonary bypass flow has been established, the patient is cooled to 18–22 C, after which the circulation is arrested. The distal ascending aorta is then transected, and an open distal anastomosis is performed (33,34). This technique allows better visualization of the distal aorta and is technically easier, because it allows better handling of the distal aorta. The flow is slowly restarted, and air is evacuated from the aorta. The graft is clamped, full flow is reestablished, and the patient is rewarmed as the proximal anastomosis is performed. A modified technique is used in the presence of associated aortic valve insufficiency and coronary ostial involvement. When the sinuses of Valsalva are not grossly dilated, supracoronary grafting and conventional aortic valve replacement is the procedure of choice, but care must be taken to prevent hemorrhage, damage to the coronary ostia, or the formation of pseudoaneurysms. If the sinuses of Valsalva are involved in the aneurysmal dilation and the coronary ostia are displaced 2 cm or more cephalad, one should use a valved conduit and reimplant the coronary ostia into the graft (Fig. 3) (4). Normally, we prefer the classic technique of Bentall and De Bono (35) for repairing annuloaortic ectasia. Still, this approach can result in postoperative bleeding and false aneurysm formation at the anastomotic site between the coronary orifices and the valve-containing graft. To minimize the risk of these complications, we routinely create a fistula between the perigraft space and the right atrium, as recommended by Cabrol et al. (36). This step is accomplished by sewing the proximal apex of the aortotomy to a 2-cm slit in the medial aspect of the right atrial appendage. The rest of the aorta is wrapped snugly around the graft (37).

medwedi.ru

900

Part Six: The Peripheral Vascular System

Figure 4 Graft replacement of a type C aortic arch aneurysm, with reimplantation of the great vessels into the graft. Source: From Ref. 4.

Figure 3 (A) Graft replacement of the ascending aorta with a valved conduit. (B) Reimplantation of the coronary ostia into the conduit. Source: From Ref. 4.

Transverse Arch The treatment of transverse aortic arch aneurysms presents a special challenge to the cardiovascular surgeon. The most serious surgical complications are (i) cerebral damage resulting from cerebral ischemia and (ii) air or particulate embolization during graft replacement. Because of these risks, indications for surgery should be evaluated on an individual basis; elective surgical intervention should be reserved for lesions that approach 6 to 8 cm in diameter and cause symptoms related to the compression of vital structures. Strategies for treating these lesions have included insertion of a temporary tube bypass, placement of temporary and permanent bypass grafts, cardiopulmonary bypass with separate perfusion of the brachiocephalic vessels, and cardiopulmonary bypass with profound hypothermia and circulatory arrest (4,38–40). Bypass techniques are complicated, however, as is separate perfusion of the brachiocephalic vessels, and the results are inconsistent. Surgeons at the Texas Heart Institute in Houston have used hypothermic circulatory arrest, which provides adequate cerebral protection during arch replacement and eliminates the need for perfusion cannulas and excessive clamps, thereby offering a simplified operative field (41). The patient’s core temperature is lowered to between 18 C and 22 C with a pump oxygenator and heat exchanger. The circulation is arrested, and the aneurysm is then repaired with a low-porosity woven polyethylene terephthalate

fiber (Dacron) graft, which is impregnated with collagen (Hemashield; Meadox Medicals, Oakland, New Jersey, U.S.A.) and does not require preclotting with autologous plasma and autoclaving (42). The proximal and distal anastomoses are created with a running, nonabsorbable monofilament suture (Fig. 4). Circulation is resumed gradually, with care to allow the air–fluid level of the blood to increase slowly, thus minimizing the risk of gross air embolization. The patient is gradually rewarmed at a rate of 1 C every three minutes, to minimize the production of gaseous microemboli. This simplified technique of moderate hypothermia satisfactorily protects the cerebrum and myocardium for 20 to 30 minutes during circulatory arrest. Most of the neurologic deficits that result from this technique are transient; however, most fixed deficits appear to be caused by emboli; so special precautions should be taken to avoid particulate embolization from atherosclerotic aneurysms during graft replacement. In recent years, further attempts at reducing neurologic injuries have included various forms of limited cerebral perfusion during the period of circulatory arrest. These techniques involve several approaches to perfusion: retrograde perfusion, which can be accomplished through the superior vena caval cannula; various antegrade methods, which may include direct cannulation of the great vessels; or cannulation of the right axillary artery, which perfuses the brain through the right vertebral and carotid arteries. Descending Aorta Most cardiovascular surgeons consider graft replacement the best surgical treatment for descending aortic aneurysms. They disagree, however, as to which approach should be used to avoid the complications related to this procedure. Since the early days, when Carrel (43) found postoperative paraplegia in animals, this problem has been the most dreaded complication associated with operations on the descending thoracic aorta. The mechanism that causes spinal cord injury after cross-clamping of the proximal descending thoracic aorta is poorly understood. Several factors are probably responsible, but the primary ones appear to be interruption of blood flow and distal ischemia of the spinal cord, in addition to elevation of the cerebrospinal fluid pressure as a result of proximal hypertension (44,45). Accordingly,

Chapter 47:

special attention has been devoted to understanding how blood is supplied to the distal spinal cord. The arteria radicularis magna anterior, also known as the artery of Adamkiewicz, originates between T9 and T12 and is responsible for supplying most of the blood to this segment of the spinal cord. Isolated ligation of this vessel in animals, without proximal cross-clamping or other hemodynamic alterations, results in a paraplegia rate of 71.4% (46), thereby establishing this artery’s importance. During the early days of aortic surgery, the value of systemic hypothermia as an adjunct for preventing ischemic spinal cord injury was demonstrated experimentally and clinically by Cooley et al. (4), DeBakey et al. (47), and by Pontius et al. (48). Nevertheless, the risk of cardiac arrhythmias and coagulopathies resulting from systemic hypothermia remained a problem (49). Other researchers have recommended the use of various shunts and partial bypass techniques (50–53), but the results have been inconsistent. Furthermore, these techniques are relatively complicated, so the operation is prolonged and made more difficult for surgeons who do not use these techniques routinely. Because the problem of perioperative paraplegia remains so serious, investigations have continued. Among the more commonly reported are techniques in serial clamping, selective cannulation and perfusion of the mesenteric and renal vessels, more extensive reimplantation of the intercostal arteries, and drainage of cerebrospinal fluid (54–59). On the basis of their experience with these complex lesions, experts at two major vascular surgical centers advocate a simple cross-clamping technique without the use of adjuncts to prevent ischemia (40,60–62). They also recommend preventing hypotension, expeditiously removing the aneurysm and restoring distal flow, and avoiding crossclamp times longer than 30 minutes, which are associated with a higher risk of postoperative paraplegia (63). We favor an ‘‘open’’ distal anastomosis technique, in which a single cross-clamp is placed proximal to the aneurysm to exsanguinate the lower body. The exsanguinated blood is collected by an autotransfusion device and returned to the patient. This approach minimizes the risk of spinal cord injury and renal insufficiency yet allows the distal anastomosis to be completed efficiently, with a short ischemic time (33,34).

Diseases of the Thoracic Aorta

901

to be influenced by intrinsic characteristics of the vessel wall itself, but medial scarring related to atherosclerotic plaque formation seems to be the factor that usually limits the dissection (64). A working classification of aortic dissections according to site of origin and extension provides a practical approach to these lesions and aids in their management (64). Type A dissections originate from a tear in the ascending aorta and may extend distally into the descending aorta. These dissections carry the greatest risk of rupture and are associated with acute aortic regurgitation and myocardial infarction related to dissection and obstruction of the coronary arteries. Type B dissections originate in the descending aorta, distal to the arch (Fig. 5). The dissecting process usually extends distally, but proximal dissection is also possible. The cause of aortic dissection is still a subject of debate. This lesion was previously called a dissecting aneurysm, but the term ‘‘acute aortic dissection’’ is more appropriate, because the pathologic process is different from that of a true aneurysm, and aneurysmal expansion is seldom a particularly prominent feature. Although dissection was formerly attributed to cystic medial necrosis, Schlatmann and Becker (17) showed that the morphologic changes of aortic dissection may result from injury and repair within the aortic wall. Such changes alter the structural properties of the vessel wall, leading to dilation. The local hemodynamic circumstances determine whether further dilation, dissection, or rupture occurs. Patients with MFS, who most frequently have aortic dissections, have an underlying connective tissue disorder that makes them susceptible to aortic complications at an early age (65). Arterial hypertension is present in approximately 70% of patients with aortic dissection and is the most common predisposing factor for this condition. Other associated findings include trauma, a bicuspid aortic valve, aortic isthmic coarctation, and a previous aortotomy for cannulation in cardiopulmonary bypass.

Aortic Dissection Pathophysiology Dissection of the thoracic aorta is a unique entity characterized by a spontaneous tear of the tunica intima and part of the tunica media of the aortic wall. Blood escapes under pressure into the aortic laminae, causing a pathologic separation of the tunica media along the longitudinal axis of the aorta, parallel to the blood flow. This ‘‘false’’ dissecting channel in the middle of the aortic wall spreads downstream for a variable distance. It usually starts 2 cm distal to the aortic valve cusps (4,64). In most cases, a transverse intimal tear marks the beginning of the dissection, but this finding can vary. A tear in the ascending aorta is usually located in the right lateral aortic wall, and the dissection progresses along the greater curvature of the aorta. A reentry tear occurs much less frequently and may be difficult to identify. Dissections may also begin in the transverse arch or the proximal descending thoracic aorta, usually at the level of the isthmus, distal to the origin of the left subclavian artery. Once the dissecting process has begun, it progresses rapidly, depending mainly on the systemic blood pressure and the velocity of blood flow. The extent of the dissection appears

Figure 5 Classification of aortic dissections. (A) Type A lesions comprise the ascending aorta and may extend into the aortic arch. (B) Type B lesions originate in the proximal descending aorta, extending distally. Source: From Ref. 4.

medwedi.ru

902

Part Six: The Peripheral Vascular System

Diagnosis Clinical Presentation The presenting symptoms of aortic dissection vary according to the location of the tear, the associated complications, and the degree of ischemia of vital organs in the presence of a blood supply that has been compromised by the dissecting process. The most common symptom is acute, severe chest pain that radiates to the back and abdomen. When the dissection extends into the innominate artery, compromising the right subclavian artery, the patient may also report numbness or pain in the right arm. Proximal dissections may result in aortic valve insufficiency, in which case, a diastolic murmur can be heard. In severe cases, the clinical presentation may involve signs and symptoms compatible with congestive heart failure. Complications of acute aortic dissection are varied. Rupture of the aorta is the most devastating complication, leading to immediate exsanguination. Rupture may occur anywhere between the pericardial sac and the abdominal cavity. Obstruction of blood flow to vital organs by a medial hematoma of the wall vessel that supplies those particular organs may result in ischemia, producing myriad symptoms, depending on which organs are involved. Myocardial infarction, cerebrovascular insufficiency, stroke, transient ischemic attacks, renal failure, mesenteric ischemia, and even paraplegia may be the presenting manifestation of aortic dissection. As noted earlier, proximal dissection can result in dilation of the aortic annulus, causing acute aortic regurgitation and congestive heart failure. Special Diagnostic Techniques As with thoracic aneurysmal disease, aortography remains the gold standard for establishing the diagnosis of aortic dissection. The most common angiographic findings are opacification of the false lumen, visualization of the intimal flap, and deformity of the true lumen (Fig. 6). Other, less invasive techniques are being used with increasing frequency. Two-dimensional echocardiography, particularly TEE, is useful in diagnosing dissection of the ascending aorta. In fact, many experts now consider TEE the method of choice in this setting (26,28,29,66). It has the advantage of being a bedside procedure, and it provides other useful information regarding the differential diagnosis. Moreover, it is faster and more accurate than aortography or computed tomography (CT) (67). The criteria for aortic dissection are (i) an aortic root measuring at least 42 mm, (ii) an intraluminal structure within the proximal aorta consistent with an intimal flap, and (iii) a high frequency of intimal flap oscillations, which is the most specific sign (68). Although computed axial tomography may be useful in elucidating various features of aortic dissection, 2-D echocardiography, especially TEE, offers better resolution, because it can more easily identify the intimal flap in cases of dissection (69). Ultimately, MRI may prove the most useful of the new techniques. Currently, it is limited by high cost, long image-acquisition time, nonportability, and unsuitability for patients in a hemodynamically unstable condition. When further refined, however, MRI could rival TEE for diagnosing aortic dissection (70).

Treatment Treatment of aortic dissection depends on location and associated complications. Type A dissections should undergo immediate surgical intervention and repair.

Figure 6 Arteriogram of a type B aortic dissection. Notice the opacification of the false lumen (large arrow) and compression of the true lumen (small arrow).

Uncomplicated type B lesions may be managed medically with close observation, intravenous administration of peripheral vasodilators to lower the systemic blood pressure, and b-adrenergic blockers to reduce the cardiac ejection velocity (71). Nevertheless, patients must be watched carefully to prevent associated complications, and not all authorities agree that medical management is the best approach. After analyzing results of surgical treatment of type B lesions, Reul et al. (72) recommended that patients with acute and chronic descending aortic aneurysms undergo early surgical repair before extension, rupture, or massive enlargement occurs. Prophylactic surgery for aortic dissection is indicated in cases of MFS, in which the ascending aorta reaches a diameter of 6 cm, or twice the diameter of the normal aorta, as measured by echocardiography or CT scan. These patients are candidates for a composite graft repair, and early intervention has proved highly beneficial (73).

TRAUMATIC PSEUDOANEURYSMS The present-day ubiquity of motor vehicles has produced a high incidence of blunt deceleration injuries. Traumatic rupture of the thoracic aorta occurs in approximately 10% to 21% of fatal traffic accidents (74,75). When traumatic aortic pseudoaneurysm occurs, only 20% of patients survive the initial injury. For this small group, mortality rate increases with time, with 49% dying within the first 48 hours, and

Chapter 47:

only 2% surviving for more than four months if left untreated (76). Death results from rupture with immediate exsanguination. Disruption is a result of shearing stresses at the junction of the fixed and mobile parts of the aorta (74), usually distal to the left subclavian artery at the ligamentum arteriosum. If the tear is complete, exsanguination is immediate, resulting in death at the scene. If the tunica intima and tunica media are disrupted but the tunica adventitia remains intact, a false aneurysm forms. The tunica adventitia, which contains the pulsating hematoma, cannot withstand the bursting pressure that an intact aorta could. Moreover, the tunica adventitia is susceptible to rupture during aggressive fluid resuscitation in the emergency department or at induction of anesthesia, when measures to counteract hypotension are taken (77). For this reason, if aortic rupture is suspected, careful monitoring of the systemic blood pressure to avoid extremes and rapid changes is mandatory. Aortic transection should be suspected in any patient with blunt chest trauma. Chest roentgenography is the initial step in making the diagnosis. Loss of the aortic knob contour appears to be the most consistent and reliable sign of aortic laceration. Other findings include (i) a mediastinalwidth/chest-width ratio greater than 0.25 on a supine chest radiograph, (ii) a left apical cap, (iii) rightward displacement of the nasogastric tube, the trachea, or both, (iv) displacement of the right paraspinous interface, and (v) depression of the left main stem bronchus (Fig. 7) (78). If the chest roentgenogram appears suspect, immediate aortography is indicated to confirm the diagnosis and localize the tear in order to plan a surgical approach (Fig. 8). Alternatively, TEE or CT may be used to screen patients for aortography (25). Acute aortic transection and false aneurysm formation should be treated with immediate surgical repair through a left thoracotomy. Most of these lesions can be repaired primarily or with an interposition graft. Whether adjunctive measures to prevent spinal cord ischemia and renal failure are necessary, or even useful, remains controversial. As a rule, during operation for aortic transection, one should make sure that the left ventricle is not subjected to excessive

Diseases of the Thoracic Aorta

903

Figure 8 Digital-subtraction angiogram of the thoracic aorta in a patient with traumatic aortic transection and development of a false aneurysm distal to the left subclavian artery at the level of the ligamentum arteriosum (arrow).

stress as a result of proximal cross-clamping and that the total distal ischemic time is minimized. To accomplish these goals, surgeons have used numerous adjuncts, including partial bypass techniques and different types of shunts. Bypass techniques entail a higher mortality rate than do shunting and simple cross-clamping (79), probably because bypass necessitates the use of heparin (with its attendant complications) in the presence of multiple injuries. Simple aortic cross-clamping and use of an expeditious surgical technique to keep the ischemic time to less than 30 minutes form the procedure of choice for repairing acute traumatic rupture of the aorta (79,80).

SUMMARY

Figure 7 Chest X-ray of a patient with aortic transection. Note the widened mediastinum (large arrow), which indicates a mediastinal hematoma. Other findings include a left apical cap, loss of the aortic knob contour, and fracture of the left second and third ribs (small arrow).

Because of the increasing size of the elderly population, aneurysmal disease of the thoracic aorta is usually related to chronic degenerative processes involving the different layers of the vessel wall. The concept of cystic medial necrosis as a primary disease of the ascending aorta has been challenged. Aneurysms are now believed to be a response to local hemodynamic factors that stress the aortic wall. Distal to the ascending aorta, arteriosclerosis is usually responsible for aneurysmal dilation of the aorta. The cause of arteriosclerosis is still uncertain, and preventive measures are controversial. In addition, the genetic basis of aortic aneurysms is being currently investigated, in particular for Marfan kindreds, such that screening may be offered to the relatives and descendants of these patients (81–83). Ascending aortic

medwedi.ru

904

Part Six: The Peripheral Vascular System

aneurysms leading to type A dissections [thoracic aortic aneurysms and dissections (TAAD)] are the major cardiovascular complications of MFS, a pleiotropic disorder with involvement of the cardiovascular, ocular, and skeletal systems (84). MFS is inherited in an autosomal-dominant manner, and is caused by mutations in the fibrillin gene (FBN) 1 on chromosome 15q. FBN1 encodes fibrillin-1, a large glycoprotein that is a component of extracellular matrix structures called microfibrils. Clinical studies have indicated that up to 19% of nonsyndromic TAAD patients referred for surgery have affected first-degree relatives, supporting the hypothesis that genetic factors influence the formation of TAAD in individuals who do not have MFS. Aortic imaging of individuals at risk and analysis of the pedigrees determined that the condition is inherited primarily as an autosomaldominant disorder with decreased penetrance and variable expression. Mapping studies using families with TAAD have identified three loci for the condition, TAAD1 on 5ql3-14, TAAD2 on 3p24–25, and FAA1 on 11q (85). Therefore, it is possible that, someday, gene therapy may even be available for some patients with aortic aneurysms. The clinical presentations of thoracic aneurysms and dissections have been well described, and aortography has generally been the procedure of choice in confirming the diagnosis. Recently, however, there has been a trend toward the use of less invasive techniques. In some cases, particularly those involving thoracic aortic dissection, TEE has begun to supplant aortography. MRI, magnetic resonance angiography, and 3–D CT scan reconstruction are also very useful imaging methods. Surgical repair is the treatment of choice for thoracic aneurysms and dissections. Because of the availability of cardiopulmonary bypass, improved anesthesia, advanced hypothermic techniques, and better prosthetic grafts, patients with these difficult lesions now have a greater chance of survival. Nonetheless, surgical repair retains a considerable amount of risk. As a result, the development of endovascular methods of excluding abdominal aortic aneurysms (86) has inspired several groups of investigators to attempt endovascular exclusion of thoracic and thoracoabdominal aneurysms. Reports of these studies describe mortality and paraplegia rates similar to or lower than those of surgery, but still less than optimal (87–90). Additionally, the long-term outcomes of these procedures are still being evaluated. Combined surgical and endovascular approaches are also being tried. In these ‘‘hybrid’’ techniques, the endoluminal insertion of a stent graft to exclude the aneurysm may be preceded by surgical revascularization of adjacent arteries or followed by surgical fixation of the graft to the aorta (91–93). These techniques have only been tried in a small number of patients, however, and their long-term sequelae are not yet known. In conclusion, judging from the greatest improvements of the last 50 years, the management of thoracic aortic disease will continue to inspire surgeons for generations to come.

REFERENCES 1. Safi HJ, Miller CC, Huynh TTT, et al. Distal aortic perfusion and cerebrospinal fluid drainage for thoracoabdominal and descending thoracic aortic repair: ten years of organ protection. Ann Surg 2003; 238:372–381. 2. Svensson L, Crawford E, Hess K, Coselli J, Safi H. Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 1993; 17:357–370.

3. Richards MA. Medionecrosis aortae idiopathica cystica. Am J Pathol 1932; 8:717. 4. Cooley DA, Kneipp M, Lawrence EP. Surgical Treatment of Aortic Aneurysms. Philadelphia: Saunders, 1986. 5. Crawford ES, Cohen ES. Aortic aneurysm: a multifocal disease. Arch Surg 1982; 117:1393–1400. 6. Robicsek F, Tam W, Daugherty HK, Mullen DC. The applicability of Bernoulli’s law in the process of enlargement and rupture of aortic aneurysms. J Thorac Cardiovasc Surg 1971; 61:472–475. 7. De Takats G, Pirani CL. Aneurysms: general considerations. Angiology 1954; 5:173–208. 8. Pomerance A, Yacoub MH, Gula G. The surgical pathology of thoracic aortic aneurysms. Histopathology 1977; 1:257–276. 9. Benjamin HB, Becker AB. Etiologic incidence of thoracic and abdominal aneurysms. Surg Gynecol Obstet 1967; 125: 1307–1310. 10. Klima T, Spjut HJ, Coelho A, et al. The morphology of ascending aortic aneurysms. Hum Pathol 1983; 14:810–817. 11. Erdheim J. Medionecrosis aortae idiopathica. Virchows Arch Pathol Anat 1929; 273:454. 12. Baer RW, Taussig HB, Oppenheimer EH. Congenital aneurysmal dilatation of the aorta associated with arachnodactyly. Bull Johns Hopkins Hosp 1943; 72:309–331. 13. Bahnson HT, Nelson AR. Cystic medial necrosis as a cause of localized aortic aneurysms amenable to surgical treatment. Ann Surg 1956; 144:519–529. 14. Rotino A. Medial degeneration, cystic variety in unruptured aortas. Am Heart J 1940; 19:330. 15. Savunen T, Aho HJ. Annulo-aortic ectasia: light and electron microscopic changes in aortic media. Virchows Arch A Pathol Anat Histopathol 1985; 407:279–288. 16. Chapman DW, Beazley HL, Peterson PK, Webb JA, Cooley DA. Annulo-aortic ectasia with cystic medial necrosis: diagnosis and surgical treatment. Am J Cardiol 1965; 16:679–687. 17. Schlatmann TJ, Becker AE. Histologic changes in the normal aging aorta: implications for dissecting aortic aneurysm. Am J Cardiol 1977; 39:13–20. 18. Holman E, Peniston W. Hydrodynamic factors in the production of aneurysms. Am J Surg 1955; 90:200–209. 19. Lande A, Berkmen YM. Aortitis: pathologic, clinical and arteriographic review. Radiol Clin North Am 1976; 14:219–240. 20. Henochowicz SI, Lindsay J Jr, Furlong MJ, Fulenwider AK, Greenfield DI, Ross EM. Multiple saccular aortic aneurysms in nonspecific aortitis. Am J Cardiol 1986; 57:377–378. 21. Crawford JL, Stowe CL, Safi HJ, Hallman CH, Crawford ES. Inflammatory aneurysms of the aorta. J Vasc Surg 1985; 2:113–124. 22. Moore EH, Webb WR, Verrier ED, et al. MRI of chronic posttraumatic false aneurysms of the thoracic aorta. AJR Am J Roentgenol 1984; 143:1195–1196. 23. Hoffmann U, Frank H, Stefenelli T, Kaiser B, Klaar U, Globits S. Afterload reduction in severe aortic regurgitation. J Magn Reson Imaging 2001; 14:693–697. 24. Kim WY, Danias PG, Stuber M, et al. Coronary magnetic resonance angiography for the detection of coronary stenoses. N Engl J Med 2001; 345:1863–1869. 25. Earls JP, Ho VB, Foo TK, Castillo E, Flamm SD. Cardiac MRI: recent progress and continued challenges. J Magn Reson Imaging 2002; 16:111–127. 26. Blanchard DG, Kimura BJ, Dittrich HC, DeMaria AN. Transesophageal echocardiography of the aorta. JAMA 1994; 272:546–551. 27. Earnest FT, Muhm JR, Sheedy PF II. Roentgenographic findings in thoracic aortic dissection. Mayo Clin Proc 1979; 54:43–50. 28. Goldstein SA, Mintz GS, Lindsay J Jr. Aorta: comprehensive evaluation by echocardiography and transesophageal echocardiography. J Am Soc Echocardiogr 1993; 6:634–659. 29. Wiet SP, Pearce WH, McCarthy WJ, Joob AW, Yao JS, McPherson DD. Utility of transesophageal echocardiography in the diagnosis of disease of the thoracic aorta. J Vasc Surg 1994; 20:613–620. 30. Ballal RS, Nanda NC, Gatewood R, et al. Usefulness of transesophageal echocardiography in assessment of aortic dissection. Circulation 1991; 84:1903–1914.

Chapter 47: 31. Pressler V, McNamara JJ. Aneurysm of the thoracic aorta: review of 260 cases. J Thorac Cardiovasc Surg 1985; 89:50–54. 32. Moreno-Cabral CE, Miller DC, Mitchell RS, et al. Degenerative and atherosclerotic aneurysms of the thoracic aorta: determinants of early and late surgical outcome. J Thorac Cardiovasc Surg 1984; 88:1020–1032. 33. Cooley DA, Baldwin RT. Technique of open distal anastomosis for repair of descending thoracic aortic aneurysms. Ann Thorac Surg 1992; 54:932–936. 34. Scheinin SA, Cooley DA. Graft replacement of the descending thoracic aorta: results of ‘‘open’’ distal anastomosis. Ann Thorac Surg 1994; 58:19–22. 35. Bentall H, De Bono A. A technique for complete replacement of the ascending aorta. Thorax 1968; 23:338–339. 36. Cabrol C, Pavie A, Mesnildrey P, et al. Long-term results with total replacement of the ascending aorta and reimplantation of the coronary arteries. J Thorac Cardiovasc Surg 1986; 91:17–25. 37. Lewis CT, Cooley DA, Murphy MC, Talledo O, Vega D. Surgical repair of aortic root aneurysms in 280 patients. Ann Thorac Surg 1992; 53:38–45. 38. Cooley DA. Aneurysms of the ascending aorta: surgical treatment using hypothermic arrest. Cardiology 1990; 77:373–387. 39. Crawford ES, Saleh SA, Schuessler JS. Treatment of aneurysm of transverse aortic arch. J Thorac Cardiovasc Surg 1979; 78:383–393. 40. Kay GL, Cooley DA, Livesay JJ, Reardon MJ, Duncan JM. Surgical repair of aneurysms involving the distal aortic arch. J Thorac Cardiovasc Surg 1986; 91:397–404. 41. Livesay JJ, Cooley DA, Reul GJ, et al. Resection of aortic arch aneurysms: a comparison of hypothermic techniques in 60 patients. Ann Thorac Surg 1983; 36:19–28. 42. Cooley DA, Romagnoli A, Milam JD, Bossart MI. A method of preparing woven DACRON aortic grafts to prevent interstitial hemorrhage. Cardiovasc Dis 1981; 8:48–52. 43. Carrel A. Experimental surgery of the aorta and heart. Ann Surg 1910; 52:83–95. 44. Blaisdell FW, Cooley DA. The mechanism of paraplegia after temporary thoracic aortic occlusion and its relationship to spinal fluid pressure. Surgery 1962; 51:351–355. 45. Oka Y, Miyamoto T. Prevention of spinal cord injury after crossclamping of the thoracic aorta. Jpn J Surg 1984; 14:159–162. 46. Wadouh F, Lindemann EM, Arndt CF, Hetzer R, Borst HG. The arteria radicularis magna anterior as a decisive factor influencing spinal cord damage during aortic occlusion. J Thorac Cardiovasc Surg 1984; 88:1–10. 47. DeBakey ME, Cooley DA, Creech O Jr. Resection of the aorta for aneurysms and occlusive disease with particular reference to the use of hypothermia; analysis of 240 cases. Trans Am Coll Cardiol 1955; 5:153–157. 48. Pontius RG, Brockman HL, Hardy EG, Cooley DA, Debakey ME. The use of hypothermia in the prevention of paraplegia following temporary aortic occlusion: experimental observations. Surgery 1954; 36:33–38. 49. Cooley DA, Ott DA, Frazier OH, Walker WE. Surgical treatment of aneurysms of the transverse aortic arch: experience with 25 patients using hypothermic techniques. Ann Thorac Surg 1981; 32:260–272. 50. Donahoo JS, Brawley RK, Gott VL. The heparin-coated vascular shunt for thoracic aortic and great vessel procedures: a ten-year experience. Ann Thorac Surg 1977; 23:507–513. 51. Laschinger JC, Cunningham JN Jr, Nathan IM, Knopp EA, Cooper MM, Spencer FC. Experimental and clinical assessment of the adequacy of partial bypass in maintenance of spinal cord blood flow during operations on the thoracic aorta. Ann Thorac Surg 1983; 36:417–426. 52. Lawrence GH, Hessel EA, Sauvage LR, Krause AH. Results of the use of the TDMAC-heparin shung in the surgery of aneurysms of the descending thoracic aorta. J Thorac Cardiovasc Surg 1977; 73:393–398. 53. Zacharopoulos L, Symbas PN. Internal temporary aortic shunt for managing lesions of the descending thoracic aorta. Ann Thorac Surg 1983; 35:240–242.

Diseases of the Thoracic Aorta

905

54. Coselli JS, Conklin LD, LeMaire SA. Thoracoabdominal aortic aneurysm repair: review and update of current strategies. Ann Thorac Surg 2002; 74:S1881–1884. 55. Koksoy C, LeMaire SA, Curling PE, et al. Renal perfusion during thoracoabdominal aortic operations: cold crystalloid is superior to normothermic blood. Ann Thorac Surg 2002; 73:730–738. 56. Coselli JS. The use of left heart bypass in the repair of thoracoabdominal aortic aneurysms: current techniques and results. Semin Thorac Cardiovasc Surg 2003; 15:326–332. 57. LeMaire SA, Miller CC III, Conklin LD, Schmittling ZC, Koksoy C, Coselli JS. A new predictive model for adverse outcomes after elective thoracoabdominal aortic aneurysm repair. Ann Thorac Surg 2001; 71:1233–1238. 58. Coselli JS, Lemaire SA, Koksoy C, Schmittling ZC, Curling PE. Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: results of a randomized clinical trial. J Vasc Surg 2002; 35:631–639. 59. Coselli JS, LeMaire SA, Conklin LD, Koksoy C, Schmittling ZC. Morbidity and mortality after extent II thoracoabdominal aortic aneurysm repair. Ann Thorac Surg 2002; 73:1107–1115. 60. Crawford ES, Rubio PA. Reappraisal of adjuncts to avoid ischemia in the treatment of aneurysms of descending thoracic aorta. J Thorac Cardiovasc Surg 1973; 66:693–704. 61. Crawford ES, Walker HS III, Saleh SA, Normann NA. Graft replacement of aneurysm in descending thoracic aorta: results without bypass or shunting. Surgery 1981; 89:73–85. 62. Livesay JJ, Cooley DA, Ventemiglia RA, et al. Surgical experience in descending thoracic aneurysmectomy with and without adjuncts to avoid ischemia. Ann Thorac Surg 1985; 39:37–46. 63. Safi HJ, Winnerkvist A, Miller CC III, et al. Effect of extended cross-clamp time during thoracoabdominal aortic aneurysm repair. Ann Thorac Surg 1998; 66:1204–1209. 64. Roberts WC. Aortic dissection: anatomy, consequences, and causes. Am Heart J 1981; 101:195–214. 65. Schlatmann TJ, Becker AE. Pathogenesis of dissecting aneurysm of aorta: comparative histopathologic study of significance of medial changes. Am J Cardiol 1977; 39:21–26. 66. Borner N, Erbel R, Braun B, Henkel B, Meyer J, Rumpelt J. Diagnosis of aortic dissection by transesophageal echocardiography. Am J Cardiol 1984; 54:1157–1158. 67. Erbel R, Engberding R, Daniel W, Roelandt J, Visser C, Rennollet H. Echocardiography in diagnosis of aortic dissection. Lancet 1989; 1:457–461. 68. Granato JE, Dee P, Gibson RS. Utility of two-dimensional echocardiography in suspected ascending aortic dissection. Am J Cardiol 1985; 56:123–129. 69. Iliceto S, Ettorre G, Francioso G, Antonelli G, Biasco G, Rizzon P. Diagnosis of aneurysm of the thoracic aorta: comparison between two noninvasive techniques: two-dimensional echocardiography and computed tomography. Eur Heart J 1984; 5:545–555. 70. Amparo EG, Higgins CB, Hoddick W, et al. Magnetic resonance imaging of aortic disease: preliminary results. AJR Am J Roentgenol 1984; 143:1203–1209. 71. Doroghazi RM, Slater EE, DeSanctis RW. Medical therapy for aortic dissections. J Cardiovasc Med 1981; 6:187. 72. Reul GJ, Cooley DA, Hallman GL, Reddy SB, Kyger ER III, Wukasch DC. Dissecting aneurysm of the descending aorta: improved surgical results in 91 patients. Arch Surg 1975; 110: 632–640. 73. Gott VL, Pyeritz RE, Magovern GJ Jr, Cameron DE, McKusick VA. Surgical treatment of aneurysms of the ascending aorta in the Marfan syndrome: results of composite-graft repair in 50 patients. N Engl J Med 1986; 314:1070–1074. 74. Greendyke RM. Traumatic rupture of aorta; special reference to automobile accidents. JAMA 1966; 195:527–530. 75. Richens D, Kotidis K, Neale M, Oakley C, Fails A. Rupture of the aorta following road traffic accidents in the United Kingdom 1992–1999: the results of the co-operative crash injury study. Eur J Cardiothorac Surg 2003; 23:143–148. 76. Parmley LF, Mattingly TW, Manion WC, Jahnke EJ Jr. Nonpenetrating traumatic injury of the aorta. Circulation 1958; 17:1086–1101.

medwedi.ru

906

Part Six: The Peripheral Vascular System

77. Stiles QR, Cohlmia GS, Smith JH, Dunn JT, Yellin AE. Management of injuries of the thoracic and abdominal aorta. Am J Surg 1985; 150:132–140. 78. Sefczek DM, Sefczek RJ, Deeb ZL. Radiographic signs of acute traumatic rupture of the thoracic aorta. AJR Am J Roentgenol 1983; 141:1259–1262. 79. Mattox KL, Holzman M, Pickard LR, Beall AC Jr, DeBakey ME. Clamp/repair: a safe technique for treatment of blunt injury to the descending thoracic aorta. Ann Thorac Surg 1985; 40:456–463. 80. Svensson LG, Antunes MD, Kinsley RH. Traumatic rupture of the thoracic aorta: a report of 14 cases and a review of the literature. S Afr Med J 1985; 67:853–857. 81. Khau Van Kien P, Wolf JE, Mathieu F, et al. Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity. Eur J Hum Genet 2004; 12:173–180. 82. Hasham SN, Willing MC, Guo DC, et al. Mapping a locus for familial thoracic aortic aneurysms and dissections (TAAD2) to 3p24–25. Circulation 2003; 107:3184–3190. 83. Kakko S, Raisanen T, Tamminen M, et al. Candidate locus analysis of familial ascending aortic aneurysms and dissections confirms the linkage to the chromosome 5ql3–14 in Finnish families. J Thorac Cardiovasc Surg 2003; 126:106–113. 84. Milewicz DM, Urban Z, Boyd C. Genetic disorders of the elastic fiber system. Matrix Biol 2000; 19:471–480. 85. Hasham SN, Guo DC, Milewicz DM. Genetic basis of thoracic aortic aneurysms and dissections. Curr Opin Cardiol 2002; 17:677–683.

86. Howell MH, Strickman N, Mortazavi A, Hallman CH, Krajcer Z. Preliminary results of endovascular abdominal aortic aneurysm exclusion with the AneuRx stent-graft. J Am Coll Cardiol 2001; 38:1040–1046. 87. Dake MD, Miller DC, Mitchell RS, Semba CP, Moore KA, Sakai T. The ‘‘first generation’’ of endovascular stent-grafts for patients with aneurysms of the descending thoracic aorta. J Thorac Cardiovasc Surg 1998; 116:689–703. 88. Fattori R, Napoli G, Lovato L, et al. Descending thoracic aortic diseases: stent-graft repair. Radiology 2003; 229:176–183. 89. Czerny M, Cejna M, Hutschala D, et al. Stent-graft placement in atherosclerotic descending thoracic aortic aneurysms: midterm results. J Endovasc Ther 2004; 11:26–32. 90. Scheinert D, Krankenberg H, Schmidt A, et al. Endoluminal stent-graft placement for acute rupture of the descending thoracic aorta. Eur Heart J 2004; 25:694–700. 91. Lawrence-Brown M, Sieunarine K, van Schie G, et al. Hybrid open-endoluminal technique for repair of thoracoabdominal aneurysm involving the celiac axis. J Endovasc Ther 2000; 7:513–519. 92. Kotsis T, Scharrer-Pamler R, Kapfer X, et al. Treatment of thoracoabdominal aortic aneurysms with a combined endovascular and surgical approach. Int Angiol 2003; 22:125–133. 93. Flye MW, Choi ET, Sanchez LA, et al. Retrograde visceral vessel revascularization followed by endovascular aneurysm exclusion as an alternative to open surgical repair of thoracoabdominal aortic aneurysm. J Vasc Surg 2004; 39:454–458.

48 Secondary Hypertension: Pathophysiology and Operative Treatment James C. Stanley and Gerard M. Doherty

INTRODUCTION Hypertension is a common clinical abnormality in the Western world. Even though its precise etiology remains to be elucidated, it can be effectively managed in most patients with lifestyle changes, such as exercise and weight control, either alone or in conjunction with a variety of pharmacological agents, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-adrenergic antagonists. In contrast, surgically correctable forms of hypertension are infrequently encountered in clinical practice. Two diseases of the adrenal gland exhibiting abnormal aldosterone and catecholamine production and a number of renal artery occlusive lesions associated with excess renin–angiotensin activity, often present clinically with blood pressure elevations. Several other endocrine diseases, including hyperthyroidism, pituitary-dependent Cushing’s disease, ectopic adrenocorticotropin (ACTH) production by pancreatic tumors, and reninomas can all cause hypertension, however, they are very rare. Similarly, renal artery occlusions and secondary hypertension due to emboli and dissections are quite uncommon. Contemporary practice requires a thorough understanding of the more common correctable forms of hypertension associated with adrenal and renal diseases. An understanding of these abnormalities is the focus of this chapter. For a more comprehensive discussion of adrenal gland physiology and pathophysiology, the reader is referred to the chapter on that subject.

ADRENAL DISEASE AND HYPERTENSION Normal Adrenal Anatomy and Mineral Corticoid Production The adrenal glands are paired organs with a normal combined weight of 7 to 12 g (1). They can expand 100-fold in the setting of adrenal hyperplasia or tumors. The right adrenal gland is located superior to the right kidney and directly posterior to the inferior vena cava along the right crus of the diaphragm. The left adrenal gland resides atop the left renal vein, medial to the superior pole of the left kidney, just lateral to the aorta, and posterior to the tail of the pancreas. The adrenal gland arterial blood supply varies, with each gland often supplied by numerous, small branches from the aorta, inferior phrenic artery, renal artery, gonadal artery, and intercostal arteries. The venous drainage is more constant, with a single, main adrenal vein. The right adrenal vein is several millimeters in both width and length, draining directly from the anterior surface of the gland into the posterolateral aspect of the inferior vena cava. The left adrenal vein drains from the mid-portion of the posterior

gland into the left renal vein. It is often joined by the left inferior phrenic vein. The majority of the lymphatic drainage from the adrenal glands is to the para-aortic, paracaval, and perirenal lymph nodes. The adrenal gland is divided into an outer cortex and inner medulla. The zona glomerulosa of the cortex, where aldosterone is produced, and the medulla, which produces catecholamines, are the two important functional areas of the gland.

Aldosterone Aldosterone is the principal mineralocorticoid, secreted by zona glomerulosa cells, and regulated by the renin–angiotensin system, by plasma potassium concentration, and, to a lesser degree, by ACTH and plasma sodium concentration. Physiologic states that stimulate the renin–angiotensin system and aldosterone release include dehydration, hemorrhage, and upright posture. Postural effects are mediated by the sympathetic nervous system. Volume repletion decreases the activity of the renin–angiotensin system. Normal daily aldosterone production is 100 to 150 mg. This hormone binds to albumin and transcortin, with only a small percentage of free aldosterone remaining available to target tissues. Plasma aldosterone half-life is 15 minutes. Aldosterone is metabolized in the liver and conjugated to glucuronidase, leading to its excretion in the urine. In liver failure, metabolism of aldosterone is impaired, leading to its elevated levels with subsequent fluid retention. Aldosterone is the major regulator of extracellular fluid volume and potassium homeostasis. Its receptors are expressed on cells of the distal renal tubule, which is the major site of its action. Aldosterone binds to these receptors with high affinity. This results in retention of sodium and excretion of potassium. Sodium retention then leads to passive reabsorption of water and an increase in extracellular fluid volume. To balance aldosterone-mediated retention of positively charged sodium ions, the kidney epithelium releases intracellular potassium into the distal convoluted tubule for excretion in the urine. Hydrogen ion is also released, acidifying the urine (2).

Hyperaldosteronism Hyperaldosteronism is a syndrome manifest by hypertension and hypokalemia, due to the autonomous adrenal secretion of aldosterone. It may result from an adrenal neoplasm with suppressed plasma renin, or it may be secondary, as a result of elevated plasma renin. Primary hyperaldosteronism is twice as common in women as in men, and usually occurs between the ages of 30 and 50. Screening of hypertensive patients with plasma aldosterone and plasma renin activity (PRA) has revealed

medwedi.ru 907

908

Part Six: The Peripheral Vascular System

that primary hyperaldosteronism may be the underlying cause of up to 10% of cases of essential hypertension (3). Primary hyperaldosteronism is due to an aldosteroneproducing adrenal adenoma in approximately a third of cases. This is responsible for Conn’s syndrome. Idiopathic bilateral adrenal hyperplasia is responsible for the remaining cases. Adrenocortical carcinoma is a rare cause of primary hyperaldosteronism, as is an autosomal-dominant glucocorticoid-suppressible hyperaldosteronism resulting from the fusion of the ACTH-responsive 11-beta-hydroxylase gene promoter to the aldosterone synthase gene. Secondary hyperaldosteronism is a physiologic response to the activated renin–angiotensin system, in cases of renal artery stenosis, cirrhosis, congestive heart failure, and normal pregnancy. In these situations, the adrenal cortex functions normally and secretes aldosterone in response to an elevated plasma renin and angiotensin. Secondary hyperaldosteronism is responsive to treatment of the underlying cause (3). Clinical manifestations of primary hyperaldosteronism are attributable to aldosterone-mediated retention of sodium and excretion of potassium and hydrogen ion by the kidney, causing moderate diastolic hypertension. Edema is absent. Hypokalemia affects 80% to 90% of patients with primary hyperaldosteronism and can be easily provoked in the remaining patients. Potassium depletion in this setting frequently causes symptoms of muscle weakness and fatigue, polyuria and polydipsia, as well as impaired insulin secretion and fasting hyperglycemia. Primary hyperaldosteronism should be suspected in hypertensive patients with spontaneous hypokalemia (serum potassium concentration < 3.5 mEq/L), moderate hypokalemia (serum potassium concentration < 3.0) during diuretic therapy despite supplementation with oral potassium or use of potassium-sparing diuretics, or refractory hypertension without explanation. Because as many as 50% of hypertensive patients with hyperaldosteronism are normokalemic, it is advocated that all newly diagnosed hypertensive patients be screened by determining the aldosterone to renin ratio. A ratio of greater than 30 on two separate occasions in a normokalemic patient warrants further investigation (4,5). The essential hallmarks of primary hyperaldosteronism are (i) diastolic hypertension without edema; (ii) suppression of plasma renin in the face of volume depletion; and (iii) hypersecretion of aldosterone, which fails to suppress with intravascular volume expansion. Diagnostic evaluation must establish primary hyperaldosteronism, differentiate a surgically correctable adrenal adenoma from medically treatable idiopathic hyperplasia, and localize an adrenal tumor, if present. Demonstration of an elevated plasma aldosterone concentration (PAC) in the setting of suppressed PRA is the best test to establish a diagnosis of primary hyperaldosteronism. The ratio of PAC to PRA in normal subjects and patients with essential hypertension is 4 to 10, compared to more than 30 in most patients with primary aldosteronism. A PAC >20 ng/dL and a PAC/PRA ratio greater than 30 are diagnostic of an aldosteronoma, with almost 90% sensitivity. A serum potassium value less than 3.5 mEq/L and urinary potassium excretion greater than 30 mEq/dL also support the diagnosis of primary hyperaldosteronism. Hypokalemia and inappropriate kaliuresis may be present as well. It is important to recognize that before biochemical evaluation, patients need to be potassium repleted, have an adequate sodium intake, and medications including ACE inhibitors and spironolactone should be withheld for at least four weeks before testing.

An elevated PAC/PRA ratio alone does not establish the diagnosis of primary hyperaldosteronism, which must be confirmed by demonstrating inappropriate aldosterone secretion of less than 14 mg/24 hr in the urine with salt loading. This involves a 24-hour urine collection for sodium and aldosterone after three days of a high-sodium diet. An intravenous saline infusion test, fludrocortisone suppression test, and captopril challenge test are also reliable methods to confirm the diagnosis of primary hyperaldosteronism, although these tests are not usually required (3). Once the diagnosis of primary hyperaldosteronism is established, distinction must be made between an aldosteronoma and idiopathic adrenal hyperplasia. Postural testing can give some indication of the source of hyperaldosteronism; however, a more definitive diagnosis depends on radiographic imaging and functional localization (6,7). High-resolution computed tomography (CT) of the adrenal gland is adequate for localization of aldosteroneproducing adenomas in more than 90% of cases (Fig. 1). The presence of a unilateral mass greater than 1 cm on CT and supportive biochemical evidence of an aldosteronoma are generally all that is needed to make the diagnosis in patients less than 40 years of age. The contralateral adrenal gland must be examined in patients presumed to have an aldosterone-producing adenoma, to ensure that bilateral hyperplasia is not present. Magnetic resonance imaging (MRI ) may be useful during pregnancy or in situations in which administration of intravenous contrast medium is undesirable. NP-59 scintigraphy may also identify functional tumors but requires a tumor size greater than 1 cm for the imaging to be dependable (8). Adrenal vein sampling to lateralize the source of aldosterone production is useful in patients with hyperaldosteronism when there is no adrenal abnormality on cross-sectional imaging, or when both adrenal glands are abnormal but asymmetric. Further, patients over 40 years of age, in whom the possibility of a nonfunctioning adenoma is statistically higher, may benefit from routine sampling. Percutaneous transfemoral cannulation of both

Figure 1 Computed tomography evidence of typical small, benignappearing adrenal aldosterone-producing adenoma.

Chapter 48:

Secondary Hypertension: Pathophysiology and Operative Treatment

adrenal veins is performed and simultaneous blood samples for aldosterone and cortisol are taken before and after ACTH injection, and their ratios are determined. The aldosterone concentration should be at least fourfold higher on the side of an adenoma, whereas there is little or no gradient in patients with bilateral adrenal hyperplasia. A tenfold gradient of cortisol in adrenal veins to a peripheral sample ensures adequacy of adrenal vein cannulation. The former study is greater than 90% accurate and alters management in 30% to 50% of patients, even in those with an apparent unilateral adenoma. The test is technically difficult and may be unsuccessful in 25% of patients. Emerging data suggest that adrenal vein sampling may be superior to CT in differentiating the source of aldosterone production in patients with hyperaldosteronism (5,9). Surgical removal of an aldosterone-secreting adenoma results in a durable improvement regarding hypertension and hypokalemia in 70% to 90% of patients. Laparoscopic adrenalectomy is the preferred approach to remove these tumors. Morbidity and mortality following these procedures are negligible. Preoperative spironolactone and potassium are given to replenish potassium stores and correct any existing alkalosis. A good response to spironolactone predicts a successful outcome after adrenalectomy. Response to adrenalectomy is also influenced by the duration and severity of hypertension. Age greater than 50 years, male gender, and the presence of multiple nodules within the adrenal are associated with a poor response to surgery. Management of idiopathic adrenal hyperplasia is medical. In fact fewer than 20% of patients with this particular disease are cured by adrenalectomy. Idiopathic adrenal hyperplasia is treated with spironolactone or with the newer aldosterone antagonist eplerenone. Other potassium-sparing diuretics may be used, including triamterene and amiloride. Treatment of glucocorticoid-suppressible hyperaldosteronism includes dexamethasone 0.5 to 1.0 mg daily. Glucocorticoids are used in small doses to avoid Cushing’s syndrome (5).

Normal Adrenal Catecholamine Production Catecholamines of the adrenal medulla include epinephrine, norepinephrine, and dopamine. These vasoactive hormones are derivatives of the amino acid tyrosine. The biosynthetic pathway that converts tyrosine to active catecholamines involves four sequential enzymatic reactions: (i) tyrosine is converted to l-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase; (ii) dopa is converted to dopamine by aromatic-l-amino acid decarboxylase; (iii) dopamine is converted to norepinephrine by dopamine beta-hydroxylase; and (iv) norepinephrine is converted to epinephrine by phenylethanolamine-N-methyltransferase(PNMT).Epinephrine is the major (80%) catecholamine stored in the adrenal medulla, followed by norepinephrine (20%) and dopamine (<1%). Tissue expression of the enzyme PNMT is limited to cells of either the adrenal medulla or the organ of Zuckerkandl, located near the aortic bifurcation; thus, most extra-adrenal pheochromocytomas produce norepinephrine, rather than epinephrine (10). A complex regulatory network governs synthesis and secretion of catecholamines. Catecholamines are stored and secreted from granules within cells of the medulla, in association with the matrix protein chromogranin. Chromogranin A is measurable in the blood and its quantitation may support the biochemical testing for pheochromocytoma, as well as other functional neuroendocrine tumors. Catecholamines act upon target tissues through membrane-bound adrenergic receptors. Pharmacologic

909

distinction of adrenergic receptors is made based on their relative responsiveness to natural and artificial bioamines. The affinity of alpha-adrenergic receptors is highest for norepinephrine, less for epinephrine, and least for isoproterenol. Beta-adrenergic receptors are most responsive to isoproterenol and least responsive to norepinephrine. In addition, specific antagonists recognize each receptor class: alpha receptors are antagonized by phentolamine and phenoxybenzamine, and beta receptors are blocked by propranolol and related compounds. Beta-adrenergic receptor subtypes include beta-1 receptors, present in cardiac muscle, adipose tissue, and small intestine, and beta-2 receptors that occur in vascular, tracheal, and uterine smooth muscle, skeletal muscle, and liver. Alpha-adrenergic receptors are similarly subdivided: a-1 receptors mediate vasoconstriction, whereas a-2 receptors modulate presynaptic norepinephrine release and platelet aggregation (10).

Metabolism of Catecholamines Metabolism of catecholamines occurs through three mechanisms: (i) specific uptake by sympathetic neurons, (ii) nonspecific uptake and degradation by peripheral tissues, and (iii) excretion in the urine. Catecholamines are metabolized in liver and kidney by two enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). MAO and COMT convert epinephrine or norepinephrine to normetanephrine, and metanephrine, 3,4-dihydroxy-mandelic acid, and 3-methoxy-4-hydroxy-mandelic acid. These inactive metabolites are excreted by the kidney and are measurable in the plasma and the urine, either as free compounds or as conjugates of glucuronide or sulfate (10).

Adrenal Medullary Hyperfunction: Pheochromocytoma Pheochromocytomas are rare adrenal tumors that are usually benign. However, primary tumors can occur outside of the adrenal gland, and tumors that arise either within or outside the adrenal gland can be malignant. This tumor is often described by the rule of ten’s, that is, 10% familial, 10% bilateral, 10% extra-adrenal, 10% malignant, and 10% occurring in children. However, these figures underestimate the incidence of both malignancy and extra-adrenal primary tumors, each of which probably occur in closer to 20% of patients with pheochromocytoma (11). Unilateral pheochromocytoma that occurs without evidence of familial tendency, based on family history, is still associated, in 25% of patients, with a germline abnormality predisposing to these tumors. This significant frequency mandates direct genetic testing in patients with apparently sporadic pheochromocytoma, to assess for multiple endocrine neoplasia type 2 syndromes, von Hippel–Lindau syndrome, and familial paraganglioma syndromes (12).

Clinical Presentation Clinical presentation of a pheochromocytoma includes baseline hypertension, ‘‘spells,’’ which classically include exacerbation of hypertension, and a variety of signs and symptoms that may include paroxysmal headache, dizziness, anxiety, tachycardia, nausea, or visual changes. The spells may occur seemingly spontaneously, or may predictably follow certain activities. This can be particularly true for some of the ectopic sites, where spells can be caused by local mechanical changes, such as micturition, sexual intercourse, or defecation, with tumors adjacent to the bladder (13). Patients may occasionally present with severe systemic illness, or death from hormone release from a previously occult tumor (10).

medwedi.ru

910

Part Six: The Peripheral Vascular System

Diagnosis Biochemical assessments should be performed before adrenal imaging in patients suspected of pheochromocytomas. The best test for the assessment of adrenal medullary hyperfunction is measurement of plasma free-metanephrine levels. This diagnostic test has supplanted the measurement of urine catecholamines and their metabolites. It is accurate and sensitive, and is marred only by some false-positive results with borderline elevated values. Measurements are interfered by use of a variety of drugs and dietary habits. In particular, patients should be withdrawn from adrenergicblocking agents, and should refrain from consumption of grapefruit. Once the biochemical diagnosis is assured, then diagnostic imaging is appropriate. Imaging, once the biochemical diagnosis of pheochromocytoma has been made, will localize the tumor. Because most pheochromocytomas reside in the adrenal gland, the initial localizing test should be a cross-sectional study of the adrenals, either by a high-resolution CT scan or by an MRI (Fig. 2). If the study shows a unilateral adrenal mass, without suggestion of malignancy or other extra-adrenal findings, then no further testing is necessary. In a consecutive series from the University of Michigan, of the 48 patients with a biochemical diagnosis of pheochromocytoma and a unilateral adrenal mass on CT or MRI, none had additional disease defined by the 123I-metaiodobenzylguanidine (MIBG ) scan. Of the 48 patients, 47 had a single unilateral focus of uptake defined on MIBG scan, and the remaining patient had a false-negative MIBG scan. Thus, the MIBG scan can be reserved for either patients whose disease is not apparent on the cross-sectional imaging, or those who have additional abnormalities, such as bilateral adrenal masses or extra-adrenal lesions (14). In the latter group of patients,123I-MIBG scans or somatostatin-receptor scintigraphy can identify other sites of disease (15).

Extra-Adrenal Primary Pheochromocytoma Although most pheochromocytomas are unilateral adrenalbased lesions, occasional patients have tumors elsewhere in the body. Patients with disease at ectopic sites typically present with the same symptoms as those with adrenal gland tumors. Extra-adrenal tumors occur along the sympathetic chain, at any site from the skull base to the pelvis. The most common site for extra-adrenal pheochromocytomas, which are also sometimes called paragangliomas, particularly when they do not make appreciable amounts of catecholamines, is

the organ of Zuckerkandl. They may occur in the neck, posterior chest, atrium, renal hilum, and bladder. A common location of extra-adrenal tumors is between the aorta and vena cava at the level of the left renal vein, cephalad to the organ of Zuckerkandl tumors arising on either side of the superior mesenteric artery or more distally to the aortic bifurcation, where such may be mistaken for a lymph node metastasis. Middle mediastinal tumors, which may involve the heart, occur more frequently than was previously recognized. Extra-adrenal tumors have a higher reported malignancy rate of 25% to 40%, although not all reports agree on the differential aggressiveness of the extra-adrenal lesions (16,17). Increased recognition of ectopic sites of primary pheochromocytomas is due a variety of newer diagnostic options. First, it is the improved accuracy of biochemical testing for pheochromocytoma with the current testing methods, particularly with the widespread availability of plasma metanephrine testing, and then, with the subsequent increased level of diagnostic certainty, improved imaging can be selectively and diligently applied. Current imaging, including high-resolution CT scan, MRI, and nuclear imaging with 123I-MIBG or somatostatin-receptor scintigraphy, can localize tumors in many sites, which were simply not practical in the past, particularly if the biochemical diagnosis was equivocal (Fig. 3) (15,18). Pheochromocytomas can also produce hormones other than catecholamines, including ACTH, calcitonin, somatostatin, vasoactive intestinal peptide (VIP), or serotonin. The production of these unusual hormones and their syndromes can lead to an extensive work-up to identify the responsible tumor.

Surgical Management The best therapy for a localized pheochromocytoma at any site is resection, because this is the only potentially curative treatment. Regardless of site or number of tumors, all patients should be prepared with an a-adrenergic antagonist for one to two weeks preoperatively. One proven agent is phenoxybenzamine (Dibenzyline), which can be administered three times a day. Starting with a dose of 30 mg/day, the dose is increased every third day by 30 mg. The endpoint of therapy is orthostatic hypotension, although a clinical sign that the dose is adequate is the development of nasal congestion. This may be achieved with the starting dose, although some patients have required as much as 360 mg/day. An experienced and prepared

Figure 2 Ectopic pheochromocytoma during pregnancy. Worsening hypertension led to a biochemical evaluation that diagnosed pheochromocytoma. Initial imaging with ultrasound and abdominal magnetic resonance imaging (MRI) showed no evidence of the site of disease. (A) Chest x-ray revealed a left thoracic mass (arrow), and a (B) subsequent MRI provided improved anatomic delineation (arrow) facilitating second-trimester resection of the tumor.

Chapter 48:

Secondary Hypertension: Pathophysiology and Operative Treatment

911

surgery precluding insufflation. Extra-adrenal lesions, like those confined to the adrenal gland itself, now can be approached with minimally invasive resection techniques.

Malignant Pheochromocytoma

Figure 3 Metaiodobenzylguanidine scan demonstration of systemic malignant pheochromocytoma disease, with diffuse intra-abdominal and intrathoracic nodal disease.

anesthesiologist should be considered essential in managing the patient during surgery. Central venous and arterial pressure lines are placed for monitoring during induction of anesthesia and throughout the operative procedure (10). A wide variety of operative approaches to the adrenal gland have evolved during the last eight decades. Each approach has its utility, and all belong in the repertoire of any surgeon operating on the adrenal gland. The initial approach to the adrenal glands was anterior, through bilateral subcostal or vertical midline incision. This allows wide exposure and the opportunity to explore both adrenal beds. A right thoracoabdominal incision allows access to the right chest and abdomen, to permit resection of large right adrenal tumors. It has the added advantage of facilitating vena cava and right atrium control for adrenal tumors with significant vascular invasion. The retroperitoneal approach uses posterior incisions in a prone patient. This offers the least morbidity to the patient, but is inadequate for resection of large adrenal tumors. However, the posterior approach offers advantages after extensive prior abdominal or retroperitoneal surgery. It has otherwise been superseded by laparoscopic adrenalectomy (19). Minimally invasive approaches to the adrenal gland include anterior or lateral transabdominal laparoscopy (1,20, 21). Further, endoscopic retroperitoneal adrenalectomy can use either traditional laparoscopic instruments or 2 mm needlescopic instruments (22,23). Several authors have demonstrated the technical feasibility of a laparoscopic resection of lesions up to 15 cm. Because most hormonally active tumors are benign, and are identified at less than 5 cm diameter, the laparoscopic approach has proved ideal for most resections (24–28). Numerous high-quality studies have compared traditional, open adrenalectomy to laparoscopic adrenalectomy (29–38). These have consistently demonstrated that patients who have the laparoscopic approach have decreased intraoperative blood loss, decreased length of hospital stay, decreased use of postoperative analgesics, increased rate of return to normal activities, improved cosmesis, and decreased late morbidity. Laparoscopic adrenalectomy has reduced overall costs, compared with open surgery (34,39). In spite of these advances, the traditional open approach retains utility for management of very large tumors, tumors with local invasion, and patients with extensive prior

Malignant pheochromocytomas account for 10% to 15% of all cases, although various authors have reported an incidence ranging from 5% to as high as 46%. Extra-adrenal pheochromocytomas have been associated with a higher incidence of malignancy in most series reported, ranging from 20% to 40%, but this is not uniform (16). When collected series of pheochromocytomas are evaluated, and taking into account for selective referral bias, an overall malignancy incidence of 15% appears to be a reasonable estimate (11). There are no certain histologic criteria that distinguish benign from malignant tumors. Even upon retrospective review, the distinction is often impossible because vascular and capsular invasion as well as mitotic figures can be readily identified in both benign and malignant lesions. Tumors without evidence of capsular or vascular invasion may have metastasized to distant sites, while other tumors with local capsular or even major venous invasion have apparently been cured by surgical excision. Malignancy can be positively diagnosed only when there is local invasion of tumor into surrounding soft tissue, or when the presence of tumor in nonchromaffinbearing tissue outside the region of the sympathetic chain is identified. Tumors, also at increased risk for malignancy, are those pheochromocytomas that secrete only dopamine (10). The median time of recurrence or identification of metastases is five to six years. Long-term follow-up is therefore advised, which should include regular blood pressure monitoring as well as annual biochemical studies for catecholamines and their metabolites. The current approach is to evaluate using plasma metanephrine measurements at least annually, except in those tumors that make only dopamine or ACTH, in which case, the specific biochemical follow-up depends upon the initial biochemical presentation (40–43). The most common site for metastatic lesions is bone, where they present as lytic lesions of the spine, skull, or ribs. Other sites include liver, lung, and retroperitoneal or mediastinal lymph nodes. Malignant pheochromocytomas usually are slow-growing tumors, and long-term survival, although rare, has been reported, provided that control of symptoms caused by increased catecholamines is possible (10). Once the diagnosis of malignant pheochromocytoma is established or suspected,123I-MIBG scintiscanning has proven effective in detecting the extent of the disease in most patients. CT and MRI may give additional anatomic information that may be helpful in determining resectability in patients whose disease is limited to soft tissue. Octreotide scanning and technetium bone scans have also proved useful in some cases (15).

Therapy Therapy of malignant pheochromocytomas should initially be with an a-adrenergic-blocking drug, with the exception of those rare tumors secreting only dopamine. Most prefer phenoxybenzamine, gradually increasing the dose, to control hypertension. Small doses of a b-blocking drug, even when epinephrine levels are not excessively high, may also prove beneficial. In patients whose symptoms or blood pressure cannot be readily controlled with an a-blockade, additional antihypertensive therapy may be required. For patients with unresectable metastatic disease, alphamethyltyrosine should be considered. This drug inhibits the

medwedi.ru

912

Part Six: The Peripheral Vascular System

Table 1 Clinical Reports of Therapy for Pheochromocytoma with Cyclophosphamide, Dacarbazine, and Vincristine Institution National Cancer Institute, USUHS (47) University of Tsukuba, Japan (46) University of Michigan (45)

Patients

Biochemical responses

Tumor responses

14

11

8

3

3

Not reported

6

3

3

synthesis of catecholamines and may, in conjunction with an adrenergic blockade, offer long-term control of catecholaminerelated symptoms. After appropriate blockade, management of metastatic disease or recurrences includes wide local excision of surgically resectable disease as a first line of treatment. Unfortunately, this may only be palliative because of the presence of bone metastases. However, when tumor is limited to soft tissue, surgical excision may offer long-term palliation and even cure. Complete resection may require retroperitoneal lymph node dissection, liver resection, or soft tissue resection that includes other organs (e.g., kidney, bowel, and distal pancreas). Careful preoperative planning and imaging can help to ‘‘draw the dotted lines’’ sufficiently widely around the tumor to give the best opportunity for cure (16). Until the past decade, no effective chemotherapeutic regimen had been reported. No single agent such as adriamycin or streptozotocin has ever been shown to be bene ficial. However, a combination of cyclophosphamide, vincristine, and dacarbazine has resulted in a high incidence of both biochemical improvement (decrease in catecholamines) and tumor growth inhibition (Table 1) (44–47). This combination is currently considered the drug regimen of choice when chemotherapy is indicated. External beam radiation treatment is effective for the palliation of bone pain. Therapeutic 131I-MIBG has been used to treat patients with functioning metastases with encouraging results in selected patients with respect to decrease in both tumor size and circulating catecholamines (46,48–50). Less than a third of patients are candidates for treatment, which is based on the tumor’s ability to concentrate sufficient 131I-MIBG to be irradiated effectively. Although regression of tumor has been well documented

in some cases, the duration of effect has been limited to approximately two years and no patient has been cured.

RENAL ARTERY OCCLUSIVE DISEASE AND HYPERTENSION Normal Physiology of the Renin–Angiotensin System The renin–angiotensin system is of paramount importance in renovascular hypertension. Elements of this system that contribute to blood pressure control include (i) renin, produced in the kidney; (ii) angiotensinogen, produced in the liver; (iii) ACE, which is most active in the endothelium of the lung; (iv) angiotensin II, produced from angiotensin I by ACE; and (v) aldosterone, produced in the adrenal gland (Fig. 4).

Renin Renin is produced by the juxtaglomerular apparatus of the kidney (Fig. 5). Major components of this anatomic region include (i) myoepithelioid cells or granular cells, located on the wall of the afferent arterioles; (ii) the macula densa, which is a specialized region of tubular epithelial cells, located in the glomerular hilus at the transition of Henle’s loop to the distal convoluted tubule; and (iii) lacis cells, located in the region of the efferent glomerular arteriole and the macula densa. The lacis cells are intimately associated with the glomerulus and are anatomically similar to mesangial cells. An interrelationship clearly exists between these structures, with the function of the juxtaglomerular apparatus being translation of various signals into altered glomerular filtration and secretion of renin. Mechanisms controlling renin production and its release from the kidney are very complex. Renal baroreceptors appear responsible for release of renin from juxtaglomerular cells, with these cells specifically acting as stretch receptors. The cellular basis for activation of these receptors seems to involve the calcium ion, with experimental evidence documenting an inverse relationship between renin release and intracellular calcium levels. Stimuli for renin release also include pressure changes at the afferent renal arteriole level, and renal interstitial volume and pressure changes. The importance of the tubular fluid milieu and the macula densa has been well established, with

Renin substrate Kininosen Prekallikrein

Renin

Kallikrein Bradykinin

Kinase II

Inactive peptides

Angiotensin I

Converting enzyme

Angiotensin II

Angiotensin III

Inactive fragments

Cholesterol

Blood pressure

Pregnenolone

Aldosterone

Figure 4 Renin–angiotensin system interrelation with aldosterone and bradykinin in the regulation of blood pressure. Source: From Ref. 51.

Chapter 48:

Secondary Hypertension: Pathophysiology and Operative Treatment

913

Figure 7 Human renin gene, consisting of nine exons and eight introns, with a 9bp miniexon (5a) of unknown function located between exon five and six. This gene is approximately 12.18 kb in length. The coding sequence (black boxes) is contained in the second to eighth exons and portions of the first and ninth exons.

Figure 5 Anatomic components of the juxtaglomerular apparatus.

changes in sodium and chloride content of tubular fluid altering renin release. However, the relative importance of macula densa receptors in activation of the renin–angiotensin system in renovascular hypertension is uncertain. Stimulation of postganglionic sympathetic neurons to renal arterioles, many of which end in the region of the juxtaglomerular apparatus, also causes increased renin release. This may be due to afferent arteriolar constriction with decreased stretch of intrarenal vascular receptors and decreased sodium load to the macula densa, but it is more likely a direct result of catecholamine action on b-adrenergic receptors of the juxtaglomerular cells. Renin, a proteolytic enzyme, is active at a neutral pH on its only known substrate, angiotensinogen. The renin gene in humans is located on chromosome 1 (Figs. 6 and 7).

Figure 6 Chromosome 1 contains both the human renin and angiotensinogen genes.

It consists of nine exons and an additional miniexon, interrupted by eight introns. The renin gene is transcribed into renin mRNA and translated into a pre-prorenin molecule with a molecular weight of 45,000. Following cleavage and glycosylation in the rough endoplasmic reticulum, prorenin is produced with a molecular weight of 47,000. It is transferred into the Golgi complex, where it is rapidly secreted and processed to active renin, a single-chain polypeptide with a molecular weight of approximately 38,000. Extrarenal renin or renin-like enzymes (isorenins) have been found in the submaxillary salivary gland, uterus, placenta, and brain. No documentation exists that these latter substances are functionally important in elevating blood pressure. Renin, once synthesized, is stored as granules within the juxtaglomerular cells, and, in some instances, as granules within the arteriolar wall. The release of both protein and renin into the extracellular space occurs by exocytosis. Renin has a half-life of approximately 20 to 30 minutes. Peripheral levels of circulating renin appear to be in a steady state, the sum of renin activity from both renal veins being approximately 48% greater than that in the infrarenal vena cava or arterial circulation (52). The major site for removal and clearance of renin is the liver (53). Biochemical events related to the renin–angiotensin system have been relatively well defined (Fig. 8). The primary and perhaps only function of renin is the hydrolysis of the circulating renin substrate, angiotensinogen, to form angiotensin I. Angiotensinogen is an a2-globulin with a molecular weight of 60,000, produced in the liver. The human gene for angiotensinogen is located on chromosome 1 (Figs. 6 and 9). It is composed of five exons interrupted by four introns. Gene expression is subject to a variety of physiologic and pathophysiologic stimuli, including steroid

Figure 8 Biochemical composition of renin substrate and the angiotensins.

medwedi.ru

914

Part Six: The Peripheral Vascular System

Figure 9 Human angiotensinogen gene, consisting of five exons and four introns. This gene is approximately 14.55 kb in length. The coding sequence (black boxes) for angiotensinogen is contained in the second to fifth exon. The second exon contains the coding sequence for angiotensin I.

hormones, angiotensin II, salt loading, and various drugs. Angiotensinogen itself is not vasoactive.

Angiotensin I Angiotensin I, the decapeptide produced by the renin substrate–renin reaction, is relatively inactive. It does exert some effect on the adrenal medulla, the sympathetic and central nervous systems, and the renal arterioles. Quantitation of this intermediary is the basis for many radioimmunoassays of renin activity.

Angiotensin II Angiotensin II is produced when two C-terminal peptides are cleaved from angiotensin I by a carboxypeptidase known as ACE. The resulting octapeptide is the major contributor to the vasoactive element of renovascular hypertension. Angiotensin II stimulates liver production of angiotensinogen, but in normal individuals, it provides a continuous negative feedback on the renal release of renin. Angiotensin II has a half-life of approximately four minutes.

Angiotensin III Angiotensin III, which is a heptapeptide, is derived by aminopeptidase cleavage of angiotensin II to 1-des-aspartyl angiotensin II. Angiotensin III has biologic activity, although its levels are so low that its physiologic importance is questioned. Angiotensin III inhibits angiotensin II. Perhaps, its most relevant effect is stimulation of aldosterone synthesis.

Aldosterone Aldosterone, a mineralocorticoid, is secreted from the zona glomerulosa of the adrenal cortex. The biosynthesis of this substance initially involves cleavage of the side of cholesterol to form pregnenolone. This step is facilitated by both angiotensin II and III. Aldosterone increases renal conservation of sodium and water, with a resultant expansion of the extracellular fluid volume and an eventual increase in blood pressure.

Angiotensin Converting Enzyme ACE is a zinc metallopeptidase responsible for the generation of angiotensin II from angiotensin I by removing C-terminal peptides. The enzyme has a molecular weight of 150,000 to 180,000. Its gene has been mapped to chromosome 17 in humans. ACE has its highest concentration in the lung on the surface of endothelial cells. It also can be found at lower levels in the blood and kidney, as well as in other vascular beds. Conversion of angiotensin I to angiotensin II, at

physiologic concentrations, has been shown to occur in a single passage through the lungs. ACE also plays an important role in the metabolism of the vasodepressor bradykinin. At least two enzymes appear to be responsible for the inactivation of bradykinin. The first is kinase I, which cleaves the carboxyl-terminal arginine of bradykinin. The second enzyme, kinase II, cleaves the carboxyl-terminal dipeptide group, Phe–Arg. Kinase II and ACE are considered the same, in that they have nearly identical substrate specificities, cofactor requirements, and antigenic specificities. The most common technique for determination of PRA involves measurement of angiotensin I generation using a radioimmunoassay. PRA is expressed as the hourly rate of angiotensin I generation per unit of volume assayed. The assay involves two phases: (i) incubation of plasma to generate angiotensin I and (ii) measurement of generated angiotensin by the radioimmunoassay. Actual renin secretion is calculated as the renal arteriovenous difference in renin activity multiplied by renal plasma flow, and it is usually expressed as ng/mL/hr. Assay methods may vary among laboratories, often making interlaboratory comparisons difficult. Angiotensins have actions on the cardiovascular system, central nervous system, adrenal gland, and kidneys (Fig. 10). The effects on cardiac activity, vascular smooth muscle reactivity, and salt and water metabolism are profound, and all contribute to increased arterial pressure. The most important consequence of renal artery occlusive disease is the production of angiotensin II, which by weight is one of the most potent pressor substances known. Angiotensin II acts directly on the arteriolar smooth muscle of nearly all vascular beds. The splanchnic, renal, and cutaneous circulations are most sensitive to its effects. Despite an acceptance of the central importance of angiotensin in the generation of renovascular hypertension, the relevance of absolute plasma levels remains unknown. The end-organ sensitivity to these vasoactive substances is often impossible to predict, because it is different in various physiologic and pathologic settings. In addition, the exact role in renovascular hypertension of locally secreted renin and locally generated angiotensin remains poorly defined.

Renal Blood Flow–Mediated Changes in the Renin–Angiotensin System Hemodynamic responses to activation of the renin– angiotensin system by changes in renal artery blood flow depend on the rate at which renal blood flow is decreased, as well as whether one or both kidneys are at risk. Acute reductions in renal blood flow result in prompt blood pressure increases and increased plasma renin levels. Experimental animal models of renovascular hypertension are defined as two kidney–one clip (2K–1C), two kidney–two clip (2K–2C), or one kidney–one clip (1K–1C), depending on whether one or both renal arteries are constricted. In instances of 2K–1C renovascular hypertension, where the total renal mass is not affected, the hypertension is characterized by renin hypersecretion from the affected kidney and contralateral suppression of kidney renin production (55,56). Sodium avidity within the affected kidney is counterbalanced by continuous sodium excretion from the contralateral kidney, resulting in relative intravascular volume depletion. This form of hypertension is angiotensin II dependent and responds to angiotensin antagonists and ACE inhibitors. When the entire renal mass is at risk with 2K–2C or 1K–1C renovascular hypertension, pathophysiologic

Chapter 48:

Vascular smooth muscle

Nervous system

Angiotensins

Adrenal cortex

Secondary Hypertension: Pathophysiology and Operative Treatment

915

Arteriolar constriction Sympathetic activity ADH secretion

Renal H 2O reabsorption

Renal filtration fraction

Increased arterial pressure

Na and H2O retention

Aldosterone secretion

Renal tubules

Cardiac output

Renal Na absorption

Renal arterioles

Figure 10 Effects of angiotensins contributing to increased arterial pressure. Source: From Ref. 54.

Renal glomerular filtration rate

alterations are quite different and undoubtedly relate to changes other than vasoconstriction. Angiotensin II is known to be involved with sodium retention, decreases in glomerular filtration, stimulation of aldosterone production, and stimulation of norepinephrine release from the adrenergic nervous system. These effects may occur acutely, but in chronic 2K–2C or 1K–1C renovascular hypertension, it appears that sodium retention accounts for late reductions in renin secretion, although the absolute renin activity may be abnormal in relation to the existing state of sodium balance. Studies have been unable to demonstrate that blood pressure elevations depend on the renin–angiotensin system in sodium-replete chronic renovascular hypertension. In fact, angiotensin receptor antagonists or ACE inhibitors are effective in reducing elevated blood pressures only when the subjects are depleted of sodium.

atherosclerosis (Fig. 11). Such lesions are bilateral in threequarters of patients. When unilateral, the lesions seemingly affect the right and left sides with equal frequency, although the left renal artery often appears more severely diseased. Subendothelial and medial accumulation of cholesterolladen foam cells and fibrosis are present in these lesions. Necrosis, hemorrhage, deposition of cholesterol crystals, calcification, and luminal thrombus formation are characteristic of complicated atherosclerotic plaques associated with advanced disease.

Pathologic Types of Renal Artery Occlusive Disease Various occlusive diseases affect the renal arterial circulation, ranging from common macrovascular narrowings to unusual microvascular arteriopathies associated with connective tissue diseases. Although relatively uncommon, renal artery emboli, spontaneous dissections, and traumatic occlusions are occasionally associated with acute forms of renin-mediated hypertension. The most often encountered causes of hypertension, secondary to renal artery occlusive disease, are those associated with atherosclerosis, arterial fibrodysplasia, and developmental renal artery stenoses (57–63).

Atherosclerosis Atherosclerosis is the most common renal artery occlusive disease, accounting for approximately 95% of reported cases of renovascular hypertension. Atherosclerotic renovascular lesions are usually recognized in the sixth decade of life. Men are twice as likely as women to exhibit this disease. It is important to note that some degree of atherosclerotic renal artery stenotic disease affects nearly half the elderly population and that this is not always associated with elevated blood pressures. Atherosclerotic renal artery occlusive disease typically involves the proximal third of the vessel with eccentric or concentric stenoses. In nearly 80% of patients, these lesions represent a ‘‘spill-over’’ stenosis associated with aortic

Figure 11 Characteristic proximal aortic spillover plaque of an arteriosclerotic renal artery stenosis.

medwedi.ru

916

Part Six: The Peripheral Vascular System

Arterial Fibrodysplasia Arterial fibrodysplasia is the second most common type of renal artery disease, affecting nearly 5% of patients with renovascular hypertension. Renal artery stenoses caused by dysplastic disease are a heterogeneous group of lesions classified by the specific pathologic process and the region of the vessel wall most affected. These lesions include intimal fibroplasia, medial fibrodysplasia, and perimedial dysplasia. The latter two entities appear to be a continuum of the same disease process. Each category has certain characteristic features that deserve mention.

Intimal Fibroplasia Intimal fibroplasia accounts for approximately 5% of all dysplastic renal artery lesions. It affects infants and young adults more often than the elderly, and occurs with equal frequency in female and male patients. The cause of primary intimal fibroplasia is unknown, although some of these lesions may represent persistent myointimal cushions, originally occurring during fetal development. Secondary intimal fibroplasia has been attributed to trauma and the sequela of an earlier arteritis. Progression of intimal fibroplasia may cause an accelerated proliferation of fibrous tissue and rapid compromise of the arterial lumen. Intimal fibroplasia usually appears as long, tubular stenoses of the main renal artery or web-like segmental renal artery lesions in young patients and as smooth, focal stenoses in adults. Proximal intimal stenoses are, most often, secondary lesions associated with aortic hypoplasia or coarctations, frequently in patients with neurofibromatosis. Subendothelial accumulations of irregularly arranged mesenchymal cells surrounded by loose fibrous connective tissue are typical of these intimal lesions that protrude as hillocks of tissue into the vessel lumen. The internal elastic lamina is usually intact, but partial fragmentation may occur.

Medial Fibrodysplasia Medial fibrodysplasia is the most common dysplastic renal artery disease, accounting for 85% of such stenoses. It invariably affects women. Clinical presentation occurs most often during the fourth decade of life. This disease in its classic form has not been encountered before menarche. Medial fibrodysplasia appears to be a systemic arteriopathy in certain patients, with the internal carotid, superior mesenteric, and external iliac arteries being the extrarenal vessels most often affected. The cause of medial fibrodysplasia remains poorly defined, but appears to be associated with estrogenic effects on smooth muscle in women during their reproductive years, unusual stretch forces on affected vessels, and mural ischemia resulting from a paucity of vasa vasorum blood flow. Morphologic changes of medial fibrodysplasia range from solitary stenoses in the middle and distal main renal artery to multiple constrictions with intervening mural dilations. The latter produce the lesion’s classic string-of-beads appearance (Fig. 12). Actual macrovascular aneurysms, usually occurring at branchings, affect a little more than 10% of patients with arterial fibrodysplasia, but are rarely a cause of hypertension. Extension of medial fibrodysplasia into segmental branches occurs in approximately 25% of cases. Bilateral disease affects nearly 60% of patients and is usually most severe in the right renal artery. Unilateral lesions more commonly involve the right renal artery, with isolated disease of the right and left renal arteries existing in 30% and 10% of patients, respectively. Progression has

Figure 12 Characteristic string-of-beads appearance of renal artery medial fibrodysplasia.

been recognized in approximately 20% of patients, occurring more frequently in premenopausal women. Diffuse medial fibrodysplasia is typified by severe disorganization of smooth muscle and the predominance of myofibroblasts, which appear responsible for excessive accumulations of ground substance encroaching on the vessel lumen. These stenoses occur adjacent to areas of atrophic smooth muscle and medial thinning, which are responsible for the mural dilations. Peripheral medial fibrodysplasia is a second form of this disease. It is characterized by fibroproliferative changes and loss of normal smooth muscle limited to the outer portion of the media. The latter findings are usually associated with less severe stenoses than with diffuse disease. Both the diffuse and peripheral forms of this disease may be observed in the same vessel.

Perimedial Dysplasia Perimedial dysplasia accounts for nearly 10% of dysplastic renal artery disease. It invariably affects women, with its recognition usually occurring during the fifth decade of life. This particular dysplastic lesion appears to be more progressive than medial fibrodysplasia. Only 20% of patients have bilateral disease. Perimedial disease appears as solitary or multiple constrictions without intervening mural dilations. These stenoses involve distal portions of the main renal artery, usually without branch involvement. Excessive accumulation of elastic tissue in inner adventitial regions is characteristic of perimedial dysplasia. Abnormal increases in medial ground substances may also accompany this type of renal artery dysplasia. Certain histologic and ultrastructural features are common to both perimedial dysplasia and medial fibrodysplasia. Although perimedial dysplasia is classified as a separate pathologic entity, this may not be an appropriate distinction.

Chapter 48:

Secondary Hypertension: Pathophysiology and Operative Treatment

917

Developmental Renal Artery Stenoses Developmental renal artery stenoses represent a third category of renal artery occlusive disease. Most are ostial in location, and many are associated with abdominal aortic narrowings. There is no gender predilection for any of the developmental lesions. Most are encountered in late childhood. Nearly 80% of patients with these stenoses have multiple renal arteries. It is believed that most of these lesions evolve because of faulty union of the metanephric vessels to the aorta during fetal development; at the same time, the two embryonic aortas fuse to become a single vessel. Other developmental stenoses are seen in association with neurofibromatosis, in which case, a growth disturbance of mesenchymal tissue is likely to underlie the hypoplastic character of these renal arteries. Fragmentation of the internal elastic lamina, incomplete formation of the media, and excesses of perimedial elastic tissue typify the stenoses of these diminutive vessels.

Renovascular Hypertension The exact prevalence of renovascular hypertension among all patients with elevated diastolic blood pressures is unknown, but is probably close to 1%. It clearly occurs much more often in individuals having moderate or severe diastolic blood pressure elevations, with as many as 5% of such patients exhibiting underlying renovascular hypertension. Clinical findings suggestive of renovascular hypertension include (i) systolic–diastolic upper abdominal bruits, (ii) initial diastolic blood pressures greater than 115 mmHg or sudden worsening of mild preexisting essential hypertension, (iii) development of hypertension during childhood, or (iv) sudden development of high blood pressure after the age of 50. Drug-resistant hypertension and malignant hypertension are also more likely to be associated with renovascular hypertension. Patients whose renal function deteriorates while receiving multiple antihypertensive drugs, especially ACE inhibitors, must also be tested for renal artery stenotic disease and renovascular hypertension. Clinical screening of patients is important before undertaking diagnostic studies for suspected renovascular hypertension. Otherwise, the costs of indiscriminate evaluations for this type of hypertension would be prohibitive. Many diagnostic and prognostic tests for renovascular hypertension represent methods of defining the anatomic presence of renal artery disease or pathophysiologic derangements of renal function due to the stenotic disease.

Contrast Arteriography In the past, conventional contrast arteriography has been a standard study for the evaluation of all patients with suspected renovascular hypertension. Oblique aortography and multiple-plane selective renal arteriography can precisely define the morphologic character and extent of a stenotic lesion. Collateral vessels circumventing a stenosis are evidence of a lesion’s hemodynamic and functional importance. Pressure gradients of approximately 10 mmHg are necessary for development of collateral circulation, and the same degree of pressure change is associated with activation of the renin system. Accordingly, collateral vessels circumventing a renal artery stenosis are invariably associated with increased renin release. Thus the importance of an otherwise benign-appearing stenosis may be established when collateral vessels are present (Fig. 13), or when dilution defects representing noncontrast-containing blood from collateral vessels entering the poststenotic portion of the vessel are identified with selective renal arteriography.

Figure 13 Arteriogram of a benign-appearing renal artery stenosis (black arrow) associated with a large collateral vessel (white arrow) circumventing the lesion, defining hemodynamic significance of the stenosis and implicating its functional importance. Source: From Ref. 64.

Digital subtraction arteriography following intraarterial contrast injection has become commonplace. This technique allows the use of smaller amounts of contrast agents as compared to conventional arteriography, lessening potential nephrotoxicity. This is especially relevant in patients with preexisting impairment of renal function. The use CO2 or gadolinium in the latter circumstances is also appealing, but may not always provide sufficient anatomic detail for clinical decision-making in patients with segmental arterial disease. Arteriography evidence of arterial nephrosclerosis should not be considered an indication that renal revascularization or angioplasty will not have a beneficial effect on blood pressure. This is in keeping with previous reports that biopsy evidence of nephrosclerosis is of limited prognostic value (65).

Computed Tomographic Arteriography Computed tomographic arteriography (CTA) is another frequently used means of assessing coexistent renal artery and aortic disease. It allows computer generated visualization of the vessels from many different angles not possible with conventional biplanar studies. Newer 64-slice CTA images are likely to replace catheter-based angiographic studies. However, CTA does carry a similar risk of contrast-induced nephrotoxicity, which accompanies conventional iodinerelated angiography.

Magnetic Resonance Angiography Application of magnetic resonance technology to vascular imaging, especially with gadolinium enhancement, has evolved to a sufficient extent that it often provides highresolution images of the renal arteries (66). Magnetic resonance angiography is not available at all institutions, and recent advances require further evaluation before it becomes widely used in assessing patients suspected of renovascular disease. Nevertheless, its noninvasiveness and lack of nephrotoxicity make it an attractive diagnostic test.

medwedi.ru

918

Part Six: The Peripheral Vascular System

Deep Abdominal Renal Artery Ultrasonography Hemodynamically significant renal artery narrowings and, in many instances, functionally important narrowings may often be identified by imaging the renal arteries and characterizing renal resistive indices and flow-velocity patterns with abdominal duplex ultrasonography (67–69). Such studies have been advocated in screening for renovascular disease and are useful in establishing the existence of a stenosis when peak systolic velocities are in the range of 180 to 200 cm/sec and the ratio of these velocities to those in the aorta approaches 3.5. Unfortunately, this technology does not provide discrimination of renal artery lesions exceeding 60% cross-sectional narrowing. Failure to identify a main renal artery in cases where no parenchymal flow signal exists suggests existence of a main renal artery occlusion. However, occluded accessory or segmental renal arteries may go unrecognized and thus contribute to false-negative assessments.

Renin Activity of Peripheral and Renal Venous Blood Renin activity in peripheral and renal venous blood provides information about the functional importance of renal artery disease. To reduce interpretive errors evolving from minor fluctuations in basal renin activity, the renin– angiotensin system should be stimulated before sampling blood for renin assays. Blood samples for renin assays in the peripheral and renal circulations should be obtained simultaneously, or nearly simultaneously, with the patient tilted to a semi-upright position. Sodium intake should be limited to 20 mEq/day and a diuretic administered for three days before testing. Renin-suppressing drugs are discontinued when possible. Blood pressure elevations in such circumstances should be controlled with renin-stimulating agents such as hydralazine. The effect of ACE inhibitors in stimulating renin release and thus improving renin-assay results has not been achieved in general practice.

Figure 14 Renal:systemic renin indices, depicting their prognostic usefulness. Source: From Ref. 70.

RSRI documentation of renin hypersecretion and suppression allows the differentiation of patients most likely to be cured or improved following treatment (Fig. 9). The validity of ischemic renin hypersecretion (RSRI >0.48) from the kidney being revascularized and the contralateral renin suppression (RSRI < 0.24, approaching 0) in identifying patients who will be cured has been well documented (55,56,60). However, the prognostic accuracy of RSRI may be limited in that approximately 10% of patients who are cured do not exhibit contralateral renin suppression.

Renal Vein Renin Ratios

Hypertensive Urography

Renal vein renin ratios (RVRRs) are calculated by dividing the renin activity in venous blood from the affected kidney by that from the contralateral kidney. An RVRR >1.48 indicates functionally important renovascular disease (55,56). Because this test compares one kidney to another, it is not helpful in the presence of bilateral disease when both kidneys exhibit equal elevations of renin secretion. In fact, approximately 15% of patients benefiting from surgery have an RVRR <1.48.

It is a poor diagnostic test for renovascular hypertension, because of its limited sensitivity (71). Bilateral or segmental disease often precludes recognition of gross differences in contrast excretion between the two kidneys. In a large series of patients with proven renovascular hypertension, urograms were abnormal in only 27% of pediatric patients, 48% of patients with arterial fibrodysplastic disease, and approximately 72% of patients with atherosclerotic lesions (72). Nevertheless, rapid-sequence urography may contribute to the diagnosis of renovascular hypertension when (i) at least a two-minute delay in contrast appearance occurs within the collecting system of the affected kidney compared to that of the contralateral kidney; (ii) a length discrepancy is found, with the right kidney being 2 cm shorter than the left, or the left being 1.5 cm shorter than the right; and (iii) hyperconcentration of contrast in the collecting system of the affected kidney is observed on late urograms. Ureteral or pelvic irregularities caused by large collateral vessels may also accompany these urographic features.

Renal:Systemic Renin Index Renal:systemic renin index (RSRI) is an expression of a single kidney’s renin secretion. It is calculated by subtracting systemic renin activity from an individual kidney’s venous renin activity and dividing the remainder by the systemic renin activity (55). In nonrenovascular hypertension, renal venous activity from each kidney is usually 24% higher than systemic activity (52). Thus the total of both kidneys’ activity is usually 48% higher than systemic levels, balancing hepatic degradation and establishing a steady state. In renovascular hypertension, the RSRI of the affected kidney becomes greater than 0.24. This is normally accompanied by suppression of contralateral kidney renin production with a drop in its RSRI < 0.24. In the case of bilateral renal artery disease, this servomechanism may be lost, and autonomous release of renin from both kidneys may cause the sum of the individual RSRIs to be greater than 0.48. Renin production then exceeds normal hepatic degradation, and a hyperreninemic state evolves (Fig. 14).

Isotopic Renography It has been used with both imaging and analysis of the washout curve of several tracers, the most common being 99mTc-DTPA (diethylenetriamine penta acetic acid),123I or 131iorthoiodohippurate,99mTc-MAG3 (mercaptoacetylglycyl glycylglycine),99mTc-DMSA (dimercaptosuccinic acid), and 99m glucoheptonate. These compounds provide an assessment of both renal blood flow and excretory function. Unfortunately, different states of hydration and intrarenal vascular resistance

Chapter 48:

Secondary Hypertension: Pathophysiology and Operative Treatment

919

often result in flow abnormalities with false-positive studies in nonrenovascular hypertensive patients. The specificity and sensitivity of current studies are both approximately 75%. However, the sensitivity may be improved by administration of an ACE inhibitor to block the compensatory change in glomerular filtration, causing it to fall on the side of a stenosis. The sensitivity of the renogram increases to more than 80%, and the specificity of such a modified study approaches 85%. Renal perfusion–excretion ratios and more sophisticated computer programs offer a potential means of increasing the predictive value of radionuclide screening for renovascular hypertension, but they are not yet in widespread use.

Treatment Treatment outcomes following interventions for renovascular hypertension relate to an accurate diagnosis and proper execution of an appropriate intervention, whether the intervention is arterial reconstructive surgery, ablative surgery, transcatheter renal infarction, percutaneous transluminal angioplasty, or institution of drug therapy. The specific type of renovascular disease being treated is also relevant to the expected therapeutic outcome. Although prospective randomized studies comparing medical and surgical therapy have yet to be published, long-term drug therapy has not been favored by most physicians responsible for the care of these patients. Antihypertensive Drugs Antihypertensive drugs developed during the past two decades have resulted in major improvements in the medical management of patients with renovascular hypertension. Vasoconstriction assumes greatest importance with a unilateral stenosis in patients having a normal contralateral kidney (2K–1C). Excessive sodium retention and hypervolemia become important factors in patients with bilateral renal artery stenoses (21C–2C), in those with unilateral stenoses affecting a solitary kidney (1K–1C), or in patients with contralateral parenchymal disease. Blood pressure elevations in most, if not all, patients with renovascular hypertension may be reduced by appropriate drug interventions. However, side effects, compliance, and effects on renal function must be considered before pursuing drug treatment. Beta-blocking agents are usually the first drugs administered in known cases of renovascular hypertension, with subsequent reductions in renin release causing a lowering of the blood pressure (73). Propranolol and atenolol are most frequently used, although other b-blockers are also effective in treating renovascular hypertension. High doses of these drugs may be required to control the blood pressure, although in most cases, suppression of renin release may be accomplished with very small doses. In instances of more refractory hypertension, especially that caused by bilateral renal artery stenoses or unilateral lesions with contralateral parenchymal disease, addition of a standard diuretic such as a thiazide, a hydrogenated thiazide, or substituted compound is recommended. In cases of impaired renal function secondary to decreased blood flow, a loop diuretic such as furosemide provides a more effective diuretic action. ACE inhibitors, such as captopril and enalapril, are used for treating hypertension in general. Antihypertensive effects other than decreased angiotensin II generation, such as those involving bradykinin, probably occur with the use of these agents. ACE inhibitors may be supplemented with b-blockers or diuretics in resistant hypertension. In more severe hypertension, vasodilators such as minoxidil may be required. It is important to recognize the deleterious

Figure 15 Percutaneous transluminal angioplasty. Renal artery stenosis: (A) before dilation and (B) after dilation.

effects of ACE inhibitors on renal function. This becomes especially evident in patients with bilateral renal artery stenoses, in cases of unilateral stenosis together with contralateral parenchymal disease, or when stenosis occurs in a solitary kidney (74). In these instances, severe deterioration of glomerular filtration may occur, and use of these agents is contraindicated. Percutaneous Transluminal Renal Angioplasty Percutaneous transluminal angioplasty (PTA) of renal arteries for the management of renovascular hypertension has important patient safety and cost benefits (Fig. 15). However, certain issues must be considered, including (i) differences in treating various types of renal artery disease, (ii) the frequency of being unable to catheterize or dilate a given type of stenosis, (iii) the long-term effects of angioplasty on the vessel wall, (iv) the incidence of renal and extrarenal complications, and (v) the durability of a successfully performed dilation. Renal Artery Fibrodysplasia PTA provides the most benefits and fewest complications compared to PTA for other forms of renovascular disease. Medial dysplastic stenoses are most amenable to PTA and this is considered primary therapy for those lesions limited to the main renal artery. Excellent early technical and clinical results usually follow renal artery PTA in these patients (75–80). Similarly, these patients have experienced excellent long-term clinical results, with a primary patency rate of 87% after more than three years of follow-up (Table 2).

Table 2 Percutaneous Transluminal Angioplasty for Fibrodysplastic Renovascular Hypertension

Institution Mayo Clinic University of Virginia University Hospital, Zurich, Switzerland University of Florida University Hospitals, Leuven, Belgium Hospital Broussais, Paris Source: From Ref. 81.

medwedi.ru

Postprocedural blood pressure response (%) Follow-up Patients mean (mo) Cured Improved Failed 105 66 28

43 39 15

22 39 50

41 59 39

37 2 11

23 22

6 26

52 95

22 –

26 5

20

19

68

16

15

920

Part Six: The Peripheral Vascular System

Table 3 Percutaneous Transluminal Angioplasty with Stent Placement for Arteriosclerotic Renovascular Disease Post procedural blood pressure response (%)a

Indication Institution Dorros-Feuer Foundation University Hospital, Freiburg, Germany Ochsner Clinic Polyclinique D’Essey Hotel-Dieu de Montreal University of Texas Health Center (Multicenter Study) a

Patients

Hypertension

Renal insufficiency

Follow-up mean (mo)

Cured

Improved

Failed

76 68 66 59 33 28

76 68 66 59 33 28

48 29 Unknown 10 17 14

6 27 19 14 13 7

6 16 2 19 6 11

46 62 64 57 61 54

48 22 34 24 33 36

Outcomes defined in reports from individual institutions.

Developmental renal artery narrowings represent true hypoplastic vessels that are less likely to be successfully dilated (82). In a like fashion, less common causes of renovascular hypertension in children, including arteritis, William’s syndrome, and neurofibromatosis, do not respond well to renal artery PTA. Aortic spill-over arteriosclerosis and isolated renal artery arteriosclerosis are quite different in regard to longterm clinical results (83–92). Historically, PTA alone, without stent placement, has resulted in a technical success rate of only 70% to 80%. Ostial spill-over lesions treated by PTA alone have a technical success rate of only 30% to 50%. These latter stenoses often manifest excessive recoil and many exhibit acute dissections. As a result of high early post-PTA restenosis rates, stenting of atherosclerotic lesions is considered appropriate in most patients. Results following renal artery stenting for atherosclerotic disease vary depending on outcome definitions and the indication for intervention, yet many studies have good long-term technical results (Table 3). In treating patients for hypertension, long-term benefits have been reported in 50% to 75% of cases. PTA with stenting for progressive ischemic nephropathy is not as effective at reversing renal failure. In these cases, benefits appear related to the degree and duration of ischemic nephropathy prior to PTA, with those having a serum creatinine of less than 2 mg/dL demonstrating the best response. Complications accompanying renal artery PTA, for either atherosclerotic or fibrodysplastic disease, are

uncommon, with severe complications occurring in less than a few percent of cases. Intimal disruption occurs more often with proximal renal artery dilation, where the vessel elasticity is greater and medial disruption is less likely. Medial tears are more common with distal renal artery dilation where vessel elasticity is less. Surgery following failed renal artery PTA is much more hazardous than primary surgery alone. PTA failures are associated with a much higher incidence of emergent repair and nephrectomy, and blood pressure benefits are significantly lower, being 57% after reoperation versus 89% for a primary operation (93). Bypass Procedures These are the most frequently used means of open renal revascularization for both atherosclerotic and fibrodysplastic stenoses (Fig. 16). Autogenous saphenous vein is the graft employed most often (59). Autogenous internal iliac arteries are the preferred graft when undertaking bypasses in pediatric patients (63), in that vein grafts placed in younger patients are often associated with late aneurysmal changes (94). Prosthetic grafts of knitted Dacron or expanded Teflon are used when autogenous conduits are not available. Limitations of prosthetic grafts relate to their potential for infection and technical difficulties in anastomosing them to small arteries. Although most bypass procedures are fashioned as aortorenal reconstructions, the aorta may be an inappropriate site for the graft to originate. In these latter circumstances, nonanatomic reconstructions with grafts originating from the hepatic or splenic arteries may be best for

Figure 16 Renal revascularization. Bypass procedure with autogenous saphenous vein.

Chapter 48:

Secondary Hypertension: Pathophysiology and Operative Treatment

921

Figure 17 Renal revascularization by performance of an endarterectomy.

the patient (95,96). In some patients with ostial disease, especially in the pediatric-aged group (63), aortic reimplantation of the normal renal artery beyond its stenosis may be better than a conventional bypass. Ex Vivo Renal Artery Reconstruction It is an alternative to in situ repair for treating select cases of complex renovascular hypertension (97–99). This technique allows temporary removal of the kidney for precise microsurgical repair of the diseased vessel. Disruption of preexisting collateral channels, the need to cool the kidney, and the longer duration of such procedures are disadvantages of ex vivo reconstructions. This form of reconstruction is most applicable when treating multiple stenoses and aneurysms of segmental vessels. Endarterectomy Endarterectomy has been advocated in the treatment of most atherosclerotic renal artery stenoses (59,100–105). A transaortic approach with an aortotomy, extending along the lateral aorta from the level of the superior mesenteric artery to below the renal orifices anteriorly, is usually preferable to a direct longitudinal renal arteriotomy and local endarterectomy (Fig. 17). Endarterectomy through the transected infrarenal aorta during aortic reconstructive procedures has gained favor over bypass reconstructions in certain patients. Conventional Surgical Therapy Results of conventional surgical therapy for renovascular hypertension have been documented from many centers.

Loss of life during renovascular surgery occurs infrequently today, with overall operative mortality in most large series usually being less than 0.5%. Renal preservation and maintenance of renal function is clearly very important in assessing clinical experiences. Cumulative primary and secondary nephrectomy rates should not exceed 10%. Nephrectomy may provide good early results but obviously leaves the patient at considerable risk if contralateral disease evolves later. The incidence of nephrectomy during second surgery, for failed primary procedures, approaches 50% and emphasizes the importance of an appropriately performed primary revascularization (106). Contemporary surgical treatment differences among the various series usually reflect the most prevalent renal artery disease entity causing the secondary hypertension (Table 4) (59). Pediatric patients with renovascular hypertension are most likely to be cured after restoration of renal blood flow, with a beneficial response expected in approximately 95% of such cases (Table 5). Adults with arterial fibrodysplasia benefit from surgery more often than those with atherosclerotic disease, which probably reflects the fact that coexisting essential hypertension and nephrosclerosis is quite uncommon in younger patients with arterial fibrodysplasia, compared to those with atherosclerosis (Tables 6 and 7). Atherosclerotic renovascular hypertension has often been considered a homogenous disease entity. However, at least two clinical subgroups of patients with atherosclerotic lesions exist: (i) those having focal renal artery disease, whose only clinical manifestation of their atherosclerosis is secondary renovascular hypertension,

Table 4 Comparative Results of Surgical Treatment of Renovascular Hypertension in Specific Patient Subgroups, University of Michigan Experience Postoperative statusa Subgroup Pediatric disease Arterial fibrodysplasia Arteriosclerosis Focal renal artery disease Overt extrarenal disease

Patients

Cure rate (%)

Improvement rate (%)

Failure rate (%)

34 144

85 55

12 39

3 6

64 71

33 25

58 47

9 28

a

Operative mortality rate (%) 0 0 0 8.5

Represents outcome of 405 operations (346 primary, 59 secondary), including initial nephrectomy in 17 patients. Cure: Blood pressures were 150/90 mmHg or less for a minimum of six months postoperatively, during which no antihypertensive medications were administered. Improvement: Normotensive while on drug therapy, or if diastolic, blood pressures ranged between 90 and 100 mmHg, but were at least 15% lower than preoperative levels. Failure: Diastolic blood pressures greater than 90 mmHg but less than 15% lower than preoperative levels or greater than 110 mmHg. Lower pressure standards were used in evaluating children. Source: From Ref. 72.

medwedi.ru

922

Part Six: The Peripheral Vascular System

Table 5 Renovascular Hypertension in Children

Table 7 Arteriosclerotic Renovascular Hypertension in Adults

Operative outcome (%) Institution

Patients

University of Michigan Cleveland Clinic University of California, Los Angeles Vanderbilt University University of Pennsylvania Argentinean Institute, Buenos Aires University of California, San Francisco

Cured

Improved

57

79

19

27 26

59 84.5

18.5 7.5

Failed

Surgical mortality rate (%)

2

0

18.5 4

4 4

21

68

24

8

0

17

76.5

23.5

0

0

15

53

13

27

7

14

86

7

0

7

Source: From Ref. 59.

and (ii) those with clinically overt extrarenal atherosclerosis. The severity and duration of hypertension, age, and sex distribution in these two subgroups are often similar, but the surgical outcomes are very different. Improved renal function following revascularization is a well-recognized event, occurring most often among patients with profound preoperative impairment in renal function.

SUMMARY Although most forms of hypertension can be effectively managed nonoperatively, three abnormalities fall under the umbrella of surgically correctable hypertension. These include two diseases of the adrenal gland exhibiting abnormal aldosterone and catecholamine production and a number of renal artery occlusive lesions associated with excessive renin–angiotensin activity. Of the three, renovascular hypertension is the most common cause of surgically

Operative outcome (%) Institution

Surgical mortality Improved Failed rate (%)

Patients

Cured

500

12

73

15

4.6

135

29

52

19

4.4

84

39

23

38

2.4

78 67

40 58

51 21

9 21

2 Unstated

66

49

24

27

0.9

65

45

40

15

1.1

63

50

45

5

9

Wake Forrest University University of Michigan University of California, San Francisco Cleveland Clinic Columbia University University of Lund, Malmo, Sweden Hospital Aiguelongue, Montpellier, France Vanderbilt University Source: From Ref. 59

correctable high blood pressure and results from altered renal circulatory hemodynamics causing the release of renin. This form of hypertension can be altered by several drug interventions, including those that diminish the release of renin, block the conversion of angiotensin I to angiotensin II. However, derangements of renovascular hypertension are best reversed by correction of the altered renal hemodynamics that usually result from renal artery stenosis. Surgical intervention with renal revascularization and PTA are presently the most appropriate means to this end. With respect to aldosterone or catecholamine-secreting tumors of the adrenal gland, surgical removal of the affected gland usually results in permanent cure of the hypertension. In most situations, this can be accomplished laparoscopically.

REFERENCES Table 6 Fibrodysplastic Renovascular Hypertension in Adults Operative outcome (%) Institution University of Michigan Baylor College of Medicine Cleveland Clinic University of California, San Francisco Mayo Clinic University Hospital Leiden, The Netherlands Vanderbilt University Columbia University Bowman Gray University of Lund, Malmo, Sweden Source: From Ref. 59.

Failed

Surgical mortality rate (%)

Patients

Cured

Improved

144 113

55 43

39 24

6 33

92 77

58 66

31 32

11 1.3

Unstated 0

63 53

66 53

24 34

10 13

Unstated 2

44 42 40 40

72 76 33 66

24 14 57 24

4 10 10 10

2.3 Unstated 0 0

0 0

1. Lal G, Duh QY. Laparoscopic adrenalectomy—indications and technique. Surg Oncol 2003; 12:105–123. 2. Linos D, van Heerden JA, eds. Adrenal glands: diagnostic aspects and surgical therapy. Berlin: Springer, 2005. 3. Gordon RD, Stomacher M. Overview of mineralocorticoid excess syndromes. In: Linos D, van Heerden JA, eds. Adrenal Glands: Diagnostic Aspects and Surgical Therapy. Berlin: Springer, 2005:115–126. 4. Stomacher M, Gordon RD, Gunasegaram TG, et al. High rate of detection of primary aldosteronism, including surgically treatable forms, after ’non-selective’ screening of hypertensive patients [see comment]. J Hypertens 2003; 21:2149–2157. 5. Stowasser M, Gordon RD. Primary aldosteronism. Best Pract Res Clin Endocrinol Metabol 2003; 17:591–605. 6. Radin DR, Manoogian C, Nadler JL. Diagnosis of primary hyperaldosteronism: importance of correlating CT findings with endocrinologic studies. AJR 1992; 158:553–557. 7. Doppman JL, Gill J, John R, et al. Distinction between hyperaldosteronism due to bilateral hyperplasia and unilateral aldosteronoma: reliability of CT. Radiology 1992; 184:677–682. 8. Dunnick NR, Leight J, George G, et al. CT in the diagnosis of primary aldosteronism: sensitivity in 29 patients. AJR 1993; 160:321–324.

Chapter 48:

Secondary Hypertension: Pathophysiology and Operative Treatment

9. Stowasser M, Gordon RD. Primary aldosteronism—careful investigation is essential and rewarding. Mol Cell Endocrinol 2004; 217:33–39. 10. Gray DK, Thompson NW. Pheochromocytoma. In: Doherty GM, Skogseid BS, eds. Surgical Endocrinology. Philadelphia: Lippincott Williams & Wilkins, 2001:247–262. 11. Stenstrom G, Svardsudd K. Pheochromocytoma in Sweden 1958–1981. An analysis of the National Cancer Registry Data. Acta Med Scand 1986; 220:225–232. 12. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma [see comment]. NEJM 2002; 346:1459–1466. 13. Thrasher JB, Rajan RR, Perez LM, Humphrey PA, Anderson EE. Pheochromocytoma of urinary bladder: contemporary methods of diagnosis and treatment options. Urology 1993; 41:435–439. 14. Miskulin J, Shulkin BL, Doherty GM, Sisson JC, Burney RE, Gauger PG. Is preoperative iodine 123 meta-iodobenzylguanidine scintigraphy routinely necessary before initial adrenalectomy for pheochromocytoma? Surgery 2003; 134: 918–922. 15. Kaltsas G, Korbonits M, Heintz E, et al. Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors. J Clin Endcrinol Metabol 2001; 86:895–902. 16. Pommier RF, Vetto JT, Billingsly K, Woltering EA, Brennan MF. Comparison of adrenal and extraadrenal pheochromocytomas. Surgery 1993; 114:1160–1165; discussion 1165–1166. 17. Lumachi F, Polistina F, Favia G, D’Amico DR. Extraadrenal and multiple pheochromocytomas. Are there really any differences in pathophysiology and outcome? J Exp Clin Cancer Res 1998; 17:303–305. 18. Velchik MG, Alavi A, Kressel HY, Engelman K. Localization of pheochromocytoma: MIBG, CT and MRI correlation. J Nucl Med 1989; 30:328–336. 19. Kebebew E, Duh QY. Operative strategies for adrenalectomy. In: Doherty GM, Skogseid BS, eds. Surgical Endocrinology. Philadelphia: Lippincott Williams & Wilkins, 2001:273–290. 20. Kumar U, Albala DM. Laparoscopic approach to adrenal carcinoma. J Endourol 2001; 15:339–342; discussion 342–333. 21. Heniford BT, Arca MJ, Walsh MR, Gill IS. Laparoscopic adrenalectomy for cancer. Semin Surg Oncol 1999; 16:293–306. 22. Walz MK, Peitgen K, Hoermann R, Giebler RM, Mann K, Eigler FW. Posterior retroperitoneoscopy as a new minimally invasive approach for adrenalectomy: results of 30 adrenalectomies in 27 patients. World J Surg 1996; 20:769–774. 23. Gagner M, Garcia-Ruiz A. Technical aspects of minimally invasive abdominal surgery performed with needlescopic instruments. Surg Laparosc Endosc 1998; 8:171–179. 24. Gagner M, Pomp A, Heniford BT, Pharand D, Lacroix A. Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg 1997; 226:238–246; discussion 246–237. 25. Hobart MG, Gill LS, Schweizer D, Sung GT, Bravo EL. Laparoscopic adrenalectomy for large-volume ( > or ¼ 5 cm) adrenal masses. J Endourol 2000; 14:149–154. 26. Brunt LM, Moley JF, Doherty GM, Lairmore TC, DeBendetti MK, Quasebarth MA. Outcomes analysis in patients undergoing laparoscopic adrenalectomy for hormonally active adrenal tumors. Surgery 2001; 130:629–634. 27. Wells SA, Merke DP, Cutler GB Jr, Norton JA, Lacroix A. Therapeutic controversy: the role of laparoscopic surgery in adrenal disease. J Clin Endocrinol Metabol 1998; 83:3041–3049. 28. Kebebew E, Siperstein AE, Duh QY. Laparoscopic adrenalectomy: the optimal surgical approach. J Laparoendosc Adv Surg Tech A 2001; 11:409–413. 29. Bonjer HJ, Lange KF, Kazemoer G, De Herder WW, Steyerberg EW, Bruining HA. Comparison of three techniques for adrenalectomy. Br J Surg 1997; 84:679–682. 30. Duh QY, Siperstein AE, Clark OH, et al. Laparoscopic adrenalectomy. Comparison of the lateral and posterior approaches. Arch Surg 1996; 131:870–875; discussion 875–876.

923

31. Dudley NE, Harrison BJ. Comparison of open posterior versus transperitoneal laparoscopic adrenalectomy. Br J Surg 1999; 86:656–660. 32. Thompson GB, Grant CS, vanHeerden JA, et al. Laparoscopic versus open posterior adrenalectomy: a case-control study of 100 patients. Surgery 1997; 122:1132–1136. 33. Imai T, Kikumori T, Ohiwa M, Mase T, Funahashi H. A casecontrolled study of laparoscopic compared with open lateral adrenalectomy. Am J Surg 1999; 178:50–53; discussion 54. 34. Jacobs JK, Goldstein RE, Geer RJ. Laparoscopic adrenalectomy. A new standard of care. Ann Surg 1997; 225: 495–501; discussion 501–492. 35. Smith CD, Weber CJ, Anderson JR. Laparoscopic adrenalectomy: new gold standard. World J Surg 1999; 23:389–396. 36. Prinz RA. A comparison of laparoscopic and open adrenalectomies. Arch Surg 1995; 130:489–494. 37. Barreca M, Presenti L, Renzi C, et al. Expectations and outcomes when moving from open to laparoscopic adrenalectomy: multivariate analysis. World J Surg 2003; 27: 223–228. 38. Brunt LM, Doherty GM, Norton JA, Soper NJ, Quasebarth MA, Moley JF. Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms. J Am Coll Surg 1996; 183:1–10. 39. Hobart MG, Gill IS, Schweizer D, Bravo EL. Financial analysis of needlescopic versus open adrenalectomy. J Urol 1999; 162:1264–1267. 40. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Kesier HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von HippelLindau disease and multiple endocrine neoplasia type 2. NEJM 1999; 340:1872–1879. 41. Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines [comment]. J Clin Endocrinol Metabol 2003; 88: 553–558. 42. Eisenhofer G. Editorial: biochemical diagnosis of pheochromocytoma—is it time to switch to plasma-free metanephrines? [comment]. J Clin Endocrinol Metabol 2003; 88:550–552. 43. Eisenhofer G, Keiser H, Friberg P, et al. Plasma metanephrines are markers of pheochromocytoma produced by catechol-Omethyltransferase within tumors. J Clin Endocrinol Metabol 1998; 83:2175–2185. 44. Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988; 109:267–273. 45. Tada K, Okuda Y, Yamashita K. Three cases of malignant pheochromocytoma treated with cyclophosphamide, vincristine, and dacarbazine combination chemotherapy and alphamethyl-p-tyrosine to control hypercatecholaminemia. Hormone Res 1998; 49:295–297. 46. Sisson JC, Shapiro B, Shulkin BL, Urba S, Zempel S, Spaulding S. Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy. Am J Clin Oncol 1999; 22:364–370. 47. Rao F, Keiser HR, O’Connor DT. Malignant and benign pheochromocytoma: chromaffin granule transmitters and the response to medical and surgical treatment. Ann NY Acad Sci 2002; 971:530–532. 48. Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrin Invest 1997; 20:648–658. 49. Pujol P, Bunger J, Faurous P, Jaffiol C. Metastatic pheochromocytoma with a long-term response after iodine-131 metarodobenzylguanidine therapy. Eur J Nucl Med 1995; 22:382–384.

medwedi.ru

924

Part Six: The Peripheral Vascular System

50. Nakabeppu Y, Nakajo M. Radionuclide therapy of malignant pheochromocytoma with 131I-MIBG. Ann Nucl Med 1994; 8:259–268. 51. Stanley JC, Graham LM, Whitehouse WM Jr. Renovascular hypertension. In: Miller TA, Rowland BJ, eds. Physiologic Basis of Modern Surgical Care. St Louis: CV Mosby, 1988: 734–739. 52. Sealey JE, Buhler FR, Laragh JH, Vaughan ED Jr. The physiology of renin secretion in essential hypertension: estimation of renin secretion rate and renal plasma flow from peripheral and renal vein renin levels. Am J Med 1973; 55:391–401. 53. Schneider EG, Davis JO, Baumber JS, Johnson JA. The hepatic metabolism of renin and aldosterone: a review with new observations on the hepatic clearance of renin. Circ Res 1970; 175:26–27. 54. Stanley JC, Graham LM. Renovascular hypertension. In: Miller TA, ed. Physiologic Basis of Modern Surgical Care. 2nd. St Louis: Quality Medical Publishing, 1998:918–934. 55. Stanley JC, Gewertz BL, Fry WJ. Renal:systemic renin indices and renal vein renin ratios as prognostic indicators in remedial renovascular hypertension. J Surg Res 1976; 20:149–155. 56. Vaughan ED Jr, Buhler FR, Laragh JH, Sealey JE, Baer L, Bard RH. Renovascular hypertension: renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow, and score for surgical curability. Am J Med 1973; 55:402–414. 57. Graham LM, Zelenock GB, Erlandson EE, Lindenauer SM, Coran AG, Stanley JC. Abdominal aortic coarctation and segmental hypoplasia. Surgery 1979; 86:519–529. 58. Cherr GS, Hansen KJ, Craven TE, et al. Surgical management of atherosclerotic renovascular disease. J Vasc Surg 2002; 35:236–245. 59. Stanley JC. The evolution of surgery for renovascular occlusive disease. Cardiovasc Surg 1994; 2:195–202. 60. Stanley JC, Fry WJ. Renovascular hypertension secondary to arterial fibrodysplasia in adults: criteria for operation and results of surgical therapy. Arch Surg 1975; 110:922–928. 61. Stanley JC, Gewertz BL, Bove EL, Sottiurai VS, Fry WJ. Arterial fibrodysplasia: histopathologic character and current etiologic concepts. Arch Surg 1975; 110:561–566. 62. Stanley JC, Graham LM, Whitehouse WM Jr, et al. Developmental occlusive disease of the abdominal aorta and the splanchnic and renal arteries. Am J Surg 1981; 142:190–196. 63. Stanley JC, Zelenock GB, Messina LM, Wakefield TW. Pediatric renovascular hypertension: a thirty-year experience of operative treatment. J Vasc Surg 1995; 21:212–227. 64. Stanley JC, Graham LM, Whitehouse WM Jr. Limitations and errors of diagnostic and prognostic investigations in renovascular hypertension. In: Bernhard VM, Towne JM, eds. Complications in Vascular Surgery. Orlando: Grune & Stratton, 1985: 213–222. 65. Vidt DG, Yutani FM, McCormack LJ, et al. Surgical treatment of unilateral renal vascular disease: prognostic role of vascular changes in bilateral renal biopsies. Am J Cardiol 1972; 30:827–831. 66. Prince MR, Narasimham DL, Stanley JC, et al. Gadoliniumenhanced magnetic resonance angiography of abdominal aortic aneurysms. J Vasc Surg 1995; 21:656–669. 67. Hansen KJ, Tribble RW, Reavis SW, et al. Renal duplex sonography: evaluation of clinical utility. J Vascular Surg 1990; 12:227–236. 68. Hoffman U, Edwards JM, Carter S, et al. Role of duplex scanning for the detection of atherosclerotic renal artery disease. Kidney Int 1991; 39:1231–1239. 69. Motew SJ, Cherr GS, Craven TE, et al. Renal duplex sonography: main renal artery versus hilar analysis. J Vasc Surg 2000; 32:462–471. 70. Stanley JC, Fry WJ. Surgical treatment of renovascular hypertension. Arch Surg 1977; 112:1291. 71. Thornbury JR, Stanley JC, Fryback DC. Hypertensive urogram: a nondiscriminatory test for renovascular hypertension. AJR 1992; 138:43–49.

72. Stanley JC, Whitehouse WM Jr, Graham LM, Cronenwett JL, Zelenock GB, Lindenauer SM. Operative therapy of renovascular hypertension. Br J Surg 1982; 69:S63–S66. 73. Buhler FR, Laragh JH, Baer L, Vaughan ED Jr, Brunner HR. Propranolol inhibition of renin secretion. NEJM 1972; 287: 1209–1214. 74. Hricik DE, Browning PJ, Kopelman R, Goorno WE, Madias NE, Dzau VJ. Captopril-induced renal insufficiency in patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney. NEJM 1983; 308:373–376. 75. Bonelli FS, Mckusick MA, Textor SC, et al. Renal artery angioplasty: technical results and clinical outcome in 320 patients. Mayo Clin Proc 1995; 70:1041–1052. 76. Cluzel P, Raynaud B, Beyssen B, Pagny JY, Gaux JC. Stenoses of renal branch arteries in fibromuscular dysplasia: results of percutaneous transluminal angioplasty. Radiology 1994; 193: 227–232. 77. Davidson R, Barri Y, Wilcox CS. Predictors of cure of hypertension in fibromuscular renovascular disease. Am J Kidney Dis 1996; 28:334–338. 78. Luscher TF, Keller HM, Imhoff HG, et al. Fibromuscular hyperplasia: extension of the disease and therapeutic outcome. Results of the University Hospital Zurich Cooperative Study on Fibromuscular Hyperplasia. Nephron 1986; 44:109–114. 79. Sos TA, Pickering TG, Sniderman K, et al. Percutaneous transluminal renal angioplasty in renovascular hypertension due to atheroma or fibromuscular dysplasia. NEJM 1983; 309: 274–279. 80. Tegtmeyer CJ, Selby JB, Hartwell GD, Ayers C, Tegtmeyer V. Results and complications of angioplasty in fibromuscular disease. Circulation 1991; 83:1155–1161. 81. Stanley JC, Upchurch GR Jr. Renal artery occlusive disease. In: Greenfield LJ, Mulholland MW, Oldham KT, Zelenock GB, Lillimoe KD, eds. Surgery, Scientific Principals and Practice. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2001: 1708–1724. 82. Martin EC, Diamond NC, Casarella WJ. Percutaneous transluminal angioplasty in nonatherosclerotic disease. Radiology 1980; 135:27–33. 83. Ayerdi J, Hodgson KJ. Balloon angioplasty and stenting for renovascular occlusive disease. Pers Vasc Surg Endovasc Ther 2004; 16:25–42. 84. Blum U, Krumme B, Flugel P, et al. Treatment of ostial renal artery stenoses with vascular endoprostheses after unsuccessful balloon angioplasty. NEJM 1997; 336:459–465. 85. Boisclair C, Therasse E, Oliva VL, et al. Treatment of renal angioplasty failure by percutaneous renal artery stenting with Palmaz stents: midterm technical and clinical results. AJR 1997; 168:245–251. 86. Dorros G, Jaff M, Mathiak L, et al. Four-year follow-up of Palmaz-Schatz stent revascularization as treatment for renal artery stenosis. Circulation 1998; 98:642–647. 87. Harjai K, Khosla S, Shaw D, et al. Effect of gender on outcomes following renal artery stent placement for renovascular hypertension. Cathet Cardiovasc Diagn 1997; 42:381–386. 88. Henry M, Amor M, Henry I, et al. Stent placement in the renal artery: three-year experience with the Palmaz stent. J Vasc Intervent Radiol 1996; 7:343–350. 89. Knipp BS, Dimick JB, Eliason JL, et al. Diffusion of new technology for the treatment of renovascular hypertension in the United States: surgical revascularization versus catheterbased therapy, 1998–2001. J Vasc Surg 2004; 40:717–723. 90. Leertouwer TC, Gussenhoven EJ, Bosch JL, et al. Stent placement for renal arterial stenosis: where do we stand? A meta-analysis. Radiology 2002; 216:78–85. 91. Rees CR, Palmaz JC, Becker GJ, et al. Palmaz stent in atherosclerotic stenoses involving the ostia of the renal arteries: preliminary report of a multicenter study. Radiology 1991; 181:507–514. 92. Weibull H, Bergqvist D, Bergentz SE, Jonsson K, Hulthen L, Manhem P. Percutaneous transluminal renal angioplasty versus surgical reconstruction of atherosclerotic renal artery

Chapter 48:

93.

94.

95.

96.

97. 98.

99.

Secondary Hypertension: Pathophysiology and Operative Treatment

stenosis: a prospective randomized study. J Vasc Surg 1993; 18:841–852. Wong JM, Hansen KJ, Oskin TC, et al. Surgery after failed percutaneous renal artery angioplasty. J Vasc Surg 1999; 30: 468–482. Stanley JC, Ernst CB, Fry WJ. Fate of 100 aortorenal vein grafts: characteristics of late graft expansion, aneurysmal dilatation, and stenosis. Surgery 1973; 74:931–944. Khauli RB, Novick AC, Ziegelbaum M. Splenorenal bypass in the treatment of renal artery stenosis: experience with sixtynine cases. J Vasc Surg 1985; 2:547–551. Moncure AC, Brewster DC, Darling RC, Atnip RG, Newton WD, Abbott WM. Use of the splenic and hepatic arteries for renal revascularization. J Vasc Surg 1986; 3:196–203. Belzer PO, Raczkowski A. Ex vivo renal artery reconstruction with autotransplantation. Surgery 1982; 92:642–645. Brekke IB, Sodal G, Jakobsen A, et al. Fibromuscular renal artery disease treated by extracorporeal vascular reconstruction and renal autotransplantation: short- and long-term results. Eur J Vasc Surg 1992; 6:471–476. van Bockel JH, van den Akker PJ, Chang PC, Aarts JC, Hermans J, Terpstra JL. Extracorporeal renal artery reconstruction for renovascular hypertension. J Vasc Surg 1991; 13:101–110.

925

100. Cambria RP, Brewster DC, L’Italien G, et al. Simultaneous aortic and renal artery reconstruction: evolution of an eighteen-year experience. J Vasc Surg 1994; 21:916–925. 101. Clair DG, Belkin M, Whittemore AD, Mannick JA, Donaldson MC. Safety and efficacy of transaortic renal endarterectomy as an adjunct to aortic surgery. J Vasc Surg 1995; 21:926–933. 102. Dougherty MJ, Hallett JW Jr, Naessens J, et al. Renal endarterectomy versus bypass for combined aortic and renal reconstruction: is there a difference in clinical outcome? Ann Vasc Surg 1995; 9:87–94. 103. Hansen KJ, Starr SM, Sands RE, Burkart JM, Plonk GW Jr, Dean RH. Contemporary surgical management of renovascular disease. J Vasc Surg 1992; 16:319–331. 104. McNeil JW, String ST, Pfeiffer RB Jr. Concomitant renal endarterectomy and aortic reconstruction. J Vasc Surg 1994; 20: 331–336. 105. Stoney RJ, Messina LM, Goldstone J, Reilly LM. Renal endarterectomy through the transected aorta: a new technique for combined aortorenal arteriosclerosis—a preliminary report. J Vasc Surg 1989; 9:224–233. 106. Stanley JC, Whitehouse WM Jr, Zelenock GB, Graham LM, Cronenwett JL, Lindenauer SM. Reoperation for complications of renal artery reconstructive surgery undertaken for treatment of renovascular hypertension. J Vasc Surg 1985; 2:133–144.

medwedi.ru

PART SEVEN: The Endocrine System

49 Calcium and Phosphorus Metabolism and the Parathyroid Gland Fiemu E. Nwariaku

INTRODUCTION The parathyroid glands comprise a group of endocrine structures (usually 4 in number) that either hug the posterior surface of the thyroid gland or are in close proximity to it. Although exceedingly small in size, they play crucial roles in the maintenance of calcium and phosphorus balance. Their function spans a range of activities, including blood coagulation, modulation of membrane permeability, muscle contraction, neuromuscular excitability, and the regulation of various signal transduction processes within cells. Their importance to the surgeon is usually related to states of overactivity in which hypercalcemia may ensue. Occasionally, these glands also become important in surgical practices when a state of hypocalcemia results, as may occur after total thyroidectomy for goiter or neoplasia. The intricate control systems regulated by the parathyroid glands to maintain calcium and phosphorus balance are the subject of this chapter.

CALCIUM HOMEOSTASIS Intracellular signaling systems are exquisitely sensitive to the intracellular calcium concentration. Increased intracellular calcium concentrations generate further release of calcium stores in the sarcoplasmic reticulum, triggering the desired cellular response. Calcium-dependent intracellular signaling systems are affected by serum and extracellular fluid calcium concentration, necessitating tight control of serum calcium levels. This is especially true for neuromuscular and secretory cells whose functions are disrupted by small alterations in extracellular calcium concentrations. Serum calcium concentration is tightly regulated by the intestinal tract (absorption), bone (calcium stores), and kidney (excretion). Regulation of these processes occurs through the actions of several hormones, including parathyroid hormone (PTH) and vitamin D 1,25dihydroxy vitamin D (1,25-(OH)2D), calcitonin, estradiol, glucocorticoids, and the growth hormone. Of these, PTH and (1,25-(OH)2D) appear to be the main regulators of calcium homeostasis in humans. Both hormones stimulate bone-resorbing osteoclasts, promoting calcium release into the extracellular fluid. PTH also stimulates renal hydroxylation of 25-(OH)D3 to 1,25-(OH)2D1 and distal renal tubular calcium reabsorption. More than 98% of the total body calcium is present in bone and about 1% appears to be freely exchangeable with the extracellular fluid through both physicochemical and cell-mediated mechanisms. Figure 1 illustrates the exchangeable calcium compartments. Calcium circulates in the extracellular fluid in three distinct fractions: about 50% comprises

the biologically important ‘‘free’’ or ‘‘ionized’’ fraction, 40% is protein-bound and not filterable by the kidney, and 10% is complexed to anions such as bicarbonate, citrate, sulphate, phosphate, and lactate. Most of the protein-bound calcium is bound to albumin, the remainder being complexed to globulins. Disorders that lower serum albumin also lower total concentration of serum calcium, but have a lesser effect on the free ‘‘ionized’’ calcium level. In general, 1 g/dL of albumin binds about 0.2 mmol/L (0.8 mg/dL) of calcium, allowing for a simple estimate of an acceptable value for serum calcium when patients have hypoalbuminemia. If one begins with a normal serum value of 4.0 g/dL and subtracts 0.2 mmol/L from the total calcium concentration for each 1 g/dL decrease in albumin concentration, an expected value for serum calcium will be obtained, which can be compared to the patient’s actual value to determine the presence of hypercalcemia or hypocalcemia. Figure 2 illustrates this relationship. Binding of calcium to albumin is also affected by the extracellular fluid pH. Acidemia decreases protein binding and increases the ionized calcium fraction. For each 0.1 decrease in pH, ionized calcium rises by about 0.05 mmol/L. Extracellular calcium compartments are of interest to the clinician because multiple factors may influence the metabolically active, ionized fraction. During venipuncture, the prolonged use of a tourniquet that causes ischemia and acidosis could artificially elevate ionized calcium. Similarly, inappropriate specimen collection could cause an elevation in pH and subsequent artificial lowering of ionized calcium measurement. Electrodes used to measure ionized calcium are sensitive to temperature, calcium-chelating anticoagulants, and loss of carbon dioxide; thus, these methods generally underestimate the ionized calcium fraction.

Figure 1 Physicochemical state of calcium in serum.

medwedi.ru 927

928

Part Seven: The Endocrine System

of bone mass, but 80% of bone surface area. Because most calcium stores are in bone, it may act as a ‘‘calcium sink’’ storing excess calcium or providing additional calcium in times of need. Many derangements of calcium metabolism, such as hyperparathyroidism, result in changes in bone density.

Kidneys

Figure 2 Alterations of serum calcium due to changes in albumin concentration and pH.

Intestine Calcium absorption varies by location in the gastrointestinal (GI) tract. The stomach does not absorb calcium, but facilitates its absorption by solubilizing the mineral in acid. The rate of calcium absorption is greatest at the duodenum and progressively decreases in the jejunum and ileum. Although the duodenum has the greatest ability to absorb calcium, it is relatively short. Because the jejunal length and transit time are greater than that of the duodenum, quantitatively greater amounts of calcium are absorbed in the jejunum. The colon is also capable of absorbing calcium, but sequestration of calcium within stool prevents contact with the colonic epithelial surface. Calcium absorption may be active or passive. Active absorption is very efficient, but of limited magnitude. Calcium active transport systems are mediated by saturable protein carriers that transport up to a maximal rate and not beyond it. These systems are important when calcium must be transported against steep concentration gradients. Calcium absorption also occurs across steep gradients by passive transport. Because passive transport is not saturable, when there is a large concentration gradient, large quantities of calcium can be absorbed. This is what occurs when the dietary calcium content is high. When there is little calcium in the diet, calcium absorption is facilitated by active transport systems. The small intestine demonstrates two levels of control, immediate and long term. The fraction of calcium absorbed will differ according to the quantity delivered to the GI tract. During ingestion of small quantities of calcium, most of the ingested calcium (80–100%) is absorbed. With larger amounts (100–500 mg), less calcium (20–60%) is absorbed. With long-term dietary changes in the intake of calcium, adaptation is regulated by changes in calciotropic hormones. For example, poor calcium intake will lead to lower blood calcium and, in turn, higher serum PTH and 1,25(OH)2D, which then boosts intestinal calcium absorption. The opposite occurs when dietary calcium intake is excessive. Soluble fiber and phosphate may inhibit calcium absorption by binding it within the intestinal lumen. PTH indirectly increases both active and passive calcium absorption by increasing vitamin D synthesis and release.

Bone Bone is a dynamic structure that is in constant flux by a process known as remodeling. Cortical bone which constitutes 80% of bone mass is commonly found in the appendicular skeleton (arms and legs) and accounts for only 4% of remodeling compared to trabecular bone which accounts for 20%

The kidneys are critically important for the maintenance of calcium homeostasis. Amongst the most common causes of abnormal calcium metabolism are the renal failure syndromes. The kidney filters very large amounts of calcium, 10 g daily and must resorb almost all of it to maintain normal calcium levels. Consequently, only 100 to 200 mg of calcium is excreted into the urine daily. Because of the large amount of calcium passing through the kidney, relative minor alterations in renal function can have a large impact on calcium homeostasis. Sixty to seventy percent of calcium reabsorption occurs in the proximal tubule. Another 20% is reabsorbed in the thick ascending loop of Henle, 5% to 10% in the distal tubule, and the remainder is reabsorbed in the collecting ducts. If renal filtration decreases due to volume depletion or declining renal function, less calcium is lost in the urine. Alternatively, if renal filtration increases due to volume overload, more calcium is excreted into the urine. This observation explains the efficacy of forced diuresis as a treatment for hypercalcemia. PTH regulates the degree of renal tubular calcium resorption. During hypocalcemia, PTH secretion from the parathyroid glands is increased resulting in an enhanced calcium resorption from the renal tubules. In contrast, when serum calcium increases with a resultant decrease in serum PTH levels, there is less renal tubular resorption of calcium. Dumping calcium into the urine is one of the mechanisms utilized to lower serum calcium levels. Acidosis and dietary acid loads impair renal calcium reabsorption; alkalosis and dietary alkali loads produce the opposite effect. Excess dietary intake of salt enhances calcium excretion by increasing extracellular fluid volume and by impairing renal calcium reabsorption. Finally, loop diuretics such as furosemide increase renal calcium losses, while thiazide diuretics and lithium act on the distal tubule to reduce urinary calcium resorption.

HORMONAL REGULATION OF EXTRACELLULAR CALCIUM CONCENTRATION Parathyroid Hormone PTH is produced by the parathyroid glands, located adjacent to the thyroid gland in the neck. While most humans have four parathyroid glands, in some there may be as few as two glands or up to eight glands. PTH is initially synthesized as part of a larger (112 amino acid) molecule, pre-pro-PTH, which is immediately shortened to pro-PTH. Enzymatic cleavage of the nonbiologically active pro-PTH frees the 84–amino acid peptide, PTH, for release into the circulation, where it is broken into two fragments, principally in the liver and kidney. The parathyroid gland also releases hormone fragments. There are three forms of circulating PTH: the 84–amino acid molecule (intact PTH), an amino-terminal fragment with a short half-life, and a carboxylterminal fragment with a longer half-life. Only the whole molecule and the amino-terminal fragment are biologically active. These

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

are rapidly cleaved within the circulation resulting in a serum half-life of less than five minutes. The short half-life is indicative of the importance in maintaining tight control of calcium levels. Rapid degradation of parathyroid hormone facilitates the rapid response to changes in calcium levels, enabling the body to keep serum calcium levels at nearly constant levels. When serum calcium levels fall, PTH secretion immediately increases with the opposite occurring when serum calcium rises, facilitating the minute-by-minute control of serum calcium concentration. The immediate response to changes in serum calcium levels by PTH secretion is mediated by a calciumsensing receptor (CaSR) on the surface of the parathyroid cells. PTH secretion is 50% of the maximal level at a serum ionized calcium level of 4 mg/dL (1 mmol/L), which is the calcium set point for PTH secretion. Exploitation of the short half-life of PTH has been useful during intraoperative monitoring of PTH and has improved our ability to ensure that all hypersecreting parathyroid tissue has been resected during parathyroidectomy in patients with primary hyperparathyroidism (pHPT). In addition, serum phosphate concentration indirectly affects PTH secretion. Hyperphosphatemia directly raises serum PTH, and phosphorus binds calcium leading to low serum calcium concentrations, which in turn stimulate PTH secretion. This has important implications for the management of patients with severe renal insufficiency, which leads to hyperphosphatemia and secondary to hyperparathyroidism from chronic parathyroid stimulation. Phosphate-reduction therapy (phosphate-binding agents, etc.) is frequently required to reduce the high PTH levels in such patients. PTH maintains the serum calcium level by several mechanisms and by acting on several organ systems to raise serum calcium and lower serum phosphate concentrations. It directly and indirectly promotes calcium entry into the blood at the three sites of calcium exchange: gut, bone, and kidney. PTH indirectly contributes to the net GI absorption of calcium by inducing the renal synthesis of calcitriol. PTH directly inhibits the synthetic function of osteoblasts, indirectly stimulates osteoclast differentiation, stimulates tubular calcium reabsorption, enhances phosphate clearance, and stimulates the enzyme that completes the synthesis of calcitriol in the kidney. Under physiologic conditions, PTH feedback loops prevent serious derangements of calcium concentrations, such as hypercalcemia or hypocalcemia. The net effects of PTH are enhancement of bone resorption, decreased loss of urinary calcium, and increased intestinal calcium absorption. Although it is well known that pHPT is caused by the overproduction of PTH, the cause of this overproduction and the development of sporadic pHPT are unknown. Clearly, the normal negative feedback loop is altered and the abnormal parathyroid gland(s) continue to secrete excessive amounts of PTH despite high serum calcium levels. Circulating PTH is now measured using antibodies that detect intact PTH. This sandwich technique uses two antibodies, one for the amino-terminus and another for the carboxy-terminus. These double-antibody immunoassays are highly sensitive and specific and have replaced other assays due to their improved accuracy in detecting the intact (biologically active) hormone. In patients with pHPT, there is an inappropriate and excessive secretion of PTH, relative to the serum calcium level, from the abnormal parathyroid gland(s) allowing the clinician to specifically establish pHPT as the cause of hypercalcemia.

929

Vitamin D (1,25-(OH)2D) The active form of vitamin D, 1,25-(OH)2D, is produced by a complicated pathway involving the skin, liver, and kidneys. First, 7-dehydrocholesterol in the skin is converted to previtamin D3 by ultraviolet light, and this product is converted to vitamin D3 by isomerization, a process that is impaired in the elderly. At northern latitudes in the winter, the lack of sufficient ultraviolet light prevents adequate synthesis of vitamin D3. Patients with highly pigmented skin require greater duration of exposure to ultraviolet light to synthesize adequate amounts of vitamin D3, because melanin also absorbs these ultraviolet spectrum wavelengths. Vitamin D3 is transported in the blood by the vitamin D–binding protein (VDBP) to the liver, where it is 25-hydroxylated to 25-hydroxyvitamin D (25-(OH)D) or calcifediol. Vitamin D2 (plant sources) and vitamin D3 (animal sources) may also reach the liver after dietary ingestion via the portal circulation. 25-(OH)D is then transported to the kidney also by VDBP. Most of the 25-(OH)D in the kidneys is shunted to the first step of a degradation pathway by 24-hydroxylase (CYP24) and is converted into 24,25-dihydroxyvitamin D in the kidneys, but a small amount of 25-(OH)2D is converted to the active hormone, 1,25-(OH)2D or calcitriol by the 1-a-hydroxylase (or CYP1a) in a tightly regulated process. Calcitriol appears to be the major active form of vitamin D in humans. Although its plasma level of 25 to 40 pg/mL is much lower than that of calcifediol, it is over 100 times as potent on a weight basis. An understanding of vitamin D metabolism allows the clinician to understand the derangements in calcium metabolism that occur with liver and kidney diseases. Liver disease impairs 25-hydroxylation of 7-dehydrocholesterol in the liver and decreases the concentration of precursors of active vitamin D needed in the kidney. Renal disease suppresses the 1a-hydroxylation resulting in low levels of the most active form of vitamin D. Both diseases thus result in low vitamin D levels and subsequent aberrations in calcium metabolism. Hypophosphatemia and high serum PTH stimulate production of active vitamin D. In addition, active vitamin D inhibits its own production by suppressing PTH and the 1-a-hydroxylase and enhances its own degradation by upregulating transcription of 24-hydroxylase through negative feedback loops. Similar to PTH, 1,25-(OH)2D raises serum calcium primarily by increasing intestinal calcium absorption, but it also increases bone resorption and serum phosphate concentrations. Although 1,25-(OH)2D directly increases intestinal phosphate absorption and renal phosphate reabsorption to a modest degree, its main effect on serum phosphate is probably better explained by its direct suppression of PTH secretion. The normal range for calcitriol varies with the season (lower in winter), age (lower in older persons), and serum calcium level. Although, calcitriol production is autoregulated, other hormones such as prolactin, growth hormone, and sex steroids may also modulate its production. Receptors for calcitriol are present in many tissues other than bone, kidney, and intestine, including the parathyroid glands, pancreatic islets, mammary glands, and fibroblasts, indicating that it has effects that reach beyond the three organs that are primarily involved in calcium metabolism.

Calcitonin The role of calcitonin in humans is unclear, but in fish, the hormone plays an important role in calcium metabolism.

medwedi.ru

930

Part Seven: The Endocrine System

The 32–amino acid polypeptide is derived from the C-cells of the thyroid glands. Secretion of calcitonin is stimulated by hypercalcemia and the GI hormone, gastrin. Because gastrin secretion is also increased by calcium, calcitonin has been postulated to prevent postprandial hypercalcemia. Binding of calcitonin to its receptor on the surface of osteoclasts is responsible for the hormone’s main action, to decrease bone resorption. In humans, calcitonin seems to play a minor role in calcium metabolism. Calcitonin insufficiency (postthyroidectomy) or excess (medullary thyroid carcinoma) both have no effect on bone mineral density. However, pharmacologic doses of calcitonin effectively decrease bone turnover in humans, and parenteral or intranasal formulations are approved to treat osteoporosis, hypercalcemia and Paget’s disease of the bone, a disease characterized by high bone turnover, bone pain, and bone deformities. At pharmacologic doses in humans, calcitonin may also increase renal calcium excretion, though the effects of calcitonin on hypercalcemia are modest. As such, the role of calcitonin in managing hypercalcemia is as an adjuvant.

cause of humoral hypercalcemia of malignancy, PTH-related protein, or its messenger RNA, has been identified in many tissues, including the placenta, fetal parathyroid, and adult keratinocytes, neurons, pancreatic islets, kidney, and bone. This molecule closely resembles PTH at its amino-terminal end, but it is longer and more complex than PTH. The first 13 amino acids of PTHrP are almost identical to those of PTH, but there is no homology in the remainder of the 141–amino acid structure. There are two important aspects of PTH-related protein. First, it shares a single receptor with PTH. Second, PTH-related protein appears to have a second biologically active domain in addition to the PTH-like region. This second active site plays a role in calcium transport in the placenta, thereby making PTH-related protein the important hormone regulating calcium metabolism in the fetus. One clinically relevant effect of PTHrP is the excess secretion by tumors thus producing the humoral hypercalcemia of malignancy.

The CaSR and Calcium Regulation

Growth hormone increases both bone resorption and bone formation, but greater stimulation of bone formation generally leads to gain in bone mass. Patients with growth hormone deficiency have a low bone mass, and their bone mineral density increases with growth hormone treatment. In contrast, acromegalic patients who have excessive secretion patterns of growth hormone tend to have low bone mass probably because of concomitant changes caused by the pituitary tumor such as hypogonadism. Thyroid hormone increases bone resorption and bone loss. The resulting higher ionized calcium suppresses PTH, 1,25-(OH)2D, and intestinal calcium absorption. Modest hypercalcemia may occur in up to 20% of patients with Graves’ disease.

Since the CaSR was cloned in 1993, much investigation has focused on its function and the effect of receptor mutations in human disease. Inactivating mutations have been shown to cause hypercalcemic disorders [familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism, etc.] while activating mutations cause hypocalcemia (autosomal dominant hypoparathyroidism) (1,2). The calcium sensing receptor is located in the parathyroid glands, C-cells of the thyroid, kidney, intestine, and focal areas of the brain. In the parathyroid gland, a rise in serum calcium activates the CaSR and results in suppression of PTH secretion. On the other hand, hypocalcemia results in higher serum PTH because the CaSR provides less inhibition. Thus, a CaSR may act as a short-feedback loop to avoid hypercalcemia. CaSR has also been shown to bind gadolinium, neomycin, and magnesium. Several clinical scenarios may be explained by these observations. First, hypermagnesemia often accompanies hypercalcemia in patients who have inactivating mutations of the CaSR; and hypomagnesemia and hypocalcemia arise in patients with activating mutations. Second, in patients without CaSR mutations, either high serum calcium or magnesium induces renal wasting of both calcium and magnesium. Finally, magnesium excess decreases the secretion of PTH. The receptor is potentially an important therapeutic target for disorders in which the receptor is inappropriately overactive or underactive. Clinical trials are currently underway to assess the efficacy of calcimimetic CaSR agonists in the treatment of primary and uremic HPT. In these trials, calcimimetics decrease the circulating PTH level more than 50% within minutes in patients with pHPT. In patients with HPT, calcimimetics reset the elevated calcium set point, which controls the response of pathological parathyroid glands to the serum calcium level. It is also likely that a CaSR antagonist would be very useful in the treatment of calcium-containing renal stones. A kidney-selective CaSR antagonist would produce, in effect, benign FHH, without altering the set point of the parathyroid to calcium therefore, producing hypercalcemia (3). In fact, a recent study demonstrated marked improvement in serum PTH levels in patients with secondary hyperparathyroidism given a calcimimetic (4).

Parathyroid Hormone-Related Protein

Physicochemical Effect

The precise role of parathyroid hormone-related protein (PTHrP) has not been determined. First found to be the

At very high levels of blood calcium or phosphate, metastatic calcification (deposition of calcium phosphate) occurs

Other Hormones Estradiol Estradiol prevents bone resorption, increases renal calcium reabsorption, and augments intestinal calcium absorption. After menopause, rapid bone loss occurs transiently for three to seven years, after which the rate of bone loss returns to baseline. Estradiol has been used to prevent bone loss due to hyperparathyroidism with mixed results. This effect is discussed below.

Glucocorticoids Steroids act via a vitamin D–independent mechanism to decrease intestinal calcium absorption. In the short term, high-dose glucocorticoids increase renal calcium loss by reducing renal calcium reabsorption. The combined effects on the kidney and the intestine may cause compensatory secondary hyperparathyroidism in some patients. However, the main effect of glucocorticoids is on bone, where glucocorticoids increase bone resorption, decrease bone formation, and cause apoptosis of osteoblasts and osteocytes. Of these mechanisms, the latter two appear to be most important. When a patient is treated with glucocorticoids, rapid bone loss occurs within the first six months, and then continues at a slower rate.

Growth Hormone and Thyroid Hormone

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

in the soft tissues. The location of the involved tissues varies. With hypercalcemia, metastatic calcification occurs in lung, conjunctiva, lining of stomach, and/or endothelium of arteries. The distribution is different in the setting of hyperphosphatemia. It may occur in cerebral basal ganglia and lens thus causing cataracts, or in the dermis. Either hypercalcemia or hyperphosphatemia may calcify the kidneys or periarticular tissues. This can sometimes be manifested by the clinical condition of calciphylaxis, which is associated with tissue ischemia and necrosis. High urinary calcium concentrations are a major cause of calcium-containing stones in nephrolithiasis. This clinical presentation occurs most frequently in patients with hypercalciuria due to pHPT.

931

Table 1 Nonparathyroid Nonmalignant Causes of Hypercalcemia Benign FHH Granulomatous disease (sarcoidosis, berylliosis, and tuberculosis) Hyperthyroidism Hypothyroidism Vipoma Addison’s disease Pheochromocytoma Excessive vitamin A and D intake Calcium intoxication Milk-alkali syndrome Immobilization Thiazides Lithium Abbreviation: FHH, familial hypocalciuric hypercalcemia.

DISORDERS OF CALCIUM METABOLISM Hypercalcemia Calcium regulatory mechanisms are highly effective under physiologic circumstances. For example, when dietary calcium suddenly increases, a smaller fraction of each dose is absorbed. If this adjustment is not sufficient, ionized calcium rises and, via the CaSR, suppresses serum PTH and, in turn, 1,25-(OH)2D secretion. Moreover, calcitonin secretion is stimulated by activation of calcium sensors within the C-cells of the thyroid. These hormonal changes correct serum calcium by reducing intestinal calcium absorption, bone resorption, and renal calcium reabsorption. The CaSR further corrects hypercalcemia by augmenting urinary calcium excretion. Despite these safeguards, hypercalcemia occurs when calcium influx into the extracellular fluid from the intestine and/or bone exceeds the efflux to bone and/or excretion by the kidney. For example, an influx of calcium from bone often occurs in patients with malignancy or increased PTH (pHPT), while increased influx from the intestine occurs in patients with hypervitaminosis D. Hypercalcemia occurs when these influxes exceed the capacity of the kidney to excrete the excess calcium presented to it. Symptoms due to hypercalcemia vary depending on duration and severity of hypercalcemia. For example, a normal volunteer infused with calcium would become lethargic or even comatose once serum calcium exceeds 14 mg/dL. In contrast, individuals with chronic hypercalcemia (i.e., slowgrowing parathyroid carcinoma) present with minimal changes in mental status even when calcium exceeds 19 mg/dL. Because a variety of common disorders are responsible for abnormalities in serum calcium, the treatment of both hypercalcemia and hypocalcemia depends on the underlying disorder, the magnitude of the deviation of the serum calcium, and the severity of symptoms.

disease (e.g., tuberculosis, and sarcoidosis) and hyperthyroidism cause hypercalcemia. Macrophages activated by the granulomas metabolize 25(OH) vitamin D to the more active calcitriol, and the resulting endogenous hypervitaminosis D increases the intestinal absorption of calcium, thus leading to hypercalciuria, hypercalcemia, and suppression of PTH. Hypercalcemia due to hyperthyroidism is caused by a direct stimulation of osteoclastic bone resorption by thyroxine; however, this rarely causes hypercalcemic crisis because the marked symptoms of hyperthyroidism manifest earlier and are usually controlled before the hypercalcemia becomes apparent. When hypercalcemia does complicate hyperthyroidism, it may mask the hypermetabolic symptoms and signs of thyrotoxicosis, which may then become more difficult to diagnose. In the hypercalcemia of hyperthyroidism, PTH secretion is suppressed. Locally produced cytokines that stimulate osteoclastic bone resorption may also be the most important cause of hypercalcemia associated with metastases. However, local skeletal destruction may also occur without stimulation of osteoclasts; furthermore, many skeletal metastases secrete PTH-related polypeptide, which is the most common cause of hypercalcemia of malignancy. Table 2 lists the common mechanisms of hypercalcemia.

Hypercalcemia of Malignancy The three main mechanisms of hypercalcemia of malignancy [PTHrP, local factors, and 1,25-(OH)2D] are discussed below. The most common malignancies associated with hypercalcemia include lung or breast carcinoma (60%), renal cell carcinoma (10–15%), head and neck squamous cell carcinoma

Table 2 Mechanisms of Hypercalcemia

Differential Diagnosis of Hypercalcemia With routine biochemical screening, hypercalcemia is detected with a prevalence of 1 per 600 to 1 per 1000 people, depending on the population screened. The upper limit of normal for serum calcium is about 10.5 mg/dL (2.6 mmol/L) and severe, potentially life-threatening hypercalcemia occurs when levels exceed 14 mg/dL (3.5 mmol/L). The most common cause of hypercalcemia in hospitalized patients is malignancy, while pHPT is most commonly the cause in nonhospitalized patients. Table 1 lists the other causes of hypercalcemia. Hypercalcemia may be the most common metabolic complication of cancer and, overall, 10% to 20% of cancer patients develop hypercalcemia at some time during their disease. Less commonly, granulomatous

Mechanism Increased bone resorption

Increased intestinal calcium absorption Decreased renal calcium excretion

Decreased bone formation

Cause Hyperparathyroidism, malignancy, granulomatous disease, immobilization, hyperthyroidism, hypervitaminosis A or D Hyperparathyroidism, granulomatous disorders, hypervitaminosis D, milk-alkali syndrome Renal failure, volume depletion, hyperparathyroidism, FHH, milkalkali syndrome, thiazides, lithium Immobilization

Abbreviation: FHH, familial hypocalciuric hypercalcemia.

medwedi.ru

932

Part Seven: The Endocrine System

(10%), and myeloma or lymphoma (10%). Patients with humoral hypercalcemia of malignancy have manifestations similar to those seen in hyperparathyroid patients, including mild hypophosphatemia and an elevated urinary cyclic adenosine monophosphate (cAMP) level. However, the patients with humoral hypercalcemia of malignancy are more likely to be anemic and less likely to be hyperchloremic compared to patients with pHPT. Perhaps the most valuable difference between humoral hypercalcemia of malignancy (HHM) and pHPT is that both the PTH and the calcitriol levels are in the low or lower normal range in patients with humoral hypercalcemia of malignancy.

Role of PTHrP PTHrP-induced hypercalcemia, also known as HHM, is the most common cause of hypercalcemia of malignancy (80%). PTHrP is expressed only in neoplasms associated with HHM, such as squamous carcinomas, carcinomas of the breast, kidney, and bladder, and some lymphomas. Local implantation of such tumors in animal models results in hypercalcemia before metastases occur, and antibodies to PTHrP reverse this effect. Finally, the majority of patients with HHM have elevated PTHrP. Although the actions of PTHrP share similarities to those of PTH, there are several differences worthy of discussion. Similar to patients with pHPT, those with HHM have elevated serum calcium, lownormal or low serum phosphate, and elevated urinary calcium, phosphate and cAMP. Both PTH and PTHrP raise serum 1,25-(OH)2D by stimulating the renal 1-a-hydroxylase. However, serum 1,25-(OH)2D in patients with HHM is generally low, for unclear reasons. Further, patients with HHM tend to have more hypercalciuria, more bone resorption, but less bone formation compared to those with pHPT.

Local Osteolytic Hypercalcemia In about 20% of patients with hypercalcemia of malignancy, elaboration of paracrine factors by the tumor in the skeleton causes hypercalcemia. These factors, which include interleukin (IL)-1, IL-6, tumor necrosis factor, and prostaglandin E2 (PGE2), drive osteoclastogenic bone resorption and bone loss. If coupled with impaired renal calcium excretion, hypercalcemia may result. Tumors believed to cause local osteolytic hypercalcemia (LOH) include multiple myeloma, breast carcinoma, and lymphoma.

Vitamin D–Mediated Hypercalcemia of Malignancy Rarely, lymphomas contain 1-a-hydroxylase, which may produce 1,25-(OH)2D in quantities high enough to cause hypercalcemia. This hormone drives intestinal calcium absorption and bone resorption. The body compensates by increasing renal calcium excretion. With renal impairment or severe calcium overload, hypercalcemia may result.

Nonparathyroid, Nonmalignant Causes of Hypercalcemia Vitamin D–mediated hypercalcemia, either by excess intake or by excess production, is the most common cause of nonparathyroid, nonmalignant hypercalcemia. Hypercalcemia is mediated by increased intestinal calcium absorption, and to a lesser degree, increased bone resorption. Hypercalcemia occurs only after the kidney’s excretory reserve is overwhelmed. Vitamin D, either ingested from the diet or supplements or that produced in the skin, is converted to

25-(OH)D. However, the renal 1-a-hydroxylase is normally so tightly regulated that 1,25-(OH)2D should not increase in hypercalcemic patients despite excess substrate. Because 25-(OH)D is much less potent at the vitamin D receptor (VDR), hypercalcemia requires very high concentrations in 25-(OH)D-driven disease. This only occurs after pharmacologically excess intake of 25-(OH)D or vitamin D, which is readily converted to 25-(OH)D in the liver. In contrast, 1,25-(OH)2D may be produced in granulomatous tissue in multiple disorders (most commonly sarcoidosis and tuberculosis) or prescribed by a physician. In these cases, serum 25-(OH)D would be low or normal, but 1,25-(OH)2D would be elevated. Patients with hypercalcemia from granulomatous disease tend to have other symptoms related to their disease to suggest the diagnosis. Other causes of hypercalcemia include vitamin A intoxication and hyperthyroidism. Both of these increase bone resorption, and hypercalcemia results when renal calcium excretion is overwhelmed. Alkali, thiazides, and lithium decrease renal calcium excretion. When coupled with excess calcium intake or bone resorption, hypercalcemia ensues. Long-term therapy with lithium is also associated with pHPT. This effect is believed to be due to elevation of the set point for PTH secretion by effects on the CaSR. Withdrawal of lithium therapy usually resolves the condition; however, parathyroidectomy may be required for patients with severe hypercalcemia who are unable to avoid lithium therapy. The milk-alkali syndrome results from huge intake of calcium and alkali (often from milk and antacids). Over time, the high delivery of calcium and alkali to the kidney additionally causes renal insufficiency. Again, hypercalcemia only develops when the mechanisms of renal calcium excretion are overwhelmed. In addition, it has been noted that hypercalcemia of immobilization is more common in conditions with very high bone turnover, such as childhood (active bone modeling and remodeling), or metabolic bone diseases, such as Paget’s (osteitis deformans). The differential diagnosis of hypercalcemia is further refined by excluding pseudoelevation of serum calcium and by obtaining a serum PTH level. Conditions that potentially affect the measured serum calcium level include the following: (i) serum albumin level changes greater than 1 g/dL (alters the protein-bound serum calcium by 0.8 mg/dL in the same direction), (ii) serum globulin concentration changes greater than 1 g/dL (alters protein-bound calcium by 0.16 mg/dL in the same direction), (iii) a change in the serum pH of greater than 0.1 (alters the protein-bound calcium level by 0.17 mg/dL in the same direction), and (iv) dehydration (volume depletion) falsely increases in serum protein-bound calcium concentration. The serum level of intact PTH is elevated in patients with pHPT and suppressed in patients with nonparathyroid causes of hypercalcemia except the following three conditions: lithium intake, FHH, and, rarely, secretion of true PTH by a tumor. The intact PTH immunoradiometric assay as well as the mid-region–specific radioimmunoassay of PTH demonstrate equivalent sensitivity in differentiating between malignancy associated with hypercalcemia and pHPT. However, most laboratories now perform intact (1-84) PTH measurements using the chemiluminescent assay. This intact PTH assay is highly sensitive. Mallette and associates observed that the intact PTH assay is much more accurate for identifying the cause of hypercalcemia in patients with renal insufficiency, because the results of the mid-region–specific assay are sensitive to changes in renal function and biologically inactive fragments of PTH

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

933

Figure 3 Algorithm to work-up confirmed hypercalcemia.

are mainly cleared by the kidneys (5,6). Our preferred algorithm for evaluation and management of hypercalcemia is shown in Figure 3. If the serum PTH level is high in the presence of hypercalcemia, then pHPT is very likely. Normal or low PTH levels should trigger additional evaluation. The serum phosphate level is useful in identifying patients with vitamin D abnormalities. Numerous studies have documented the high sensitivity of inappropriately elevated serum PTH levels in patients with pHPT. Figure 4 illustrates the separation of serum calcium and PTH levels in normal and hyperparathyroid patients. Urinary cAMP levels may be of distinguishing value in patients with pHPT. Because cAMP levels are often elevated in primary HPT and only variably elevated in hypercalcemia of malignancy, the detection of low levels of urinary cAMP would make the possibility of coexisting HPT less likely in a patient with malignancy. While serum 1,25-(OH)2D levels are elevated in primary HPT, they are rarely elevated in hypercalcemia of malignancy, which typically shows decreased measurable, 1,25-(OH)2D metabolites. Patients with lymphoma can have elevated levels of 1,25-(OH)2D, but they represent a minority of patients with hypercalcemia of malignancy. In 1974, Palmer and associates suggested using the serum chloride–phosphate ratio to differentiate hypercalcemia caused by primary HPT from other causes of hypercalcemia. They found that 96% of patients with pHPT had a serum chloride–phosphate ratio greater than 33, whereas 92% of patients with hypercalcemia due to other causes had a serum chloride–phosphate ratio of less than 30 (7). In pHPT, serum levels of phosphate and bicarbonate are commonly decreased, and the serum chloride level usually exceeds 102 mg/L.

Clinical Manifestations of Hypercalcemia Intravascular volume contraction is present in almost all patients with severe hypercalcemia and this forms the basis for volume repletion as first line therapy for severe hypercalcemia. Other features depend on the severity of the hypercalcemia and the rapidity of the rise in serum calcium. Anorexia, nausea, vomiting, and mental obtundation are concerning clinical findings in hypercalcemic crisis. The dehydration that is invariably present should result in hypotension, but hypercalcemia increases vascular tone, so the blood pressure may be an inaccurate reflection of the severity of volume contraction. Malignancy is the most common cause of hypercalcemic crisis, and it is important to establish whether the patient has humoral hypercalcemia of malignancy or skeletal metastases. Reliable assays for PTH-related polypeptide are now available, but the results of PTH and calcitriol assays may not be available for several days; therefore, blood studies have a limited role in establishing an early diagnosis of the cause of hypercalcemic crisis. With newonset localized skeletal pain, radiographs of the affected area should confirm a diagnosis of skeletal metastases. A complete blood count provides clues to the presence of multiple myeloma or other hematologic malignancy, with confirmatory bone marrow examination when indicated. Bradyarrhythmias, bundle-branch blocks, complete heart block, and even cardiac arrest are all well documented complications of acute hypercalcemia. Hypercalcemia potentiates the action of digoxin on the heart, such that any cardiac side effects of this drug may become clinically more significant during hypercalcemic crisis. Clinical manifestations of hypercalcemia present mainly in the kidney, bone, GI tract, and nervous system.

medwedi.ru

934

Part Seven: The Endocrine System

Figure 4 Relationship between PTH values and serum calcium. Abbreviation: PTH, parathyroid hormone.

These conditions include nephrolithiasis, nephrocalcinosis, and renal insufficiency. Bone manifestations reflect increased bone turnover (bone pain, pathologic fractures, and osteitis fibrosa cystica). Peptic ulcer disease and pancreatitis reflect GI involvement, whereas neuromuscular derangements are reflected by proximal muscle weakness, atrophy, tongue fasciculations, depression, anxiety, confusion, and in extreme stages, lethargy and coma.

Severe Hypercalcemia Although severe hypercalcemia is often treated as a medical emergency, it is rarely fatal; therefore cautious, methodical management is recommended. Hypercalcemia of malignant origin is, however, a grave complication, with a survival rate of 45% at three months. Hypercalcemia due to malignant tumors usually develops rapidly and is associated with weight loss. It is also associated with a serum calcium level often exceeding 14 mg/dL, low serum chloride level, elevated or normal serum phosphate and bicarbonate, elevated alkaline phosphatase level, and erythrocyte sedimentation rate. Only 25% of patients with pHPT have a serum calcium level exceeding 14 mg/dL. The acute clinical findings during hypercalcemic crisis invariably include evidence of volume depletion, metabolic encephalopathy, and GI symptoms. There may be associated renal and cardiovascular manifestations beyond those attributable to volume contraction. As with most metabolic emergencies, the clinical presentation depends on acuity of onset and absolute level of hypercalcemia. Treatment of Severe Hypercalcemia General Measures. Two chief mechanisms causing hypercalcemic crisis include increased bone resorption and inability of the kidneys to excrete the huge increased filtered load of calcium. Therefore the treatment of hypercalcemia should include efforts to decrease bone resorption and increase

urinary calcium excretion. Prompt treatment of severe hypercalcemia should be targeted toward a specific etiology. However, the general treatment measures outlined in Table 3 should begin prior to determination of etiology. Severe hypercalcemia is always associated with water and sodium depletion; therefore, volume expansion with isotonic saline solution is the essential first step of any therapeutic regimen. In addition to providing the necessary fluid, there is an obligatory calcium diuresis with a sodium-induced diuresis. This maneuver dilutes extracellular fluid calcium, expands extracellular volume, and increases urinary calcium excretion. Volume expansion (2–4 L/day) for the first 48 hours improves the glomerular filtration rate and enhances renal excretion of calcium, and lowers the serum calcium level by 1.5 to 2.0 mg/dL during the first 24 to 48 hours. Although volume expansion rarely returns serum calcium levels to normal in patients with severe hypercalcemia, a loop diuretic (e.g., furosemide or ethacrynic acid) enhances the calciuric effects of volume expansion by Table 3 Acute Management of Severe Hypercalcemia Encourage saline-induced diuresis (Infuse NaCl 2–4 L daily) After appropriate diuresis, add loop diuretic (furosemide), 40–80 mg, q 2– 4 hourly Add calcitonin 4 IU/kg subcutaneously or intramuscularly q 12 hourly Monitor serum sodium, potassium, calcium, and magnesium, q 2–4 hourly Obtain serum phosphate, chloride, and parathyroid hormone levels Consider bisphosphonates (Pamidronate 90 mg IV over 24 hr, Alendronate) Consider steroids if malignancy is confirmed or highly suspected Consider dialysis for patients with renal insufficiency or unresponsive to prior interventions Urgent parathyroidectomy may be necessary for patients with parathyroid carcinoma Abbreviation: IV, intravenous.

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

inhibiting calcium reabsorption in the thick ascending limb of the loop of Henle. However diuretics should not be administered until there is clear evidence of adequate intravascular volume expansion documented by brisk diuresis or vascular monitoring. If signs of fluid overload develop, the saline infusion is slowed, and a loop diuretic such as furosemide can be given to control volume overload and promote both a sodium and calcium diuresis. However, loop diuretics increase sodium excretion more profoundly than calcium excretion, and if the sodium excretion exceeds the intravenous saline replacement, renal sodium-conserving mechanisms are activated, thus limiting calcium excretion and probably aggravating hypercalcemia. Volume repletion is clearly ineffective in hypercalcemic crisis patients with severely impaired renal function for reasons other than volume contraction. In such patients, first-line therapy must be hemodialysis, which can be administered with any available dialysate, until a low- or zero-calcium dialysate fluid is available, because the calcium concentration in all dialysis fluids is less than the plasma level in patients with hypercalcemic crisis. Thiazide diuretics are contraindicated because they enhance distal tubular calcium reabsorption. A review of medications and nutritional status is prudent to identify and discontinue drugs such as calcium supplements, vitamin D preparations, and other agents known to increase the serum calcium level or inhibit calcium excretion. Ongoing efforts at identifying the etiology of hypercalcemia should not be interrupted during the management of acute hypercalcemia. Specific Therapy. The administration of inhibitors of osteoclast-mediated bone resorption (e.g., bisphosphonates, plicamycin, and calcitonin) is the next step in the treatment of hypercalcemia. Recently, the Food and Drug Administration approved gallium nitrate, which blocks PTH-induced calcium resorption of bone, for parenteral treatment of hypercalcemia. Ideally, if the cause of the hypercalcemia is known, specific therapy is preferable, e.g., glucocorticoids for hypercalcemic crisis due to granulomatous disease. The bisphosphonates directly inhibit osteoclast function, and the first-line bisphosphonate for hypercalcemic crisis is pamidronate (Aredia1). These agents are poorly absorbed from the GI tract, but when given intravenously, the bisphosphonates reduce serum calcium levels to normal in most patients with hypercalcemia of malignancy. Pamidronate is more potent and possibly less toxic than etidronate. In clinical trials using 24-hour infusions of pamidronate, 70% to 100% of patients had lower serum calcium levels within 24 hours of initiation of treatment. Thus, pamidronate, in conjunction with vigorous saline hydration, is indicated for moderate or severe hypercalcemia due to malignancy. If normocalcemia is not achieved with an initial infusion, a second infusion will certainly decrease serum calcium levels. One disadvantage of bisphosphonates is that plasma calcium levels typically do not become normal for three to six days after their administration. This may be unduly long for critically ill patients in hypercalcemic crisis. The more common adverse reactions to pamidronate include transient mild temperature elevation soon after the drug is given, local infusion site reactions, mild GI symptoms, mild hypophosphatemia, hypokalemia, and hypomagnesemia. The first-generation bisphosphonate, Etidronate (Didronel1), is also FDA-approved for treating acute hypercalcemia, but it is considered less effective compared to pamidronate, because pamidronate lowers the calcium level more rapidly and predictably than etidronate. Because excretion of

935

etidronate occurs mainly in the kidneys, it is important to adjust the dose for impaired renal function. Possible adverse reactions to Etidronate include elevations of BUN or serum creatinine, metallic or altered taste in up to 5% of patients, and transient elevations of serum phosphate levels. Calcitonin inhibits osteoclastic bone resorption and thereby decreases serum calcium concentrations. It is a naturally occurring peptide produced by the C-cells of the thyroid gland. In addition to its osteoclast inhibiting effect, it has a moderate calciuric effect and an analgesic effect as well. The greatest advantage of this particular antiresorptive agent is that it has a fairly rapid onset of action. Serum calcium concentrations may begin to decline within several hours of the initiation of administration. At a dosage of 4 to 8 units/kg every 6 to 12 hours subcutaneously or intravenously, some degree of calcium lowering is seen in approximately 75% of patients. The disadvantage of this medication is that, in general, it is not as potent as either of the bisphosphonates, gallium nitrate, or plicamycin (mithramycin), and the hypocalcemic effect of calcitonin is fairly shortlived. Thus, for the treatment of hypercalcemic crisis, calcitonin should be considered an adjunctive rather than a primary therapy. The most common adverse reactions to calcitonin are nausea, with or without vomiting. Local inflammatory reactions at the site of calcitonin injection also occurs in about 10% of patients receiving this agent, and flushing of the face or hands occurs in a small percentage of patients. Plicamycin (mithramycin) is produced by a Streptomyces microorganism and is effective for treating hypercalcemia. It acts by inhibiting cellular RNA synthesis and reduces the serum calcium level more quickly than do the bisphosphonates. With a plicamycin dose of 25 mg/kg of body weight administered intravenously in 5% dextrose in water over a period of four to six hours, most patients achieve normocalcemia within one to three days. If necessary, it may be readministered for three or four consecutive days. Plicamycin is more potent than calcitonin, but its effectiveness is often limited by hepatotoxicity, nephrotoxicity, and thrombocytopenia. Gallium nitrate can be used in the management of severe hypercalcemia of malignancy. It inhibits bone resorption, although the precise mechanism of action is not clear. It may be administered as a continuous intravenous infusion of 200 mg/m2 body surface area for five consecutive days. In clinical trials, this dose of gallium nitrate reduces the serum calcium level to normal in 75% to 82% of treated patients, but its maximum effect may require five to six days of treatment. Gallium nitrate is indicated for the treatment of clearly symptomatic cancer-related hypercalcemia that has not responded to general measures (i.e., volume repletion with or without loop diuretics). A serious adverse effect of gallium nitrate is nephrotoxicity. For this reason, it is generally recommended that gallium nitrate not be administered to patients with baseline serum creatinine levels greater than 2.5 mg/dL. Transient hypophosphatemia, mild respiratory alkalosis, anemia, nausea, vomiting, and hypotension have also been reported with gallium nitrate. However, the lack of familiarity with gallium combined with the availability of other effective and less toxic hypocalcemic agents limit the widespread use of gallium nitrate for hypercalcemia. Glucocorticoids are the treatment of choice for hypercalcemia caused by vitamin D toxicity, certain malignancies (such as multiple myeloma and lymphoma), sarcoidosis, or other granulomatous diseases in which the production of

medwedi.ru

936

Part Seven: The Endocrine System

1,25-(OH)2D is the known mechanism for causing hypercalcemia. Typically a 200 to 300 mg dose of hydrocortisone is administered intravenously daily for three to five days. However, the maximal calcium-lowering effect does not occur for at least several days after initiating therapy. Glucocorticoids act by inhibiting the inflammatory cell proliferation within granulomatous tissue and hematologic malignancies and thereby decreasing the 1,25-(OH)2D levels that cause hypercalcemia. In most patients with hypercalcemic crisis, the glucocorticoids are of limited utility because, although they decrease intestinal calcium absorption and increase urinary calcium excretion, their onset of action is relatively slow. They are best reserved as an adjunctive therapy for hypercalcemic crisis. Phosphate Therapy. Although phosphate therapy was initially proposed for the treatment of hypercalcemia, concerns regarding the precipitation of calcium-phosphate salts in soft tissue have limited the enthusiasm for intravenous phosphate administration in patients with hypercalcemia.

Hypocalcemia Hypocalcemia, which results when calcium excretion exceeds intake, may result in several clinical manifestations. The most common symptoms relate to neuromuscular excitability. The first symptoms, paresthesias, occur particularly in perioral and acral (hands and feet) positions. Numbness and tingling also occur with hyperventilation in normal individuals, because ionized calcium falls when respiratory alkalosis shifts free calcium to the albumin-bound fraction. Muscular cramping usually starts at the hands and feet (carpopedal spasm) but may occur elsewhere. Tetany may become generalized across the body during severe hypocalcemia. Smooth muscle spasm may lead to abdominal pain, bronchospasm, and laryngospasm. The latter two conditions could result in wheezing and shortness of breath. Severe hypocalcemia may also result in confusion or even psychosis. Conduction abnormalities may result in seizures. Hypocalcemia also may affect cardiac function resulting in palpitations, due to arrhythmia or shortness of breath and other symptoms of congestive heart failure. Physical findings of neuromuscular excitability may be induced at the bedside in patients with hypocalcemia. Chvostek’s sign is a contraction of facial muscles on the side of the face on tapping the facial nerve 1 to 2 cm anterior to the external auditory meatus. When floridly positive, the facial muscles on the same side contract at the eye, nose, and lips. Chvostek’s sign is not pathognomonic for hypocalcemia because 10% of normal subjects may demonstrate a mild response such as twitching of the lips toward the side of the tapping. Unlike hypocalcemic patients, the response in normal individuals is usually blunted with repeated stimulation, i.e., repeated tapping progressively extinguishes the response. Trousseau’s sign, a carpal spasm elicited by inflating a blood pressure cuff on the arm 20 mm above systolic blood pressure for three minutes, is more specific for hypocalcemia. Adduction of the thumb, extension of the phalanges, and flexion of the metacarpophalangeal joints and the wrist characterize the spasm.

Mechanisms of Hypocalcemia The causes of hypocalcemia are grouped according to the main mechanisms: lack of PTH effect, lack of vitamin D effect, and calcium binding or redistribution. These are described below.

Lack of PTH Effect The most common cause in this category is postsurgical hypoparathyroidism, in which the parathyroid glands are removed or injured during surgical procedures in the neck. Autoimmune destruction is the second most common cause of lack of PTH effect. Although the latter patients may have isolated hypoparathyroidism, they often have multiple accompanying abnormalities such as moniliasis, hypoadrenalism, diabetes mellitus, Hashimoto’s thyroiditis, hypogonadism, autoimmune hepatitis, vitiligo, etc. The parathyroid glands may be congenitally absent in the 22q11.2 deletion syndrome (DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes). Infiltration of the parathyroid glands with iron (hemachromatosis), copper (Wilson’s disease), amyloid, or tumor also decreases their function. A recently discovered familial cause of hypoparathyroidism involves activating mutations of the CaSR. In these patients, serum PTH is suppressed even when serum calcium is relatively low. Hypomagnesemia causes resistance to and, with increasing severity, decreased secretion of PTH. Finally, patients suffer PTH resistance. Apart from its functions to raise serum calcium, PTH also lowers serum phosphorus by enhancing renal phosphorus excretion. Therefore patients with lack of PTH effect, have both hypocalcemia and hyperphosphatemia. The hyperphosphatemia may result in additional clinical manifestations due to soft tissue calcium deposition. Patients with hypoparathyroidism may have cataracts, calcification of the basal ganglia in the brain, and even moderate-to-severe cerebral calcification and mental retardation. Basal ganglia calcification may result in Parkinson’s disease. Lack of Vitamin D Effect The effects of vitamin D may be a result of inadequate intake, impaired production, increased destruction, or resistance to vitamin D. Inadequate Nutrition/Sunlight. Vitamin D3 is present in only few foods such as vitamin D–fortified milk (100 IU/ cup), cod liver oil, and fatty fish such as salmon. Thus, it is difficult to achieve sufficient intake (600–800 IU/day) by dietary sources alone. Vitamin D may also be produced in the skin with adequate ultraviolet light exposure. However, conditions that limit ultraviolet light exposure impair vitamin D synthesis in the skin. These include dwelling in northern latitudes and temperate climates with poor sunlight, and individuals with darker skin. Finally, the ability of the skin of older individuals to produce vitamin D is impaired. Impaired Production. Rarely, inadequate 25-hydroxylation of vitamin D may occur due to a lack of the hydroxylase enzyme or severe liver disease. Impaired production of 1,25-(OH)2D due to deficiency of the renal 1-a-hydroxylase or a phosphate-wasting disorder is a clinical rarity. In patients with hypocalcemia from hypoparathyroidism, 1,25-(OH)2D production is suppressed due to low serum PTH and high serum phosphate, thus the need for concurrent vitamin D and calcium replacement in patients with postoperative hypoparathyroidism. Catabolism or Loss. This is a poorly recognized but common cause of vitamin D insufficiency. Drugs such as phenobarbital and phenytoin increase catabolism of 25-(OH)D, or vitamin D substrates may be lost in the stool or urine. Fat malabsorption impairs the absorption of vitamin D, a fatsoluble vitamin, because vitamin D is normally secreted into

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

the bile and reabsorbed in the ileum. Diarrhea may interrupt this enterohepatic loop by increasing bowel motility. In proteinuric states, vitamin D insufficiency results because VDBP with its bound vitamin D and 25-(OH)D is expelled into the urine. Resistance. The key effects of vitamin D are mediated via its nuclear receptor, the VDR. Mutations in VDR result in a resistant state characterized by low serum calcium and phosphate, but elevated serum PTH and 1,25-(OH)2D. Binding/Redistribution of Calcium. A common cause of hypocalcemia is binding of calcium by phosphates, citrate, or other substances in blood or tissue. Phosphate binds calcium avidly, and if both calcium and phosphate concentrations are sufficiently high, calcium phosphate may precipitate in soft tissues. Elevated serum phosphate occurs due to reduced urinary excretion in renal failure or by shift out of other compartments such as massive lysis of tumor cells or necrosis of muscle with tissue injury (rhabdomyolysis). Citrate, a preservative in blood to prevent clotting by binding calcium, may cause symptomatic hypocalcemia by lowering ionized calcium even though total calcium remains in the normal range. Similarly, alkalosis reduces ionized, but not total calcium, by increased albumin binding. In patients with pancreatitis, one postulated cause of hypocalcemia is calcium saponification of the fatty acids within the pancreas and intra-abdominal tissues.

Assessment and Management of Patients with Hypocalcemia Prior to beginning an extensive evaluation in patients with hypocalcemia, pseudohypocalcemia caused by hypoalbuminemia should be excluded. Moreover, patients with alkalosis and normal serum total calcium may have true symptoms of hypocalcemia, due to the shift of ionized calcium to the protein-bound fraction. It is sometimes necessary to directly measure ionized calcium and avoid these confounding variables. Once true hypocalcemia is confirmed, history and physical may provide helpful clues to its underlying cause. A specific congenital defect is suggested by onset of hypocalcemic symptoms early in life and by a positive family history. Vitamin D deficiency presents in patients with poor vitamin D intake, low sunlight exposure, diarrhea, and hyperpigmented skin, in old age, or in patients residing in northern latitudes. A history of neck surgery, cancer, or recent trauma points to decreased PTH secretion. The most clinically useful initial test in patients with normal renal function is the serum phosphate. An elevated serum phosphate (>3.5 mg/dL) indicates a diminished PTH effect, and serum PTH should be measured. If PTH is low, deficient vitamin D production or severe hypomagnesemia is likely. On the contrary, if PTH is elevated, PTH resistance should be suspected. In contrast, low serum phosphate (< 3.5 mg/dL) implicates diminished action of vitamin D. Such patients should have a compensatory increase in serum PTH. Vitamin D insufficiency is confirmed by low serum 25-(OH)D. If serum 25-(OH)D is normal, then serum 1,25-(OH)2D should be measured. Low levels of 1,25(OH)2D establish the diagnosis of 1-a-hydroxylase deficiency, whereas high 1,25-(OH)2D levels suggest vitamin D resistance. Figure 5 illustrates our preferred algorithm for evaluating patients with hypocalcemia. Patients with low serum phosphate should be treated with calcium and vitamin D. Serum calcium less than 7.0 mg/dL in a newly

937

diagnosed patient with moderately symptomatic hypocalcemia should be treated with intravenous calcium. Dairy intake, an excellent source of calcium and phosphate, should be encouraged in these patients. Moreover, calcium supplementation should be ingested separate from meals to avoid binding phosphate. In contrast, dairy should be avoided and calcium supplementation should be given with all meals to control serum phosphate in patients with hyperphosphatemia. Intravenous calcium, when necessary, should be given with extreme caution, if at all, in patients with hyperphosphatemia because of the previously mentioned risk of soft tissue deposition of calcium phosphate.

PHOSPHATE METABOLISM Inorganic phosphate (Pi) is an important regulator of bone formation, acid–base regulation, and cellular metabolism. Numerous intracellular signaling activities require the high-energy phosphate bonds present in adenosine triphosphate. The bulk of phosphate resides in bone (600–700 g) with the remainder in soft tissues. In contrast to serum calcium, the regulation of phosphate metabolism depends less on hormonal effects but primarily on GI absorption and renal excretion. Most phosphate absorption occurs in the jejunum and ileum, and in normal individuals correlates linearly with dietary phosphate intake. The cellular process of phosphate uptake is by diffusional flux and active transport, with most of the uptake occurring by the former process. Phosphate deficiency due to inadequate oral intake is rare because most diets contain abundant amounts of phosphate. In contrast, hyperphosphatemia can occur due to inadequate renal excretion. Normally, phosphate concentration in the glomerular ultrafiltrate is 90% of plasma concentrations. However approximately 70% of this amount is reabsorbed in the proximal convoluted tubule. The proximal convoluted tubules, proximal straight tubule, and distal tubule all contain a PTH-sensitive adenylate cyclase. There is evidence suggesting that PTH decreases phosphate reabsorption by cAMP-dependent and independent mechanisms. cAMP-dependent protein kinase A and phospholipase C-protein kinase C both modulate PTH effects on the renal tubular phosphate reabsorption.

Disorders of Phosphate Metabolism Hyperphosphatemia Hyperphosphatemia is the result of increased intake (intravenous administration or phosphate enemas), decreased renal excretion (renal failure, hypoparathyroidism and PTH resistance, acromegaly, etidronate, and tumoral calcinosis), increased production from tissue injury (rhabdomyolysis, tumor lysis, hemolytic anemia, leukemia, acidosis, fulminant hepatitis, and hyperthermia), or a combination of these causes. Hyperphosphatemia due to excessive intestinal phosphate is seen mainly in children receiving phosphate-containing laxatives. In adult clinical practice, hyperphosphatemia is most commonly observed as a consequence of renal insufficiency. Management of mild to moderate hyperphosphatemia is by dietary phosphate reduction. This strategy is rarely successful because low-phosphate diets tend to be unpalatable. The use of aluminum hydroxide antacids or similar compounds to bind intestinal phosphate, thus preventing its absorption, is effective in patients with renal insufficiency. Hemodialysis is also effective for acute severe hyperphospatemia.

medwedi.ru

938

Part Seven: The Endocrine System

Figure 5 Algorithm to evaluate patients with hypocalcemia.

Hypophosphatemia Hypophospatemia most frequently results from inadequate intake or increased renal excretion of phosphate. Because western diets contain abundant phosphate, inadequate absorption is usually the result of phosphate binding in the GI tract. This can be caused by aluminum or calcium, both of which avidly bind intraluminal phosphate. Renal phosphate excretion can be increased during pHPT, Fanconi’s syndrome, hypophosphatemic rickets, or oncogenic osteomalacia. Potassium deficiency may also cause phosphate wasting. The initial management of hypophosphatemia is oral phosphate administration. Oral administration of phosphate is usually well tolerated. Because oral phosphate also binds calcium in the GI tract, the preferred method of oral phosphate administration is in divided doses. Phosphate is also better tolerated when administered with food. Oral phosphate is administered as a total of 1 to 2 g of elemental phosphate daily in divided doses. Diarrhea limits the total amount of oral phosphate that can be administered. Intravenous phosphate administration may be necessary in patients with acute severe hypophosphatemia, however it should be given very cautiously, especially when serum calcium levels are elevated. This is to avoid the risk of precipitation of calcium/phosphate salts in soft tissues. Intravenous phosphate should be considered only for severe hypophosphatemia (< 1.0 mg/dL) or symptomatic hypophosphatemia. Rates of administration should be less than 2 to 8 mmol/hr over four to eight hours and serum calcium and phosphate levels should be monitored every 6 to 12 hours.

THE PARATHYROID GLANDS Anatomy of the Parathyroid Glands During the end of the first month in utero, the inferior parathyroids (parathyroid III) proliferate from the third pharyngeal pouch along with the thymus, while the superior parathyroids (parathyroid IV) proliferate from the fourth branchial pouches in association with the lateral anlage of the thyroid. Parathyroid III (the inferior parathyroids) descends with the thymus usually to the lower border of the thyroid. Because parathyroid III migrates further than parathyroid IV (the superior parathyroids) during embryogenesis, the lower parathyroid glands are more likely to be situated in abnormal locations. Parathyroid IV (the superior parathyroids) migrates with the thyroid gland and usually comes to rest on the posterolateral aspect of the thyroid where the recurrent laryngeal nerve enters posterior to the cricothyroid muscle. Supernumerary (> 4) parathyroid glands can occur in up to 22% of patients and up to eight glands have been reported. In contrast, fewer than four glands are present in 3% to 5% of individuals. The superior parathyroid glands are usually located on the posteromedial aspect of the thyroid gland, within a 2 cm circumference and 1 cm above the point of intersection of the recurrent laryngeal nerve and inferior thyroid artery. The inferior parathyroids usually lie on the posterolateral aspect of the lower pole of the thyroid gland, below (inferior to) the inferior thyroid artery and anterior to the recurrent laryngeal nerve but may be found within the thymus, carotid sheath, thyroid gland, or in an undescended position. Lower parathyroid glands can also be located at the level

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

of the carotid bulb, (parathymus) or in the aortopulmonary window. This information is helpful when one parathyroid gland cannot be identified intraoperatively. It allows a directed search for missing parathyroid glands in the neck. The most common ectopic site for the inferior parathyroid glands is in or near the thymus, whereas the most common ectopic site for the superior glands is deep in the neck, in the tracheoesophageal groove, or posterior superior mediastinum posterior to the inferior thyroid artery. The inferior thyroid artery usually supplies the superior and the inferior parathyroid glands, although some parathyroids receive their blood supply from the superior thyroid artery and from anastomoses between the inferior and superior thyroid artery.

Primary Hyperparathyroidism pHPT is the most common cause of hypercalcemia in the ambulatory setting. In hospitalized patients, pHPT is second in frequency to cancer as a cause of hypercalcemia; thus pHPT and cancer together account for 90% of all cases of hypercalcemia. Until the early 1970s, when routine serum electrolyte tests became widely available using multichannel laboratory analyzing machines, renal colic and kidney stones were the main presenting features of pHPT. Currently, most patients with pHPT are identified during routine biochemical screening (8,9). The estimated incidence of pHPT in the United States is one new case each year per 2000 to 4000 persons in the general population (80,000–100,000 new cases annually) (10–12). pHPT occurs in 0.1% to 0.3% of the general population and is more common in women (1/500 women) than in men (1/2000 men). Primary HPT is also common in peri- or postmenopausal women and is rare in children. Approximately 87% of patients with pHPT have parathyroid adenomas, 12% have multigland hyperplasia, while 0.1% harbor a parathyroid cancer (5). This distribution is illustrated in Table 4.

Pathology of pHPT Normal parathyroid glands in adults are usually ovoid shaped, yellow–brown, encapsulated, weighing about 35 to 40 mg, and measuring 5 3 1 mm. The color varies with the amount of stromal fat present. Early in life, the glands are composed of sheets of chief cells lacking stromal fat and appear reddish brown. With increasing age, stromal fat increases to approximately 30% to 40% of the gland volume. The stromal fat also depends on body size and composition, thus overweight individuals tend to develop fatty parathyroid glands. The normal parathyroid glands tend to be soft and flabby, often taking the shape of the surrounding structures. Histologically, the normal gland has a thin fibrous capsule. Cell types identified in parathyroid glands include chief cells, oxyphil cells, water clear cells, and transitional cells. Chief cells usually predominate Table 4 Distribution of Parathyroid Abnormalities Type Adenoma Double adenoma Hyperplasia Carcinoma Parathyroid cyst Parathyromatosis Ectopic hyperparathyroidism

Frequency (%) 80—85 1—2 10—15 <1 1—3 < 0.1 Few reported cases

939

with two subgroups, dark and light (or clear, glycogencontaining) cells. The latter are defined by pale eosinophilic vacuolated staining. The dark chief cells are responsible for the synthesis and secretion of PTH. Parathyroid Adenoma The first molecular genetic abnormality identified in patients with parathyroid adenoma results from two breaks and an inversion in chromosome 11 that move the 50 regulatory region of the PTH gene away from the coding sequence to a distinct gene known as proline-rich attachment domain (PRADI). The protein encoded by PRADI is a cyclin, which stimulates cell proliferation without malignant change. The unmutated chromosome, with its 50 regulatory and coding regions adjacent and unchanged, is presumably the source of excess PTH secretion. This defect occurs in about 5% of parathyroid adenomas. However, up to 25% of parathyroid adenomas show losses of large segments of one allele of chromosome 11, which, in association with deletions or with mutations of the other allele, could lead to adenoma formation. Adenomas are principally monoclonal. In contrast, parathyroid hyperplasia, especially as seen in multiple endocrine neoplasia type 1 (MEN 1), is typically polyclonal, presumably because of an inherited mutation in a tumor suppressor locus on chromosome 11. Parathyroid Hyperplasia Multiglandular pHPT or parathyroid hyperplasia is defined as the presence of two or more enlarged glands weighing greater than 50 mg. Multiglandular hyperparathyroidism patients account for approximately 15% to 20% of patients with sporadic primary HPT. Chief-cell hyperplasia occurs more commonly than clear-cell hyperplasia. Grossly, chiefcell hyperplastic glands appear yellow to tan to red–brown, often with small cysts, and one or two glands are significantly larger than the remainder. Clear-cell hyperplastic parathyroid glands are more markedly enlarged than in chief-cell hyperplasia. Histologically, chief-cell hyperplasia is without stromal fat and may be either diffuse or nodular. Lobular parathyroid glands with variable glandular pattern, cord arrangement, and sheets suggest chief-cell hyperplasia. In clear-cell hyperplasia, the cytoplasm is characteristically pale and vacuolated with variable enlarged cells. Multiple parathyroid tumors are more common in patients over 60 years old and in patients with familial HPT. Parathyroid adenomas generally have a follicular arrangement varying mitosis, cell, and nuclear size. A normal or atrophic rim of parathyroid tissue with fat cells external to the hypercellular tissue suggests adenomatous disease, but does occur in multiglandular disease also. In spite of these differences, the histological differentiation of parathyroid adenomas from hyperplasia is very difficult. As such, it is not possible to differentiate between single and multigland parathyroid disease using intraoperative frozen section examination of one gland. Rather all parathyroid tissue is visualized and the intraoperative decision is made on size, color, and consistency of the parathyroid tissue. Unfortunately, attempts to differentiate adenoma from hyperplasia by frozen section of a single gland, continues to be a common error during parathyroidectomy. Recently, this decision has been less difficult due to increased use of intraoperative PTH measurements. Parathyroid Cancer The incidence of parathyroid cancer is now estimated to be about 0.1% of the whole population (Hundahl) (13). Patients

medwedi.ru

940

Part Seven: The Endocrine System

with parathyroid cancer often present with florid signs and symptoms of HPT and marked hypercalcemia. The average serum calcium levels and PTH levels in patients with parathyroid cancer are usually higher compared to benign parathyroid adenoma. Neck masses are palpable in 32% to 69% of patients with parathyroid carcinomas. Intraoperative differentiation between benign and malignant parathyroid tissue is fairly clear because the latter group have a tendency for locally aggressive growth. However, differentiation of parathyroid cancer from atypical parathyroid adenoma by gross inspection is not possible. At operation, parathyroid cancers are often large and hard, and have a whitish capsule that is adherent to adjacent tissues. For the diagnosis of parathyroid carcinoma, it is imperative to have one of the three following criteria: (i) capsular invasion, (ii) metastases to local lymph nodes or distant organs (lung, liver or bone), or (iii) local recurrence following complete resection (not caused by tumor spillage at resection). Histologically, a trabecular growth pattern, numerous mitotic figures, capsular invasion, and marked neovascularization sometimes help distinguish parathyroid carcinoma from adenoma. Parathyroid cancer is treated by an en bloc resection of all the structures surrounding the neoplastic gland. Even for recurrences, surgical resection is generally the most effective treatment for controlling hypercalcemia. Hypocalcemia is the best marker for successful resection of a parathyroid cancer. Recurrences often occur many years after resection of the primary lesion. Thus, lifelong surveillance is necessary. Scant reports exist of partial responses to radiation therapy (5412 cGy) or chemotherapy (14). Parathyromatosis Parathyromatosis is a rare entity that usually occurs in patients with secondary HPT or patients with MEN 1 after parathyroidectomy. It is characterized by the finding of multiple nodules of hyperfunctioning parathyroid tissue scattered throughout the neck and mediastinum. The characteristic location of parathyromatosis is in the superior mediastinal fat, tracheoesophageal groove, or at parathyroid autotransplantation sites. The cause of parathyromatosis is unknown, but seeding at surgery, hyperplastic remnant parathyroid tissue, or parathyroid carcinoma are some of the possible causes. Seeding at surgery seems an unlikely cause of this condition because resection of local disease is rarely curative.

Clinical and Biochemical Diagnosis of pHPT The current clinical presentation of pHPT in the United States bears little resemblance to the ‘‘classical primary hyperparathyroidism,’’ described by Albright in the 1930s, which was characterized by nephrolithiasis, osteitis fibrosa cystica, and frequent neuromuscular complications in the majority of patients (15). The biochemical changes associated with pHPT often result in alterations in bone density with a predisposition to urolithiasis, skeletal fractures, neuromuscular weakness, abdominal pain, and vague mood or personality changes. Historically the constellation of these symptoms has been referred to as ‘‘stones, bones, groans, abdominal moans, and psychic overtones.’’ Primary HPT is now most commonly diagnosed by the unexpected detection of hypercalcemia by a multichannel autoanalyzer examination performed in patients with no symptoms clearly referable to hypercalcemia or increased PTH levels (16). However, population-based studies suggest that closer evaluation of ‘‘asymptomatic’’ patients with pHPT reveals that

these patients often have neuropsychiatric complaints, including lassitude, fatigue, irritability, and lack of sexual and emotional interests. These patients also have more frequent subclinical abnormalities such as lower total body, spine, and hip bone density and higher serum alkaline phosphatase, cholesterol very low density lipoprotein (VLDL), triglycerides, glucose, urate, and hemoglobin values, compared to age-matched controls. In addition, clinically detected HPT is associated with premature cardiovascular death (17–19). Others have also noted an increased association between pHPT and cardiovascular morbidity, including myocardial and valvular calcifications and hypertension. Further, numerous studies demonstrate regression of cardiac abnormalities such as left ventricular hypertrophy one year after successful parathyroid surgery (20–25). pHPT is characterized by hypercalcemia in the presence of inappropriately elevated PTH levels. Two-site or intact antibody-based assays have improved the sensitivity for documenting an inappropriately elevated intact PTH level in the serum. These assays demonstrate no crossreactivity with PTH-related peptide as occurs with earlier C-terminal or mid-regional PTH assays. Intact PTH assays have facilitated the distinction between HPT and other causes of hypercalcemia. In the latter, PTH levels are uniformly suppressed; however, PTH is frankly elevated in approximately 90%, but not all, of patients with pHPT. Even pHPT patients with ‘‘normal’’ PTH levels demonstrate a PTH level that is in the high-normal range, i.e., too high for the concurrent serum calcium. Patients with pHPT and coexisting vitamin D deficiency may also present with normal serum calcium levels, although their PTH levels are high. Vitamin D deficiency, which is not uncommon in adults in the United States, can be demonstrated by serum assays for calcifediol and/or calcitriol. In such patients, correction of the vitamin D deficiency causes an increase in the serum calcium level into the hypercalcemic range. Rarely, a patient with malignancy has an elevated PTH level due to ectopic secretion of native PTH by the tumor. More commonly, hypercalcemia in a patient with a malignancy is associated with the secretion of PTH-related protein, a molecule that does not cross-react with PTH. Other laboratory findings in patients with pHPT include low or low-normal serum phosphorus (90%), hypercalciuria, hyperchloremia or high-normal chloride (80%), elevated alkaline phosphatase (10%), elevated chloride–phosphorus ratio (33), and elevated serum uric acid. The average total urinary calcium excretion is at the upper end of normal and only about 40% of all hyperparathyroid patients have hypercalciuria. Serum 25-(OH)D levels tend to be in the lower spectrum of the normal range. Although mean values of 1,25-dihydroxyvitamin D3 are in the high-normal range, approximately one-third of patients have frankly elevated levels of this hormone. Measurements of the blood urea nitrogen level and serum creatinine level and a urinalysis can document normal renal function and rule out renal failure or calculi. The vitamin D (25-OH) level may be measured if excessive vitamin D intake is suspected. The serum level of 1,25-(OH)2D is usually in the highnormal range or mildly increased in patients with pHPT. Bone resorption and bone formation are increased by parathyroid hormone. Biochemical markers of bone turnover provide clues to the extent of skeletal involvement in pHPT. Bone formation is reflected by osteoblast products, including bone-specific alkaline phosphatase activity, osteocalcin, and Type I procollagen peptide, all of which are increased in pHPT. Although the urinary hydroxyproline

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

level is usually elevated in patients with osteitis fibrosa cystica, mild asymptomatic pHPT is typically associated with normal hydroxyproline levels. The blood urea nitrogen and serum creatinine levels must be measured because renal insufficiency alters the interpretation of the serum and urinary calcium measurements. Serum protein electrophoresis is important to exclude multiple myeloma, but patients with multiple myeloma should have a normal intact PTH level. Benign FHH is the metabolic condition that can most closely mimic HPT biochemically, with increased serum calcium and intact PTH levels. However, patients with FHH usually demonstrate low urinary calcium (< 100 mg/24 hr), whereas patients with HPT have normal or elevated urinary calcium levels (> 100 mg/24 hr). For this reason, it is important to include a 24-hour urine test for calcium and serum and urinary creatinine measurements in the diagnostic evaluation. However, urinary calcium measurement is not necessary if the patient has previously had blood tests documenting normocalcemia before the onset of primary HPT. In conclusion, pHPT can be accurately and cost-effectively diagnosed by documenting an elevated serum calcium level and an elevated serum level of intact PTH in a patient who is not hypocalciuric. Serum levels of bone-specific alkaline phosphatase and osteocalcin are also good clinical indicators of increased bone turnover in patients with pHPT, because they are elevated before parathyroidectomy and decrease after parathyroidectomy. If significantly elevated, these markers may be useful in determining the need for parathyroidectomy in patients with mild or asymptomatic hyperparathyroidism (18).

Treatment of pHPT There is little debate about the need for parathyroidectomy in patients with classic symptomatic pHPT characterized by radiologic manifestations of pHPT (significantly decreased bone density or osteitis fibrosa cystica), nephrolithiasis or nephrocalcinosis, classical neuromuscular disease characterized by generalized fatigue and muscular weakness and easy fatigability (especially quadriceps muscle weakness and fatigability), fracture, and acute pHPT (i.e., hypercalcemic crisis). Other indications for parathyroidectomy are coexisting vitamin D deficiency or inability to ensure longterm follow-up. However, much controversy exists about the appropriate management of patients with asymptomatic or minimally symptomatic pHPT. The National Institutes of Health (NIH) Consensus Conference clearly recommended surgery for patients with significant adverse effects of pHPT, complicating coexistent illnesses, age less than 50, and those in whom consistent long-term follow-up could not be assured. The Consensus Conference agreed that conscientious surveillance may be justified in patients with minimal hypercalcemia and no adverse effects, but it recognized that for many patients, the time and expense involved in rigorous follow-up could outweigh the risks of surgery. More recently the NIH convened another consensus conference. Their recommendations are published in manuscript form (26). A comparison of both recommendations is listed in Table 5. Surgery for pHPT Felix Mandl performed the first successful parathyroidectomy on a street-car driver with osteitis fibrosa cystica in 1925. After removal of a 21 15 12 mm parathyroid gland, the patient’s urine cleared within a week and recalcification of his bones was noted on follow-up radiography. In 1926, the first parathyroidectomy in the United States was

941

Table 5 Recommendations for Surgical Intervention Measurement Serum Ca (above upper limit of normal) 24 hr urinary calcium Creatinine clearance Bone mineral density

Guidelines (1990)

Guidelines (2002)

1–1.6 mg/dL

1.0 mg/dL

> 400 mg Reduced by 30% z-score < -2.0 (forearm)

> 400 mg Reduced by 30% t-score < -2.5 any site

Age < 50 years

performed on a sea captain (Charles Martell); unfortunately he required six operations, including total thyroidectomy, over a seven-year period before an elusive parathyroid adenoma was identified beneath his sternum and removed. His hypercalcemia resolved but he died soon of renal failure after the successful operation. Since then, parathyroidectomy has been demonstrated to successfully cure over 95% of patients with pHPT (27–31). Technique. Until recently, most surgeons advocated routine bilateral neck exploration and identification of all parathyroid glands. During bilateral neck exploration, abnormal glands are defined by size, weight, color, and consistency. Recent advances in Sestamibi imaging and rapid intact PTH assay have fueled the development of minimally invasive approaches for parathyroid operative procedures. Minimally invasive approaches have potential for improved cosmetic appearance, elimination of overnight hospital admission, less pain, and shorter convalescence. However, they rely heavily on the availability and accuracy of preoperative localization tests such as high-resolution ultrasonography, Sestamibi scanning, computed tomography (CT), and/or magnetic resonance imaging (MRI) (32). Abnormal glands are then localized at operation. Palpation, intraoperative ultrasonography, and radioactive probe–directed localization (see below) may be useful adjuncts to localize the enlarged glands in the operating room. Controversy abounds regarding the costs of preoperative testing in patients and the potential for missing other hyperplastic parathyroid glands in patients with multiglandular disease when limited exploration is employed, because the incidence of multiglandular disease ranges from 7% to 30%. The sensitivity of Sestamibi scan has been as high as 95% using the single photon emission computed tomography (SPECT) technique and a 3-D display (volume-rendered reprojection for visualization). However, it is associated with a high false-positive rate especially in patients with thyroid nodules. This false-positive rate may be the reason for operative failures in patients who undergo parathyroidectomy based solely on Sestamibi scans. Irvin and colleagues popularized the use of rapid intraoperative chemiluminescent PTH monitoring to confirm excision of all hyperfunctioning parathyroid tissue. In 61 patients who underwent 63 explorations for pHPT, there was a 54% decrease in the serum PTH level 10 minutes after excision of a parathyroid adenoma in patients who were rendered normocalcemic postoperatively. Their 10-minute assay had a sensitivity of 96%, a specificity of 100%, and a positive predictive value of 97% (33,34). Our group and others have since validated the benefits of rapid intact PTH as a reliable method of ensuring excision of all hyperfunctioning parathyroid tissue (35). Many surgeons now use the threshold of greater than 50% decline in PTH levels 10 minutes after excision, and a decline into the normal

medwedi.ru

942

Part Seven: The Endocrine System

range, to confirm adequate parathyroidectomy. If the criteria are not met, it should be assumed that there is additional disease and full neck exploration is indicated. Many surgeons exploit the property of parathyroid adenomas to retain Sestamibi as a guide to direct resection using radioactive assessment with a hand-held gamma probe (Neoprobe Corp., Columbus, Ohio, U.S.A.). This technique involves excising the suspected parathyroid adenoma previously identified on preoperative Sestamibi scan. After excision, radioactive counts of the excised parathyroid over 20% of background radioactivity in the neck confirm that the excised tissue is the Sestamibi-identified gland. Reports of successful application of this technique indicate an accuracy of up to 95% (36). This technique clearly depends on high sensitivity Sestamibi scans, which can be achieved using SPECT techniques or oblique views. Further, proponents of this method indicate that such patients need to undergo surgery soon after Sestamibi injection. Using these techniques, radio-guided parathyroidectomy has been successful in more than 90% of patients with a positive Sestamibi scan. This technique, however, requires seamless communication between the nuclear radiologists and surgical teams. Others have used a directed approach based on both preoperative Sestamibi scan and high-resolution ultrasonography, with or without intraoperative PTH measurement. When both the Sestamibi and ultrasound scans are concordant, success rates of 95% to 98% are observed. We have successfully used the directed approach with Sestamibi, ultrasonography, and intraoperative PTH measurement. Our preferred algorithm for evaluating surgical candidates for directed parathyroidectomy is shown in Figure 6. Using this technique, we have been able to perform successful directed parathyroidectomy in 70% of our patients with pHPT with a mean hospital stay of 12 hours (37). In summary, directed parathyroidectomy using any of these approaches can be performed with cure rates equivalent to those seen after conventional bilateral neck exploration. Further, directed parathyroidectomy involves less operating time, morbidity, and cost. Choice of technique should depend on local expertise (radiologic, surgical, laboratory, and pathology), patient choice, and institutional resources. For patients with multiglandular disease, directed approaches are usually unsuccessful due to inability to localize a single gland preoperatively or decrease the PTH level after excision of a single gland. Such patients require bilateral neck exploration, however controversy exists regarding the extent of parathyroidectomy. Both subtotal parathyroidectomy and total parathyroidectomy with autotransplantation help achieve excellent results in patients with primary HPT due to multiglandular disease. The latter approach is based on the belief by many surgeons that all parathyroids are potentially hyperfunctioning when there is multiglandular disease, even when they are not all enlarged (38). Ectopic Parathyroid Glands. Although as many as 20% of parathyroid glands in pHPT are located in the mediastinum, most mediastinal parathyroid glands are intrathymic (inferior glands) and can be removed transcervically. Preoperative imaging including sestamibi scintigraphy in combination with an anatomic study such as CT or MRI is necessary to determine the optimal approach. The CooperTM thymectomy retractor has been useful in facilitating transcervical resection of deep mediastinal ectopic parathyroid glands.

Other options for the management of mediastinal parathyroid glands include the use of anterior mediastinotomy (Chamberlain procedure), mini thoracotomy, video-assisted thoracic surgery, and angiographic ablation (39). Using these techniques, only about 2% of deep mediastinal parathyroid glands cannot be extracted through a cervical incision and have required median sternotomy for removal. Figure 7 shows a mediastinal ectopic parathyroid gland. The importance of accurate, preoperative localization studies prior to undertaking these operative approaches cannot be overemphasized. Multiple preoperative studies are frequently used, and the diagnosis is more certain with two or more concordant studies (40). Results of Parathyroidectomy. Successful parathyroidectomy results in normalization of serum calcium concentrations and reverses the other adverse effects of the disease. For example, serum levels of PTH, bone-specific alkaline phosphatase, and osteocalcin when elevated before parathyroidectomy, decrease significantly after parathyroidectomy (41). This is manifested by a significant increase in bone mineral density of the spine, femoral neck, hip, and trochanter. Surgical Treatment of Renal Hyperparathyroidism Secondary (renal) HPT induced by chronic renal failure is one of the most serious complications for long-term hemodialysis patients. Parathyroidectomy is indicated in patients with secondary renal HPT refractory to medical treatment. However, skeletal deformity, vessel calcification, and remarkable reduction of bone content are irreversible in these patients, so it is important to perform parathyroidectomy prior to the onset of these changes. HPT complicating renal failure is characterized by several pathogenic factors including hypocalcemia, phosphate retention, deficiency of active vitamin D, decreased number of calcitriol receptors in parathyroid cells, and skeletal resistance to PTH action. The purpose of medical treatment is to reduce hyperphosphatemia, elevate the serum calcium level, reduce serum PTH levels, and improve skeletal turnover. However, it is very difficult to maintain a normal serum phosphate level by phosphate restriction, and the use of phosphate binders. Currently, vitamin D (calcitriol) administration is the most promising form of prophylaxis and treatment for secondary HPT. Vitamin D is usually prescribed as an ‘‘intermittent high-dose treatment’’ (42). Indications and Technique of Parathyroidectomy in Patients with Renal Hyperparathyroidism Parathyroidectomy may be considered for normocalcemic patients with radiographic evidence of bone disease (osteitis fibrosa cystica), high serum PTH level, imaging studies showing parathyroid glands weighing over 500 mg; and bone metabolic markers or bone scintigraphy showing high rates of bone turnover. Patients with a functioning kidney graft are rarely considered for parathyroidectomy except in circumstances such as the presence of persistent or progressive hypercalcemia, progressive osteodystrophy, nephrolithiasis, or deterioration of graft function. Total parathyroidectomy with a forearm autograft is preferred for renal HPT requiring surgical treatment, because it is convenient and safer to remove the residual parathyroid tissue from the forearm if the HPT recurs compared to a reoperative procedure in the neck. Moreover, the function of the autografted parathyroid tissue can be easily determined by measuring PTH samples from both arms. The removal of all parathyroid

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

943

Figure 6 Algorithm for evaluating surgical candidates for directed parathyroidectomy.

tissue, including supernumerary glands, at the initial operation, and choice of adequate parathyroid tissue for the autograft, are important to prevent persistent and recurrent HPT. Supernumerary glands and rudiments of parathyroid tissue are present in 13% to 15% of all individuals. For this reason, concurrent routine thymectomy is recommended during parathyroidectomy for renal hyperparathyroidism. After confirmation of parathyroid tissue by frozen-section

examination of each gland, suitable parathyroid tissue is selected for autografting. The parathyroid autotransplants are preferably excised from the smallest gland in each case, avoiding macroscopically visible nodules. The glandular tissue is sliced into 1 1 3 mm pieces, and approximately 20 to 30 pieces weighing a total of about 90 mg should be used for autotransplantation by implantation into separate pockets in the brachioradialis muscle of the arm, without hemodialysis access. Calcium replacement therapy is crucial during the first three weeks after operation because PTH secretion from the autografted parathyroid tissue is insufficient and the bone formation is accelerated after parathyroidectomy. Calcium replacement therapy is usually begun after the serum calcium level falls below 3.5 mEq/L, confirming adequate excision of all parathyroid tissue. Initially, intravenous calcium gluconate injection is given, after which oral 1-acalcitriol and calcium carbonate are given to maintain a normal serum calcium level. After the serum alkaline phosphatase level becomes normal, an adequate amount of vitamin D and calcium salts should be given to prevent recurrent HPT and to avoid adynamic bone disease.

Medical Approaches to pHPT

Figure 7 Demonstration of a mediastinal ectopic parathyroid gland.

Because parathyroidectomy is associated with high cure rates and low complication rates, parathyroidectomy is the treatment of choice for most patients with pHPT. A small fraction of patients with pHPT are not candidates for parathyroidectomy. These include elderly, poor

medwedi.ru

944

Part Seven: The Endocrine System

operative risk patients, and patients who refuse surgery. Acceptable nonoperative alternatives for primary HPT include bisphosphonates, estrogen replacement, and calcimimetics. Oral phosphate treatment has also been examined for this subgroup of patients. However the potential danger of ‘‘parathyroid poisoning,’’ caused by deposition of calcium phosphate salts in the kidney and other organs has caused oral or intravenous phosphate therapy to fall out of favor. Bisphosphonate Therapy of pHPT Bisphosphonates are analogs of inorganic pyrophosphate in which the central oxygen atom is replaced by a carbon atom, yielding the core structure P-C-P. These agents reduce serum calcium levels by direct inhibition of bone resorption by osteoclasts and caspase-mediated apoptosis of osteoclasts. Oral administration of the potent second-generation bisphosphonate clodronate (dichloromethylene bisphosphonate) reduces serum calcium level to almost normal. The hypocalcemic effect of clodronate waned over time, and the level of PTH rises. The increasing circulating PTH levels consistently observed with bisphosphonate administration points to a fundamental difficulty with such therapy. Estrogens and Progestins High doses of estrogen can correct hypercalcemia and hypercalciuria (43). However there are no randomized, controlled trials comparing hormonal therapy with parathyroid surgery. In addition, the effect of hormonal therapy on other symptoms of HPT such as renal stones and neurologic function has not been addressed. Hormonal replacement therapy is further limited to postmenopausal women who have no contraindications to estrogen treatment. Although a randomized trial is needed to resolve the differences between the effects of hormonal replacement therapy and parathyroidectomy on bone, current evidence suggests that medical treatment with estrogens and progestins provides a reasonable alternative to parathyroidectomy for postmenopausal women with primary HPT (especially in those with no other indication for parathyroidectomy and in those who are poor surgical candidates). It is not clear whether postmenopausal estrogen therapy for pHPT offers any advantage over bisphosphonate treatment with regard to bone mass; however, the disadvantage of bisphosphonates is that they may increase the serum PTH level (44). Studies of postmenopausal HPT confirm the benefit of postmenopausal hormone replacement treatment on bone mass and the size of the parathyroid glands (45–47). Calcimimetics The newest and potentially most useful class of drugs for the treatment of HPT is calcimimetic agents. Unlike the other therapeutic agents that work primarily by inhibiting bone resorption in response to PTH, the calcimimetics target the calcium-sensing mechanism in the parathyroid glands. The molecular basis of calcium sensing by the parathyroid glands was elucidated with the identification of a calcium receptor on the surface of the parathyroid cell. On binding calcium, the receptor signals the interior of the parathyroid cell to inhibit the secretion of PTH. The predominant intracellular second messenger that carries this signal is intracellular calcium. Thus, an increase in extracellular calcium induces an increase in intracellular calcium, which, in turn, inhibits the secretion of PTH from secretory granules within the parathyroid cell. The calcium receptor is also present in the renal tubule, where it regulates renal calcium excretion, and in

calcitonin-secreting C-cells of the thyroid, where it mediates the stimulation of calcitonin release by hypercalcemia. Calcimimetic drugs alter the sensitivity of the parathyroid calcium receptor to extracellular calcium. These phenylalkylamine compounds decrease the responsiveness of cells to low extracellular calcium. The net effect of these actions is to increase the sensitivity of parathyroid cells to the suppressive effects of high extracellular calcium, markedly decreasing the rate of PTH secretion at ambient calcium levels of about 1 mmol present in both normal and hyperparathyroid states. The administration of a single 160 mg dose of the calcimimetic, NPS R-568 to postmenopausal women caused a maximal 51% decrease in the serum PTH level. However, there was only a small decrease in the serum level of ionized calcium detected with the administration of NPS R-568. Acute administration of NPS R-568 to dialysis patients achieved a dose-dependent repression of PTH secretion and an increase in calcitonin levels (48). In a placebo-controlled study of 21 dialysis patients treated for 15 days, NPS R-568 significantly decreased the serum PTH level and the serum levels of total and ionized calcium. The serum ionized calcium level fell to less than 1 mmol/L in approximately half of the patients receiving the drug; five patients withdrew from the study because they developed hypocalcemia caused by the drug. In addition, in a patient with parathyroid carcinoma who presented with parathyroid crisis, monotherapy with NPS R-568 controlled the hypercalcemia for two years with no adverse side effects (49). Although NPS R-568 can acutely reduce serum PTH levels, it has a short half-life because it is rapidly metabolized by the liver, thus reducing its clinical usefulness. Second-generation calcimimetics with longer half-lives and a more predictable therapeutic effect are currently in clinical trials in patients with primary and secondary HPT (50). In fact, small studies have documented the efficient lowering of serum PTH in patients with primary hyperparathyroidism, suggesting that this approach may soon gain widespread acceptance (51).

MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES Multiple endocrine neoplasias are inherited endocrine diseases that manifest in several endocrine glands including the pituitary, parathyroid, thyroid, pancreas, and adrenal glands. Based on a kindred with medullary thyroid carcinoma, pheochromocytomas, and parathyroid hyperplasia, Steiner and his colleagues introduced the term ‘‘multiple endocrine neoplasia’’ in 1968 (52). MEN 1 is used to describe the multiple endocrine adenomatosis syndrome described by Wermer, which includes pituitary adenomas, parathyroid hyperplasia, and pancreatic islet tumors. MEN 2 is used to describe the kindred that manifest with medullary thyroid cancer, pheochromocytoma, and either parathyroid hyperplasia (MEN 2A) or ganglioneuromas (MEN 2B). In addition to these syndromes, Foley and his colleagues described an inherited hypercalcemic condition that was distinct from the MEN syndromes, which they termed ‘‘familial benign hypercalcemia.’’ In the MEN syndromes, generalized HPT is a common feature. It occurs much more frequently in patients with MEN type 1 as compared to patients with MEN type 2A. Unlike the MEN syndromes, patients with FHH have only hypercalcemia with no associated endocrinopathies. The HPT in patients with either of the MEN syndromes is managed by parathyroidectomy, whereas patients with FHH are managed nonoperatively.

Chapter 49: Calcium and Phosphorus Metabolism and the Parathyroid Gland

The specific genetic defects associated with MEN type 2 syndromes and FHH have been identified (53).

SUMMARY Calcium and phosphorus balance are critically important for normal neuromuscular excitation, contraction, and relaxation. When a perturbation in calcium occurs, a corresponding derangement in phosphorus also results. Because an alteration in calcium is the driving force behind consequent phosphorus alterations, a clear understanding of calcium homeostasis is mandatory. Key sites of calcium regulation include absorption from the gut, resorption from bone, and excretion by the kidneys. Thus, hypocalcemia can result from any dysfunction of these processes, such as excess intake and absorption from the intestine, decreased renal excretion, or increased tone resorption. Conversely, hypocalcemia is caused by decreased calcium intake, increased calcium binding in the gut, increased excretion, or decreased bone resorption. The parathyroid glands are the master regulators of these actions. They accomplish these goals by sensing ionized calcium in the blood as well as effecting normal calcium homeostasis through parathormone secretion, which controls bone resorption and calcium excretion by the kidneys. Primary hyperparathyroidism is the major disorder affecting the parathyroid glands as well as the major disorder responsible for hypercalcemia. Although hypercalcemia can be acutely managed by a variety of medical strategies, when caused by hyperfunction of the parathyroid glands, surgical management is the most effective means of control. This can range from removal of a single gland if an adenoma is involved to resection of 3-1/2 glands if diffuse hyperplasia is the cause of the hyperfunction. Primary hypoparathyroidism is extremely rare and usually of no consequence to the surgeon. The major reason for hypoparathyroidism in the surgical setting is that the glands have been removed or severely compromised in terms of blood supply during total thyroidectomy. If the former situation occurred, permanent calcium replacement therapy will be required. If the latter circumstance exists, some parathyroid function may ultimately return, but even in this setting, adjunctive calcium replacement treatment is often needed.

REFERENCES 1. Stewart AF. Translational implications of the parathyroid calcium receptor. N Engl J Med 2004; 351:324–326. 2. Thakker RV. Diseases associated with the extracellular calciumsensing receptor. Cell Calcium 2004; 35:275–282. 3. Brown EM. Physiology and pathophysiology of the extracellular calcium-sensing receptor. Am J Med 1999; 106:238–253. 4. Urena Torres PA, Chanard J. Cinacalcet for secondary hyperparathyroidism in hemodialysis recipients. N Engl J Med 2004; 351:188–189; author reply 188–189. 5. Mallette LE, Coscia AM. Rapid radioimmunoassay for parathyroid hormone: its use in hypercalcemic crisis. South Med J 1984; 77:323–326. 6. Mallette LE. Immunoreactivity of human parathyroid hormone (28–48): attempt to develop an assay for intact human parathyroid hormone. Metab Bone Dis Relat Res 1983; 4:329–332. 7. Palmer FJ, Nelson JC, Bacchus H. The chloride-phosphate ratio in hypercalcemia. Ann Intern Med 1974; 80:200–204. 8. Lendel I, Horwith M. An update from the latest workshop on asymptomatic primary hyperparathyroidism. Otolaryngol Clin North Am 2004; 37:737–749.

945

9. Ahmad R, Hammond JM. Primary, secondary, and tertiary hyperparathyroidism. Otolaryngol Clin North Am 2004; 37: 701–713. 10. Adami S, Marcocci C, Gatti D. Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res 2002; 17(suppl 2): N18–N23. 11. Melton LJ III. The epidemiology of primary hyperparathyroidism in North America. J Bone Miner Res 2002; 17(suppl 2):N12–N17. 12. Bilezikian JP, Potts JT Jr. Asymptomatic primary hyperparathyroidism: new issues and new questions—bridging the past with the future. J Bone Miner Res 2002; 17(suppl 2): N57–N67. 13. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985–1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1999; 86:538–544. 14. Favia G, Lumachi F, Polistina F, D’Amico DF. Parathyroid carcinoma: sixteen new cases and suggestions for correct management. World J Surg 1998; 22:1225–1230. 15. Silverberg SJ, Bilezikian JP, Bone HG, Talpos GB, Horwitz MJ, Stewart AF. Therapeutic controversies in primary hyperparathyroidism. J Clin Endocrinol Metab 1999; 84:2275–2285. 16. Lundgren E RJ, Thrufjell E, Akerstrom G, Ljunghall S. Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women. Surgery 1997; 121:287–294. 17. Hedback GM, Oden AS. Cardiovascular disease, hypertension and renal function in primary hyperparathyroidism. J Intern Med 2002; 251:476–483. 18. Palmer M, Adami HO, Bergstrom R, Jakobsson S, Akerstrom G, Ljunghall S. Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of followup. Lancet 1987; 1:59–62. 19. Nilsson IL, Aberg J, Rastad J, Lind L. Left ventricular systolic and diastolic function and exercise testing in primary hyperparathyroidism-effects of parathyroidectomy. Surgery 2000; 128:895–902. 20. Stefenelli T, Abela C, Frank H, Koller-Strametz J, Niederle B. Time course of regression of left ventricular hypertrophy after successful parathyroidectomy. Surgery 1997; 121:157–161. 21. Stefenelli T, Abela C, Frank H, et al. Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up. J Clin Endocrinol Metab 1997; 82:106–112. 22. Langle F, Abela C, Koller-Strametz J, et al. Primary hyperparathyroidism and the heart: cardiac abnormalities correlated to clinical and biochemical data. World J Surg 1994; 18:619–624. 23. Stefenelli T, Mayr H, Bergler-Klein J, Globits S, Woloszczuk W, Niederle B. Primary hyperparathyroidism: incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am J Med 1993; 95:197–202. 24. Stefenelli T, Globits S, Bergler-Klein J, Woloszczuk W, Langle F, Niederle B. Cardiac changes in patients with hypercalcemia. Wien Klin Wochenschr 1993; 105:339–341. 25. Stefenelli T, Pacher R, Woloszczuk W, Glogar D, Kaindl F. Parathyroid hormone and calcium behavior in advanced congestive heart failure. Z Kardiol 1992; 81:121–125. 26. Bilezikian JP, Potts JT Jr, Fuleihan Gel H, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Bone Miner Res 2002; 17(suppl 2):N2–N11. 27. Conroy S, Moulias S, Wassif WS. Primary hyperparathyroidism in the older person. Age Ageing 2003; 32:571–578. 28. Inabnet WB, Fulla Y, Richard B, Bonnichon P, Icard P, Chapuis Y. Unilateral neck exploration under local anesthesia: the approach of choice for asymptomatic primary hyperparathyroidism. Surgery 1999; 126:1004–1009; discussion 1009–1010. 29. Irvin GL III, Molinari AS, Figueroa C, Carneiro DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999; 229:874–878; discussion 878–879. 30. Peix JL, el Khazen M, Mancini F, Binet A, Berger N, Lapras V. Surgery for primary hyperparathyroidism in 1998. Apropos

medwedi.ru

946

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

Part Seven: The Endocrine System of 66 patients and 3 methods of approach. Ann Chir 1252000346–352. Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000; 232:331–339. Moka D, Voth E, Dietlein M, Larena-Avellaneda A, Schicha H. Technetium 99m-MIBI-SPECT: a highly sensitive diagnostic tool for localization of parathyroid adenomas. Surgery 2000; 128:29–35. Boggs JE, Irvin GL III, Molinari AS, Deriso GT. Intraoperative parathyroid hormone monitoring as an adjunct to parathyroidectomy. Surgery 1996; 120:954–958. Irvin, Molinari AS, Carneiro DM, Rivabem F, Ruel MM, Boggs JE. Parathyroidectomy: new criteria for evaluating outcome. Am Surg 1999; 65:1186–1188; discussion 1188–1189. Gordon LL, Snyder WH III, Wians F Jr, Nwariaku F, Kim LT. The validity of quick intraoperative parathyroid hormone assay: an evaluation in seventy-two patients based on gross morphologic criteria. Surgery 1999; 126:1030–1035. Murphy C, Norman J. The 20% rule: a simple, instantaneous radioactivity measurement defines cure and allows elimination of frozen sections and hormone assays during parathyroidectomy. Surgery 1999; 126:1023–1028; discussion 1028–1029. Burkey SH, Snyder WH III, Nwariaku F, Watumull L, Mathews D. Directed parathyroidectomy: feasibility and performance in 100 consecutive patients with primary hyperparathyroidism. Arch Surg 2003; 138:604–608; discussion 608–609. Proye C, Carnaille B, Quievreux JL, Combemale F, Oudar C, Lecomte-Houcke M. Late outcome of 304 consecutive patients with multiple gland enlargement in primary hyperparathyroidism treated by conservative surgery. World J Surg 1998; 22:526–529; discussion 529–530. Heller HJ, Miller GL, Erdman WA, Snyder WH III, Breslau NA. Angiographic ablation of mediastinal parathyroid adenomas: local experience and review of the literature. Am J Med 1994; 97:529–534. Medrano C, Hazelrigg SR, Landreneau RJ, Boley TM, Shawgo T, Grasch A. Thoracoscopic resection of ectopic parathyroid glands. Ann Thorac Surg 2000; 69:221–223. Tominaga Y, Numano M, Tanaka Y, Uchida K, Takagi H. Surgical treatment of renal hyperparathyroidism. Semin Surg Oncol 1997; 13:87–96.

42. Thorsen K, Kristoffersson AO, Lorentzon RP. Changes in bone mass and serum markers of bone metabolism after parathyroidectomy. Surgery 1997; 122:882–887. 43. Marcus R, Madvig P, Crim M, Pont A, Kosek J. Conjugated estrogens in the treatment of postmenopausal women with hyperparathyroidism. Ann Intern Med 1984; 100:633–640. 44. Strewler GJ. Medical approaches to primary hyperparathyroidism. Endocrinol Metab Clin N Am 2000; 29:523–539, vi. 45. Diamond T, Ng AT, Levy S, Magarey C, Smart R. Estrogen replacement may be an alternative to parathyroid surgery for the treatment of osteoporosis in elderly postmenopausal women presenting with primary hyperparathyroidism: a preliminary report. Osteoporos Int 1996; 6:329–333. 46. Guo CY, Thomas WE, al-Dehaimi AW, Assiri AM, Eastell R. Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81:3487–3491. 47. McDermott MT, Perloff JJ, Kidd GS. Effects of mild asymptomatic primary hyperparathyroidism on bone mass in women with and without estrogen replacement therapy. J Bone Miner Res 1994; 9:509–514. 48. Antonsen JE, Sherrard DJ, Andress DL. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure [Rapid communication]. Kidney Int 1998; 53:223–227. 49. Goodman WG, Frazao JM, Goodkin DA, Turner SA, Liu W, Coburn JW. A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 2000; 58(1):386–387. 50. Weigel RJ. Nonoperative management of hyperparathyroidism: present and future. Curr Opin Oncol 2001; 13:33–38. 51. Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M. The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 2003; 88:5644–5649. 52. Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine (Baltimore) 1968; 47:371–409. 53. Herfarth KK, Wells SA Jr. Parathyroid glands and the multiple endocrine neoplasia syndromes and familial hypocalciuric hypercalcemia. Semin Surg Oncol 1997; 13:114–124.

50 Pituitary Dysfunction Henry Ty and Kathryn Holloway

INTRODUCTION The pituitary gland secretes hormones that affect the functions of the endocrine organs. These are essential in maintaining the internal homeostasis of the body as it adapts to the environment. They establish communications between distant cells to facilitate the gathering of nutrients, water, and minerals, their metabolism and their use for growth, repair, and reproduction. The function of the pituitary gland ultimately determines the ability to cope with the environment and the chances for a successful propagation of progenies. Pituitary dysfunction results when there is a relative excess or deficiency in the amount or activity of one or more of its hormones. It can be caused by tumors, vascular lesions, inflammation, infection, trauma, systemic disease, surgery, radiation, medication, congenital abnormalities, or genetic defects. These may involve primarily the hypothalamus, the pituitary gland, or the target endocrine organs. Different causes can produce the same symptoms. The clinical presentation is dependent on how fast the lesion progresses. A tuberculum sella meningioma may cause the insidious development of pituitary deficiency and have few symptoms until it reaches a large size, while pituitary apoplexy may present with sudden loss of consciousness and result in death if untreated. Although hormonal excess is usually caused by a pituitary adenoma, it can be secondary to hypothalamic lesions such as a hamartoma that increases the secretion of pituitary gonadotropins, ectopic sources of hormones such as an adrenocorticotropic hormone (ACTH)-secreting lung tumor, or oversecretion by the target organs. On the other hand, hormonal deficiency, while common in pituitary macroadenomas due to their mass effect on the adjacent normal gland, may be caused by failure of the hypothalamus, target organs, or hormonal receptors. The diagnosis of pituitary dysfunction necessitates recognition of the part of the hypothalamic-pituitary-target organ axis that is involved. Treatment involves the removal of the cause of the dysfunction, replacement of deficient hormones, and control of hormonal oversecretion. This chapter reviews pituitary physiology and focuses on surgical lesions in the sellar area that causes pituitary dysfunction.

constitutes about 80% of the hypophysis and is divided into pars distalis, pars intermedia, and pars tuberalis, which partially wraps around the pituitary stalk. The pars intermedia are vestigial in adults. The smaller multinodular posterior lobe (pars nervosa) is attached to the stalk (infundibular stem), which is continuous with the median eminence of the hypothalamus. The pars nervosa, infundibular stem, and median eminence form the neurohypophysis. The pituitary gland is located within the sella turcica, a bony fossa at the central part of the sphenoid bone, which is lined by dura mater. Anterior to it is the tuberculum sella. Posteriorly, the dorsum sella curves down to form the clivus. The cavernous sinuses are adjacent to the pituitary gland bilaterally (Fig. 1). Within each sinus are cranial nerves III, IV, V1, V2, VI, and the internal carotid artery (ICA). The optic chiasm is above the gland and normally is anterior to the infundibulum. The basilar artery and pons are posterior to it. The inferior surface of the gland conforms

ANATOMY OF THE PITUITARY GLAND The pituitary gland (hypophysis) is an ovoid organ weighing about 0.6 g. It is approximately 6 mm high, 13 mm wide, and 9 mm long (1). Its width is usually equal to or greater than its length. It is larger in females, especially during pregnancy. It is composed of the anterior and posterior lobes. The larger anterior lobe (adenohypophysis)

Figure 1 Coronal magnetic resonance imaging showing the pituitary gland (p) with its stalk adjacent to the optic chiasm (oc) and optic nerves (CN II). Lateral to the gland on each side is the cavernous sinus (cs) with the internal carotid artery within it. The frontal horn of the lateral ventricles (v) can be seen.

medwedi.ru 947

948

Part Seven: The Endocrine System

to the shape of the sellar floor but its lateral and superior margins vary in shape because they are bounded by soft tissue rather than bone. Below the sellar floor is the sphenoid sinus, which separates the gland from the nasal cavity (Fig. 2). Its size, shape, and degree of pneumatization are variable and are important considerations prior to a transsphenoidal surgery. The diaphragma sella is a thin, rectangular dural structure that forms the roof of the sella turcica. It lies below the plane of the anterior clinoid processes. It has a round to ellipsoid central opening through which the pituitary stalk passes. This opening measures at least 5 mm and is larger than the diameter of the stalk. The arachnoid membrane lies above the diaphragma sella but protrudes through this opening in about half of the patients (2). When the cerebrospinal fluid (CSF) fills the top half of the sella and pushes the gland to the sellar floor, this is called an empty sella, which is not pathologic. A lesion located above the diaphragma sella, e.g., an aneurysm, may protrude downward and appear to be within the sella. The superior hypophyseal arteries arise from the supraclinoid ICA to supply the median eminence, proximal infundibulum, and the optic chiasm. Their capillaries drain into the hypophyseal portal veins that join another capillary bed in the pars distalis. The inferior hypophyseal arteries arise from the intracavernous ICA to supply the pars nervosa. The hypophyseal veins drain into the adjacent dural sinuses, and eventually to the cavernous and petrosal sinuses. The median eminence has fenestrated capillaries that allow transport of polypeptide hormones. There is no blood brain barrier in the neurohypophysis. Lesions in the adjacent structures, e.g., hypothalamic tumor, may result in pituitary dysfunction. Similarly, lesions in the sellar area, e.g., pituitary adenoma, may become large

enough to compress the surrounding structures such as the optic chiasm and alter their functions.

PHYSIOLOGY OF THE PITUITARY GLAND The pituitary gland releases hormones that alter the metabolism of their target organs. The hypothalamus in turn controls the pituitary gland by its neural projections to the neurohypophysis and by a vascular network through the adenohypophysis. It secretes releasing hormones and inhibiting factors that regulate the synthesis and release of pituitary hormones. The hormones produced by the pituitary and target organs modulate further secretion from the pituitary and the hypothalamus. This complex integration of neurohormonal functions by both nervous and endocrine systems regulates the metabolic activities that affect homeostasis, growth, development, and reproduction. The adenohypophysis produces hormones that are stored prior to their release. The parvocellular neurons in the arcuate and paraventricular nuclei of the hypothalamus produce factors that control the release of hormones from the adenohypophysis. These factors are transported from the cell bodies of the paired nuclei, along the tuberohypophyseal (tuberoinfundibular) tract, to the neuronal terminals at the median eminence. They are released into the capillaries of the median eminence and proximal infundibulum in response to action potentials. From here, they travel via the portal vessels to reach the pars distalis. The hypophyseal portal system serves as a vascular connection between the hypothalamus and the adenohypophysis. There is no direct neuronal connection between the two. The magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus produce vasopressin and oxytocin (OT). The hormones are produced in the cell bodies and are bound to carrier polypeptides called neurophysins. They are transported within membrane-bound vesicles by axoplasmic flow along the supraopticohypophyseal and the paraventriculohypophyseal tracts that arise from the paired nuclei and terminate at the pars nervosa. In response to an action potential, both hormone and neurophysin are released into the capillaries in the neurohypophysis (3). The hormones secreted by the target organs provide feedback to the hypothalamus and the pituitary gland. Failure of the target organs results in increased secretion of both the releasing hormones and the pituitary hormones. In addition to hypothalamic and feedback inputs, factors secreted within the pituitary gland influence its function. The list of intrapituitary factors has been steadily expanding over the past decade (4). Ongoing studies on the synthesis and secretion of these factors, the regulation of their receptors, and their response mechanisms will add to our understanding of the complex processes that occur within the pituitary gland.

HORMONES OF THE ADENOHYPOPHYSIS Figure 2 Sagittal MRI showing the pituitary gland (p) connected to the hypothalamus (h) by its stalk (s). Anterior to the stalk is the optic chiasm (oc). Posterior to the sphenoid sinus (ss) is the clivus (c). The corpus callosum (cc), midbrain (m), pons, cerebellum (cer), pharynx (ph), and tongue (t) are identified. Abbreviation: MRI, magnetic resonance imaging.

The adenohypophysis produces growth hormone (GH), prolactin (PRL), ACTH, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) (Table 1). GH, PRL, and ACTH are polypeptides. TSH, FSH, and LH are glycoproteins that have a and b subunits. They have identical a subunits consisting of 92 amino acids. Their b subunits are different and confer the

Chapter 50: Pituitary Dysfunction

949

Table 1 Hormones of the Adenohypophysis Hypothalamic factors Hormones GH

Target organs

ACTH

Liver, bone, epiphyseal growth plate, muscle, adipose tissue, lymphocytes, gonads Breasts, liver, gonads, prostate Adrenal cortex

TSH

Stimulated by

Inhibited by

Feedback inhibition by

GHRH

Somatostatin

TRH, OT, VIP

Dopamine

CRH, ADH

CRIF

Cortisol, ACTH

Thyroid gland

TRH

Dopamine, somatostatin

Thyroid hormones

FSH

Gonads

LHRH

Estrogen, progesterone, androgens, folliculostatin, inhibin

LH

Gonads

LHRH

Estrogen, progesterone, androgens, inhibin

PRL

IGF-1, GH

Effects Growth, production of IGF-1, decreased glucose metabolism, increased lipolysis and redistribution of fat, increased nitrogen retention Mammary gland development, milk secretion, inhibits FSH/LH secretion Cortisol synthesis and secretion, adrenal gland growth and maturation Thyroid hormone synthesis and secretion, thyroid gland growth and maturation Females: development of ovarian follicle, secretion of estrogen and inhibin; males: development of testicular tubules, spermatogenesis, secretion of inhibin Females: luteinization, secretion of progesterone; males: development of Leydig cells, secretion of testosterone

Abbreviations: ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CRIF, corticotropin release inhibiting factor; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, GH releasing hormone; IGF, insulin-like growth factors; LH, luteinizing hormone; LHRH, lutenizing hormone-releasing hormone; OT, oxytocin; PRL, prolactin; TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone; VIP, vasoactive intestinal peptide.

specificity for a particular receptor site. The b subunit becomes biologically active when coupled with the a subunit (5). GH is a polypeptide with 191 amino acids and occurs in several forms. Its secretion by the somatotrophs is stimulated by GH releasing hormone (GHRH) and inhibited by somatostatin (somatotropin release-inhibiting factor). It has no specific target organ but affects the liver, muscles, adipose tissues, lymphocytes, gonads, and the epiphyseal growth plate. It has early insulin-like effects such as hypoglycemia, increased protein synthesis, glycogenolysis, and lipogenesis. Its predominant effects are diabetogenic or anti-insulin and include decreased glucose transport and metabolism and increased lipolysis and free fatty acid levels (6). It induces insulin resistance in the liver, with or without hyperglycemia, ketonemia, or hyperinsulinemia (7–9). It also redistributes fat, increases nitrogen retention, and promotes body growth. Each GH molecule binds to two cytokine receptors on the membrane of the target organs (dimerization) to activate the Janus kinase (JAK) intracellular tyrosine kinases and the signal transducers and activators of transcription (STAT) proteins (10,11). After phosphorylation, STAT proteins move into the nucleus, bind with DNA, and activate transcription. GH forms complexes with plasma GH-binding proteins, resulting in a longer half-life and a larger volume of distribution (12). Some actions of GH are believed to be mediated by the somatomedins or insulin-like growth factors (IGF), specifically Sm-C or IGF-1 (13). These are peptides that resemble proinsulin and are present in many tissues but mainly in the liver (14). They have insulin-like activity in extraskeletal tissues, promote sulfation in cartilage, and stimulate DNA synthesis and cell multiplication. Their plasma concentration is GH-dependent. They are believed to be mitogens that stimulate clonal growth of the cells that were induced to differentiate by GH (15). With aging, secretion of both GH and IGF is decreased, resulting in loss of muscle mass and increased adipose tissue (16,17). PRL is the largest of the polypeptide hormones with 198 amino acids. Like GH, it occurs in several forms (18). Its secretion by the lactotrophs is under constant suppression

by dopamine but may be enhanced by various PRL-releasing factors including thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide. It stimulates glandular development and milk secretion of the mammary gland in females. In males, it may be essential for normal spermatogenesis. The main target organ is the breast, although PRL receptors are also present in the liver, ovary, testis, and prostate. These receptors are part of the cytokine receptor superfamily and can be stimulated by GH. During pregnancy, estrogen, progesterone, PRL, and placental mammotropic hormones stimulate breast development together with insulin, cortisol, and thyroid hormones. Lactation is inhibited by high levels of estrogen and progesterone. Corticotropin (ACTH) is a polypeptide with 39 amino acids. It is formed by proteolytic cleavage of proopiomelanocortin (POMC) into b-lipotropin and pro-ACTH, which is further processed into ACTH, N-proopiomelanocortin, and joining peptide. ACTH is cleaved into a-melanocytestimulating hormone and corticotropin-like intermediate lobe peptide. The secretion of ACTH by the corticotrophs is stimulated by corticotropin-releasing hormone (CRH) and vasopressin, and inhibited by glucocorticoids and the recently characterized corticotropin-release inhibiting factor (19). Its target is the zona fasciculata and zona reticularis of the adrenal cortex, where it stimulates the secretion of cortisol. Within minutes, it increases the adrenal blood flow and stimulates the conversion of cholesterol to pregnenolone (5). It is essential not only for adrenal growth and maturation, but also for life. It binds to membrane receptors on the adrenocortical cells with the help of extracellular calcium. This activates adenylate cyclase and increases intracellular cyclic adenosine monophosphate (cAMP) levels, protein kinase A activity, and phosphorylation of proteins that synthesize and release the steroid hormones. Because these are lipophilic, they are secreted shortly after being produced. At very high levels present in Nelson’s syndrome or Addison’s disease, ACTH can act on melanocytes to increase skin pigmentation. The thyrotropin (TSH) b subunit consists of 112 amino acids. TSH secretion by the thyrotrophs is stimulated by the

medwedi.ru

950

Part Seven: The Endocrine System

thyrotropin-releasing hormone (TRH). A TSH-inhibiting hormone has not been demonstrated. TSH stimulates the production and secretion of thyroid hormones and is essential for the function of the thyroid gland, increasing its size and vascularity. It binds to membrane receptors on the thyroid cell, activating adenylate cyclase and increasing the cAMP levels, protein kinase A activity, and phosphorylation of proteins that regulate thyroid functions (20). The follicular epithelium develops and there is increased iodide transport, thyroglobulin synthesis, and production of T3 and T4. The follitropin (FSH) b subunit consists of 115 amino acids. FSH secretion by the gonadotrophs is regulated by the gonadotropin-releasing hormone, also known as lutenizing hormone-releasing hormone (LHRH). Its secretion is inhibited by estrogen, folliculostatin, and inhibin (21). In females, it stimulates the growth of ovarian follicles and the secretion of estrogen and inhibin. In males, it stimulates Sertoli cells and inhibin secretion, promotes testicular tubule development and spermatogenesis, and controls the number of LH receptors on the Leydig cells. The FSH receptors are in the granulosa cells and the Leydig cells. The lutropin (LH) b subunit also consists of 115 amino acids. LH secretion by the gonadotrophs is also regulated by LHRH. Its secretion is stimulated by estrogen and progesterone. It initiates the resumption of meiosis and release of the first polar body and is required for ovulation. It causes luteinization of the granulosa cells in the mature ovarian follicle by increasing cAMP levels. There is subsequent production and secretion of progesterone. LH is also known as the interstitial cell-stimulating hormone and is important in the development of the Leydig cells. It stimulates the production and secretion of testosterone (5).

HORMONES OF THE NEUROHYPOPHYSIS The neurohypophysis secretes arginine vasopressin (AVP) and OT (Table 2). They contain nine amino acids and have both antidiuretic and uterus-contracting properties. AVP has mainly antidiuretic activity but has minimal oxytocic activity. OT has some antidiuretic activity. Both hormones are synthesized as prohormones with their neurophysins in the supraoptic and paraventricular neurons. Their release in the pars nervosa is stimulated by acetylcholine and influenced by cathecholamines and endorphins. AVP is also known as antidiuretic hormone (ADH). It maintains the blood osmolality within 2% of 282 mOsm/kg by its actions on renal water absorption and thirst (22). Above the osmotic threshold, ADH is secreted. It increases the reabsorption of water at the collecting ducts by binding to V2 receptors on the peritubular surface. This activates adenylate cyclase, which catalyzes the formation of cAMP, resulting in activation of protein kinases and phosphorylation of aquaporin 2, a water-channel protein that controls

the pore size of the luminal membrane of the collecting duct cells. ADH also stimulates the reabsorption of urea in the inner medullary collecting ducts by a similar mechanism involving the urea transporter 1 protein, which mediates the facilitated diffusion and accumulation of urea (3). Maximal antidiuresis is seen when serum osmolality reaches about 295 mmol/L, at which point thirst becomes more important in lowering osmolality (23). ADH may raise blood pressure through vasoconstriction by binding to the V1 receptors of the vascular smooth muscle cells. It also stimulates pituitary ACTH secretion. OT stimulates contraction of uterine and mammary smooth muscles and is important in parturition and milk ejection. It also potentiates the release of ACTH, PRL, FSH, and LH from the adenohypophysis. It binds to G protein– coupled receptors, which are present in the uterine myometrium, mammary gland, pituitary, spinal cord, kidney, thymus, gonads, heart, and vascular endothelial cells (24). This results in activation of protein kinase C and intracellular calcium mobilization. In the myometrial cells, activation of myosin light chain kinase initiates contraction. The onset of labor is triggered by a decrease in progesterone. The uterine contraction that follows stimulates OT secretion, which peaks during delivery. OT is used to induce labor and control uterine hemorrhages.

REGULATION OF HORMONE SECRETION Many hormones produced by the hypothalamus and adenohypophysis are secreted in pulses with periods of inactivity. GH, PRL, ACTH, and TSH have circadian rhythms (25). The hormones secreted by the hypothalamus control the pituitary cellular proliferation and its hormonal synthesis and release. One hypothalamic hormone may affect more than one pituitary hormone. Both releasing and inhibiting factors interact to modulate their effects. Their secretion is regulated by the interaction of neurotransmitters, neuropeptides, and other hormones.

Somatotropin GH is secreted in multiple bursts occurring at anytime of the day but usually within the first hour of sleep, reaching its peak levels at night. A delay in the onset of deep sleep delays the onset of the major GH peak. GHRH stimulates GH synthesis and the release of preformed GH by binding to G protein–coupled receptors on the somatotrophs, activating adenylate cyclase and increasing cAMP and intracellular calcium levels. Somatostatin inhibits GH pulsed release by binding to receptors and decreasing intracellular calcium levels (26). Somatostatin has a more dominant effect than GHRH. GH exerts a short-loop negative feedback on the hypothalamus. IGF-1 from the peripheral tissues provides negative feedbacks by enhancing somatostatin release

Table 2 Hormones of the Neurohypophysis Hormones

Target organs

Stimulated by

Inhibited by

Effects

ADH

Kidneys, vascular smooth muscles

Serum hypoosmolality, fluid overload, ANP, alcohol, phenytoin

Antidiuresis, vasoconstriction, stimulates ACTH secretion

OT

Uterus, breasts

Serum hyperosmolality, rapid intravascular volume depletion, NE , angiotensin II, opiates, nausea, stress, pain Vaginal distention, suckling of nipples, NE, nausea

Opiates, stress

Uterine contraction, milk ejection

Abbreviations: ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; ANP, atrial natriuretic peptides; NE, norepinephrine; OT, oxytocin.

Chapter 50: Pituitary Dysfunction

from the hypothalamus and by inhibiting GH gene transcription in the pituitary. GH secretion is stimulated by fasting, exercise, stress, low insulin levels, and in certain conditions like anorexia, non-insulin dependent diabetes mellitus (IDDM), and liver cirrhosis. It is also stimulated by central a2-adrenergic agonists(clonidine), acetylcholine agonists, dopamine agonists (levodopa), b2-adrenergic antagonists (propranolol), opioids, glucagon, arginine, leucine, estrogen, and GH secretagogues like MK-677 (27,28). GH secretion is decreased with obesity, emotional deprivation, aging, hyperglycemia, hyperinsulinemia, and hypothyroidism.

Prolactin PRL is secreted in a pulsatile manner with its lowest levels at noon that gradually increase in the afternoon. The levels increase further after the onset of sleep and peak at around midnight (29). It is under tonic inhibition by dopamine produced in the hypothalamus. Dopamine inhibits PRL synthesis and release by binding to membrane receptors and inhibiting adenylate cyclase, which results in decreased cAMP, intracellular calcium, and PRL gene transcription in the lactotrophs. PRL secretion is stimulated by stress, estrogen, TRH, OT, lesions to the hypothalamus or the pituitary stalk, and chronic use of opioids, dopamine antagonists (chlorpromazine, haloperidol, metoclopramide), antidepressants (amitriptyline, fluoxetine), antihypertensives (a-methyldopa, reserpine), H2-blockers (cimetidine, ranitidine), and calcium channel blockers (verapamil) (30). Medications rarely increase PRL levels to more than 30 to 50 ng/mL (31). PRL levels are higher in premenopausal women than in men and rise during menarche and pregnancy. In postpartum women, suckling also increases PRL levels. Mild PRL elevation caused by increased TRH secretion seen in primary hypothyroidism may take months to normalize even with thyroid hormone replacements. GH-secreting adenoma, chronic renal failure, and hepatic cirrhosis may elevate PRL levels.

Corticotropin ACTH is secreted in bursts that become more frequent after three to five hours of sleep and peak just prior to and about an hour after awakening. The levels decrease during the day to reach the lowest in the evening. This rhythm is not affected by temporary sleep deprivation as long as the normal sleep pattern is preserved. However, changing time zones alters the rhythm and may take several days to normalize (32). CRH stimulates ACTH secretion by binding to receptors, increasing cAMP levels, protein kinase A activity, and ACTH synthesis and release. This process is potentiated by ADH (33). Glucocorticoids exert negative feedbacks on the pituitary, hypothalamus, and hippocampus by binding to receptors and forming complexes that affect the genome (34). They inhibit ACTH, CRH, and ADH secretion and synthesis of their mRNAs. A fast feedback within minutes and an intermediate feedback over a few hours target the hypothalamus to reduce CRH secretion and its action on ACTH release. A slow feedback over days reduces gene transcription and peptide synthesis of POMC, a precursor of ACTH (35). Glucocorticoids act on both the mineralocorticoid and the glucocorticoid receptors in the hippocampus. They may injure hippocampal neurons during prolonged stress. The amount of cortisol needed for negative feedback is directly correlated to the level of CRH. ACTH also inhibits its own secretion.

951

Trauma, burn injury, surgery, fever, hypoglycemia, and stress increase ACTH and cortisol secretion. Fever releases cytokines interleukin (IL) -1, IL-2 and IL-6, which enhance CRH release.

Thyroid-Stimulating Hormone TSH levels are high during the night and decrease in the morning to low levels in the evening (36). TRH is a tripeptide that stimulates TSH secretion by binding to membrane receptors, with subsequent hydrolysis of phosphatidylinositol, activation of protein kinases, and increase in intracellular free calcium and TSH a and b mRNAs (25). Thyroid hormones inhibit TSH secretion by binding to intranuclear receptors and by inhibiting TRH synthesis in the hypothalamus. Cold exposure increases TSH secretion. Stress, starvation, infection, and inflammation inhibit TSH secretion. Dopamine and somatostatin also inhibit TSH secretion (37).

Gonadotropins Both FSH and LH are secreted in a pulsatile manner following an LHRH pulse delivered by the hypothalamus about once every 90 minutes. When the LHRH pulses become more frequent, LH secretion is increased. At slower LHRH pulses, FSH secretion is increased (38,39). During childhood, there is maximal inhibition of LHRH secretion. This intrinsic suppression of LHRH gradually decreases as puberty is reached, resulting in an increased FSH and LH secretion seen in puberty. LHRH causes a sequential release of FSH and LH during the normal menstrual cycle. LHRH action is mediated by receptor binding and G-protein activation on the gonadotrophs (40). Estrogens, progestogens, and androgens bind to nuclear receptors to modulate FSH and LH secretion. Gonadotropin secretion in both sexes is suppressed by estrogens and androgens. This negative feedback requires an intact hypothalamus and is gender specific and dose dependent. Estrogen and progesterone also exert a positive feedback in women, resulting in a surge of gonadotropins at midcycle, which induces ovulation. This response is not seen in men. In lactating women, elevated PRL can decrease LHRH, LH, and estrogen secretion, resulting in amenorrhea (30). In menopausal women, there is an increase in the production of LH and FSH.

Vasopressin The release of ADH is mainly controlled by osmoreceptors that are believed to be located in the supraoptic nuclei. Rising osmolality increases ADH secretion, resulting in renal water absorption and lowering of the osmolality. As the osmolality normalizes, further release of ADH is reduced. Baroreceptors located in the carotid sinus, aortic arch, and the heart, mainly in the left atrium, also control ADH secretion by relaying impulses to the supraoptic and periventricular nuclei (41). When blood volume is rapidly depleted by about 10%, ADH is released even when the osmolality is still below threshold. ADH secretion is stimulated by norepinephrine, angiotensin II, opiates, and prostaglandin E2. Inflammatory cytokines IL-1, IL-2, and IL-6 induce ADH release. It is also enhanced by hypoxia, hypercapnea, nicotine, cholinergic, and b-adrenergic agents, metoclopramide, barbiturates, carbamazepine, histamine, and halothane (42). Nausea, stress, and pain can trigger ADH release. Adrenal insufficiency lowers the set point for osmotic control, resulting in

medwedi.ru

952

Part Seven: The Endocrine System

syndrome of inappropriate antidiuretic hormone (SIADH) secretion, which is reversed by glucocorticoid treatment (25). Atrial natriuretic peptides (ANP) released from stretched myocytes in the left atrium during fluid overload inhibits ADH release and thirst, and promotes renal sodium excretion and diuresis. ANP also blocks the effects of angiotensin II, including thirst (43). ADH release is suppressed by alcohol, phenytoin, and a-adrenergic agents. Mood, anxiety, and emotional stress influence ADH secretion (42).

Oxytocin OT release is stimulated by mechanical vaginal distention or suckling of the nipples. During pregnancy, uterine OT receptors are upregulated and a strong uterine sensitivity to OT is seen just before parturition. After parturition, uterine OT binding sites decrease while those in the mammary gland reach their maximum and remain elevated throughout lactation (24). In nursing females, OT results in the milk let-down reflex, which can be conditioned in response to a crying infant. OT secretion is also stimulated by nausea and norepinephrine. It is inhibited by emotional stress and opiates.

HYPOPITUITARISM The deficiency of one or more pituitary hormones presents with increased mortality. The most common cause in adults is pituitary adenoma (Table 3). Many patients with pituitary macroadenomas (greater than 1 cm in diameter) have hypopituitarism, usually from compression of the pituitary stalk and portal vessels. Other sellar or parasellar lesions cause hypopituitarism by cellular infiltration or mechanical compression of the hypophysis or hypothalamus and by disruption of the hypothalamic-pituitary axis. Head injuries, particularly with fracture of the sella, are known to result in hypopituitarism. Surgical resections of sellar or parasellar tumors may result in transient or permanent hormonal deficiency. Radiation therapy is associated with a high incidence of hypopituitarism. Genetic defects may result in isolated deficiencies of GH, LHRH, TSH, or ACTH (44). The symptoms vary from mild to severe insufficiency. The most severe involves failure of all pituitary hormones, resulting in panhypopituitarism. There is a wide spectrum of clinical findings. Patients may present with fatigue, weakness, cold intolerance, pale and dry skin, low blood pressure, orthostatic hypotension, regression of secondary sexual characteristics, amenorrhea, or impotence. In children, cessation of growth and delayed puberty are common and mental retardation may ensue. Fever, shock, coma, and death may follow relatively minor stresses due to lack of the ACTH–cortisol response. These symptoms are similar to those seen in primary target organ failure, which has decreased or absent hormonal

secretion. The main difference is the elevated levels of pituitary hormones seen in primary organ failure. In contrast, hypothalamic or pituitary dysfunction generally presents with low levels of pituitary hormones. Pituitary failure usually presents with a deficiency of GH initially, followed by that of the gonadotropins, and then of ACTH and TSH. An excess of PRL, rather than its deficiency, is more common. Pituitary stalk compression from a mass lesion results in decreased delivery of dopamine and loss of its tonic inhibition of PRL secretion. Moreover, the most common secretory adenoma is a prolactinoma. The diagnosis of hypopituitarism is made with clinical suspicion. Further imaging and endocrine work-ups help in identifying the specific causes of pituitary failure. Visual examination is essential in detecting peripheral visual loss due to chiasmal compression. Compression of adjacent structures should be evaluated by magnetic resonance imaging (MRI). Although computed tomography (CT) scan is helpful in showing calcifications and the bony anatomy, it is a poor second choice to an MRI (compare Figs. 1 and 3). Endocrine evaluation requires both baseline and stimulated hormone levels. Retesting is indicated in those with likelihood of progression of hypopituitarism, e.g., following radiation, surgery, or those with hypothalamic or pituitary lesions that are being monitored. Treatment is aimed at removal of the cause and normalization of the hormonal environment. Hypothalamic lesions, even in the best of hands, may only be subtotally resected and usually require hormonal replacement. Endocrine replacement should be as close to normal levels as possible because overtreatment can be deleterious. Surgical removal of a lesion in the sellar and parasellar areas requires a careful consideration of the extent of involvement of the adjacent structures, the patient’s risk stratification prior to surgery, and the availability of other treatment options.

Table 3 Causes of Hypopituitarism Pituitary macroadenoma Other sellar and parasellar lesions Trauma Surgery Radiation Pituitary apoplexy Sheehan’s syndrome Genetic Idiopathic

Figure 3 Coronal computed tomography showing the sellar floor (sf) and the pituitary stalk adjacent to the optic chiasm (oc). The sphenoid sinus (ss) is directly inferior to the sella. The cavernous sinus (cs) and lateral ventricles (v) are also seen.

Chapter 50: Pituitary Dysfunction

Somatotropin Deficiency GH deficiency in childhood is usually idiopathic while in adults, it is often due to adenoma, pituitary surgery, or radiotherapy. In children, there is dwarfism, truncal deposition of fat, prominence of the forehead, depressed midfacial development, and delay in dentition or onset of puberty. In adults, there is increased total body fat, lower than normal bone density with increased fracture rate, decreased lean body mass, muscle strength, exercise capacity, and libido, and reduced sense of physical and psychological well-being (45). Patients may complain of being less energetic, with emotional liability and a sense of social isolation. GH replacement therapy has been used successfully in childhood for several decades. Its use in adults, however, has only recently begun to be evaluated. GH replacement in adults has been shown to reduce fat mass, increase lean body mass, improve physical performance, oxygen uptake, and bone mineral density (46). The recommended starting dose is 0.15 to 0.3 mg SC daily, increasing every four to six weeks based on clinical and biochemical responses (47). At least six months of steady maintenance dose is necessary to determine the benefits of the treatment. Regular measurement of weight, blood pressure, Hb A1c, IGF-1, lipid profile, and fat distribution is taken. Side effects include peripheral edema, arthralgia, and myalgia.

Gonadotropin Deficiency Gonadotropin deficiency results from a pituitary lesion or deficiency of hypothalamic LHRH stimulation of the gonadotrophs. Hyperprolactinemia may also cause hypogonadal features. The symptoms are similar to those of primary gonadal failure and depend on whether the onset is before or after puberty. Boys present with small genitalia and eunuchoid habitus. Girls have primary amenorrhea and absent breast development. Adolescents present with delayed or arrested puberty. In men, there is reduction of testicular size, loss of facial and body hair, thinning of the skin, decreased bone density and muscle mass, poor libido, impotence, and infertility. Spermatogenesis may be preserved but the seminal volume is reduced. Symptoms develop more slowly and they are diagnosed later than in women. In women, there is amenorrhea, oligomenorrhea, dyspareunia, breast atrophy, and infertility. There is no loss of pubic and axillary hair unless there is concurrent ACTH deficiency. Gonadotropin replacement is indicated in patients who want to maintain fertility. Otherwise, replacement with progesterone and estrogen for women and testosterone for men is sufficient to maintain the normal body composition, bone density, and sexual function.

953

that adrenal crisis is less common than in Addison’s disease. However, in chronic untreated cases, mineralocorticoid deficiency may develop. In contrast to ACTH deficiency, Addison’s disease presents with hyperpigmentation of the skin and mucous membranes because of the elevated ACTH levels. Hyponatremia also occurs with Addison’s disease and is less common in ACTH deficiency except in the elderly. Acute cortisol deficiency is a medical emergency that must be considered when patients present with these symptoms, especially with a history of acute headache, pituitary surgery, radiotherapy, or significant head injury. It is important to remember that this may also follow an abrupt cessation of glucocorticoids or ACTH intake, even when they have been given for only a few weeks. To prevent this, steroids are usually tapered over several weeks before being discontinued. Diagnosis is confirmed by low levels of cortisol and ACTH. Blood samples obtained at 8 A.M., just after the peak of cortisol secretion, are measured for levels of cortisol and ACTH. Cortisol levels below 100 nmol/L with normal or low ACTH levels are consistent with ACTH deficiency. In Addison’s disease, the ACTH level is high. In suspected acute adrenal insufficiency, blood samples are sent for evaluation but hormonal replacement is started immediately without waiting for the results. If an adrenal crisis is suspected, fluid resuscitation with normal saline is done to correct hypotension and electrolyte imbalance. Hydrocortisone 100 mg IV is given immediately and then every six hours (48). When the patient is stable, other tests are performed to determine the cause of adrenal sufficiency. Treatment for ACTH deficiency is similar to that for Addison’s disease. Replacement with oral hydrocortisone at 10 mg on awakening and 5 mg at noon, and at 6 P.M. is recommended by some authors (44). The dose may be increased to 10 mg three times daily based on serum cortisol levels. Synthetic glucocorticoids like prednisone and dexamethasone are preferred by some because of their longer duration of action (49). Oral prednisone 5 mg or dexamethasone 0.5 mg is given once daily at bedtime. Clinical symptoms are monitored to avoid over-replacement, which can cause bone loss and Cushing’s syndrome. The dose is increased during illness, injury, or surgery. During febrile illness, minor stress, surgery, or injury, the dose is increased two to threefold for about three days. For major surgery or severe illnesses, hydrocortisone 100 mg IV is given every eight hours, with the first dose given before induction of anesthesia. The dose is tapered daily by half to maintenance level, depending on the patient’s course.

TSH Deficiency Corticotropin Deficiency This is the most life threatening. Patients may present with hypovolemic shock, fever, and acute abdomen. They may die from trivial illnesses due to vascular collapse and coma. Symptoms include weakness, fatigue, anorexia, weight loss, nausea, diarrhea, headache, orthostatic hypotension, dizziness, and skin pallor. In women, there is loss of pubic and axillary hair. In severe deficiency, there may be hyponatremia, increased insulin sensitivity, and decreased glycogen reserves, resulting in hypoglycemia. The symptoms of glucocorticoid deficiency are similar to those of Addison’s disease. The difference is that only cortisol and adrenal androgens are decreased in ACTH deficiency. The mineralocorticoid secretion, which is regulated by renin and angiotensin, is normal in ACTH deficiency so

TSH deficiency (secondary hypothyroidism) occurs relatively late in the course of hypopituitarism and is characterized by malaise, fatigue, weakness, inability to lose weight, weight gain, lack of energy, cold intolerance, dry skin, or constipation. It can also cause moderate hyperprolactinemia. The degree of hypothyroidism depends on the duration of TSH deficiency. The symptoms are similar to those of primary hypothyroidism, but generally are milder because some thyroid hormone is still being produced. In TSH deficiency, the serum T4 level is low but most patients will have normal TSH levels (50). In primary hypothyroidism, T4 level is even lower while TSH level is increased. A TRH test with absent or impaired TSH response is suggestive of TSH deficiency; a normal or delayed response may indicate TRH deficiency.

medwedi.ru

954

Part Seven: The Endocrine System

TSH deficiency is treated with levothyroxine (L-T4), a prohormone that is converted to T3. ACTH deficiency must be excluded or treated prior to L-T4 replacement to prevent any worsening of the symptoms of cortisol deficiency. Oral L-T4 once a day is started at 100 mg in young patients and 25 to 50 mg in the elderly or in those with chronic hypothyroidism or ischemic heart disease (51). The dose is adjusted based on the clinical response and free T4 levels. Chronic over-replacement is associated with osteoporosis and atrial fibrillation. Surgery in hypothyroid patients is associated with increased risks of minor complications as well as heart failure, gastrointestinal, and neuropsychiatric symptoms (52). L-T4 is given preoperatively to hypothyroid patients.

the responsiveness to ADH. In polydipsic polyuria, the responsiveness to ADH is decreased by the washout of interstitial solutes including urea. Patients with DI need careful monitoring of fluid intake and urine output. The treatment of choice for severe central DI is DDAVP, a synthetic analog of ADH, which has increased antidiuretic activity and half-life and minimal pressor activity (55). It is available in oral, intranasal, and parenteral forms. The oral form is not reliably absorbed and the intranasal and parenteral forms are preferred. The dosage varies between the different forms and among patients as well. Milder DI may be managed with oral fluid replacement alone.

PRL Deficiency PRL deficiency results in failure of lactation and reproductive difficulty (30). It is rare except in Sheehan’s syndrome wherein pituitary tissues are destroyed. Sheehan’s syndrome is secondary to shock, hemorrhage, or sepsis associated with childbirth, which results in spasm of the hypophyseal arteries and necrosis of the adenohypophysis. Pituitary thrombosis and scar formation result in secondary atrophy of the thyroid, adrenal cortex, and ovaries (53). The symptoms of Sheehan syndrome are secondary to the resultant hormonal deficiencies. Prognosis is good with prompt hormonal replacement. No replacement for PRL is required.

Vasopressin Deficiency ADH deficiency results in neurogenic or central diabetes insipidus (DI). It usually indicates a hypothalamic or stalk disorder and not a pituitary disease. Most of the cases are acquired and result from vascular insufficiency of the pituitary gland, cranial or pituitary surgery, meningitis, encephalitis, suprasellar lesions, or head injury. About 30% are idiopathic, with some patients exhibiting antibodies to ADH-secreting neurons (54). It may also be familial, with autosomal dominant inheritance affecting the processing of the precursor ADH molecule. Neurogenic DI must be differentiated from nephrogenic DI, which is due to a partial or total unresponsiveness of the renal tubules to ADH. Nephrogenic DI may be genetic, idiopathic, or secondary to chronic renal disease, hypercalcemia, hypokalemia, and use of lithium or mannitol. Hypothalamic diseases such as sarcoidosis may cause excessive inappropriate drinking (primary polydipsia). This condition of polyuria with normal ADH secretion and renal responsiveness is known as dipsogenic DI (23). DI is associated with hypernatremia and polyuria, with daily urine output usually greater than 3 L. Patients may have polydipsia, nocturia, nighttime thirsts, and hypotension. Those incapable of adequate oral fluid replacement may present with dehydration, hypovolemia, hyperosmolality, fever, hyperpnea, stupor, coma, and death. Evaluation of possible ADH deficiency should be done only after suspected anterior pituitary hormone deficiency is corrected because ACTH deficiency can mask ADH deficiency (44). Diagnosis is suspected when there is hypernatremia and dilute urine. In milder cases, patients may drink enough to prevent hypernatremia. They can be diagnosed with a water deprivation test. With central DI, plasma osmolality rises with dehydration and urine osmolality remains low. A decrease in urine output after 1-deamino8-D-arginine vasopressin (DDAVP) administration is diagnostic of central DI. This is in contrast to nephrogenic DI and polydipsic polyuria, which do not respond to DDAVP. In nephrogenic DI, there is a primary defect in

SELLAR AND PARASELLAR LESIONS Various tumors and non-neoplastic lesions arise in the sellar and parasellar areas and present with mass effects on the adjacent structures in addition to hypopituitarism. Most of these are benign but may grow aggressively to involve contiguous structures. Stretching of the diaphragma sella or dural impingement by a macroadenoma produces headache (56). Pressure on the optic chiasm results in a progression from scotomas to bitemporal hemianopia to blindness. Involvement of the cavernous sinus may result in ptosis, diplopia, ophthalmoplegia, facial hypesthesia, or pain. Lesions in the hypothalamus are far less common and may affect the regulation of temperature, appetite, thirst and water metabolism, the sleep–wake cycle, circadian rhythms, the control of autonomic nervous system, emotional expression, behavior, and memory (57). Patients frequently present with DI, obesity, hypogonadism, dysthermia, and sleep disturbances. Children may present with precocious puberty. Frontal lobe involvement may result in anosmia, personality disorders, or seizures. Tumors large enough to involve the third ventricle and occlude the foramina of Monro or the aqueduct of Sylvius may cause hydrocephalus. Hydrocephalus and increased intracranial pressure may cause nausea, vomiting, and eventually coma (Table 4). MRI is the imaging study of choice. It can delineate the tumor as well as the adjacent structures along three axes (Figs. 4 and 5). For patients who cannot have an MRI, a coronal CT provides images with less soft tissue distinction but with more details on bony structures and calcification. Pituitary microadenomas usually appear hypointense to the normal gland on T1W images and have delayed contrast enhancement. They also appear hypoattenuated within the gland on enhanced and nonenhanced CT (58). Imaging studies are essential in establishing an anatomic diagnosis, in surgical planning, and follow-up evaluations. A baseline endocrine test consists of PRL, IGF-1, LH, FSH, a subunit, 24-hour urinary free cortisol, am cortisol, ACTH, free T4, TSH, testosterone (male), and estradiol (female) (59). When clinically indicated, provocative tests such as insulin tolerance test and metyrapone test may be needed to evaluate the pituitary reserve and hypopituitarism. Dynamic tests may also be needed to identify hypersecretion in acromegaly and Cushing’s disease. These tests identify hormonal excess or deficiency and establish an endocrine diagnosis. Any consideration for surgical resection of these lesions must be based on the natural history of the lesion, signs of compression of adjacent structures, need for tissue diagnosis, alternative treatments available, patient safety,

Chapter 50: Pituitary Dysfunction

955

are to safely recover and preserve as much function of the adjacent structures to these lesions as possible, and improve or normalize the endocrine function. Endocrine deficiency is relatively easy to treat with the appropriate replacement. Most tumors in this area are treated with surgery. The exceptions are prolactinomas, asymptomatic tumors in the elderly, and nonsecretory microadenomas. Radiation is used as an adjunctive therapy for subtotal tumor resection, aggressive tumors, recurrence, and in patients with poor surgical risks or failure of medical management (60). The risk of hypopituitarism following radiotherapy must be considered. It occurs in a delayed fashion over 10 years and requires vigilant monitoring for detection and treatment. Long-term risks of conventional radiotherapy include depression, decreased memory, and glioma formation. Stereotactic radiosurgery has recently been used instead of conventional radiotherapy. It offers lesser complications but long-term results are still forthcoming.

Table 4 Sellar and Parasellar Lesions Tumors Pituitary adenoma Secretory—PRL, GH, ACTH, TSH, mixed, LH, FSH, a subunit Nonsecretory Craniopharyngioma Meningioma Metastasis Glial tumors Glioma Optic nerve glioma Hypothalamic glioma Pilocytic astrocytoma High grade glioma Granular cell tumor/choristoma Trigeminal schwannoma Germ cell tumors Germinoma Teratoma Embryonal carcinomas Endodermal sinus tumor Choriocarcinoma Neuronal tumors Gangliocytoma Hypothalamic Hamartoma Olfactory neuroblastoma Lipoma Primary lymphoma Primary melanoma Mesenchymal tumors Chordoma Giant-cell tumor of bone Fibroma/fibrosarcoma Osteogenic sarcoma Hemangiopericytoma Vascular tumors Cavernous angioma Hemangioblastoma Glomus tumor Paraganglioma Plasmacytoma/multiple myeloma Cysts Rathke’s cleft cyst Arachnoid cyst Epidermoid cyst Dermoid cyst Echinococcal cyst Aneurysms Inflammation Infiltrative Lymphocytic hypophysitis Idiopathic granulomatous hypophysitis Xanthomatous hypophysitis Sarcoidosis Langerhan’s cell histiocytosis Giant-cell granuloma Infectious Pituitary abscess Tuberculoma Pituitary hyperplasia Empty sella

Pituitary Adenoma Pituitary adenoma is the most common neoplasm of the sellar region (61). It is a benign tumor arising within the adenohypophysis. It accounts for about 10% of all intracranial tumors in adults and is found in 6% to 22% of adults during autopsy. More than 50% occur between the third and fifth decades. The incidence is higher in women (62). About 10% of adults with pituitary adenoma are asymptomatic (63). Pituitary adenomas are classified as microadenomas (less than 1 cm in diameter) and macroadenomas. Among the microadenomas, only secretory tumors are of significance. Medication is the primary treatment for prolactinomas. All other adenomas are treated with surgery. Pituitary adenomas present with hormonal dysfunction, mass effects, or both. The dysfunction may be hypopituitarism or hyperpituitarism. A nonsecretory adenoma lacks the early symptoms of hormonal oversecretion and tends to be large when it presents, usually with visual symptoms and hypopituitarism. It is more common in older patients while a secretory adenoma is more common in younger patients. Some prolactinomas, GH-secreting adenomas, and nonsecretory adenomas are associated with multiple endocrine neoplasia type 1 (MEN-1). Nearly half of MEN-1 patients develop pituitary adenomas. On the other hand, only 1% to 15% of pituitary adenomas have MEN-1 (64). Prolactinoma is the most common adenoma occurring in MEN-1. MEN-1 is an autosomal dominant disorder associated with tumors of the pituitary, parathyroid, and pancreas. A mutated MEN-1 tumor suppressor gene is passed on to the affected individual. Tumor growth is caused by mutation of the remaining normal MEN-1 allele. This loss of heterozygosity of the allele is seen in parathyroid adenomas and islet cell tumors including insulinomas and gastrinomas. These endocrine tumors usually present in young adulthood with high levels of PTH, gastrin, or PRL. These are treatable with medication or surgery. In patients with a pituitary adenoma, calcium levels should be checked to exclude primary hyperparathyroidism.

Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid stimulating hormone.

and prognosis. The lesions may be removed totally or partially, depending on the possible benefits and weighing against risks of complications and bad outcome. The goals

Prolactinoma Prolactinoma is the most common type of pituitary adenoma. It usually presents as microadenomas in women and macroadenomas in men. Microadenomas usually occur at the lateral portion of the gland. Overall, microprolactinomas are more common than macroprolactinomas (65). Microprolactinomas present with symptoms of PRL hypersecretion rather than visual symptoms or mass effects.

medwedi.ru

956

Part Seven: The Endocrine System

Figure 4 (A) Axial T1W MRI shows a large adenoma (ad) compressing the midbrain (m). The lateral ventricles are enlarged because of obstruction at the aqueduct of Sylvius within the midbrain. (B) Delayed enhancement of the adenoma with gadolinium.

Women usually seek medical attention earlier because of galactorrhea, amenorrhea, and infertility. They may also present with hirsutism, acne, mood changes, dyspareunia, decreased libido, and osteopenia. Men usually present with impotence, loss of libido, and visual complaints. They may also present with galactorrhea, anxiety, depression, and irritability similar to the mood changes seen in menopausal women (66). The hypogonadism and infertility associated with hyperprolactinemia result from its central inhibitory effects on the pulsatile LHRH secretion and in women, its blockage of the positive feedback of estrogen, which induces the LH surge (67). Adolescents may present with delayed puberty. Some prolactinomas in men and postmenopausal women are asymptomatic when they are first discovered incidentally during imaging studies. Some prolactinomas are mixed adenomas that cosecrete GH, ACTH, TSH, and rarely FSH and/or LH. They may be derived from two different cell lines or from a single cell line, which secretes both hormones. Patients present initially with symptoms of hyperprolactinemia and later on with the clinical picture of the cosecreted hormones.

Diagnosis is based on PRL levels greater than 200 ng/mL and radiologic images of a sellar tumor. The degree of hyperprolactinemia correlates with the size of the prolactinoma. Pregnancy, primary hypothyroidism, renal or hepatic failure, and use of drugs that can cause hyperprolactinemia must be excluded during the initial evaluation. Modest elevation of PRL levels (less than 200 ng/mL) may be secondary to a microprolactinoma or compression of the pituitary stalk by other tumors. Because most microprolactinomas do not enlarge and some may regress, they may be observed with annual evaluation of PRL levels and MRI studies. Treatment is started when the hypogonadal effects of hyperprolactinemia are present or when the tumor enlarges. Macroprolactinomas, because of their potential for further growth and mass effects, are treated upon diagnosis. The primary therapy for prolactinomas is with bromocriptine, a dopamine agonist. It binds to the D2 receptors of both normal and prolactinoma cells and normalizes the PRL level in most patients. It also induces regression of the tumor size. Large adenomas disappear with effective medical treatment but will immediately recur when

Figure 5 (A) Coronal MRI showing the adenoma (ad) with involvement of the cavernous sinus. The internal carotid artery is surrounded by tumor. Note the enlargement of the lateral ventricles and the third ventricle because of hydrocephalus. (B) Sagittal MRI showing the same tumor (ad) compressing the optic chiasm (oc), midbrain (m), and pons (p).

Chapter 50: Pituitary Dysfunction

the treatment is discontinued. Therefore it is necessary to continue medication for the lifetime of the patient. The hypogonadal symptoms are reversed within months. Long-term treatment has been associated with perivascular fibrosis in some tumors, which may affect subsequent surgery. Bromocriptine is generally well tolerated. Common side effects include nausea, headache, vomiting, postural hypotension, and nasal congestion (68). These often occur with dose increases and may be relieved by temporarily reducing the dose. In some macroprolactinomas with sellar floor erosion, shrinkage of the tumor may result in CSF rhinorrhea. The effective daily dose is 5 to 7.5 mg taken with meals and is gradually increased from a low starting dose. Cabergoline is an oral dopamine agonist that has less frequent side effects. Its dose is 0.25 to 1.0 mg twice a week. Pergolide, a dopamine agonist used in the treatment of Parkinson’s disease, has been used successfully in those who did not respond to bromocriptine. Surgery is preferred for apoplectic or cystic prolactinomas, which do not respond well to dopamine agonists (69). It is also indicated in patients who do not respond to dopamine agonists, cannot tolerate their side effects, or prefer surgery to lifelong medication. In women with macropro lactinoma, who are planning pregnancy, surgical resection may prevent the consequences of tumor growth that occurs during pregnancy, including apoplexy. Surgery in pregnant women may pose a greater risk for the fetus than continuing bromocriptine during pregnancy. Generally, curative resection with return of PRL levels to normal is likely in microprolactinomas and unlikely in macroprolactinomas. Thus macroprolactinomas will generally require continuous bromocriptine treatment even after resection. Radiation has been shown to normalize PRL levels and decrease tumor size years after treatment (60). However, it is generally reserved for those who failed combined medical and surgical treatment.

Acromegaly Acromegaly is a rare, slowly evolving disease that results from excessive GH secretion. The most common cause is a GH-secreting pituitary adenoma, which sometimes cosecretes PRL or other hormones. It may rarely be due to the overproduction of GHRH by a hypothalamic hamartoma, gangliocytoma, or carcinoid tumors in the lungs, pancreas, or GI tract (70). GH hypersecretion results in acromegaly if it occurs after the closure of the epiphysis of the long bones. The soft tissues in the hands and feet are thick. Carpal tunnel syndrome is common. The skin and hair are thickened and sweating may be increased. There is excessive growth of the supraorbital rim, nose, and jaw, resulting in elongation of the face, tooth gaps, macrognathia, and malocclusion. Few patients seek help because the gradual change in appearance may go unnoticed for years. Joint pain and osteoarthritis are common. Although cortical bone is thick, the trabecular bone may be osteopenic. Myopathy with weakness of the proximal muscles may be seen. Often there is enlargement of the tongue, thyroid, heart, liver, spleen, and thymus. MI is a common cause of death. The longer the GH excess remains untreated, the more severe the cardiomyopathy becomes. Left ventricular hypertrophy results in decreased diastolic volumes and diastolic hypertension. These may be irreversible when interstitial fibrosis is present. Patients present with hypertension, atherosclerosis, and congestive heart failure. Diabetes mellitus, sleep apnea, and daytime sleepiness are also common. There is

957

an increased risk for colonic polyps and GI cancer (71). Regular colonoscopy is recommended. Diagnosis is confirmed with radiologic images of a sellar tumor and biochemical tests showing elevation of serum IGF-1 and GH. GH levels fluctuate depending on the activities and time of day during sampling. Serum IGF-1 levels, on the other hand, are more constant and reflect the GH secretion of the preceding day (72). Thus, IGF-1 is the preferred screening test. Because IGF-1 levels are normally higher in females, during puberty and pregnancy, and lower in the elderly, the levels are interpreted based on values adjusted for age and sex. An elevated age- and sex-matched IGF-1 level is consistent with acromegaly. GH hypersecretion may be further demonstrated by the oral glucose tolerance test (OGTT). Normally, GH is suppressed after an oral glucose load. Acromegaly is diagnosed when GH levels do not fall below 1 ng/mL two hours after intake of 75 g of glucose (73). Hypercalciuria and hyperphosphatemia are also commonly seen. Aggressive treatment is important. The main goal is to normalize GH and IGF-1 levels. Transsphenoidal resection is the preferred treatment because with tumor removal, cure may be permanent. It provides good remission and avoids lifelong therapy with medications. Remission is defined by normal IGF-1 levels and GH suppression to less than 1 ng/ mL in OGTT. Macroadenomas, which usually present at the time of diagnosis, have lower remission. This is more so when the tumor involves the cavernous sinus, which precludes complete resection. Possible complications include hypopituitarism, DI, CSF leak, and meningitis. When there is failure of remission after surgery, octreotide is usually started. If this is still unsuccessful, dopamine agonists, radiation, repeat surgery, or GH receptor antagonists may be considered (72). Octreotide is a long-acting somatostatin analogue that inhibits the secretion of GH, glucagon, and insulin. It lowers GH and IGF-1 levels and may shrink the tumor. It relieves the headache, joint pain, sweating, carpal tunnel syndrome, and sleep apnea in acromegalic patients. Its effectiveness is limited but it can be used as primary treatment in patients who refuse surgery or with poor surgical risks. It is also used in an attempt to shrink the tumor prior to surgery. Side effects include GI discomfort, diarrhea, cholelithiasis, and chronic gastritis. Bromocriptine is used at high doses (20–30 mg/day) to lower GH levels in some acromegalic patients. The mechanism of action is unclear because dopamine normally stimulates GH secretion. Unlike in prolactinomas, bromocriptine is much less effective in GH-secreting adenomas. Radiation is used as an adjunct and is reserved for recurrence or failure of remission with surgery and medical therapy. It may take years for GH levels to normalize.

Cushing’s Disease Cushing’s disease is hypercortisolism secondary to an ACTH-secreting pituitary adenoma. It is more common in women. It comprises the majority of Cushing’s syndrome in adults. Cushing’s syndrome is characterized by glucocorticoid excess from various causes. It may be due to hypothalamic, pituitary, or adrenocortical tumors, or ectopic tumors secreting ACTH or CRH. Patients present with truncal obesity, loss of muscle bulk, moon facies, buffalo hump, fragile skin, which bruises easily, purple striae, and hirsutism. Hypertension, diabetes mellitus, hypercalciuria, osteopenia, and hypogonadism are common. Frequent infections and hypercoagulability are also seen. Patients may present with

medwedi.ru

958

Part Seven: The Endocrine System

anxiety, depression, emotional lability, or psychosis. Cataracts and glaucoma are known complications. ACTH-secreting pituitary adenomas are usually microadenomas. Diagnosis is made by confirming hypersecretion of cortisol and pituitary ACTH. Hypercortisolism is established by elevated 24-hour urinary free cortisol and failure of dexamethasone to suppress cortisol secretion. Dexamethasone 1 mg given orally at 11 PM normally suppresses the 8 AM serum cortisol level to less than 5 mg/L. In hypercortisolism, the cortisol level is usually greater than 10 mg/L (74). Measurement of late-night salivary cortisol has also been used as a screening test for hypercortisolism (75). Certain conditions of hypercortisolism thought to be due to increased CRH secretion must be excluded. These pseudo-Cushing states include severe stress, illness, depression, renal failure, alcoholism, ethanol withdrawal, and morbid obesity. The CRH test is helpful because these states show poor responsiveness to CRH given following the twoday low-dose dexamethasone suppression test. In contrast, with Cushing’s syndrome, serum cortisol becomes elevated 15 minutes after CRH is injected (76). ACTH excess is readily diagnosed by immunoradiometric assays. Elevated ACTH levels in the presence of hypercortisolism are usually consistent with Cushing’s disease when a pituitary adenoma is seen on MRI. In cases wherein no tumor is visualized, a pituitary source of ACTH must be differentiated from other sources including adrenocortical tumors and ectopic ACTH secreted by carcinoma of the lungs, thymus, pancreas, and bronchial carcinoids. Cavernous sinus and inferior petrosal sinus samplings showing higher ACTH levels than in peripheral samples are suggestive of Cushing’s disease. Transsphenoidal resection is the treatment of choice. Exploration may be required for those with negative imaging. The adenomas are usually in the anteromedial areas deep within the gland. Immediate correction of hypercortisolism is seen. Patients are maintained on steroids postoperatively which are tapered gradually over weeks. Microadenomas have better remission and less frequent recurrence compared to macroadenomas. Radiotherapy is used as primary treatment in patients with poor surgical risks, incompletely resected macroadenomas, or recurrent tumors. Because it may take years before the cortisol levels are normalized, medications are generally used to reduce the cortisol levels after radiation. Medical therapy is used as an adjunct to radiotherapy. Ketoconazole is an antifungal agent that blocks various enzymes in cortisol production and inhibits pituitary ACTH secretion. It is effective in lowering the cortisol levels. Side effects include gynecomastia and hepatotoxicity. Metyrapone is an inhibitor of 11b-hydroxylase and is used in combination with ketoconazole or aminoglutethimide for more severe cases. Aminoglutethimide blocks the conversion of cholesterol to pregnenolone, decreasing cortisol production. Mitotone is a drug that destroys the adrenal cortex and inhibits steroid production. Other drugs have been used to control ACTH secretion with limited success. These include valproic acid, octreotide, cyproheptadine, and bromocriptine. In cases wherein surgery, radiotherapy, and medical treatment have failed to control hypercortisolism, bilateral adrenalectomy is an option. Patients will require lifelong steroid replacement. They are also monitored for Nelson’s syndrome, which is characterized by a rapidly enlarging pituitary adenoma, elevated ACTH levels, and hyperpigmentation. The treatment of choice for Nelson’s syndrome is transsphenoidal resection with or without postop radiation.

Thyrotropinoma TSH-secreting adenomas are rare, comprising 0.5% to 1% of pituitary adenomas (77). The most common cause of an elevated TSH with an enlarged pituitary gland is primary hypothyroidism with reactive pituitary hyperplasia. Most TSH-secreting adenomas secrete TSH alone, but some may secrete the a subunit. Others cosecrete GH, PRL, or gonadotropins. Most are macroadenomas, which are locally invasive. Patients usually present with goiter and hyperthyroidism, which may have been previously treated with thyroid ablation. Thyroidectomy or radioiodine ablation removes the negative feedback and results in further growth of the TSH-secreting adenoma. Some patients have hyperprolactinemia with acromegaly. Macroadenomas may present with mass effects and hypopituitarism. Diagnosis is suggested by elevated levels of free T4 and TSH, and CT or MRI showing a sellar tumor. Treatment is with transsphenoidal resection. The adenoma is usually fibrous and located in the anteromedial portion of the gland. Larger tumors with involvement of adjacent structures are generally less favorable. Thioamines, potassium iodide, or b-blockers are used for short-term control of hyperthyroidism prior to surgery (78). Octreotide and propranolol may also be used prior to surgery. After surgery, T4 replacement may be needed temporarily or permanently. Other hormonal replacement may be required. Radiotherapy is indicated in patients who refuse surgery, are poor surgical risks, or have failed surgery. Octreotide has been used successfully in shrinking the tumor and normalizing TSH and thyroid hormone levels. This requires continuous therapy.

Gonadotroph Adenoma Gonadotroph adenomas are common. They comprise about half of all macroadenomas and a large proportion of clinically nonfunctioning adenomas (79). Their hypersecretion is minimal compared to other secreting adenomas. It usually involves FSH and a combination of a and b subunits of FSH and LH. The relative amounts of each incomplete hormone are not consistent among gonadotroph adenomas (80). Patients usually present with headache and visual symptoms. Macroadenomas may result in hypopituitarism and mild hyperprolactinemia. They may be found incidentally on radiologic work-ups. Diagnosis is made with images showing sellar tumor and elevated levels of gonadotropins and their subunits, which are often increased further with the administration of TRH (81). Treatment is transsphenoidal resection. Most cases have improvement of visual symptoms. Postop hormonal levels are measured and replacement is given as required. Radiotherapy is indicated in patients who decline surgery, have poor surgical risks, or incomplete resection. Medical therapy has not been successful in decreasing tumor size.

Nonsecretory Adenoma Pituitary adenomas may secrete clinically insignificant amounts of hormone, inactive hormones, or none at all (82). Nonsecretory adenoma is the most common type of macroadenoma. It usually presents with mass effects, hypopituitarism, and mild hyperprolactinemia from stalk effect. Diagnosis is suggested by images of a sellar tumor and absence of hormonal hypersecretion. In patients with a history of primary cancer, pituitary metastasis is possible. Treatment is aimed at restoring vision and pituitary function by decompressing the adjacent structures. This is

Chapter 50: Pituitary Dysfunction

usually done with transsphenoidal resection but may require a combined transcranial approach as well. Recurrent tumors are treated with repeat surgery. Radiotherapy is reserved for patients with poor surgical risks or recurrent tumors that are inaccessible by surgery. No medical therapy is effective in decreasing the tumor size. For patients with nonsecretory microadenomas that are discovered incidentally, no treatment is indicated unless there is tumor growth or pituitary dysfunction.

Pituitary Apoplexy Pituitary apoplexy is a sudden hemorrhagic or ischemic infarction of the pituitary gland or tumor that may result in transient or permanent hypopituitarism. It may be clinically silent or acutely life threatening. It is associated most often with rapidly growing adenomas and less frequently with head injury, bromocriptine therapy, hypertension, and systemic anticoagulation (83). Ischemic infarction of the normal gland may be seen following obstetric hemorrhage (Sheehan’s syndrome). Predisposing factors include DM, bleeding disorders, and radiation (5). Patients may present with headache, nausea, vomiting, visual loss, ophthalmoplegia, diplopia, ptosis, mydriasis, fever, stiff neck, stroke, seizure, altered mental status, or coma. CT or MRI is usually diagnostic. Blood density or intensity in the sellar area with occasional fluid level is seen (Fig. 6). Baseline hormone levels must be obtained. Treatment is directed at replacement of deficient hormones, especially the steroids. Emergent transsphenoidal surgery must be planned if there are visual deficits or altered sensorium. Pituitary function may recover. With modern imaging techniques, hormonal replacement, and surgical decompression, most symptomatic pituitary apoplexy should have a good outcome.

Other Sellar and Parasellar Lesions Craniopharyngioma is the most common parasellar tumor in children, comprising 5% to 13% of pediatric intracranial tumors (84). Up to one-third occurs in adults, making up 1.2% to 4% of adult intracranial tumors (85). It is a benign, slowly growing encapsulated tumor with cystic and solid components and frequent calcification. It is more commonly suprasellar than intrasellar. Treatment with surgery and

959

radiation is individualized to maximize long-term tumor control while minimizing morbidity. Meningiomas of the olfactory groove, tuberculum sella, and medial sphenoid wing comprise about 14% of parasellar tumors (86). These are benign, slowly growing well-circumscribed tumors that are usually solid and enhance with contrast. They are more common in women. They usually present with visual symptoms. The majority of these can be resected totally. Metastatic tumors may be sellar or suprasellar. About 70% involve the neurohypophysis (63). They arise commonly from the lungs and breasts but may also come from the nasopharynx, kidney, and GI tract. They are usually solid and enhance with contrast. Surgery may be indicated for tissue diagnosis and decompression of adjacent structures. The treatment is combined with radiotherapy and chemotherapy for palliation. A giant aneurysm (greater than 2.5 cm in diameter) of the anterior communicating artery may present as a suprasellar mass with occasional calcification seen on head CT. Aneurysms of the ICA and anterior and posterior communicating arteries in the parasellar and suprasellar areas can present clinically like a pituitary tumor. Compression of adjacent structures may result in visual deficits and hypopituitarism. Rupture into the cavernous sinus may result in an arteriovenous fistula. Angiography is diagnostic. Treatment is with surgical clipping, endovascular coiling, or both. Lymphocytic hypophysitis is a lymphocytic infiltration of the pituitary gland typically seen in pregnant women or during the postpartum period. The gland is often enlarged due to the lymphocytic infiltrates and may resemble a tumor. The etiology is unknown but may be autoimmune. Many of the patients have immunopathies such as thyroiditis, autoimmune gastritis, and lupus erythematosus (45). Patients present with hypopituitarism and a pituitary mass. Clinical suspicion in a patient with headache, visual disturbance, weakness, and fatigue may prevent possible death from unrecognized adrenal insufficiency. Treatment with steroids has been effective in reducing inflammation. A therapeutic trial with a dopamine agonist may be started to treat hyperprolactinemia but this does not affect the enlargement, which may regress spontaneously. Surgery may be indicated in patients with progressive symptoms of compression or failure of medical treatment.

Figure 6 (A) Coronal MRI showing acute hemorrhage (A) within the large adenoma. The internal carotid artery on each side of the tumor can be seen. (B) Sagittal MRI showing the adenoma eroding through the sellar floor into the sphenoid sinus. The hemorrhage (A) is confined within the tumor.

medwedi.ru

960

Part Seven: The Endocrine System

Sarcoidosis is a granulomatous disease that affects multiple organs. About 5% of patients with sarcoidosis have clinical signs of neurosarcoidosis and less than 1% of patients have symptoms of hypothalamic or pituitary dysfunction (87). Neurosarcoidosis primarily involves the leptomeninges at the base of the brain and posterior fossa, but may also affect the infundibulum and the optic nerves. Surgical biopsy provides a definitive tissue diagnosis. Treatment is with steroids. Cyclophosphamide may be considered for resistant cases (88). In chronic primary hypothyroidism, pituitary hyperplasia resulting from an increased TRH secretion may mimic the appearance of a tumor. The pituitary gland may become large enough to cause optic nerve compression. Because TRH stimulates PRL, these patients may present with hyperprolactinemia and hypogonadism. An elevated TSH level with low T3 and T4 levels in these patients confirm the diagnosis. Treatment with L-T4 will shrink the pituitary gland to its normal size. Empty sella syndrome is a condition wherein the subarachnoid space extends into the sella turcica. It is primary if a defect in the diaphragma sella results in herniation of the arachnoid membrane and compression of the pituitary gland against the sellar floor. This generally does alter the parenchymal structure of the compressed pituitary gland. It may be an incidental finding in patients with morbid obesity or pseudotumor cerebri. It is secondary if previous surgery, radiation, or remote tumor infarction (apoplexy) has decreased the volume of the pituitary and caused the sella to be filled with CSF. In these cases, hypopituitarism may be present. No treatment is usually necessary unless there is pituitary dysfunction.

Surgical Approaches to Sellar and Parasellar Lesions Lesions in the sellar area may be approached transsphenoidally or transcranially. With either approach, intraoperative use of microscope or endoscope is essential to visualization. Fluoroscopy and stereotactic imaging guidance are helpful in localization (Fig. 7). The transsphenoidal approach is preferable for most pituitary adenomas and cystic lesions (Fig. 8). Even large adenomas with significant suprasellar extension can be completely resected as long as there is no significant constriction at the diaphragma sella, which results in a dumbbell-shaped tumor. Meningiomas and aneurysms should not be approached with this route. The incision is made either sublabially or endonasally, followed by a submucosal dissection along the cartilaginous septum and the floor of the nasal cavity (Fig. 9). The sellar lesion is reached by removing the wall of the sphenoid sinus and the floor of the sella. The improvement in optics and video technology has allowed the use of endoscopes not only as adjuncts to the microscope but more recently also as the main optical instruments in endoscopic endonasal transsphenoidal surgery. The transsphenoidal approach has the advantages of providing a direct access to the sella, visualization of the pituitary gland and its adjacent lesion, and allowing decompression of the optic chiasm without directly manipulating it. The transcranial approach is used for meningiomas, aneurysms, and lesions above the diaphragma sella. It may be used as the second stage operation following a transsphenoidal resection. It involves a scalp incision, craniotomy, dural opening, and brain retraction to visualize the sellar and parasellar areas. The angle of the approach may be subfrontal, pterional, subtemporal, or a combination of these.

Figure 7 Intraoperative fluoroscopy showing a probe (p) passing through the anterior wall of the sphenoid sinus (ss) and pointing at the floor of an enlarged sella turcica (s). The Hardy speculum (H) rests on the floor of the nasal cavity and provides a corridor through which the sellar tumor can be removed. The endotracheal tube and oropharyngeal packing can be seen.

SYNDROME OF INAPPROPRIATE SECRETION OF ADH SIADH is a condition of continued secretion of ADH even when the plasma osmolality falls below the threshold. It

Figure 8 Schematic representation of the transnasal, trans-septal, transsphenoidal approach to the pituitary gland. 1, Bivalve speculum in place; 2, ring curette in the sella; 3, open sphenoidal sinus; 4, pituitary gland; 5, resected nasal cartilage; and 6, open sellar floor.

Chapter 50: Pituitary Dysfunction

961

Figure 9 (A) Draping for a transsphenoidal procedure. Patient’s nose and upper lip remain exposed. (B) After a sublabial incision, the mucosa (m) is separated from the maxillary bone to create inferior submucosal tunnels (t). The septal cartilage (sc) will be detached from the maxillary crest (mc) and pushed to the left to enlarge the right anterior tunnel that is being developed. The joining of the tunnels will create a space through which the speculum can be placed. A retractor (r) is holding the upper lip. (C) The Hardy speculum (H) in place.

presents with hyponatremia with low plasma osmolality and elevated urine osmolality that is usually higher than plasma osmolality (23). The patient must be euvolemic with normal renal, adrenal, and thyroid functions. Patients remain asymptomatic unless serum sodium decreases rapidly or fall below 115 mmol/L (89). Symptoms include headache, fatigue, nausea, vomiting, anorexia, cramps, ileus, confusion, irritability, seizures, ataxia, and coma. Personality changes, inattentiveness, and forgetfulness may progress to paranoia and delusions. SIADH may be seen in head trauma, intracranial bleeding, brain tumors, meningitis, encephalitis, porphyria, bronchial carcinoma, and other ectopic tumors producing ADH. Hypothyroidism and hypocortisolism may result in a similar euvolemic hypotonic hyponatremia. Nicotine, morphine, barbiturates, vincristine, and some tricyclic antidepressants stimulate ADH secretion. Phenytoin, chlorpropamide, clofibrate, thiazides, and mono-amine oxidase (MAO) inhibitors may cause SIADH. Treatment consists of the removal of possible causes of SIADH and restriction of daily water intake to 500 mL. Demeclocycline 600 to 1200 mg/day is used to block the antidiuretic action of ADH. Oral furosemide with salt supplementation may also be used (90). Severe hyponatremia is corrected very slowly to at least 125 mmol/L with hypertonic saline. Rapid correction of hyponatremia must be avoided to prevent central pontine myelinolysis, which usually occurs within a few days after rapid correction and presents with seizures, brain edema, and coma.

SUMMARY The hypothalamic-pituitary-target organ axis provides an intercellular communication that is essential in maintaining internal homeostasis and metabolism. Its dysfunction affects normal growth, development, and reproduction. Various lesions in the sellar and parasellar areas cause excessive or deficient secretion of pituitary hormones and compression of adjacent tissues. The most common sellar tumor is a pituitary adenoma. Diagnosis is facilitated by modern imaging technology and bioassay techniques. Treatment is aimed at removal of the etiology of hormonal dysfunction or mass

effects, preservation and improvement of pituitary, visual, and neurologic functions, and normalization of the hormonal milieu by controlling hypersecretion or replacing deficient hormones. Current medical therapy provides crucial hormonal replacement and is able to control hypersecretion in prolactinomas and, to a minor extent, in acromegaly. Surgery is still the preferred treatment for acromegaly, Cushing’s disease, and most tumors including gonadotropin-secreting adenomas and nonsecretory adenomas. Surgery is usually indicated for tumor debulking, decompression of surrounding structures, or tissue diagnosis. Radiotherapy is used as an adjunctive therapy. With prompt diagnosis and treatment, pituitary dysfunction should not cause undue morbidity or early mortality. Multispecialty care provided by the endocrinologist, neuroradiologist, neuroophthalmologist, neurosurgeon, neuropathologist, and radiation oncologist can increase the chance of leading a normal life.

REFERENCES 1. Abboud CF, Ebersold MJ. Prolactinomas. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:279–294. 2. Asa SL, Kovacs K, Melmed S. The hypothalamic-pituitary axis. In: Melmed S, ed. The Pituitary. Cambridge: Blackwell, 1995: 3–44. 3. Baumann G, Amburn KD, Buchanan TA. The effect of circulating growth hormone-binding protein on metabolic clearance, distribution, and degradation of human growth hormone. J Clin Endocrinol Metab 1987; 64:657–660. 4. Baylis PH. Vasopressin, diabetes insipidus and syndrome of inappropriate antidiuresis. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001: 363–376. 5. Beck-Peccoz P, Amr S, Menezes Ferreira MM, et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med 1985; 312:1085–1090. 6. Beck-Peccoz P, Persani L. TSH-producing adenomas. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:321–328. 7. Brabant G, Prank K, Ranft U, et al. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab 1990; 70:4403–4409.

medwedi.ru

962

Part Seven: The Endocrine System

8. Braunstein GD. Hypothalamic syndromes. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:269–281. 9. Buchfelder M, Fahlbusch R. Thyrotroph adenomas. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:333–342. 10. Cardoso ER, Peterson EW. Pituitary apoplexy: a review. Neurosurgery 1984; 14:363–373. 11. Carroll PV, Christ ER, Bengtsson BA, et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab 1998; 83: 382–395. 12. Carter-Su C, Schwartz J, Smit LS. Molecular mechanism of growth hormone action. Annu Rev Physiol 1996; 58:187–207. 13. Chandler WF. Pituitary tumors. In: Bernstein M, Berger MS, eds. Neuro-oncology the Essentials. New York: Thieme, 2000:399–408. 14. Chapman IM, Bach MA, Van Cauter E, et al. Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab 1996; 81:4249–4257. 15. Cobb WE, Spare S, Reichlin S. Neurogenic diabetes insipidus: management with DDAVP (1-desamino-8-D arginine vasopressin). Ann Intern Med 1978; 88:183–188. 16. Copinschi G, Vanonderbergen A, Lhermitebaleriaux M, et al. Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men. J Clin Endocrinol Metab 1996; 81:2776–2782. 17. Corbetta S, Pizzocaro A, Peracchi M, et al. Multiple endocrine neoplasia type I in patients with recognized pituitary tumours of different types. Clin Endocrinol 1997; 47:507–512. 18. Daneshdoost L, Gennarelli TA, Bashey HM, et al. Identification of gonadotroph adenomas in men with clinically nonfunctioning adenomas by the LHb subunit response to TRH. J Clin Endocrinol Metab 1993; 77:1352–1355. 19. DeBold CR, Sheldon WR, DeCherney GS, et al. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest 1984; 73:533–538. 20. Decaux G, Waterlot Y, Gennette F, et al. Inappropriate secretion of antidiuretic hormone treated with furosemide. Br Med J 1982; 285:89–90. 21. Desir D, Van Cauter E, Fang VS, et al. Effects of ‘‘jet lag’’ on hormonal patterns. I: procedures, variations in total plasma proteins, and disruption of adrenocorticotropin-cortisol periodicity. J Clin Endocrinol Metab 1981; 52:628–641. 22. Emery D, Kucharczyk W. Imaging of pituitary tumors. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:201–217. 23. Essat S, Melmed S. Clinical review 18: are patients with acromegaly at increased risk for neoplasia? J Clin Endocrinol Metab 1991; 72:245–249. 24. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240:889–895. 25. Evans WS, Cronin MJ, Thorner MO. Hypogonadism in hyperprolactinemia. Proposed mechanisms. In: Ganong WF, Martini L, eds. Frontiers in Neuroendocrinology. New York: Raven, 1982:77–122. 26. Faglia G. Prolactinomas and hyperprolactinemic syndrome. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:329–342. 27. Fried LF, Palevsky PM. Hyponatremia and hypernatremia. Med Clin N Am 1997; 81:585–609. 28. Gerich JE, Lorenzi M, Bier DM, et al. Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin. J Clin Invest 1976; 57:875–884. 29. Green H, Morikawa M, Nixon T. A dual effector theory of growth hormone action. Differentiation 1985; 29:195–198.

30. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998; 83:379–381. 31. Ho KKY. Growth hormone deficiency in adults. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:520–527. 32. Holl RW, Thorner MO, Leong DA. Intracellular calcium concentration and growth hormone secretion in individual somatotropes: effects of growth hormone-releasing factor and somatostatin. Endocrinology 1988; 122:2927–2932. 33. Horseman ND. Prolactin. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:209–220. 34. Kacsoh B. Endocrine Physiology. New York: McGraw-Hill, 2000. 35. Kopchick JJ. Growth hormone. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001: 389–404. 36. Kunwar S, Wilson CB. Sellar and parasellar tumors in children. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:354–360. 37. Ladenson PW, Levin AA, Ridgway EC, Daniels GH. Complications of surgery in hypothyroid patients. Am J Med 1984; 77:261–266. 38. Lipscombe L, Asa S, Ezzat S. Management of lesions of the pituitary stalk and hypothalamus. Endocrinologist 2003; 13(1):38–51. 39. Lissett CA, Shalet SM. Hypopituitarism. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:289–299. 40. Lo JC, Tyrrell JB, Wilson CB. Corticotroph adenomas. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:317–332. 41. Loriaux DL, McDonald WJ. Adrenal insufficiency. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:1683–1690. 42. Magalini SI, Magalini SC. Dictionary of Medical Syndromes. 4th. Philadelphia: Lippincott-Raven, 1997. 43. Marshall JC, Kelch RP. Gonadotropin-releasing hormone: role of pulsatile secretion in the regulation of reproduction. N Engl J Med 1986; 315:1459–1468. 44. Mathews LS, Gaddy-Kurten D. Hormone signaling via cytokine receptors and receptor serine kinases. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:49–57. 45. McKeever PE, Blaivas M, Gebarski SS. Sellar tumors other than adenomas. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:387–447. 46. Melmed S, Jackson I, Kleinberg D, et al. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab 1998; 83:2646–2652. 47. Melmed S. Acromegaly. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001: 300–312. 48. Melmed S. Evaluation of pituitary masses. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:282–288. 49. Metcalfe P, Jonston DG, Nosadini R, et al. Metabolic effects of acute and prolonged growth hormone excess in normal and insulin-deficient man. Diabetologia 1981; 20:123–128. 50. Molitch ME. Medical therapy of pituitary tumors. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:247–267. 51. Moore KD, Couldwell WT. Craniopharyngioma. In: Bernstein M, Berger MS, eds. Neuro-oncology the Essentials. New York: Thieme, 2000:409–418. 52. Moose BD, Shaw EG. Radiation therapy of pituitary tumors. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis

Chapter 50: Pituitary Dysfunction

53. 54.

55.

56.

57.

58.

59.

60.

61.

62.

63. 64.

65.

66.

67. 68.

69.

70. 71.

and Management of Pituitary Tumors. Humana PressNew Jersey2001; 9:269–277. Morley JE. Neuroendocrine control of thyrotropin secretion. Endocr Rev 1981; 2:396–436. Moses AM, Norman DD. Diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Adv Intern Med 1982; 27:73–110. Orth DN, Kovacs WJ. The adrenal cortex. In: Wilson JD, ed. Williams Textbook of Endocrinology. 9th ed. Philadelphia: W.B. Saunders, 1998:517–664. Pohl CR, Richardson DW, Hutchinson JS, et al. Hypophysiotropic signal frequency and the functioning of the pituitary-ovarian system in the rhesus monkey. Endocrinology 1983; 112:2076–2080. Quabbe H, Plockinger U. Somatotroph adenomas. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:295–315. Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing’s syndrome. J Clin Endocrinol Metab 1998; 83:1163–1167. Reavley S, Fisher AD, Owen D, et al. Psychological distress in patients with hyperprolactinaemia. Clin Endocrinol 1997; 47:343–348. Redei E, Rittenhouse PA, Revskoy S, McGivern RF, Aird F. A novel endogenous corticotropin release inhibiting factor. Ann NY Acad Sci 1998; 840:456–469. Reeves W. Brian, Daniel G. Bichet, Thomas EA. Posterior pituitary and water metabolism. In: Wilson JD, ed. Williams Textbook of Endocrinology. 9th ed. Philadelphia: W.B. Saunders, 1998:341–387. Reichlin S. Neuroendocrinology. In: Wilson JD, ed. Williams Textbook of Endocrinology. 9th ed. Philadelphia: W.B. Saunders, 1998:165–248. Rhoton AL Jr. The sellar region. Neurosurgery 2002; 4(suppl): S1–355–374. Rinderknecht E, Humbrel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem 1978; 253:2769–2776. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 322:1–6. Rudman D, Kutner MH, Rogers CM, et al. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest 1981; 67:1361–1369. Saeger W. Tumor-like lesions of the pituitary and sellar region. Endocrinologist 2002; 12(4):300–314. Sanno N, Teramoto A, Osamura Y, et al. Pathology of pituitary tumors. In: Weiss MH, Couldwell WT, eds. Neurosurgery Clinics of North America. Philadelphia: W.B. Saunders, 2003:14(1):25–39. Sassin JF, Frantz AG, Kapen S, et al. The nocturnal rise of human prolactin is dependent on sleep. J Clin Endocrinol Metab 1973; 37:436–440. Schwartz J. Intercellular communication in the anterior pituitary. Endocr Rev 2000; 21(5):488–513. Sherwin RS, Schulman GA, Hendler R, et al. Effect of growth hormone on oral glucose tolerance and circulating metabolic fuels in man. Diabetologia 1983; 24:155–161.

963

72. Shupnik MA, Ridgway EC, Chin WW. Molecular biology of thyrotropin. Endocr Rev 1989; 10:459–475. 73. Snyder PJ. Gonadotroph adenomas. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001: 313–320. 74. Snyder PJ. Gonadotroph cell adenomas of the pituitary. Endocr Rev 1985; 6:552–563. 75. Stojilkovic SS, Reinhart J, Catt KJ. Gonadotropin-releasing hormone receptors: structure and signal transduction pathways. Endocr Rev 1994; 15:462–498. 76. Suh HK, Frantz AG. Size heterogeneity of human prolactin in plasma and pituitary extracts. J Clin Endocrinol Metab 1974; 39:928–935. 77. Sved AF. Central neural pathways in barorecptor control of vasopressin secretion. In: Schrier RW, ed. Vasopressin. New York: Raven, 1985:443–453. 78. Thapar K, Laws ER Jr. Pituitary surgery. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:225–246. 79. Thorner M, Vance ML, Laws ER Jr, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, ed. Williams Textbook of Endocrinology. 9th ed. Philadelphia: W.B. Saunders, 1998:249–340. 80. Van Cauter E, Copinschi G, Turek FW. Endocrine and other biologic rhythms. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:235–256. 81. Van Wyk JJ, Underwood LE, Hintz RL, et al. The somatomedins: a family of insulin like hormones under growth hormone control. Recent Prog Horm Res 1974; 30:259–318. 82. Vance ML. Diagnosis, management, and prognosis of pituitary tumors. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:165–172. 83. White A, Ray DW. Adrenocorticotropic hormone. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:221–233. 84. Wiersinga WM. Hypothyroidism and myxedema coma. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:1491–1506. 85. Yamada S. Epidemiology of pituitary tumors. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:57–69. 86. Yanovski JA, Cutler GB, Chrousos GP, Nieman LK. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. JAMA 1993; 269:2232–2238. 87. Yeung VT, Lai CK, Cockram CS, et al. Atrial natriuretic peptide in the central nervous system. Neuroendocrinology 1991; 53:18–24. 88. Ying SY. Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocr Rev 1988; 9:267–293. 89. Young WF Jr. Clinically nonfunctioning pituitary adenomas. In: Thapar K, Kovacs K, Scheithauer BW, Lloyd RV, eds. Diagnosis and Management of Pituitary Tumors. New Jersey: Humana Press, 2001:343–351. 90. Zingg HH. Oxytocin. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: W.B. Saunders, 2001:201–208.

medwedi.ru

51 Adrenal Glands Maria A. Kouvaraki, Douglas B. Evans, Ana O. Hoff, and Jeffrey E. Lee

INTRODUCTION Physicians must always be aware of potential adrenal pathology when evaluating and treating a surgical patient. In this way, they are more likely to detect occult adrenal insufficiency, pheochromocytomas, functioning adrenal adenomas, and aldosteronomas at an early stage. However, this requires physicians to have a fundamental understanding of both the normal and abnormal endocrine functions of the adrenal gland and a working knowledge of the surgical approaches appropriate for the treatment of the range of adrenal tumors. They must also know the natural history of diseases that can affect the adrenal gland. In particular, they must have an understanding of the natural history and epidemiology of incidental masses of the adrenal gland, functioning and nonfunctioning adenomas, pheochromocytomas, and adrenal cortical carcinomas. This will help the surgeon to evaluate thoroughly and critically a patient with an incidental adrenal mass and then, once the diagnosis is established, to recommend the most appropriate treatment. The discussion in this chapter focuses on aspects of adrenal physiology and pathophysiology important in the surgical evaluation of the patient with a known or suspected adrenal mass, adrenal hormone excess, or adrenal hormone deficiency.

EMBRYOLOGY, ANATOMY, AND HISTOLOGY The adrenal gland is composed of a cortex and medulla that have different embryologic origins. The adrenal cortex arises from the coelomic mesoderm between the fourth and sixth weeks of gestation. The adrenal medulla is derived from cells of the neural crest that migrate to the adrenal cortex. The neural crest also forms the sympathetic nervous system and ganglia. Chromaffin tissue may also develop in extra-adrenal sites, most commonly in the para-adrenal and para-aortic regions. The single most common site where extra-adrenal chromaffin tissue develops is the organ of Zuckerkandl, located adjacent to the aorta near the origin of the inferior mesenteric artery. Although the adrenal cortex is composed initially of an inner zone and a large outer fetal zone, this fetal zone involutes late in gestation and in the early postnatal period, leaving only a thin cortical layer in the mature adrenal gland. The adrenal glands are paired structures that have a pyramid shape and are located in the retroperitoneum along the superior medial aspect of each kidney. The normal adult adrenal gland weighs approximately 4 to 5 g and has a rubbery consistency. The bright yellow color of the adrenal gland helps to distinguish it from the surrounding retroperitoneal fat. On cut sections, the adrenal gland has two distinct layers: a thin (1–2 mm), bright yellow cortex that

envelops an even thinner layer of dark reddish gray tissue, the adrenal medulla. The medulla is soft and constitutes only approximately 10% to 20% of the total weight of the adrenal gland. The adrenal glands are highly vascularized; they receive arterial blood from branches of the inferior phrenic arteries, the renal artery, and directly from the aorta. The nutrient arteries coalesce and anastomose to form a capsular arterial plexus that sends capillaries coursing through the cortical cells. These capillaries combine to form a venous portal system that drains into the adrenal medulla. There, the vessels come together to join the central adrenal vein. This venous portal system supplies the adrenal medullary tissue with a high concentration of adrenal steroids. Additionally, the adrenal medulla is supplied by arteriae medullae that penetrate directly into the substance of the adrenal medulla. Although some small veins drain from the surface of the adrenal cortex, most arterial blood flows from the capsular plexus, through the cortex, into the medulla, and out of the central vein. The right adrenal vein is short and wide; it exits the gland and immediately enters the posterolateral aspect of the inferior vena cava. The left adrenal vein exits anteriorly and usually drains into the left renal vein, although it occasionally enters the inferior vena cava directly. As a result, it is easier to catheterize the adrenal vein on the left than on the right. There is a lymphatic plexus within the subcapsular portion of the adrenal cortex and the adrenal medulla that drains into the adjacent para-aortic and renal lymph nodes. Although the adrenal cortex does not appear to be innervated, the adrenal medulla is richly supplied by preganglionic sympathetic nerves that extend from the splanchnic nerve, celiac ganglia, and other plexuses. There is no parasympathetic innervation of the adrenal medulla. Histologically, the adult adrenal cortex is composed of three zones: an outer zona glomerulosa, a middle zona fasciculata, and an inner zona reticularis. Each zone has distinct histologic features under a light and electron microscope. Aldosterone is produced exclusively in the zona glomerulosa, and cortisol and androgens are produced in the zona fasciculata and zona reticularis. Adrenal medullary cells have a polyhedral shape and are arranged in cords around adrenal portal veins. They contain catecholamines and precipitated chromium salts that stain brown with hematoxylin and eosin. Electron microscopy shows vesicles in the core of these cells that contain epinephrine and norepinephrine. The hormones secreted by the adrenal cortex and the vascular supply to the gland affect adrenal medullary secretion. Adrenal medullary cells are generally clumped around blood vessels coming from the cortex, which provides these cells with a high local concentration of cortisol. Cortisol induces the enzyme phenylethanolamine

medwedi.ru 965

966

Part Seven: The Endocrine System

N-methyltransferase (PNMT), which converts norepinephrine to epinephrine. The vessels that provide a direct arterial blood supply to the adrenal medulla are surrounded primarily by cells that secrete predominantly norepinephrine.

PHYSIOLOGY Physiologically, the adrenal gland must be regarded as two separate organs. This is because the cortex and the medulla are regulated by independent control systems and their functions do not overlap.

Adrenal Cortex The adrenal cortex secretes three major products: glucocorticosteroids (cortisol and corticosterone), mineralocorticoids (aldosterone and deoxycorticosterone), and sex steroids (mainly androgens). The metabolic pathways are shown in Figure 1.

Cortisol Cortisol is secreted from the zona fasciculata in relatively large amounts (10–20 mg/day). The control of cortisol secretion begins in the central nervous system (CNS). Specifically, neurons from almost every part of the brain converge on the hypothalamus and modulate the release of a 41– amino-acid peptide, corticotropin-releasing factor (CRF), from the hypothalamus. After its release, CRF travels via a direct portal venous system to the anterior pituitary, where it stimulates the synthesis and release of adrenocorticotropic hormone (ACTH), a 39–amino-acid peptide. ACTH secretion shows a diurnal rhythm, with the highest levels occurring early in the morning and the lowest levels occurring late in the afternoon. In turn, under basal conditions, the CNS, via CRF, ACTH, and the adrenocortical cascade, causes a fluctuation in the mean plasma cortisol concentrations, which follows the fluctuation in the ACTH levels. Therefore, a peak

plasma cortisol concentration normally occurs in the early morning and a nadir concentration in the late afternoon. Regulation of Cortisol Secretion Under basal conditions, plasma cortisol concentrations are maintained within fairly narrow limits by an interplay between the concentrations of circulating cortisol, CRF, and ACTH. In particular, as the cortisol concentration exceeds its physiologic limit, as a result of either endogenous stimulation or exogenous administration, ACTH secretion is suppressed. This suppression of ACTH secretion by cortisol is exerted through three mechanisms: (i) cortisol acts directly on the pituitary to inhibit the synthesis of ACTH, (ii) cortisol suppresses the release of ACTH by CRF, and (iii) cortisol inhibits the synthesis of CRF. This negative feedback effect of cortisol on ACTH release maintains the circulating plasma cortisol level in the normal range. The stimulation of cortisol secretion by ACTH occurs via a steroidogenic pathway. ACTH’s primary action in this pathway is to convert cholesterol to d-5-pregnenolone. In general, ACTH and cortisol secretion are increased under conditions of acute stress, fever, pain, or hemorrhage, and this overrides the negative feedback effect of acute endogenous or exogenous hypercortisolemia. Indeed, ACTH secretion increases in proportion to the magnitude of the stress, and the adrenal secretion of cortisol is related linearly to the concentration of ACTH up to a range of 400 to 500 pg/mL. The maximum plasma concentration of cortisol elicited by stress is in the range of 50 to 70 g/dL. Concentrations above 70 to 80 g/dL are distinctly unusual, however, even in the context of longstanding adrenal hyperplasia caused by ectopic ACTH production. Longstanding cortisol (or synthetic steroid) excess has a lasting suppressive effect on ACTH secretion. In particular, it prevents the ACTH response to stress and other

Figure 1 Steroidogenesis in the adrenal cortex.

Chapter 51:

stimuli. The length of time that excess cortisol or cortisollike steroids must be administered before the ACTH release is suppressed has not been precisely determined in humans; however, approximately two to three weeks of chronic daily steroid therapy is sufficient to suppress the normal pituitary-adrenal axis. In the case of exogenously administered steroids, the suppressive effect is clearly dose dependent. Once the cortisol excess is abolished, however, either by removing the endogenous source or by stopping the administration of steroids, the return of pituitary-adrenal function follows a fairly predictable pattern; ACTH secretion returns within three to four months, followed a few months later by the restoration of adrenocortical responsiveness and consequent cortisol secretion. Systemic Effects of Cortisol Almost every tissue in the body is affected by glucocorticoids. Glucocorticoid-related changes in carbohydrate metabolism have the net effect of producing hyperglycemia. The two primary events responsible for hyperglycemia are decreased peripheral utilization of glucose and increased gluconeogenesis. A separate action of glucocorticoids in the context of carbohydrate metabolism is to increase hepatic glycogen synthesis, which is thought to be insulin dependent. Decreased glucose utilization is due to an inhibition of glucose transport and metabolism (especially in fat cells, resulting from a direct cellular effect of the glucocorticoids) and a resistance to the action of insulin. Glucocorticoids increase gluconeogenesis through several mechanisms, including peripheral and hepatic mechanisms. In particular, glucocorticoids act on muscle to release branched-chain and other glucogenic amino acids, which are then converted to glucose in the liver. Both the lipolytic effect of epinephrine, causing the release of glycerol from fat cells, and the glycogenolytic effect of epinephrine, causing release of lactate from muscle, appear to depend partly on the presence of glucocorticoids. Thus, glucocorticoids provide increased glucogenic amino acids, glycerol, and lactate from the periphery for glucose production in the liver through the process of gluconeogenesis. The permissive effect of glucocorticoids accounts for the dependence of epinephrine and glucagon on these steroids for their gluconeogenic action. Lastly, glucocorticoids have a direct effect on gluconeogenesis, apparently through their induction of several gluconeogenic hepatic enzymes. The effects of glucocorticoids on immune function are complex and numerous. On the basis of both their in vivo and in vitro effects, as well as those seen in response to both low-dose and high-dose steroid administration, it is evident that almost every aspect of the immune response can be modified by steroid administration. For example, the numbers and distribution of granulocytes and lymphocytes, as well as the function of these cells, are affected either directly or indirectly by glucocorticoids. Excess glucocorticoids also decrease the tensile strength of wounds, suppress contraction of the scar, and delay epithelialization. These effects have been demonstrated in several species, including humans. In vivo studies have also shown that collagen synthesis is decreased as a result of decreased protein synthesis produced by glucocorticoids. Excess or exogenously administered glucocorticoids may also exert effects on bone mineralization (by increasing bone resorption), in the cardiovascular system, in the digestive tract, and on renal function.

Adrenal Glands

967

Aldosterone Aldosterone is a steroid secreted in small amounts (100–150 mg/day) from the zona glomerulosa. It is the end product of a steroidogenic pathway that includes corticosterone and deoxycorticosterone. As with glucocorticoids, the specificity of aldosterone’s action is determined by its chemical configuration, by the conformational structure and location of steroid receptors, and by postreceptor intracellular events. The actions of aldosterone are less generalized than those of glucocorticoids because of the more limited tissue distribution of mineralocorticoid, or type I, receptors. Specifically, mineralocorticoid receptors are present in the kidney, colon, heart, brain, and blood vessels. Although corticosterone, deoxycorticosterone, and cortisol may act as mineralocorticoids, mineralocorticoid receptors are selective for aldosterone. Responsible for this selectivity is the enzyme 11b-hydroxysteroid dehydrogenase type 2, which inactivates cortisol to cortisone, thereby allowing aldosterone to bind to the mineralocorticoid receptor (1–3). Mainly through its effects on the kidneys, aldosterone plays a major role in the regulation of electrolyte excretion and extracellular fluid balance. The mineralocorticoid receptors in the kidneys are located in the distal renal tubule and cortical collecting ducts. The principal effect of aldosterone on the kidney is to increase sodium resorption and potassium secretion in the proximal portion of the collecting tubule of the distal nephron. More specifically, aldosterone increases the number of apical sodium channels, potassium conductance through specific channels, and the synthesis of the ATPase pump. Aldosterone also promotes the secretion of hydrogen ions into the renal tubule, a process that may not necessarily be directly associated with sodium resorption. Aldosterone receptors also control electrolyte balance in the salivary glands and the colonic mucosa. Chronic aldosterone excess results in depletion of total body potassium levels through increased kaliuresis. Metabolic alkalosis results from a chronic proton deficit. Moreover, excessive aldosterone secretion leads to increased sodium and water retention by the kidneys and to expansion of the extracellular fluid compartment, resulting in suppression of plasma renin activity (PRA). This eventually leads to a higher intravascular volume, which increases cardiac output and blood pressure. Regulation of Aldosterone Secretion Physiologically, the principal mechanism controlling aldosterone secretion is the renin–angiotensin system. Renin is released from the juxtaglomerular apparatus of the kidney in response to a decrease in intravascular volume, such as occurs in the setting of hemorrhage, a negative sodium balance, or dehydration. Both a decrease in pressure in the afferent arteriole entering the glomerulus and a decrease in the intratubular sodium concentration at the level of the macula densa will stimulate renin secretion. Renin released into the bloodstream then hydrolyzes a circulating protein substrate derived from the liver to produce angiotensin I. This peptide is then further cleaved in the lung by a converting enzyme to form angiotensin II. Angiotensin II is a potent vasoconstrictor and functions as a trophic hormone in the adrenal zona glomerulosa responsible for the stimulation of aldosterone secretion. A decrease in the intravascular volume therefore results in increased aldosterone secretion. Conversely, in the setting of a replete blood volume, positive

medwedi.ru

968

Part Seven: The Endocrine System

sodium balance, or overhydration, secretion is suppressed, which leads to a decrease in aldosterone secretion. Aldosterone secretion is also directly controlled by the concentration of serum potassium. Specifically, an increase in serum potassium stimulates aldosterone secretion, and a decrease in serum potassium results in a lowering of aldosterone secretion. In the anephric patient without a renin–angiotensin system, the serum potassium level appears to be the primary mechanism controlling aldosterone secretion. ACTH can also control aldosterone secretion, but to a lesser degree, because the action of ACTH is short lived (less than 24 hours). Such stimulation is normally accompanied by an increase in cortisol secretion. In contrast, angiotensin II and a high serum potassium concentration do not stimulate cortisol production. ACTH alone is not sufficient, however, to restore the full secretory capacity of the zona glomerulosa.

Androgens The three major androgenic steroids produced by the adrenal cortex are dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione, and these androgens have anabolic effects. Quantitatively, DHEA is the most prominent androgenic steroid produced by the adrenal cortex; the synthesis of testosterone by the adrenal cortex is minimal. The androgenic steroids produced by the adrenal cortex are not themselves effective androgens; however, they become so when converted to the potent androgens testosterone and 5a-dihydrotestosterone in peripheral tissues. In women, the peripheral conversion of adrenal androgens is an important source of circulating androgens (one-half of circulating testosterone); in men, most circulating androgen is produced by the testes. The adrenal cortex also produces small amounts of the estrogens, estrone, and estradiol, though most circulating estrogens in women are derived from the ovaries. Pathologically, the adrenal cortex has the potential to produce virilization, either through the secretion of excess androgens by tumors or as a consequence of enzyme defects that shunt steroidogenesis to favor androgen formation. Excess androgen secretion in adults or children is most commonly due to adrenal tumors; it can also be due to congenital adrenocortical enzymatic defects, which are found primarily in newborns and associated with sexual ambiguity. Androgen secretion by adrenal tumors is usually associated with excess cortisol secretion. Female patients with Cushing’s syndrome have masculinizing features, including the coarsening of facial hair and maldistribution of pubic hair into the male pattern. Although aspects of virilization may appear in patients with benign adrenocortical tumors, excessive adrenal androgen production, as evidenced by increased 17-ketosteroid concentrations in the urine, is characteristic of an adrenocortical carcinoma.

Adrenal Medulla Epinephrine and norepinephrine are the principal secretory products of the adrenal medulla. Dopamine is also secreted by the adrenal medulla, but its physiologic importance is unclear (undetermined functional significance). Enkephalins have recently been identified in the adrenal medulla, and their significance is also unclear. Under basal conditions, approximately 80% of the catecholamine produced by the adrenal medulla is epinephrine derived from the amino acid tyrosine. In this pathway, tyrosine is first converted to dihydroxyphenylalanine (dopa) by tyrosine

hydroxylase, the rate-limiting enzyme in the synthetic pathway. The tyrosine hydroxylase content is increased in response to sympathetic nerve stimulation. Next in the pathway, dopa is converted to dopamine by dopa decarboxylase, and the dopamine, now in catecholamine storage vesicles, is converted to norepinephrine by dopamine b-hydroxylase. PNMT then converts norepinephrine to epinephrine. Interestingly, PNMT depends on high concentrations of cortisol for its activity. Vascular connections leading from the adrenal cortex through the adrenal medulla have been demonstrated; presumably, these carry high concentrations of cortisol to the enzyme. The effects of adrenomedullary stimulation and sympathetic nerve stimulation are generally similar. In some tissues, however, epinephrine and norepinephrine may produce different effects because of the existence of two types of receptors, a-adrenergic and b-adrenergic receptors. These receptors have differing sensitivities for various catecholamines and therefore produce different responses. a-Receptors are most sensitive to epinephrine and norepinephrine, whereas b-receptors are most sensitive to isoproterenol. The a-receptors are further subdivided into the a1 group, which causes vasoconstriction, intestinal relaxation, uterine contraction, and pupillary dilation, and the a2 group, which causes platelet aggregation, vasoconstriction, and presynaptic norepinephrine release. The b-receptors are further subdivided into the b1 group, which are equally sensitive to epinephrine and norepinephrine and cause cardiac stimulation, intestinal relaxation, and lipolysis, and the b2 group, which are more sensitive to epinephrine than norepinephrine and cause vasodilation, uterine relaxation, bronchodilation, and presynaptic norepinephrine release. Catecholamine release has several metabolic effects. In particular, carbohydrate metabolism is affected by alterations in glycogenolysis in the liver and in striated muscle. In this process, b-receptor stimulation activates glycogen phosphorylase and inhibits glycogen synthetase. Concomitantly, gluconeogenesis is increased in the liver by catecholamine (especially epinephrine) secretion. Glycogenolysis produces metabolic precursors for gluconeogenesis such as lactate and pyruvate. In all, glucose levels generally rise as catecholamine secretion increases. In addition, catecholamines result in the stimulation of glucagon secretion and reduction in insulin secretion (by pancreatic islet cells), further contributing to the hyperglycemia observed in states in which catecholamine concentrations are increased. Hyposecretory states of the adrenal medulla generally produce no recognizable clinical symptoms. The most common causes include destruction of the gland by autoimmune disorders, malignant metastatic disease, or tuberculosis. The surgical removal of the gland can also, obviously, lead to a lack of secretion. In contrast, the hypersecretion of catecholamines from chromaffin cell tumors produces the well-known clinical syndrome discussed below in the section on pheochromocytoma.

NEOPLASMS OF THE ADRENAL GLAND Neoplasms of the Adrenal Cortex—Benign Neoplasms Aldosteronoma Natural History and Presentation Primary hyperaldosteronism is a clinical syndrome that was first described by Conn in 1954 and results from the

Chapter 51:

hypersecretion of aldosterone (4). Primary hyperaldosteronism occurs in 0.5% to 2.0% of unselected hypertensive patients, but its prevalence may be as high as 5% to 12% in hypertensive populations treated at specialty centers (5–11). Primary hyperaldosteronism is characterized by hypokalemia, suppressed PRA, and the increased urinary excretion of aldosterone (12–14). The signs of mineralocorticoid excess are generally nonspecific but include fatigue, hypokalemia, and metabolic alkalosis. However, up to 40% of patients with confirmed primary hyperaldosteronism are normokalemic (11,15–17). Hypertension is also almost always present but is frequently mild. Primary hyperaldosteronism is usually diagnosed in hypertensive patients in the third to sixth decades of life. Severe hypokalemia may cause muscle weakness, cramping, palpitations, or polyuria and nocturia. Mild hypernatremia can result from a decreased release of vasopressin caused by plasma volume expansion, and mild hyperglycemia can result from decreased insulin secretion caused by chronic potassium depletion. Hyperaldosteronism is caused by an aldosteroneproducing adrenal adenoma (APA) in approximately 60% of patients and by bilateral adrenal hyperplasia [idiopathic hyperplasia (IHA)] in 40% of patients (18–20). Other rare causes (<2%) of primary hyperaldosteronism include unilateral primary adrenal hyperplasia (PAH), adrenocortical carcinoma, aldosterone-secreting ovarian tumors, and familial hyperaldosteronism (Table 1) (21,22). There are two types of familial hyperaldosteronism. Familial hyperaldosteronism type I (FH-type I), or glucocorticoid-remediable hyperaldosteronism (GRA), is inherited as an autosomal dominant hybrid gene mapped on 8q22, which is a chimeric gene duplication that results in a gene containing the 30 promoter region from the 11bhydroxylase gene (ACTH responsive) fused to the 50 coding sequence of the gene that encodes aldosterone synthase. In these patients, the zona fasciculata of the adrenal cortex is able to secrete not only cortisol but also aldosterone under the regulation of ACTH. GRA is characterized by the early onset of severe hypertension that is usually refractory to conventional antihypertensives. However, because aldosterone production is regulated by ACTH, its secretion can be decreased by exogenous steroids. The diagnosis of GRA is based on family history, the finding that dexamethasone

Table 1 Causes of Primary Aldosteronism Disorder

Incidence

APA

60%

Bilateral IHA

30%

Unilateral PAH ACC Aldosterone-secreting ovarian tumors FH Glucocorticoid-remediable aldosteronism (FH-type I) FH-type II (APA or IHA)

Genetic basis Mostly sporadic, rarely familial (AD) Mostly sporadic, rarely familial (AD)

5% < 2% < 2% < 2% Chimeric gene duplication (CYP11B/CYP18) (AD) AD

Abbreviations: AD, autosomal dominant; APA, aldosterone-producing adrenal adenoma; IHA, idiopathic hyperplasia; PAH, primary adrenal hyperplasia; ACC, aldosterone-producing adrenocortical carcinoma; FH, familial hyperaldosteronism.

Adrenal Glands

969

suppresses aldosterone production, and the finding of elevated levels of the hybrid steroids 18-oxocortisol and 18hydroxycortisol. Genetic testing, however, is the best means of diagnosing the disorder and can be arranged by contacting the International GRA registry (http://www.bwh. partners.org/gra). Familial hyperaldosteronism type II (FH-type II) is an autosomal dominant pattern of APA, IHA, or both. This disorder is not suppressed with exogenous glucocorticoid, and the FH-type I gene is not involved. Recent studies have, however, identified a genetic linkage between FH-type II and chromosomal region 7p22. Increased mineralocorticoid activity may also be caused by Cushing’s syndrome. Cortisol has mineralocorticoid activity (cortisone does not), but normally circulates at a much lower concentration than aldosterone. The urinary free cortisol level, as well as the results of an overnight dexamethasone suppression test, can exclude the diagnosis of Cushing’s syndrome. In addition, the long-term use of licorice or chewing tobacco may cause mineralocorticoid hypertension and elevated urinary cortisol levels by inhibiting the enzyme 11-b-hydroxysteroid dehydrogenase, which converts hormonally active cortisol to inactive cortisone. APAs are unilateral, commonly small (0.5–2.0 cm), and are three times more common in women than in men. They produce 18-hydroxycortisol and 18-oxocortisol, which are 17a-hydroxylated analogues of 18-hydroxycorticosterone and aldosterone. These steroids cannot be synthesized in the normal zona glomerulosa or zona fasciculata. Differentiating unilateral adenoma from bilateral idiopathic hyperaldosteronism is critical, because surgical removal of the adrenal gland is helpful only in the former. Diagnostic Evaluation Mineralocorticoid excess should be suspected in any patient with hypertension, unexplained hypokalemia, and metabolic alkalosis, and such patients should be fully evaluated. Although hypokalemia is present in up to 50% of patients with primary hyperaldosteronism, and in almost all patients with GRA, screening for hyperaldosteronism should also be performed in normokalemic patients with severe, resistant hypertension. Prior to biochemical testing, all nonessential medications should be stopped for at least two weeks. However, only few antihypertensive agents (thiazide diuretics, spironolactone, and angiotensin II receptor blockers) actually interfere with the diagnosis of primary hyperaldosteronism and therefore need to be discontinued two weeks prior to the screening tests (15,23–25). Spironolactone, however, should be withdrawn at least four to six weeks before the tests (15,26,27). The first step in the diagnostic evaluation of primary hyperaldosteronism is to determine a random plasma aldosterone-to-renin ratio. In this test, the PRA should be measured simultaneously with the plasma aldosterone level. The PRA is typically very low in patients with primary hyperaldosteronism and a plasma aldosterone-to-PRA ratio (ARR) exceeding 30 (ng/dL:ng/mL/hr), along with a plasma aldosterone concentration (PAC) exceeding 20 ng/ dL, is very sensitive and specific in establishing the diagnosis of primary hyperaldosteronism (11,24,25,28–30). However, if the ARR is higher than 30 ng/dL, then additional studies that can demonstrate the inappropriate secretion of aldosterone can be used to confirm the presence of primary hyperaldosteronism. Either of the following aldosterone suppression tests may be used for this purpose: the intravenous saline suppression test, in which 2 L of normal saline is infused over four hours and then the PAC is measured, and

medwedi.ru

970

Part Seven: The Endocrine System

the three-day oral salt loading (100 mmol NaCl/day) test, in which a 24-hour urine collection is obtained on the third day of the test to measure the levels of aldosterone, sodium and potassium, and serum is obtained to measure sodium and potassium. Confirmation of hyperaldosteronism is obtained when PAC is greater than 10 ng/dL (saline-loading test) or urinary aldosterone is greater than 14 mg/24 hr (oral salt-loading test). In the latter test, it is important to demonstrate adequate salt loading; therefore the urinary sodium level should be greater than 200 mEq/24 hr. Potassium supplementation should be given to patients during the salt-loading test because severe hypokalemia can be life threatening and can inhibit aldosterone production in some patients. The captopril test, another confirmatory test, has not been widely used. Table 2 shows all the essential diagnostic tests for the screening and confirmation of primary hyperaldosteronism. An additional test that can be performed early in the evaluation of patients with possible hyperaldosteronism is a 24-hour urine collection for potassium. Patients with primary hyperaldosteronism have inappropriate urinary potassium wasting (> 30 mEq/day) as the cause for hypokalemia. This test is most useful when extrarenal losses of potassium are suspected, such as in patients with surreptitious vomiting or laxative abuse. Once the diagnosis of hyperaldosteronism is established, it is critical to differentiate unilateral APA or unilateral PAH from bilateral hyperplasia of the zona glomerulosa (IHA). Patients with a unilateral APA usually have more severe hypertension, higher plasma aldosterone levels, and therefore more profound hypokalemia; however, these findings cannot accurately differentiate patients with unilateral adenoma from those with idiopathic hyperaldosteronism. Identifying the cause of primary hyperaldosteronism may require one or more tests. Computed tomography (CT)

and magnetic resonance imaging (MRI) can confirm the presence of a unilateral adrenal nodule, and iodocholesterol (NP-59 or 131I-6b-iodomethyl-19-norcholesterol) imaging (Fig. 2) and selective adrenal venous sampling for aldosterone measurements can confirm physiologically that the nodule on CT or MRI studies is in fact responsible for the excess aldosterone production. CT may detect a solitary unilateral macroadenoma (>1 cm) and normal contralateral adrenal gland. Additional evaluation is needed, however, in patients with normal-appearing adrenals, minimal unilateral adrenal thickening, unilateral microadenomas (1 cm), or bilateral adenomas (44–47). This is because small adrenal microadenomas may be missed on CT scans or misdiagnosed as bilateral idiopathic hyperplasia. There is also a high frequency of nonfunctioning adrenal cortical adenomas in the normal population (2–8%), so the finding of a small adrenal mass on CT or MRI studies does not necessarily establish a diagnosis of a unilateral APA. In these cases, because selective venous sampling is invasive and cannulation of the right adrenal vein is often difficult and occasionally results in adrenal vein thrombosis with adrenal infarction (47,48), we frequently combine adrenal imaging (CT or MRI) with iodocholesterol imaging to confirm the presence of a unilateral functioning adrenal mass. Our current approach to the evaluation of patients suspected of having primary hyperaldosteronism is shown in Figure 3. Treatment The treatment of primary hyperaldosteronism depends on the cause. Surgery is of little value in patients with idiopathic hyperaldosteronism, and these patients should therefore be treated medically (48). IHA is best managed medically using the aldosterone antagonist spironolactone.

Table 2 Biochemical Diagnosis of Functioning Adrenal Tumors Diagnostic study Primary hyperaldosteronism Plasma K PACb and ARR (31) 4-hr IV saline-loading test (32,33) 3-day oral salt-loading (34) Cushing’s syndrome (selected tests) Overnight 1 mg DMS test (35–37)

Diagnostic values Normal or decreased PAC >20 ng/dL and ARR >30 ng/dL:ng/ml/hr PAC >10 ng/dL Ur Na >200 mEq then Ur ALD >14 mg/24 hr

Exclude hypokalemiaa Screening test, suggests hyperaldosteronism Confirmatory test Confirmatory test

PC >5 mg/dL

Screening test, suggests hypercortisolism Alternative screening test, suggests hypercortisolism Alternative screening test, suggests hypercortisolism Screening test, suggests hypercortisolism Confirmatory test, excludes pseudocushing

24-hr urine free cortisol (39)

PC >5 mg/dL at 9 AM, post-DMS for 48 hr >3 times normal level

Salivary cortisol at 11 P.M. (40)

>3.6 nmol/L

CRH–DMS test (41,42)

PC >1.4 mg/dL, 15 min post last CRH infusion

Low dose DMS test (38)

Pheochromocytoma Plasma free metanephrinesc (41,42) Urine total metanephrines and catecholaminesc (43) a

Interpretation

Increased Increased

Screening test, suggests PHEO or PG Alternative screening test, suggests PHEO or PG

Sensitivity (%)

Specificity (%)

NA 90

NA 91

96 96

93 93

100

88

98

99

100

98

92

100

100

100

99

89

90

98

Mineralocorticoid-induced hypokalemia may inhibit aldosterone production in some patients. PAC in combination with ARR to exclude hyporeninemic hypertension. c Combined measurements of plasma free metanephrines and urine total metanephrines; urine catecholamines increase the sensitivity to 100% and specificity to 98%. Abbreviations: ALD, aldosterone; ARR, plasma aldosterone-to-plasma renin activity ratio; CRH, corticotropin-releasing hormone; DMS, dexamethasone suppression; IV, intravenous; K, potassium; PAC, plasma aldosterone concentration; PC, plasma cortisol; PG, paraganglioma; PHEO, pheochromocytoma; Ur, urinary. b

Chapter 51:

Adrenal Glands

971

fluid and electrolyte balance. Surgery corrects the hypokalemia and lowers the blood pressure in all patients with an APA and unilateral adrenal hyperplasia (PAH); the hypertension resolves in approximately 70% of surgically treated patients (50–54). Surgical resection can be performed either through an open or a laparoscopic approach. Because nearly all patients with aldosteronomas have relatively small tumors with no malignant potential, they are often excellent candidates for a laparoscopic adrenalectomy (55,56). Laparoscopic adrenalectomy has become the standard surgical approach for patients with APAs because of the lower morbidity, fewer postoperative complications, and equal results in cure rates compared to open adrenalectomy (54). The early results from the surgical resection of an APA are good, and the long-term cure rate is approximately 70% (51,53,54). Approximately 2% or less of adrenocortical carcinomas (ACC) cause isolated hyperaldosteronism. In the very rare situation of a patient with hyperaldosteronism and a large adrenal mass, an open anterior approach should be taken to facilitate complete surgical resection.

Cortisol-Producing Adenoma

Figure 2 (A) Contrast-enhanced computed tomography of a left-sided aldosteronoma (arrow) arising from the lateral limb of the left adrenal gland and measuring 1.7 1.5 cm (H.U. ¼ 7). (B) Results of NP-59 (iodocholesterol) imaging of the same patient. Persistent NP-59 uptake that increased over the observation period in the area of the left adrenal gland is consistent with a functioning adrenocortical adenoma, in this case the patient’s aldosteronoma (delayed posterior images obtained at 96 hours).

Most patients can achieve adequate control of their blood pressure with this medication alone or in conjunction with other antihypertensives. However, because it is not a specific blocker of the aldosterone receptor, potential side effects include impotence, decreased libido, and gynecomastia in men and menstrual irregularities in women. Eplerenone is a new selective aldosterone receptor antagonist approved by the U.S. Food and Drug Administration in 2002 for the treatment of hypertension (49). The results of clinical trials comparing this drug with spironolactone in patients with primary hyperaldosteronism have not been published, but the anticipated starting dose in these patients is 50 mg twice daily up to a maximum dose of 200 mg twice daily. If eplerenone proves as effective as spironolactone in controlling blood pressure in patients with IHA, it will have the advantage of not causing the adverse symptoms associated with testosterone receptor blockade. When an APA is confirmed, the appropriate therapy remains surgical resection. In the three to four weeks before operation, patients should be placed on spironolactone and given potassium supplementation to help normalize

Natural History and Presentation Cushing’s syndrome is the term used to refer to the state of hypercortisolism that can result from a number of different pathologic processes (Table 3). The most common cause of Cushing’s syndrome is exogenous steroid administration. Excluding these patients, approximately 70% of the remaining cases of hypercortisolism are secondary to the hypersecretion of ACTH from the pituitary gland, a condition known as Cushing’s disease. Most of the time, a small pituitary adenoma is the cause. The ectopic secretion of ACTH, referred to as ectopic ACTH syndrome, is the cause of approximately 15% of cases of Cushing’s syndrome and usually results from bronchial carcinoids or small-cell lung carcinomas. Other tumors associated with ectopic ACTH production include pancreatic endocrine neoplasms, medullary thyroid carcinoma, malignant thymoma, and pheochromocytoma. The ectopic secretion of CRF is exceedingly rare but has been reported in a few cases. The hypersecretion of cortisol from the adrenal glands accounts for approximately 10% to 20% of cases of Cushing’s syndrome. The underlying cause of Cushing’s syndrome is an adrenal adenoma in 50% to 60% of cases, an adrenocortical carcinoma in 20% to 25%, and IHA in 20% to 30%. The signs and symptoms of hypercortisolism are listed in Table 4; the actions of glucocorticoids are discussed in the previous section on cortisol physiology. The most common symptom of hypercortisolism is weight gain; in adults, cortisol-induced obesity is usually in the classic (truncal) pattern. Diagnostic Evaluation and Treatment The evaluation of patients with possible Cushing’s syndrome starts with establishing the diagnosis and then determining the etiology. To establish the diagnosis, a state of hypercortisolism must be documented. The adult adrenal glands secrete on an average 10 to 30 mg of cortisol each day, and the secretion follows a diurnal variation: cortisol levels tend to be high early in the morning and low in the evening. A relatively sensitive initial method for detecting hypercortisolism is the overnight 1-mg dexamethasone suppression test (Table 2). In this test, 1 mg of dexamethasone is taken orally

medwedi.ru

972

Part Seven: The Endocrine System

Figure 3 Algorithm for the evaluation of the patient with suspected primary hyperaldosteronism.

at 11:00 P.M.; normal individuals have a plasma cortisol level of less than 5 mg/dL at 8:00 A.M. the following morning. Failure to suppress the 8:00 A.M. cortisol to < 5 mg/dL is consistent with hypercortisolism. However, although this Table 3 Causes of Cushing’s Syndrome Exogenous steroids Cushing’s disease (due to pituitary adenoma) Adrenal tumors Adrenal cortical adenoma Adrenal cortical carcinoma Primary adrenal cortical hyperplasia Ectopic ACTH syndrome Ectopic CRF syndrome Abbreviations: ACTH, adrenocorticotropic hormone; CRF, corticotropinreleasing factor.

test has a false-negative rate of only 2%, the false-positive rate is 30%. Therefore, although a normal overnight dexamethasone suppression test essentially excludes clinically significant hypercortisolism, an abnormal test result requires further investigation. The two-day low-dose dexamethasone suppression test (dexamethasone, 0.5 mg orally every six hours for 48 hours) can also be used to detect hypercortisolism. In this test, the measurement of plasma cortisol (9 A.M. prior to starting the dexamethasone and 48 hours later) instead of urinary free cortisol provides a higher sensitivity. This test is reported to have a sensitivity and specificity approaching 99% (57). A 24-hour urine collection for the measurement of urinary free (unmetabolized) cortisol is somewhat less sensitive than the overnight and low-dose dexamethasone suppression tests, but it is a useful complementary test because of its specificity. A urinary free cortisol level that is more than three times greater than

Chapter 51:

Table 4 Clinical Manifestations of Adrenal Cortical Hormone Excess Cortisol Truncal obesity Buffalo hump Moon faces Abdominal striae Hypertension Glucose intolerance Thin skin Osteoporosis Psychiatric changes

Androgen Male pattern baldness Hirsutism Voice change Breast atrophy Libido change Oligomenorrhea Increased muscle mass

Estrogen Gynecomastia Breast tenderness Testicular atrophy Decreased libido

Aldosterone Hypertension Hypokalemia Weakness Polyuria Polydypsia Metabolic alkalosis Glucose intolerance

the upper range of normal is consistent with Cushing’s syndrome. Urinary collection for the measurement of 17hydroxysteroids and a salivary cortisol measurement can also be used (40). Another useful way to detect Cushing’s syndrome is to measure the nocturnal plasma cortisol level. Patients with Cushing’s syndrome do not show a circadian rhythm in cortisol secretion; therefore, a midnight plasma cortisol concentration greater than 7 mg/dL is suggestive of hypercortisolism. Cushing’s syndrome with mild hypercortisolemia is often indistinguishable from that seen in pseudo-Cushing’s states such as depression and alcoholism. The diagnostic accuracy of dexamethasone suppression and corticotropinreleasing hormone (CRH) stimulation tests, when used individually in order to distinguish these conditions, is not greater than 85% (41). In such cases, in order to confirm the presence of Cushing’s syndrome, and exclude pseudoCushing syndrome, the most useful test is the combined CRH–dexamethasone test (42). Eight oral doses of dexamethasone, 0.5 mg each, are given every six hours. The last dose should be given two hours before IV injection of CRH 1 mg/kg. Response to CRH is seen in all patients with Cushing’s syndrome but in none with pseudo-Cushing’s state. Thus, plasma cortisol levels more than 1.4 mg/dL, 15 minutes after CRH injection, confirms the existence of Cushing’s syndrome and excludes pseudo-Cushing’s states. Upon the confirmation of hypercortisolism, patients should undergo an evaluation to detect its etiology. In a patient with an adrenal mass and hypercortisolism, the only additional biochemical test required is the measurement of ACTH. Plasma ACTH obtained at 8 or 9 A.M. in patients with a cortisol-secreting adrenal tumor plasma ACTH is invariably undetectable (discussed below). Additional tests are necessary when Cushing’s disease or ectopic ACTH syndrome is suspected. These tests include the high-dose dexamethasone suppression test, the metyrapone test, and the CRH test (58). ACTH secretion also follows a diurnal variation, preceding that of cortisol by one to two hours. Levels of ACTH are suppressed (<5 pg/mL) in patients with functioning adrenal adenomas, functioning ACC, or autonomously functioning adrenal hyperplasia. In such cases, the autonomous secretion of cortisol by the pathologic process within the adrenal gland inhibits pituitary ACTH release. ACTHdependent Cushing’s syndrome include Cushing’s disease (i.e., a pituitary adenoma–secreting ACTH) and ectopic ACTH secretion (i.e., a nonpituitary tumor–secreting ACTH, such as a metastatic tumor). Patients with Cushing’s disease usually have plasma ACTH levels that are elevated or within the upper limits of normal. When there is an ectopic

973

Adrenal Glands

source of ACTH secretion, the plasma ACTH level is usually markedly elevated. In patients diagnosed with ACTHdependent Cushing’s syndrome, the next step is to distinguish between a pituitary and nonpituitary ACTH– producing tumor by imaging the pituitary gland using MRI. If this shows no obvious pituitary lesion, bilateral simultaneous inferior petrosal sinus sampling is the ‘‘gold standard’’ method to distinguish central (pituitary tumor) from peripheral (nonpituitary tumor) ACTH production (59). In this method, both inferior petrosal sinuses are catheterized, and blood samples are obtained at 0, 2, 5, and 10 minutes following the administration of 1 mg/kg ovine CRH from each inferior petrosal sinus and a peripheral vein, which allows the calculation of an inferior petrosal sinus-toperipheral ACTH ratio (IPS:P). An IPS:P that exceeds 3 is considered consistent with Cushing’s disease. Patients with evidence of ACTH-independent hypercortisolism should undergo abdominal imaging to evaluate the adrenal glands. Choices for abdominal imaging include CT, MRI, and iodocholesterol scanning. CT has a high sensitivity and is the initial imaging study of choice. However, MRI has a higher specificity than CT, because chemical shift and T2-weighted image analysis can help differentiate adrenal cortical adenomas from primary or metastatic carcinomas and from pheochromocytomas (60–65). A drawback of MRI is that it has a lower resolution and therefore a lower sensitivity than CT. Finally,131I-6b-iodomethyl-19 norcholesterol (NP-59 or iodocholesterol) can demonstrate uptake in an adrenal adenoma along with suppression of the contralateral gland. If CT and MRI findings are equivocal, iodocholesterol scanning may be helpful in differentiating unilateral adrenal cortical adenoma (unilateral uptake with contralateral suppression) from bilateral micronodular hyperplasia (bilateral uptake) (66). The appropriate management of hypercortisolism depends on the underlying etiology. Patients with Cushing’s disease should undergo transphenoidal resection of their pituitary adenoma, if it is deemed resectable. Bilateral adrenalectomy is rarely indicated and should be reserved for patients who fail to respond to transphenoidal hypophysectomy and external beam radiation therapy (EBRT), and experience end organ injury from the consequences of overt hypercortisolism. If bilateral adrenalectomy is performed, patients require not only perioperative steroid coverage (Tables 5 and 6) but also lifelong replacement of both glucocorticoids and mineralocorticoids. Patients with autonomously functioning bilateral adrenal hyperplasia usually require bilateral adrenalectomy. Patients with ectopic ACTH syndrome should have the underlying malignant lesion identified and resected if possible. Bilateral adrenalectomy

Table 5 Comparison of Steroid Preparations

Steroid Cortisol Cortisone Prednisone Prednisolone Methylprednisolone Triamcinolone Betamethasone Dexamethasone

medwedi.ru

Half-life (hr)

Glucocorticoid activity (relative to cortisol)

Mineralocorticoid activity (relative to cortisol)

8–12 8–12 12–36 12–36 12–36 12–36 36–72 36–72

1 0.8 4 4 5 5 25 30–40

1 0.8 0.25 0.25 0 0 0 0

974

Part Seven: The Endocrine System

Table 6 Recommendations for Perioperative Glucocorticoid Coverage Steroid treatment Currently on steroids <10 mg/daya >10 mg/daya

HPA axis response

Normal Suppressed

Surgical stress

Any Minor Moderate

Major

High dosea (immunosuppression)

Suppressed

Any

Stopped <3 mo Stopped >3 mo

Suppressed Normal

Any Any

Perioperative steroid coverage

Not required 25 mg of hydrocortisone at induction Usual preoperative steroids þ 25 mg of hydrocortisone at inductionb 100 mg/ day for 24 hr Usual preoperative steroids þ 25 mg of hydrocortisone at induction þ 100 mg/ day for 48–72 hr Usual immunosuppressive doses during perioperative period Treat as if on steroids Not required

a

Prednisolone dose. Patients take their usual daily dose with a sip of water preoperatively. Abbreviation: HPA, hypothalamic-pituitary-adrenal axis. Source: From Ref. 171.

b

should be reserved for the small group of patients whose primary tumor is unresectable and whose symptoms of cortisol excess cannot be controlled medically. Bilateral adrenalectomy can be performed laparoscopically, via a posterior approach, or via laparotomy. Patients with a unilateral cortisol-producing neoplasm of the adrenal gland should undergo adrenalectomy. However, there is no easy way preoperatively to differentiate a benign cortical adenoma from an adrenal cortical carcinoma. As will be discussed in detail in the section entitled ‘‘Incidentalomas,’’ neoplasm size and its characteristics on CT or MRI studies can indicate whether its likely benign or malignant. In general, homogeneously enhancing tumors less than 4 cm in size with smooth borders are considered benign. Such tumors (presumed to be functioning cortical adenomas) can be removed laparoscopically (67,68). We currently favor open transabdominal laparotomy for any cortical tumor (functioning or nonfunctioning) that may be an adrenal cortical carcinoma.

Adrenogenital Syndrome–Producing Tumors Tumors (adenomas or carcinomas) of the zona reticularis produce excessive amounts of androgen or estrogen, leading to the adrenogenital syndrome. The most striking clinical examples of virilizing adrenal tumors are those producing primarily androgens. These tumors may initially go undetected in the adult male, but the female patient shows a deepening of the voice, coarsening of the skin, the thickening and darkening of facial hairs, the assumption of male hair distribution, clitoral hypertrophy, menstrual cessation, and breast atrophy. These tumors may appear in childhood (50% of the cases) and result in precocious puberty in both males and females. At postpubertal ages, the adrenogenital syndrome is far more frequent in females than males. Rarely, adrenal cortical adenomas or carcinomas produce estrogens. Additionally, peripheral conversion of

androstenedione to estrogens can result in feminization in patients with adrenal cortical tumors or adrenocortical enzymatic defects; extra-adrenal tumors or extra-adrenal enzymatic defects can also cause feminization. In such unusual cases, it is usually difficult to detect estrogen excess in the female patient, but menstrual irregularities may lead to a definitive diagnosis based on measurements of plasma or urinary estrogens. The male patient with estrogen excess has a loss of libido and onset of impotency, enlargement of breast tissue (gynecomastia), testicular atrophy, and occasionally softening of facial hair and an alteration in malepattern hair distribution.

Neoplasms of the Adrenal Cortex—Malignant Neoplasms Adrenal Corticocarcinoma Molecular Pathogenesis Molecular genetic studies have revealed that a variety of genes and chromosomal loci that are abnormal in hereditary syndromes associated with adrenocortical tumors could also be altered in sporadic ACC (69). For example, the MEN 1 gene, which is responsible for the multiple endocrine neoplasia type 1 (MEN 1) syndrome, is on chromosomal locus 11q13 and encodes the tumor suppressor menin. Comparative genomic hybridization and loss of heterozygosity (LOH) studies have also shown a loss of genetic material in chromosome 11q in sporadic ACCs and their metastatic lesions that was not associated with an MEN 1 mutation (70–72). LOH at 2p16, the locus for the Carney complex familial cancer syndrome, was also strongly associated with malignant ACCs (70). In addition, mutations in the tumor suppressor gene p53 on 17p13 or overexpression of the protein product have been detected in approximately 50% of ACCs (73). In children with sporadic ACC, the high frequency of germline p53 mutations may identify probands of the Li–Fraumeni syndrome, which has obvious geneticcounseling implications. Moreover, IGF1 and IGF2 receptors and their ligands, which are involved in the growth and differentiation of the adrenal cortex, are produced at high levels in functional ACCs, and correlate with the malignant phenotype, suggesting a possible role in ACC tumorigenesis (74). Other genetic abnormalities found in cases of sporadic ACC include a loss of genetic material at 11p15 (Beckwith–Wiedemann syndrome), 9p (p16), 3p [von Hippel Lindau (VHL) syndrome], and 13q (retinoblastoma gene), as well as mutations of the ras gene. Mutations of genes encoding gip2 and the ACTH receptor have also been found in sporadic ACCs (75,76). Studies examining the proliferative signaling pathways are therefore being performed in an attempt to elucidate the mechanisms of tumor growth; these pathways include those involving Akt/PKB and the mitogen-activated protein kinases. Epidemiology and Natural History ACC is a rare disease; there are approximately 150 to 200 new cases reported each year in the United States, and it accounts for only 0.2% of the annual cancer incidence in the United States (69,77). There is a bimodal age distribution, with the incidence peaking in young children and then again in patients between 40 and 50 years of age. Most ACCs are diagnosed at an advanced stage; this is because of the nonspecific nature of the early signs and symptoms. This delay in diagnosis, together with the aggressive histologic behavior of the disease, accounts for the poor prognosis in patients with an ACC (78–81).

Chapter 51:

Presentation and Diagnosis Patients with ACC usually present with vague abdominal symptoms secondary to an enlarging retroperitoneal mass or with the clinical manifestations of an overproduction of one or more adrenal cortical hormones. Approximately 60% of these tumors are functional, as shown by biochemical parameters. In particular, 50% secrete cortisol, producing Cushing’s syndrome. Another 10% to 20% produce steroid hormones, which can cause hypertension and varying degrees of virilization in females and feminization in males. The presence of a functioning adrenal mass can be suspected on the basis of history (e.g., hirsutism, acne, weight gain, proximal muscle weakness, or headache), physical examination findings (e.g., cushingoid features, hypertension, or hyperandrogenism), and abnormal routine serum chemistry findings such as hypokalemia and hyperglycemia. The biochemical evaluation of these patients should include (Table 2) screening for a pheochromocytoma (as shown by the plasma metanephrine level), Cushing’s syndrome (as shown by the 1-mg overnight dexamethasone suppression test), hyperandrogenism (as shown by DHEAS, androstenedione, and testosterone levels) if there are signs or symptoms, and hyperaldosteronism (as shown by the ARR and serum aldosterone concentration) if hypokalemia and/or hypertension are present (43,82). The results serve to guide perioperative replacement therapy, to exclude the diagnosis of pheochromocytoma, and to identify potential tumor markers useful during postoperative follow-up. High-resolution abdominal CT and MRI are the best modalities for imaging the adrenal glands. CT can usually identify lesions as small as 7 mm in diameter. MRI may be especially helpful, not only in identifying tumor extension into the inferior vena cava but also in differentiating between various lesions based on the adrenal-to-liver ratio on T2-weighted images. Adenomas usually have ratios of 0.7 to 1.4; malignant lesions, whether primary or metastatic to the adrenal gland, have ratios of 1.4 to 3.0; and pheochromocytomas usually have ratios greater than 3.0. Chest radiography is helpful in ruling out pulmonary metastasis. Staging The most widely used staging system for ACC is the Sullivan et al. (83) modification of the McFarlane (84) system. In contrast to most modern staging systems, the Sullivan staging system groups patients with adjacent organ invasion or fixed positive lymph nodes and patients with distant metastatic disease into stage IV. Icard et al. (85)

Adrenal Glands

975

and Lee et al. (79) have suggested a modification to this system, in which patients with locally advanced tumors are classified as having stage III disease, with the stage IV designation reserved for patients with metastatic disease (Table 7). These modifications to the Sullivan staging system more accurately reflect the natural history of the disease and are in agreement with the cancer-staging systems (TNM) used for other solid tumors; the stages also correlate with the correct treatment (surgical or medical) required. Surgical Treatment Complete surgical resection is currently the only potentially curative therapy for localized ACC. Approximately 50% of the tumors are localized to the adrenal gland at the time of initial exploration (69). Several recent studies have demonstrated, however, that contiguous organ invasion is common and that therefore adjacent organs frequently need to be resected as part of the primary treatment for a localized ACC (Fig. 4). However, results of at least two series have also demonstrated that although the kidney is frequently removed as part of an en bloc operation, in only a minority of specimens does histologic examination of the resected specimens demonstrate evidence of invasion of the kidney. Further, kidney-sparing complete resection is not associated with decreased survival (79,85,87). An open transabdominal approach is recommended to provide maximal exposure for complete resection, minimize the risk of tumor spillage, and allow vascular control of the inferior vena cava, aorta, and renal vessels when necessary. A review of the surgical complications in patients with primary ACC confirms that tumor extirpation requires complex operative procedures that are often associated with significant morbidity; despite this, a mortality of only 5% or less has been noted in most contemporary series from large referral centers. A number of investigators have evaluated predictors of survival following the resection of an ACC. By far the strongest predictor of outcome is the ability to perform a complete resection. The five-year actuarial survival rate is approximately 40% for patients who undergo a complete resection (Table 8). In the experience of the authors, however, neither the need for extended resection nor the presence of tumor thrombus in the inferior vena cava or renal vein predict a poor prognosis, as long as all diseases are completely resected. In contrast, patients who undergo incomplete resection of their ACC, including a less than total resection of the primary tumor or resection of the primary tumor in the face of unresectable distant metastatic

Table 7 Staging Systems for Adrenocortical Carcinoma Stage

Icard et al. (1992) (86)

Lee et al. (1995) (79)

I II III

T1 (5 cm), N0, M0 T1 (5 cm), N0, M0 T2 ( >5 cm), N0, M0 T2 ( >5 cm), N0, M0 T3 (local invasion without T3 (local invasion), N0, M0 or T1–2, involvement of adjacent organs) or N1 (positive lymph nodes), M0 mobile positive lymph nodes, M0

Macfarlane (1958) (84)

T1 (5 cm), N0, M0 T2 ( >5 cm), N0, M0 T3 (local invasion) and/or N1 (positive regional lymph nodes), M0

IV

T4 (invasion of adjacent organs) or T4 (local invasion), N0, M0; or T3, fixed positive lymph nodes or M1 N1, M0; or T1–4, (distant metastases) N0–1, M1 (distant metastases)

T1–4, N0–1, M1 (distant metastases)

T1 (5 cm), N0, M0 T2 ( >5 cm), N0, M0 T3/T4 (local invasion as demonstrated by histologic evidence of adjacent organ invasion, direct tumor extension to IVC, and/or tumor thrombus within IVC or renal vein) and/or N1 (positive regional lymph nodes), M0 T1–4, N0–1, M1 (distant metastases)

Abbreviation: IVC, inferior vena cava.

Sullivan et al. (1978) (83)

medwedi.ru

976

Part Seven: The Endocrine System

Figure 4 Clinical spectrum of adrenocortical carcinoma. (A) Illustration of a large left adrenal carcinoma showing the intimate relationship between the tumor and the origin of the celiac axis and the SMA. Source: From Ref. 69. (B) Contrast-enhanced CT of a large left adrenal carcinoma extending into the inferior vena cava. Source: From Ref. 69. (C) Illustration of a large right adrenal carcinoma showing the frequent finding of tumor invasion of the liver (posterior segment of the right hepatic lobe) and the IVC. (D) Contrast-enhanced CT of a large right adrenal carcinoma extending into the liver and inferior vena cava. Abbreviations: CT, computed tomography; SMA, superior mesenteric artery; IVC, inferior vena cava.

disease, have a uniformly poor prognosis with a median survival of less than one year (Table 9). Common sites of recurrence include the lungs, lymph nodes, liver, peritoneum, and bones. The complete resection of recurrent disease, including pulmonary metastases, is associated with prolonged survival in some patients and can control symptoms related to excess hormone production. After a potentially curative resection, patients whose tumors were hormonally active should be monitored with interval urinary steroid profiles as well as abdominal and chest imaging studies. Adjuvant Treatment No adjuvant treatment for patients with ACC following a complete resection has been demonstrated to prolong survival (96–98). Most investigations of adjuvant treatment for ACC have involved the use of mitotane (ortho, para-DDD), a derivative of dichlorodiphenyltrichloroethane (DDT) with direct adrenolytic activity (69,97,98). Mitotane not only inhibits steroid production, it also leads to the atrophy of

adrenocortical cells (97,98). The role of mitotane as adjuvant therapy for ACC remains controversial, largely due to the absence of randomized trials (96–98). Given the low incidence of ACC, it is unlikely that future randomized trials will be performed. Nonetheless, anecdotal reports and small series have not documented a clear benefit of mitotane in patients who receive it adjuvantly. A further drawback to the use of mitotane is that it is associated with a number of side effects, most notably gastrointestinal and neuromuscular symptoms. Mitotane also has a narrow therapeutic index, the serum levels must be closely monitored, and exogenous steroid hormone replacement must be instituted to prevent the symptoms of adrenal insufficiency. For these various reasons, it is perhaps most reasonable to consider mitotane as adjuvant therapy for those patients without evidence of disease after a first recurrence, such as after the resection of isolated pulmonary or hepatic metastases. Recently, the results of phase II trials of combination chemotherapy with mitotane have been reported; these combinations have included etoposide, doxorubicin, and

Chapter 51:

977

Adrenal Glands

Table 8 Survival of Patients Who Underwent a Potentially Curative Resection for Adrenal Cortical Carcinoma Reference

Year

No. of patients

Margin analysis

2001 2001 1999 1998 1996 1995 1994 1994 1992 1992 1992 1990 1983

182 23 46 18 91 16 47 15 127 31 53 22 31

No No No No No Yes No No No No No No No

Institution or country

Icarda (87) Favia (88) Harrison (89) Khorram–Manesha (90) Crucitti (91) Lee (79) Haak (92) Zografos (93) Icarda (85) Icard (86) Pommiera (94) Gro¨ndala (78,95) Henley (95)

France Italy MSKCC Sweden Italy MDA Netherlands Roswell Park France France MSKCC Sweden Mayo Clinic

Median follow-up (mo)

Overall survival (mo)

5-Yr actuarial survival (%) 50

20 85 43

28b 28c 46b 13b

28

44c 28c

56 58 48 46 49 38 42 45 47 32

a

Includes patients who underwent resection of synchronous metastatic disease. Median. c Mean. Abbreviations: MDA, M.D. Anderson Cancer Center; MSKCC, Memorial Sloan-Kettering Cancer Center. b

cisplatin (99) and etoposide, doxorubicin, and vincristine (99). The former trial reported an overall response rate [according to the World Health Organization (WHO) criteria] of 49% (99), and the latter trial showed a response rate of 22% (100). Other investigational studies have used combinations of systemic agents, including cisplatin with gemcitabine (101) and CYC202 (R-roscovitine) (102). Percutaneous image-guided radiofrequency ablation and percutaneous ethanol injection have also been tested for the treatment of liver metastasis (103,104). Finally, EBRT is often used for the palliation for bone metastases. In summary, resection should only be performed if preoperative imaging studies indicate that a complete margin-negative resection is possible. Rarely is resection indicated for a primary tumor when there is also synchronous metastatic disease. Nonetheless, anecdotal reports indicate that complete resection of limited metastatic disease in good-risk individuals is occasionally clinically beneficial (105,106). However, resection of the primary tumor in the face of unresectable distant metastatic disease is not indicated. Systemic treatment options for patients with unresectable local recurrence or distant metastases include treatment with mitotane, suramin, ketoconazole, and systemic chemotherapy regimens containing cisplatin. Mitotane appears to be most effective when given for the symptomatic control Table 9 Patient Survival Following Incomplete Resectiona of Adrenocortical Carcinoma Series

Institution or country

Year

No. of patients

Median survival (mo)

Crucitti (91) Lee (79) Zografos (93) Icard (85) Icard (86) Gro¨ndal (78,95) Henley (95)

Italy MDA Roswell Park France Cochin Sweden Mayo Clinic

1996 1995 1994 1992 1992 1990 1983

33 7 28 28 10 12 14

16 8.5 2 <12 <4 10 <6

a

Patients with incomplete resections included those who underwent incomplete resection of the primary tumor and those who underwent complete resection of the primary tumor in the presence of unresectable distant metastatic disease. Abbreviation: MDA, M.D. Anderson Cancer Center.

of hormonally active tumors, because a decrease in serum hormone levels is much more common than a radiographic response. Dose and serum levels of mitotane must be monitored and adjusted to maintain efficacy while minimizing toxicity.

Neoplasms of the Adrenal Medulla Pheochromocytoma Pheochromocytoma as a distinct lesion has been recognized for over a century, going back to 1886, when Frankel described his finding of bilateral adrenal tumors at autopsy in an 18-year-old woman who had suffered sudden death. In 1912, Pick described and named the tumor. In 1922, L’ Abbe´ found a pheochromocytoma at autopsy in a 28-year-old woman who had presented with paroxysmal hypertension. In 1926, Rue described the first successful resection of a pheochromocytoma; in 1927, Mayo described the first successful resection in the United States. In 1951, the biochemical basis of the disease was identified by Van Hueller, who demonstrated the increased urinary catecholamine levels. Etiology and Physiology Pheochromocytomas, or intra-adrenal paragangliomas, originate from chromaffin cells of the adrenal medulla, whereas paragangliomas arise from extra-adrenal sympathetic chromaffin tissue. Paragangliomas can also arise from parasympathetic ganglia in the head and neck, and these tumors include chemodectomas (carotid body tumors), tumors of the glomus jugulare (affecting the ninth and tenth cranial nerves), ganglioneuromas, and neuroblastomas and ganglioneuroblastomas. Chromosomal abnormalities common in pheochromocytomas include LOH at chromosomes 1p, 3p, 17p, and 22q. N-ras and c-myc mRNA can also be overexpressed. The RET proto-oncogene and the tumor suppressor gene VHL play an important role in the development of pheochromocytomas in MEN 2 kindreds and in patients with VHL, respectively. MEN 2A and 2B, as well as familial (non-MEN) medullary thyroid cancer, are associated with mutations in the RET proto-oncogene (107), which maps to chromosome 10q11.2. RET mRNA may also be overexpressed in sporadic pheochromocytomas (108). RET mutations may have a

medwedi.ru

978

Part Seven: The Endocrine System

variety of clinical consequences. In Hirschsprung’s disease, RET mutations include deletions and stop codons that result in the loss of parasympathetic innervation in the distal colon. In familial medullary thyroid cancer, MEN 2A, and MEN 2B, point mutations in RET result in amino acid substitutions, there is no loss of chromosome 10 alleles, and the point mutations probably result in altered regulation of the RET tyrosine kinase growth-factor receptor (109). However, the role of RET mutations in sporadic pheochromocytomas remains controversial (108,110,111). Mutations in the succinate dehydrogenase family of genes (SDHD, SDHB, and SDHC) are responsible for pheochromocytomas and paragangliomas that are part of the hereditary paraganglioma syndrome (112,113). A unique characteristic of pheochromocytomas is that they release catecholamines independent of neural stimulation. Because pheochromocytomas possess glucagon receptors, glucagon may mediate this catecholamine release. It is important to keep in mind that events that precipitate a hypertensive crisis in patients with pheochromocytoma can include the administration of glucagon, opiates, intraarterial contrast material, and sympathomimetics, as well as adrenal biopsy. Understanding the pathophysiology of pheochromocytoma requires an understanding of catecholamine metabolism. In this pathway, tyrosine is converted to epinephrine from norepinephrine in the adrenal medulla; dopamine represents an intermediary step. Generally, pheochromocytomas produce much more norepinephrine than epinephrine. Exceptions include very small tumors and those tumors in patients with familial endocrinopathies (e.g., MEN 2). Extra-adrenal pheochromocytomas (paragangliomas) are classically pure norepinephrine-producing tumors. The final conversion of norepinephrine to epinephrine is inefficient in most pheochromocytomas, resulting in the production of large amounts of the catecholamine metabolites—3,4-dihydroxymandelic acid, metanephrine, and normetanephrine. All three of these catecholamine metabolites can be converted to vanillylmandelic acid (VMA), and all of these metabolites can be detected in urine.

Natural History Pheochromocytomas exist in less than 0.1% of hypertensive patients and are usually benign. Pheochromocytomas are one of the most satisfying general surgical diseases to treat, because the five-year survival rate in patients with the benign tumors is approximately 97%, they recur in less than 10% of patients, and the hypertension is cured in 75% of patients. However, malignant pheochromocytomas are associated with a high incidence of recurrence and metastasis, and the five-year survival rate in patients with these tumors is less than 60%. Pheochromocytoma is known as the 10% tumor. Approximately 10% of pheochromocytomas are bilateral, with some patients presenting with multiple tumors. In addition, 10% of pheochromocytomas occur in extra-adrenal locations, where they are referred to as paragangliomas. Extraadrenal tumors that occur within the abdomen are usually in the organ of Zuckerkandl at the bifurcation of the aorta and occasionally within the bladder wall. Thoracic locations of pheochromocytomas include the posterior mediastinum and the pericardium. Extra-adrenal pheochromocytomas may also occur anywhere along the sympathetic chain because of the presence of chromaffin tissue. Histologic evidence of malignancy is demonstrated in approximately 10%

of patients with pheochromocytomas, though malignancy is more common with extra-adrenal lesions than in those with tumors arising in the adrenal glands. Documenting malignancy can be difficult, however, because invasion of adjacent organs or distant metastatic disease must be present. Adding to this difficulty is the fact that both benign and malignant lesions may penetrate the tumor capsule, invade veins draining the gland, or show cellular pleomorphism, mitoses, and atypical nuclei. Familial pheochromocytomas have been estimated to account for approximately 10% of cases, though recent data suggest that up to 25% of unselected cases of apparently sporadic pheochromocytomas are in fact hereditary (112,113). Familial tumors are more likely to be benign and bilateral, and less likely to be extra-adrenal and malignant. The familial syndromes associated with pheochromocytomas include MEN types 2a and 2b (risk for pheochromocytoma, 50%) and VHL syndrome (risk for pheochromocytoma, 10%), in which bilateral or multiple tumors are common. There is also a slight risk for pheochromocytoma in patients with neurofibromatosis type 1 ( <1%) and MEN 1 syndrome ( <1%). Pheochromocytoma can also occur in patients with the hereditary paraganglioma syndrome (mutations in SDHD, SDHB, and SDHC genes), in whom the risk may be as high as 80% (112,113). The hereditary paraganglioma syndrome predisposes to the development of both extra-adrenal and adrenal paragangliomas. For this reason, patients with these syndromes require follow-up and periodic screening for pheochromocytoma, especially before any planned surgical procedure. At The University of Texas M.D. Anderson Cancer Center, our current screening protocol for patients with suspected familial pheochromocytoma or paraganglioma includes genetic testing for the appropriate genes, depending on the patient’s personal and family history (113). Once the diagnosis of one of the above-mentioned syndromes has been established by genetic testing, periodic screening of the plasma free metanephrines is done to increase the chances of detecting a familial pheochromocytoma early (114). Presentation The classic presentation of a patient with pheochromocytoma includes the five P’s: pressure (hypertension), pain (headache), perspiration, palpitations, and pallor/diaphoresis. Sustained or paroxysmal hypertension is associated with headache and tachycardia (115,116). Paroxysmal elevation in blood pressure can vary markedly in frequency and duration and can be spontaneous or initiated by a variety of events, including heavy physical exertion and eating foods high in tyramine (e.g., chocolate, cheese, and red wine). Paroxysmal hypertension can occasionally be precipitated by trauma or surgery. The hypertension is characteristically labile and refractory to medical management; the most effective antihypertensive agents in this setting are a-adrenergic receptor blockers, calcium channel blockers, labetalol, and nitroprusside. An unrecognized pheochromocytoma may lead to death as the result of a hypertensive crisis, arrhythmia, or myocardial infarction. More than half of patients with pheochromocytomas have impaired glucose tolerance, and thus may have symptoms of diabetes mellitus, including polydipsia and polyuria. These symptoms result from the excess catecholamine secreted by the tumor and resolve with tumor resection. Patients with pheochromocytoma are rarely asymptomatic; exceptions include patients with hereditary pheochromocytomas and extra-adrenal paragangliomas.

Chapter 51:

Diagnostic Evaluation Pheochromocytoma is diagnosed by documenting the excess secretion of catecholamines. Plasma free metanephrines is the most accurate test to exclude or confirm the diagnosis (43,82). Twenty-four–hour urine collections for the testing of free catecholamines (dopamine, epinephrine, and norepinephrine) and their metabolites (normetanephrine, metanephrine, and VMA) also can be obtained. However, these tests are less sensitive. Moreover, the combination of different tests does not improve the diagnostic yield beyond that of the single test of plasma free metanephrines. Plasma catecholamine determination is only occasionally helpful; clonidine suppression tests may be useful in borderline cases. Provocative tests are potentially hazardous and now obsolete. In addition, although the adrenal glands and the organ of Zuckerkandl produce the enzyme PNMT that converts norepinephrine to epinephrine, pheochromocytomas that arise elsewhere do not contain this enzyme and thus do not produce much, if any, epinephrine. As a result, extra-adrenal pheochromocytomas secrete predominantly dopamine and norepinephrine. Patients with a biochemically based diagnosis of pheochromocytoma should undergo preoperative localization. This can be done with CT, MRI, or 131I-metaiodobenzylguanidine (MIBG) scanning. MIBG scanning may assist in lateralizing a tumor when no mass is seen on abdominal images, but this virtually never happens with the current CT technology (117). The current practice at M.D. Anderson is to obtain high-quality multidetector (multislice) CT scans, which can detect up to 95% of adrenal masses larger than 6 to 8 mm. MRI may be useful in selected cases because the T2-weighted images can clearly identify chromaffin tissue; the T2-weighted adrenal mass-to-liver ratio of pheochromocytomas or paragangliomas is usually more than 3. This ratio is much higher than that for adrenocortical adenomas, ACCs, or metastases to the adrenal gland. Thus, MRI may provide useful functional (biochemical) information. MIBG imaging may also be helpful in localizing extra-adrenal, metastatic, and/or bilateral pheochromocytomas (117). The particular advantage of this technique is that the radiolabeled amine is selectively picked up by chromaffin tissue and can identify most pheochromocytomas, regardless of their location. MIBG scanning may be used to assess atypical cases, and more commonly to determine the presence or absence of multifocal or recurrent disease. It is rare for MIBG scanning not to be able to localize a pheochromocytoma preoperatively. Preoperative Preparation Careful preoperative preparation is required to prevent a cardiovascular crisis during surgery caused by excess catecholamine secretion in a patient with a pheochromocytoma. The cornerstone of this preparation is a-adrenergic receptor blockade and the complete restoration of fluid and electrolyte balance. Phenoxybenzamine is the a-adrenergic– blocking agent of choice, and treatment is usually begun at a dose of 10 mg once or twice a day. The dosage is gradually increased over a two- to three-week period until adequate a-blockade is reached. The total dose should not exceed 1 mg/kg/day. The occurrence of orthostatic hypotension generally indicates the presence of adequate a-blockade. b-Blockade may be instituted after adequate a-blockade and may help prevent tachycardia and other arrhythmias. b-Blockade should not be instituted unless ablockade has been established; otherwise, the b-blocker will inhibit epinephrine-induced vasodilation, leading to greater

Adrenal Glands

979

hypertension and left heart strain. In addition to the pharmacologic preparation, patients with pheochromocytoma may require the correction of volume depletion and any concurrent electrolyte imbalances. Nifedipine and metyrosine may also be used preoperatively. Surgical Treatment When preoperative imaging suggests a benign-appearing pheochromocytoma with a radiographically normal contralateral gland, we currently use a unilateral laparoscopic approach to adrenalectomy. A laparoscopic approach is also appropriate for patients with MEN 2 or VHL, whose disease is limited to one adrenal gland. This is also because of the very rare incidence of malignant pheochromocytoma in these patients. Cortex-sparing adrenalectomy, either open or laparoscopic, has been performed successfully in patients with MEN 2 or VHL who have bilateral pheochromocytomas, thereby avoiding the need for long-term steroid hormone replacement and the risk of Addisonian crisis in most patients (118). Cortical-sparing and laparoscopic adrenalectomy are discussed in more detail later in this chapter. Nipride is used for the intraoperative management of blood pressure in pheochromocytoma patients because of its rapid response time and short half-life. The surgeon should manipulate the tumor as little as possible and ligate the tumor’s venous outflow via the adrenal vein as early in the procedure as possible. Postoperatively, patients should be monitored carefully for at least 24 hours because of the risk for arrhythmias. They should also be watched for hypotension secondary to the compensatory vasodilation that can occur once the source of excess catecholamine stimulation has been removed in the setting of a-blockade. Occasionally, hypertension remains a problem postoperatively, especially in those patients who had sustained hypertension preoperatively. All patients should undergo yearly evaluation postoperatively, which includes measurement of the plasma free metanephrine level or a timed urine collection for total catecholamine determination to exclude recurrence. Malignant Pheochromocytoma The most common sites of metastases from malignant pheochromocytoma are bone, liver, and lungs; less commonly, metastases arise in regional lymph nodes. Although the absolute criteria for malignancy are adjacent organ invasion and distant metastatic disease, some general pathologic characteristics can help to identify those tumors that are likely to behave in a malignant fashion. Malignant tumors tend to be larger than their benign counterparts and mitoses tend to be much more frequent in malignant pheochromocytomas. Malignant pheochromocytomas have also been reported to be aneuploid and may exhibit more necrosis than benign tumors. However, it should be emphasized that microscopic vascular or capsular invasion and nuclear pleomorphism are not reliable indicators of malignancy. Patients with known or suspected malignant pheochromocytoma should undergo staging using standard imaging studies and MIBG scanning. Therapy should be individualized on the basis of the extent of disease. Palliative therapy may include treatment with metyrosine, as well as a- and b-blockade. Resection of malignant pheochromocytoma, including resection of metastases, may be considered in good-risk individuals if the metastases are limited in extent. The best currently available palliation for patients with unresectable or metastatic pheochromocytoma is a-blockade

medwedi.ru

980

Part Seven: The Endocrine System

with phenoxybenzamine; a-methyltyrosine can also be used. The most commonly used chemotherapy regimens for pheochromocytoma are high-dose streptozocin and a combination of cyclophosphamide, vincristine, and dacarbazine (119). The overall response rate to these regimens is approximately 50%. Radiation therapy may effectively palliate symptomatic bony metastases. More recently, there has been some interest in treating metastatic lesions with therapeutic doses of radioactive 131I-MIBG (120). Unfortunately, however, a high percentage of metastatic pheochromocytomas do not take up 131I-MIBG; therefore, the response rate in patients treated with this approach, as manifested by a reduction in urinary catecholamine levels, is only about 50%. Objective responses, as determined by imaging studies, are seen even less frequently. The five-year survival rate in patients with malignant pheochromocytoma is approximately 43%, as compared with a 97% five-year survival rate in patients with benign lesions.

Adrenal Incidentaloma Natural History and Presentation Incidental adrenal masses are common; they are found in up to 4% of individuals undergoing abdominal imaging studies and at up to 9% of autopsies (121–126). In evaluating a patient who presents with an incidental adrenal mass, it is therefore important to remember that benign, nonfunctioning adrenocortical adenomas are common, ACCs are extremely rare, and isolated metastases to the adrenal glands from malignant solid tumors occurs occasionally (127– 137). Therefore, the three critical questions that must be answered in the evaluation of each patient who presents

with an incidental adrenal mass are: (i) Is the mass primary or metastatic? (ii) Is it functioning or nonfunctioning? and (iii) Is it benign or malignant? Evaluation A hormonally active cortical adenoma or pheochromocytoma should be ruled out in all patients with an incidental adrenal mass. To do this, the evaluation should include a history-taking that elicits information about symptoms secondary to a functioning tumor or an underlying malignancy (weight loss, abdominal pain, and rectal bleeding); physical examination (blood pressure; breast, lymph node, pelvic, and rectal examination; and stool analysis for occult blood); and laboratory evaluation (serum potassium concentration, chest radiograph, and mammogram in adult women). A biochemical evaluation should be performed that includes an overnight 1-mg dexamethasone suppression test to exclude Cushing’s syndrome. Patients found to have suppressed cortisol levels do not have Cushing’s syndrome and do not require further evaluation for this condition. Patients without suppressed cortisol levels, however, should undergo a 24-hour urine collection for the measurement of urinary free cortisol and 17-OHCS and 17-keto-steroid levels. Plasma free metanephrine levels should be measured to exclude pheochromocytoma (Fig. 5). In equivocal cases, further imaging studies may be helpful, such as high-resolution CT of the adrenal glands or MRI to include T1-weighted chemical-shift analysis. We advocate fine needle aspiration biopsy of the adrenal neoplasm only if the patient has a history of a prior malignancy or if there are symptoms, physical examination findings, or biochemical or radiographic

Figure 5 Algorithm for the evaluation of the patient with an incidental adrenal mass.

Chapter 51:

evidence indicating an underlying malignancy, making an adrenal metastasis the most likely diagnosis (138). The majority of small incidental adrenal masses are nonfunctioning cortical adenomas. However, we consider it reasonable to screen all patients with incidental adrenal masses for hypercortisolism, as will be discussed below. Screening for androgen or estrogen excess is unnecessary in the absence of specific signs or symptoms suggestive of overproduction of these hormones. Likewise, because the presence of normal serum potassium concentrations and a normal blood pressure virtually exclude a diagnosis of aldosteronoma, we do not recommend screening for aldosterone excess in the absence of these findings. A controversial area in the evaluation of patients with adrenal masses includes the clinical entity termed ‘‘subclinical Cushing’s syndrome’’ (139–143). Between 5% and 25% of patients with incidental adrenal masses have evidence of subclinical Cushing’s syndrome, which is defined as the absence of specific clinical manifestations and by an abnormal 24-hour urinary cortisol level, abnormal dexamethasone suppression, a suppressed ACTH level, loss of diurnal variation in cortisol production, or lateralizing findings on NP-59 nuclear medicine scintigraphy. If adrenal insufficiency develops in a patient after the removal of an apparently nonfunctioning incidental adrenal mass, this is also evidence that subclinical Cushing’s syndrome was present preoperatively. Although a 24-hour urinary free cortisol test may miss an occasional patient with cortisol overproduction, overnight cortisol suppression with 1 mg of dexamethasone can detect the overwhelming majority of patients with cortisol overproduction due to a minimally functional adrenocortical adenoma. Therefore, the overnight 1-mg dexamethasone suppression test is probably the least expensive, the most convenient, and the most sensitive screening test for hypercortisolism in the patient with an incidental adrenal mass. A summary of our diagnostic approach in the patient with an incidental adrenal mass is shown in Figure 5. On the day the patient is first evaluated, blood samples are obtained for the measurement of plasma metanephrine, electrolyte, ACTH, and cortisol levels. A 1-mg dose of dexamethasone is then given to the patient, to be taken at 10:00 o’clock that evening. On the following morning at 8:00 o’clock, the patient’s blood is drawn for determination of the plasma cortisol level. If the patient’s plasma cortisol level is not suppressed below 5.0 mg/dL, the patient undergoes a timed 24-hour urine collection for the measurement of cortisol and 17-hydroxy- and 17-keto-steroid levels. Only in the presence of a low serum potassium level or hypertension do we proceed with further evaluation for possible hyperaldosteronism. We believe this is an efficient yet appropriately thorough schema for the evaluation of patients with incidental adrenal masses. These recommendations are similar to those of the NIH State-of-the-Science Statement on Management of the Clinically Apparent Adrenal Mass (‘‘Incidentaloma’’) (http://consensus.nih.gov/ ta/021/adrenal_mass_consensus.pdf). The risk of malignancy is related to the size and radiographic characteristics of the incidentaloma. Size, however, is the single best clinical indicator of malignancy in patients with an incidental adrenal mass. ACC accounts for 2%, 6%, and 25% of incidentalomas smaller than 4, 4.1 to 6, and greater than 6 cm in size, respectively. In addition, greater than 90% of ACCs are greater than 6 cm in size, whereas adrenocortical adenomas are rarely greater than 6 cm in size. Although accurate and detailed information regarding the

Adrenal Glands

981

size distribution of adrenocortical adenomas is not available, the frequency and average size of nonfunctioning adrenal adenomas generally increase with age. This information must be taken into account when evaluating a patient who presents with an incidental adrenal mass. Treatment Any hormonally active adrenal neoplasm, regardless of size, should be resected. Furthermore, resection is indicated if the adrenal mass shows radiographic characteristics suggestive of malignancy (heterogeneous density or irregular borders) or if the tumor enlarges during follow-up (144). In general, lesions larger 6 cm should be resected, because 25% of them may be malignant. Observation and follow-up are generally recommended for nonfunctioning tumors smaller than 3 cm in diameter, but the management of tumors between 3 and 6 cm is more controversial (145). This is because, at our own institution and elsewhere, ACCs have been identified in patients whose tumors were smaller than 5 cm. Most of these small tumors, however, had CT or MRI characteristics suspicious for carcinoma. On the basis of individual experience and a review of the literature, recommendations have been made to resect nonfunctioning adrenal masses ranging from 5 cm down to 3 cm. The recent success with laparoscopic adrenalectomy has led some investigators to suggest the surgical removal of even small incidentalomas. We recommend adrenalectomy for all adrenal tumors associated with suspicious radiographic findings regardless of size. In contrast, patients with nonfunctioning tumors between 3 and 6 cm in diameter showing a benign CT appearance may be observed; most appropriately, though, the nature of management should be determined on an individual-basis consideration of patient age and general health. The following may be helpful in evaluating such patients with intermediate-sized, nonfunctioning adrenal masses: (i) CT or MRI, (ii) a more thorough endocrine evaluation, and (iii) consideration of age and comorbidity. Figure 5 provides an overview of our approach to patients with adrenal incidentalomas. These recommendations are similar to those of the NIH State-of-the-Science Statement on Management of the Clinically Apparent Adrenal Mass (‘‘Incidentaloma’’) (http://consensus.nih. gov/ta/021/adrenal_mass_consensus.pdf).

Adrenal Metastases Natural History and Presentation Metastases to the adrenal glands are relatively common. On the basis of autopsy study findings, 42% of lung cancers, 16% of gastric cancers, 58% of breast cancers, 50% of malignant melanomas, and a high percentage of renal and prostate cancers have metastasized to the adrenals at the time of death. However, only rarely is adrenal insufficiency encountered in such patients. In general, more than 90% of the adrenal gland must be replaced with tumor before clinically detectable adrenocortical hypofunction is appreciated. When adrenal insufficiency does occur, it is usually when both adrenal glands are grossly enlarged, as detected by CT. Evaluation Evaluation of the patient with an adrenal mass and a history of malignancy starts with an evaluation of hormone production, because some of these patients will have an occult, functioning adrenal tumor unrelated to their prior

medwedi.ru

982

Part Seven: The Endocrine System

malignancy (e.g., a pheochromocytoma) (Fig. 6). In addition, patients with known or suspected adrenal metastases in whom surgical resection is contemplated should undergo ACTH stimulation testing prior to adrenalectomy to document adequate adrenocortical reserve (146–148). After pheochromocytoma has been excluded, fineneedle aspiration biopsy of a suspicious adrenal mass (i.e., a mass that shows a heterogeneous appearance with a high attenuation value on CT scans) may be helpful in selected patients to confirm a diagnosis of metastasis, particularly in those who are not surgical candidates or who have not yet had their primary cancer resected (145,149). In the absence of signs or symptoms of a malignant solid tumor, unilateral adrenal metastases are uncommon. Indeed, in our recent experience with over 1600 patients, the incidence of metastasis from an occult primary cancer was only 0.2% (four patients). In all four patients, malignancy was suspected on the basis of tumor size, bilateral involvement, and/or symptoms. For these reasons, we do not routinely biopsy patients with small nonfunctioning adrenal tumors in a search for occult metastatic disease (150). Treatment Surgery for isolated metastases to the adrenal gland may be considered in highly selected patients. These include good-risk individuals who do not have extra-adrenal disease and who have a history of favorable tumor biology (151–156). A favorable tumor biology is suggested by a long progression-free interval, response to systemic therapy, and a history of isolated metachronous metastases. A long disease-free interval from the time of the primary cancer therapy to the adrenal metastasis suggests the potential for a survival duration adequate to justify adrenalectomy. The site of the primary tumor also appears to affect survival, in that longer median survival times are observed following the resection of metastases from primary kidney, colon, and lung cancers, as well as melanoma, and poorer survival is seen in patients with esophageal, liver, and unknown primary tumors and in patients with high-grade sarcomas.

CONTROVERSIES IN THE SURGICAL MANAGEMENT OF ADRENAL DISEASE Cortical-Sparing Adrenalectomy Cortical-sparing adrenalectomy represents a method of limiting the morbidity of adrenal insufficiency associated with total adrenalectomy in selected patients with bilateral pheochromocytoma. Bilateral pheochromocytoma is associated with a variety of inherited disorders, but most commonly with MEN 2A and 2B. MEN 2A and 2B are characterized by the presence of hyperparathyroidism and medullary thyroid cancer, and, in patients with MEN 2B, by a characteristic phenotype (157). Other inherited disorders associated with pheochromocytoma include neurofibromatosis, VHL (retinal angiomatosis and cerebellar hemangioblastoma), and hereditary paraganglioma syndrome (SDH gene mutations). Although, virtually all patients with MEN types 2A and 2B have bilateral adrenal medullary hyperplasia, malignancy is uncommon, occurring in 3.9% of 387 patients from 12 collected series (69). In patients with VHL, malignancy is also uncommon. In particular, although pheochromocytomas occur in 10% to 19% of patients with VHL, and bilateral pheochromocytomas develop in 40% to 60% of these individuals, malignancy occurs in less than 4% (69). Because of this low incidence of malignancy, we currently recommend cortexsparing adrenalectomy for patients with bilateral pheochromocytoma who have MEN 2 or VHL syndrome (118), to eliminate the requirement for long-term steroid hormone replacement and the resulting risk of Addisonian crisis. A review of our experience with this approach has demonstrated that bilateral adrenalectomy using the cortex-sparing technique is safe and does indeed avoid the need for longterm steroid hormone supplementation postoperatively in the majority of patients. There is, however, an approximately 20% incidence of pheochromocytoma recurrence 10 years or more after a cortex-sparing adrenalectomy, and thus, longterm follow-up is necessary. The adrenocortical reserve should be evaluated in all patients postoperatively (158,159); those patients found to have abnormal adrenocortical reserve should receive supplemental steroid hormone replacement

Figure 6 Algorithm for the evaluation and surgical treatment of the patient with extra-adrenal cancer presenting with an adrenal mass. Abbreviation: VMA, vanillylmandelic acid.

Chapter 51:

when undergoing major surgical procedures or when they develop an acute illness (Fig. 7). The treatment of unilateral pheochromocytoma in patients with MEN 2 has been controversial. Bilateral total adrenalectomy has been advocated by some. However, despite steroid replacement, bilateral total adrenalectomy results in Addisonian crisis in up to 20% of patients. Therefore, in patients with familial pheochromocytoma, we remove only the affected side. Because this management approach is associated with a risk for recurrent metachronous pheochromocytoma, patients undergo annual screening of the contralateral normal adrenal gland. On an encouraging note, malignant pheochromocytoma has not been seen in such patients undergoing annual evaluations at our institution. Finally, patients with the hereditary paraganglioma syndrome are not candidates for the cortex-sparing procedure because of the increased frequency of malignancy in these tumors.

Laparoscopic Adrenalectomy Since the first description of laparoscopic adrenalectomy in 1992 (68), use of this approach has expanded such that now it is considered the standard technique for the removal of benign adrenal tumors. Most surgeons use an anterolateral transperitoneal approach; a posterior or lateral flank retroperitoneal approach has also been reported (160,161). A retroperitoneal laparoscopic adrenalectomy is currently indicated in patients with previous abdominal operations who have benign adrenal tumors smaller than 4 cm in diameter (162–164). Carefully selected patients with relatively small adrenal masses who undergo laparoscopic adrenalectomy may experience a more rapid recovery, less discomfort, a faster return to preoperative activity level, and better cosmetic results, as compared with patients who undergo open adrenalectomy. Patients who should be considered for laparoscopic adrenalectomy include those with aldosterone-producing

Figure 7 Cosyntropin stimulation test results in selected patients after total and subtotal adrenalectomy for bilateral pheochromocytoma. Patient 1 (¤) underwent total adrenalectomy. Patient 2 (&) underwent subtotal adrenalectomy but required postoperative steroid hormone replacement. Patients 3 (m) and 4 () underwent subtotal adrenalectomy and did not require postoperative steroid hormone replacement. Source: From Ref. 118.

Adrenal Glands

983

adenomas; small (<4 cm) functioning (glucocorticoid- or androgen/estrogen-producing tumors) cortical neoplasms; unilateral, benign-appearing sporadic pheochromocytomas; and pheochromocytomas in the setting of MEN 2 or VHL syndrome. Bilateral laparoscopic adrenalectomy is also feasible for patients with IHA and for patients with hereditary bilateral pheochromocytomas. We urge caution in the use of laparoscopic adrenalectomy for patients with malignant or potentially malignant adrenal tumors. This includes occasional patients with sporadic pheochromocytoma in whom radiographic imaging findings raise a suspicion of malignancy, patients with the hereditary paraganglioma syndrome, and patients with cortical neoplasms (functioning or nonfunctioning) that exceed 4 cm in diameter or with radiographic evidence of malignancy. To reiterate, the reason for operating on patients with nonfunctioning adrenal tumors (incidentalomas) is that they are potentially malignant cortical neoplasms. Therefore, we specifically do not recommend laparoscopic adrenalectomy for patients in whom an ACC is part of the preoperative differential diagnosis.

ADRENAL INSUFFICIENCY Adrenal insufficiency was first described by Thomas Addison in 1855 (165). In this report, he described 11 patients in whom destruction of the adrenal glands was associated with a fatal outcome; six had tuberculosis, three had metastatic malignancies, one had adrenal hemorrhage, and one had adrenal atrophy. Adrenal insufficiency is rare, with only 39 to 60 cases of chronic primary adrenal insufficiency (Addison’s disease) per million population. It is convenient to segregate adrenal insufficiency into that resulting from primary mechanisms (destruction of the adrenal cortex) and that resulting from secondary mechanisms (insufficient stimulation of the adrenal cortex by ACTH) (166). The most common cause of primary adrenal insufficiency today is autoimmune adrenalitis (80–90%), which can present either as an isolated autoimmune adrenalitis or as a part of the autoimmune polyendocrine syndrome (167). Other etiologies include granulomatous diseases (histoplasmosis and tuberculosis); metastatic cancer (lung cancer and breast cancer) (146–148); hemorrhage [anticoagulant therapy, Waterhouse–Friderichsen syndrome (meningococcemia), Pseudomonas aeruginosa infection]; and inherited disorders (X-linked adrenomyeloneuropathy). Finally, acquired immunodeficiency syndrome–associated opportunistic infections are an increasingly frequent cause of adrenal destruction. Unfortunately, primary adrenal insufficiency does not usually become clinically apparent until at least 90% of adrenal cortical tissue is destroyed. Causes of secondary adrenal insufficiency include withdrawal of long-term exogenous glucocorticoids (the most frequent cause of adrenal insufficiency) and pituitary destruction [e.g., in patients after trans-sphenoidal surgery for pituitary adenoma and in patients with Sheehan’s syndrome (postpartum pituitary necrosis)]. Although neither the dose nor the duration of glucocorticoid administration accurately predicts the degree of suppression of the hypothalamic-pituitary-adrenal axis (HPA), theoretically, any patient who has received the equivalent of 20 to 30 mg of prednisone per day for five consecutive days is at risk for adrenal insufficiency. However, although such short glucocorticoid use suppresses the HPA axis, the suppression lasts for only a few days. Patients who have received more than 30 mg of prednisone per day (or

medwedi.ru

984

Part Seven: The Endocrine System

7.5 mg of prednisolone or 0.75 mg of dexamethasone per day) for more than three weeks within three months prior to a major stress or a surgical procedure are at risk for adrenal insufficiency and, in the latter case, should receive perioperative glucocorticoid coverage (168–170). Historically, recommendations for perioperative glucocorticoid replacement were based on anecdotal experience and were most likely excessive; a consensus review has now summarized the recommendations for perioperative glucocorticoid coverage (Table 6) (171–173). Adrenal insufficiency usually has a gradual, insidious onset. However, major physiologic stress, including surgical stress, may precipitate an adrenal crisis. Therefore, a history consistent with chronic primary or secondary adrenal insufficiency should be sought in any patient with suspected acute adrenal insufficiency. Characteristic, though nonspecific, symptoms include fatigue, weakness, listlessness, orthostasis, and weight loss. Gastrointestinal symptoms may include abdominal cramps, anorexia, nausea, and vomiting. Physical examination may reveal evidence of secondary adrenal insufficiency due to prior exogenous steroid hormone administration (Cushingoid features). Alternatively, patients with primary adrenal insufficiency may have hyperpigmentation or vitiligo due to the influence of ACTH and other pro-opiomelanocortin peptides. Hypotension may occur in either primary or secondary adrenal insufficiency. However, the hypotension is characteristically more severe in primary adrenal insufficiency and is due to aldosterone deficiency. In secondary adrenal insufficiency, the hypotension is due to the decreased expression of catecholamine receptors. Abnormal laboratory results include hypoglycemia, hyponatremia, hyperkalemia, azotemia, hypercalcemia, anemia, leukopenia, lymphocytosis, and eosinophilia. It is essential to consider a diagnosis of acute adrenal insufficiency in critically ill patients with unexplained catecholamine-resistant hypotension, because glucocorticoid replacement can be lifesaving in these patients (169,174). Patients with acute adrenal insufficiency may present in shock, with dehydration and hypotension out of proportion to the severity of the underlying illness or stress. Patients may complain of abdominal pain and manifest abdominal tenderness with fever. Lethargy, confusion, or coma may develop. Signs and symptoms may mimic a surgical abdomen or septic shock. The treatment of patients in a suspected adrenal crisis should begin immediately. This includes isotonic intravenous fluid replacement and a stress dose of glucocorticoid, which is also administered intravenously. Dexamethasone (4 mg) is preferred over hydrocortisone (100 mg), because it has a long duration of action and does not interfere with the subsequent measurement of serum steroids during ACTH stimulation testing. While waiting for a clinical response to the dexamethasone, one should perform a high-dose ACTH stimulation test. In this test, a baseline serum cortisol level is determined. Cosyntropin (250 mg), a synthetic ACTH subunit, is then given intravenously, and the serum cortisol level is determined 30 and 60 minutes later. A baseline serum cortisol level that exceeds 20 mg/dL (or an increase of > 7 mg/dL over baseline) indicates a normal adrenal reserve; lesser values in the face of a physiologic stress indicate HPA hypofunction (166). Patients in whom adrenal insufficiency is established require initial stress doses of glucocorticoid replacement intravenously (e.g., hydrocortisone, 300 mg/day in divided doses), followed by tapering of the dose to physiologic

replacement doses given orally (e.g., hydrocortisone, 10–12 mg/m2/day in divided doses). Additionally, patients with primary adrenal insufficiency should receive fludrocortisone (50–200 mg/day) to prevent hyponatremia due to mineralocorticoid deficiency.

REFERENCES 1. Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 1988; 242:583–585. 2. Edwards CR, Stewart PM, Burt D, et al. Localisation of 11 beta-hydroxysteroid dehydrogenase—tissue specific protector of the mineralocorticoid receptor. Lancet 1988; 2:986–989. 3. Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 1987; 237:268–275. 4. Conn J. Primary aldosteronism, a new clinical entity. J Lab Clin Med 1955; 45:3–17. 5. Young WF Jr. Minireview: primary aldosteronism-changing concepts in diagnosis and treatment. Endocrinology 2003; 144:2208–2213. 6. Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young WF Jr. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 2000; 85:2854–2859. 7. Lim PO, Dow E, Brennan G, Jung RT, MacDonald TM. High prevalence of primary aldosteronism in the Tayside hypertension clinic population. J Hum Hypertens 2000; 14:311–315. 8. Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 2000; 85:1863–1867. 9. Gordon RD, Ziesak MD, Tunny TJ, Stowasser M, Klemm SA. Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin Exp Pharmacol Physiol 1993; 20:296–298. 10. Stowasser M. How common is adrenal-based mineralocorticoid hypertension? Curr Opin Endocrinol Diab 2000; 7:143–150. 11. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol 1994; 21:315–318. 12. Merrell RC. Aldosterone-producing tumors (Conn’s syndrome). Semin Surg Oncol 1990; 6:66–70. 13. Weigel RJ, Wells SA, Gunnells JC, Leight GS. Surgical treatment of primary hyperaldosteronism. Ann Surg 1994; 219:347–352. 14. White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med 1994; 331:250–258. 15. Mulatero P, Rabbia F, Milan A, et al. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension 2002; 40:897–902. 16. Ganguly A. Primary aldosteronism. N Engl J Med 1998; 339:1828–1834. 17. Lund JO, Nielsen MD, Giese J. Prevalence of primary aldosteronism. Acta Med Scand Suppl 1981; 646:54–57. 18. Melby JC. Primary aldosteronism. Kidney Int 1984; 26:769–778. 19. Conn JW, Cohen EL, Herwig KR. The dexamethasonemodified adrenal scintiscan in hyporeninemic aldosteronism (tumor versus hyperplasia). A comparison with adrenal venography and adrenal venous aldosterone. J Lab Clin Med 1976; 88:841–856. 20. Conn JW. Part I Painting background. Part II. Primary aldosteronism, a new clinical syndrome, 1954.. J Lab Clin Med 1990; 116:253–267. 21. Grim CE, Ganguly A, Yum MN, Donohue JP, Weinberger MH. Hyperaldosteronism due to unsuspected adrenal carcinoma: discovery during investigation of hypertension in a young woman. J Urol 1981; 126:783–786.

Chapter 51: 22. Scott HW Jr, Sussman CR, Page DL, Thompson NW, Gross MD, Lloyd R. Primary hyperaldosteronism caused by adrenocortical carcinoma. World J Surg 1986; 10:646–653. 23. Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ. Diagnosis and management of primary aldosteronism. J Renin Angiotensin Aldosterone Syst 2001; 2:156–169. 24. McKenna TJ, Sequeira SJ, Heffernan A, Chambers J, Cunningham S. Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary hyperaldosteronism. J Clin Endocrinol Metab 1991; 73:952–957. 25. Hiramatsu K, Yamada T, Yukimura Y, et al. A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients. Arch Intern Med 1981; 141:1589–1593. 26. Gallay BJ, Ahmad S, Xu L, Toivola B, Davidson RC. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis 2001; 37:699–705. 27. Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001; 135:258–261. 28. Hamlet SM, Tunny TJ, Woodland E, Gordon RD. Is aldosterone/renin ratio useful to screen a hypertensive population for primary aldosteronism? Clin Exp Pharmacol Physiol 1985; 12:249–252. 29. Weinberger MH, Fineberg NS. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med 1993; 153:2125–2129. 30. Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am 2002; 31:619–632, xi. 31. Blumenfeld JD, Sealey JE, Schlussel Y, et al. Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med 1994; 121:877–885. 32. Holland OB, Brown H, Kuhnert L, Fairchild C, Risk M, Gomez-Sanchez CE. Further evaluation of saline infusion for the diagnosis of primary aldosteronism. Hypertension 1984; 6:717–723. 33. Kem DC, Weinberger MH, Mayes DM, Nugent CA. Saline suppression of plasma aldosterone in hypertension. Arch Intern Med 1971; 128:380–386. 34. Bravo EL, Tarazi RC, Dustan HP, et al. The changing clinical spectrum of primary aldosteronism. Am J Med 1983; 74: 641–651. 35. Findling JW, Raff H. Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin N Am 2001; 30:729–747. 36. Cronin C, Igoe D, Duffy MJ, Cunningham SK, McKenna TJ. The overnight dexamethasone test is a worthwhile screening procedure. Clin Endocrinol (Oxf) 1990; 33:27–33. 37. Montwill J, Igoe D, McKenna TJ. The overnight dexamethasone test is the procedure of choice in screening for Cushing’s syndrome. Steroids 1994; 59:296–298. 38. Kennedy L, Atkinson AB, Johnston H, Sheridan B, Hadden DR. Serum cortisol concentrations during low dose dexamethasone suppression test to screen for Cushing’s syndrome. Br Med J (Clin Res Ed) 1984; 289:1188–1191. 39. Mengden T, Hubmann P, Muller J, Greminger P, Vetter W. Urinary free cortisol versus 17-hydroxycorticosteroids: a comparative study of their diagnostic value in Cushing’s syndrome. Clin Investig 1992; 70:545–548. 40. Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing’s syndrome. J Clin Endocrinol Metab 1998; 83:2681–2686. 41. Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotropin-releasing hormone stimulation following lowdose dexamethasone administration. A new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA 1993; 269:2232–2238.

Adrenal Glands

985

42. Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. The dexamethasone-suppressed corticotropin-releasing hormone stimulation test differentiates mild Cushing’s disease from normal physiology. J Clin Endocrinol Metab 1998; 83: 348–352. 43. Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003; 88:553–558. 44. Young WF Jr, Stanson AW, Grant CS, Thompson GB, van Heerden JA. Primary aldosteronism: adrenal venous sampling. Surgery 1996; 120:913–919; discussion 919–920. 45. Doppman JL, Gill JR Jr. Hyperaldosteronism: sampling the adrenal veins. Radiology 1996; 198:309–312. 46. Magill SB, Raff H, Shaker JL, et al. Comparison of adrenal vein sampling and computed tomography in the differentiation of primary aldosteronism. J Clin Endocrinol Metab 2001; 86:1066–1071. 47. Rossi GP, Sacchetto A, Chiesura-Corona M, et al. Identification of the etiology of primary aldosteronism with adrenal vein sampling in patients with equivocal computed tomography and magnetic resonance findings: results in 104 consecutive cases. J Clin Endocrinol Metab 2001; 86:1083–1090. 48. Young WF Jr, Klee GG. Primary aldosteronism. Diagnostic evaluation. Endocrinol Metab Clin N Am 1988; 17:367–395. 49. Young WF. Primary aldosteronism–treatment options. Growth Horm IGF Res 2003; 13(suppl):S102–S108. 50. Proye CA, Mulliez EA, Carnaille BM, et al. Essential hypertension: first reason for persistent hypertension after unilateral adrenalectomy for primary aldosteronism? Surgery 1998; 124:1128–1133. 51. Celen O, O’Brien MJ, Melby JC, Beazley RM. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg 1996; 131:646–650. 52. Irony I, Kater CE, Biglieri EG, Shackleton CH. Correctable subsets of primary aldosteronism. Primary adrenal hyperplasia and renin responsive adenoma. Am J Hypertens 1990; 3:576–582. 53. Sawka AM, Young WF Jr, Schaff HV. Cardiac phaeochromocytoma presenting with severe hypertension and chest pain. Clin Endocrinol (Oxf) 2001; 54:689–692. 54. Shen WT, Lim RC, Siperstein AE, et al. Laparoscopic vs open adrenalectomy for the treatment of primary hyperaldosteronism. Arch Surg 1999; 134:628–631; discussion 631–632. 55. Marescaux J, Mutter D, Wheeler MH. Laparoscopic right and left adrenalectomies. Surgical procedures. Surg Endosc 1996; 10:912–915. 56. Fletcher DR, Beiles CB, Hardy KJ. Laparoscopic adrenalectomy. Aust N Z J Surg 1994; 64:427–430. 57. Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 1998; 19:647–672. 58. Findling JW, Doppman JL. Biochemical and radiologic diagnosis of Cushing’s syndrome. Endocrinol Metab Clin N Am 1994; 23:511–537. 59. Oldfield EH, Doppman JL, Nieman LK, et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med 1991; 325:897–905. 60. Ichikawa T, Ohtomo K, Uchiyama G, Fujimoto H, Nasu K. Contrast-enhanced dynamic MRI of adrenal masses: classification of characteristic enhancement patterns. Clin Radiol 1995; 50:295–300. 61. Mayo-Smith WW, Lee MJ, McNicholas MM, Hahn PF, Boland GW, Saini S. Characterization of adrenal masses (<5 cm) by use of chemical shift MR imaging: observer performance versus quantitative measures. AJR Am J Roentgenol 1995; 165:91–95. 62. Krestin GP, Steinbrich W, Friedmann G. Adrenal masses: evaluation with fast gradient-echo MR imaging and Gd-DTPAenhanced dynamic studies. Radiology 1989; 171:675–680.

medwedi.ru

986

Part Seven: The Endocrine System

63. Doppman JL, Reinig JW, Dwyer AJ, et al. Differentiation of adrenal masses by magnetic resonance imaging. Surgery 1987; 102:1018–1026. 64. Outwater EK, Siegelman ES, Radecki PD, Piccoli CW, Mitchell DG. Distinction between benign and malignant adrenal masses: value of T1-weighted chemical-shift MR imaging. AJR Am J Roentgenol 1995; 165:579–583. 65. Reinig JW, Doppman JL, Dwyer AJ, Frank J. MRI of indeterminate adrenal masses. AJR Am J Roentgenol 1986; 147: 493–496. 66. Yu KC, Alexander HR, Ziessman HA, et al. Role of preoperative iodocholesterol scintiscanning in patients undergoing adrenalectomy for Cushing’s syndrome. Surgery 1995; 118:981–986; discussion 986–987. 67. Guazzoni G, Montorsi F, Bocciardi A, et al. Transperitoneal laparoscopic versus open adrenalectomy for benign hyperfunctioning adrenal tumors: a comparative study. J Urol 1995; 153:1597–1600. 68. Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing’s syndrome and pheochromocytoma. N Engl J Med 1992; 327:1033. 69. Dackiw AP, Lee JE, Gagel RF, Evans DB. Adrenal cortical carcinoma. World J Surg 2001; 25:914–926. 70. Kjellman M, Kallioniemi OP, Karhu R, et al. Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Cancer Res 1996; 56:4219–4223. 71. Gortz B, Roth J, Speel EJ, et al. MEN1 gene mutation analysis of sporadic adrenocortical lesions. Int J Cancer 1999; 80: 373–379. 72. Heppner C, Reincke M, Agarwal SK, et al. MEN1 gene analysis in sporadic adrenocortical neoplasms. J Clin Endocrinol Metab 1999; 84:216–219. 73. McNicol AM, Nolan CE, Struthers AJ, Farquharson MA, Hermans J, Haak HR. Expression of p53 in adrenocortical tumours: clinicopathological correlations. J Pathol 1997; 181: 146–152. 74. Gicquel C, Raffin-Sanson ML, Gaston V, et al. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 1997; 82:2559–2565. 75. Reincke M, Mora P, Beuschlein F, Arlt W, Chrousos GP, Allolio B. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis. J Clin Endocrinol Metab 1997; 82:3054–3058. 76. Lyons J, Landis CA, Harsh G, et al. Two G protein oncogenes in human endocrine tumors. Science 1990; 249:655–659. 77. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003; 53:5–26. 78. Grondal S, Cedermark B, Eriksson B, et al. Adrenocortical carcinoma. A retrospective study of a rare tumor with a poor prognosis. Eur J Surg Oncol 1990; 16:500–506. 79. Lee JE, Berger DH, el-Naggar AK, et al. Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 1995; 118:1090–1098. 80. Soreide JA, Brabrand K, Thoresen SO. Adrenal cortical carcinoma in Norway, 1970–1984. World J Surg 1992; 16:663–667; discussion 668. 81. Yano T, Linehan M, Anglard P, et al. Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 1989; 81:518–523. 82. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002; 287:1427–1434. 83. Sullivan M, Boileau M, Hodges CV. Adrenal cortical carcinoma. J Urol 1978; 120:660–665. 84. Macfarlane D. Cancer of the adrenal cortex: the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl 1958; 23:155. 85. Icard P, Chapuis Y, Andreassian B, Bernard A, Proye C. Adrenocortical carcinoma in surgically treated patients: a

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 1992; 112:972–979; discussion 979–980. Icard P, Louvel A, Chapuis Y. Survival rates and prognostic factors in adrenocortical carcinoma. World J Surg 1992; 16:753–758. Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001; 25:891–897. Favia G, Lumachi F, D’Amico DF. Adrenocortical carcinoma: is prognosis different in nonfunctioning tumors? Results of surgical treatment in 31 patients. World J Surg 2001; 25: 735–738. Harrison LE, Gaudin PB, Brennan MF. Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection. Arch Surg 1999; 134:181–185. Khorram-Manesh A, Ahlman H, Jansson S, et al. Adrenocortical carcinoma: surgery and mitotane for treatment and steroid profiles for follow-up. World J Surg 1998; 22:605–611; discussion 611–612. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P. The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 1996; 119:161–170. Haak hr, Hermans J, van de Velde CJ, et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994; 69:947–951. Zografos GC, Driscoll DL, Karakousis CP, Huben RP. Adrenal adenocarcinoma: a review of 53 cases. J Surg Oncol 1994; 55:160–164. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery 1992; 112:963–970; discussion 970–971. Henley DJ, van Heerden JA, Grant CS, Carney JA, Carpenter PC. Adrenal cortical carcinoma—a continuing challenge. Surgery 1983; 94:926–931. Markoe AM, Serber W, Micaily B, Brady LW. Radiation therapy for adjunctive treatment of adrenal cortical carcinoma. Am J Clin Oncol 1991; 14:170–174. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 1993; 72:3145–3155. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 1993; 71:3119–3123. Dogliotti L, Sperone P, Berruti A, et al. Multicenter phase II study of mitotane associated with etoposide, doxorubicin and cisplatin in the treatment of advanced adrenocortical carcinoma. Vol. ASCO’s Annual Meeting, Chicago, Illinois, 2003. Abraham J, Bakke S, Rutt A, et al. A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist. Cancer 2002; 94: 2333–2343. Nagourney RA, Isaacs J, Bosserman L, Sommers BL, Evans SS. Adrenocortical carcinoma therapy with cisplatin & gemcitabine: laboratory and clinical correlates. Vol. ASCO’s Annual Meeting, Chicago, Illinois, 2003. Pierga J-Y, Faivre S, Vera K, et al. A phase I and pharmacokinetic (PK) trial of CYC202, a novel oral cyclin-dependent kinase (CDK) inhibitor, in patients (pts) with advanced solid tumors. Vol. ASCO’s Annual Meeting, Chicago, Illinois, 2003. Wood BJ, Abraham J, Hvizda JL, Alexander HR, Fojo T. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 2003; 97:554–560. Hara F, Kishikawa T, Tomishige H, Nishikawa O, Nishida Y, Kongo M. A child with adrenocortical carcinoma who underwent percutaneous ethanol injection therapy for liver metastasis. J Pediatr Surg 2003; 38:1237–1240.

Chapter 51: 105. Jensen JC, Pass HI, Sindelar WF, Norton JA. Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy. Arch Surg 1991; 126: 457–461. 106. Kwauk S, Burt M. Pulmonary metastases from adrenal cortical carcinoma: results of resection. J Surg Oncol 1993; 53: 243–246. 107. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type International RET mutation consortium analysis. JAMA 1996; 276:1575–1579. 108. Matias-Guiu X, Colomer A, Mato E, et al. Expression of the ret proto-oncogene in phaeochromocytoma. An in situ hybridization and northern blot study. J Pathol 1995; 176:63–68. 109. van Heyningen V. Genetics. One gene-four syndromes. Nature 1994; 367:319–320. 110. Beldjord C, Desclaux-Arramond F, Raffin-Sanson M, et al. The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. J Clin Endocrinol Metab 1995; 80:2063–2068. 111. Chew SL, Lavender P, Jain A, et al. Absence of mutations in the MEN2A region of the ret proto-oncogene in non-MEN 2A phaeochromocytomas. Clin Endocrinol (Oxf) 1995; 42:17–21. 112. Shapiro SE, Cote GC, Lee JE, Gagel RF, Evans DB. The role of genetics in the surgical management of familial endocrinopathy syndromes. J Am Coll Surgeons. In press. 113. Dluhy RG. Pheochromocytoma—death of an axiom. N Engl J Med 2002; 346:1486–1488. 114. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001; 134:315–329. 115. Bravo EL, Gifford RW Jr. Current concepts. Pheochromocytoma: diagnosis, localization and management. N Engl J Med 1984; 311:1298–1303. 116. Werbel SS, Ober KP. Pheochromocytoma. Update on diagnosis, localization, and management. Med Clin N Am 1995; 79: 131–153. 117. Shapiro B, Copp JE, Sisson JC, Eyre PL, Wallis J, Beierwaltes WH. Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases. J Nucl Med 1985; 26:576–585. 118. Lee JE, Curley SA, Gagel RF, Evans DB, Hickey RC. Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 1996; 120:1064–1070; discussion 1070–1071. 119. Patel SR, Winchester DJ, Benjamin RS. A 15-year experience with chemotherapy of patients with paraganglioma. Cancer 1995; 76:1476–1480. 120. Rose B, Matthay KK, Price D, et al. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer 2003; 98:239–248. 121. Abecassis M, McLoughlin MJ, Langer B, Kudlow JE. Serendipitous adrenal masses: prevalence, significance, and management. Am J Surg 1985; 149:783–788. 122. Belldegrun A, Hussain S, Seltzer SE, Loughlin KR, Gittes RF, Richie JP. Incidentally discovered mass of the adrenal gland. Surg Gynecol Obstet 1986; 163:203–208. 123. Bitter DA, Ross DS. Incidentally discovered adrenal masses. Am J Surg 1989; 158:159–161. 124. Copeland PM. The incidentally discovered adrenal mass. Ann Intern Med 1983; 98:940–945. 125. Kobayashi S, Iwase H, Matsuo K, Fukuoka H, Ito Y, Masaoka A. Primary adrenocortical tumors in autopsy records—a survey of ‘‘Cumulative Reports in Japan’’ from 1973 to 1984. Jpn J Surg 1991; 21:494–498. 126. Yamakita N, Saitoh M, Mercado-Asis LB, et al. Asymptomatic adrenal tumor; 386 cases in Japan including our 7 cases. Endocrinol Jpn 1990; 37:671–684. 127. Penn I, Moulton J, Bracken B. Diagnosis and management of adrenal masses: 1987 Du Pont lecture. Can J Surg 1988; 31:105–109.

Adrenal Glands

987

128. Siekavizza JL, Bernardino ME, Samaan NA. Suprarenal mass and its differential diagnosis. Urology 1981; 18:625–632. 129. Siren JE, Haapiainen RK, Huikuri KT, Sivula AH. Incidentalomas of the adrenal gland: 36 operated patients and review of literature. World J Surg 1993; 17:634–639. 130. Wood DE, Delbridge L, Reeve TS. Surgery for adrenal tumours: is operation for the small incidental tumour appropriate? Aust N Z J Surg 1987; 57:739–742. 131. Thompson NW, Cheung PS. Diagnosis and treatment of functioning and nonfunctioning adrenocortical neoplasms including incidentalomas. Surg Clin N Am 1987; 67:423–436. 132. Staren ED, Prinz RA. Selection of patients with adrenal incidentalomas for operation. Surg Clin N Am 1995; 75:499–509. 133. Katz RL, Shirkhoda A. Diagnostic approach to incidental adrenal nodules in the cancer patient. Results of a clinical, radiologic, and fine-needle aspiration study. Cancer 1985; 55:1995–2000. 134. Bertagna C, Orth DN. Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 1981; 71:855–875. 135. Geelhoed GW, Druy EM. Management of the adrenal ‘‘incidentaloma.’’ Surgery 1982; 92:866–874. 136. Herrera MF, Grant CS, van Heerden JA, Sheedy PF, Ilstrup DM. Incidentally discovered adrenal tumors: an institutional perspective. Surgery 1991; 110:1014–1021. 137. Jockenhovel F, Kuck W, Hauffa B, et al. Conservative and surgical management of incidentally discovered adrenal tumors (incidentalomas). J Endocrinol Invest 1992; 15:331–337. 138. Lee JE, Evans DB, Sherman SI, Gagel RF. Evaluation of the incidental adrenal mass. Am J Med 1997; 103:249–250. 139. Laudat MH, Billaud L, Thomopoulos P, Vera O, Yllia A, Luton JP. Evening urinary free corticoids: a screening test in Cushing’s syndrome and incidentally discovered adrenal tumours. Acta Endocrinol (Copenh) 1988; 119:459–464. 140. Rosen HN, Swartz SL. Subtle glucocorticoid excess in patients with adrenal incidentaloma. Am J Med 1992; 92:213–216. 141. Huiras CM, Pehling GB, Caplan RH. Adrenal insufficiency after operative removal of apparently nonfunctioning adrenal adenomas. JAMA 1989; 261:894–898. 142. Beyer HS, Doe RP. Cortisol secretion by an incidentally discovered nonfunctional adrenal adenoma. J Clin Endocrinol Metab 1986; 62:1317–1321. 143. Bogner U, Eggens U, Hensen J, Oelkers W. Incidentally discovered ACTH-dependent adrenal adenoma presenting as ‘preCushing’s syndrome’. Acta Endocrinol (Copenh) 1986; 111:89–92. 144. Barnett CC Jr, Varma DG, El-Naggar AK, et al. Limitations of size as a criterion in the evaluation of adrenal tumors. Surgery 2000; 128:973–982; discussion 982–983. 145. Grumbach mm, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (incidentaloma). Ann Intern Med 2003; 138:424–429. 146. Seidenwurm DJ, Elmer EB, Kaplan LM, Williams EK, Morris DG, Hoffman AR. Metastases to the adrenal glands and the development of Addison’s disease. Cancer 1984; 54:552–557. 147. Kung AW, Pun KK, Lam K, Wang C, Leung CY. Addisonian crisis as presenting feature in malignancies. Cancer 1990; 65:177–179. 148. Mor F, Lahav M, Kipper E, Wysenbeek AJ. Addison’s disease due to metastases to the adrenal glands. Postgrad Med J 1985; 61:637–639. 149. Saboorian MH, Katz RL, Charnsangavej C. Fine needle aspiration cytology of primary and metastatic lesions of the adrenal gland. A series of 188 biopsies with radiologic correlation. Acta Cytol 1995; 39:843–851. 150. Lee JE, Evans DB, Hickey RC, et al. Unknown primary cancer presenting as an adrenal mass: frequency and implications for diagnostic evaluation of adrenal incidentalomas. Surgery 1998; 124:1115–1122. 151. Lenert JT, Barnett CC Jr, Kudelka AP, et al. Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 2001; 130:1060–1067.

medwedi.ru

988

Part Seven: The Endocrine System

152. Paul CA, Virgo KS, Wade TP, Audisio RA, Johnson FE. Adrenalectomy for isolated adrenal metastases from non-adrenal cancer. Int J Oncol 2000; 17:181–187. 153. Soffen EM, Solin LJ, Rubenstein JH, Hanks GE. Palliative radiotherapy for symptomatic adrenal metastases. Cancer 1990; 65:1318–1320. 154. Reyes L, Parvez Z, Nemoto T, Regal AM, Takita H. Adrenalectomy for adrenal metastasis from lung carcinoma. J Surg Oncol 1990; 44:32–34. 155. Branum GD, Epstein RE, Leight GS, Seigler HF. The role of resection in the management of melanoma metastatic to the adrenal gland. Surgery 1991; 109:127–131. 156. Ettinghausen SE, Burt ME. Prospective evaluation of unilateral adrenal masses in patients with operable non-small-cell lung cancer. J Clin Oncol 1991; 9:1462–1466. 157. Evans DB, Lee JE, Merrell RC, Hickey RC. Adrenal medullary disease in multiple endocrine neoplasia type Appropriate management. Endocrinol Metab Clin N Am 1994; 23:167–176. 158. Mohler JL, Michael KA, Freedman AM, McRoberts JW, Griffen WO Jr. The evaluation of postoperative function of the adrenal gland. Surg Gynecol Obstet 1985; 161:551–556. 159. Chalmers RA, Mashiter K, Joplin GF. Residual adrenocortical function after bilateral ‘‘total’’ adrenalectomy for Cushing’s disease. Lancet 1981; 2:1196–1199. 160. Mercan S, Seven R, Ozarmagan S, Tezelman S. Endoscopic retroperitoneal adrenalectomy. Surgery 1995; 118:1071–1075; discussion 1075–1076. 161. Siperstein AE, Berber E, Engle KL, Duh QY, Clark OH. Laparoscopic posterior adrenalectomy: technical considerations. Arch Surg 2000; 135:967–971. 162. Smith CD, Weber CJ, Amerson JR. Laparoscopic adrenalectomy: new gold standard. World J Surg 1999; 23:389–396.

163. Baba S, Miyajima A, Uchida A, Asanuma H, Miyakawa A, Murai M. A posterior lumbar approach for retroperitoneoscopic adrenalectomy: assessment of surgical efficacy. Urology 1997; 50:19–24. 164. Baba S, Ito K, Yanaihara H, Nagata H, Murai M, Iwamura M. Retroperitoneoscopic adrenalectomy by a lumbodorsal approach: clinical experience with solo surgery. World J Urol 1999; 17:54–58. 165. Addison T. On the constitutional and local effects of disease of the supra-renal capsules. London: Highley, 1855. 166. Oelkers W. Adrenal insufficiency. N Engl J Med 1996; 335:1206–1212. 167. Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003; 361: 1881–1893. 168. Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA 1999; 282:671–676. 169. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003; 348:727–734. 170. Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin North Am 2003; 32:367–383. 171. Nicholson G, Burrin JM, Hall GM. Peri-operative steroid supplementation. Anaesthesia 1998; 53:1091–1104. 172. Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg 1994; 219: 416–425. 173. Glowniak JV, Loriaux DL. A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency. Surgery 1997; 121:123–129. 174. Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997; 337:1285–1292.

52 The Thyroid Gland Ronald C. Merrell and Lucian Panait

INTRODUCTION Despite its small size, the thyroid gland plays a key role in modulating and coordinating a wide variety of metabolic processes within the human body. Although many of the diseases involving this organ can be managed nonoperatively, the surgeon is frequently consulted when swallowing or breathing is adversely affected by an enlarged gland, or when a solitary module is thought to be potentially malignant. Thus, a thorough knowledge of the pathophysiology of this gland is mandatory if correct decision-making is to occur when surgical interventions are being considered. This chapter attempts to provide that understanding.

THYROID ANATOMY Gross Anatomy The thyroid gland extends from the level of the middle thyroid cartilage of the larynx superiorly, to the second tracheal ring inferiorly. In normal adults, the thyroid gland weighs 15 to 20 g. It is formed by a left and right lobe connected by an isthmus, which crosses the trachea (Fig. 1). In approximately 80% of individuals, a pyramidal lobe representing a remnant of the thyroglossal duct ascends in the midline. The lateral lobes are bordered by the carotid sheath and the sternocleidomastoid muscles laterally, the strap muscles (sternothyroid and sternohyoid) anteriorly, and the trachea medially. On the posterior aspect of the lobes lie the recurrent laryngeal nerves and the parathyroid glands.

Figure 1 Anatomy of the thyroid gland.

The thyroid gland is surrounded by a loose connective tissue fascia, which results from the division of the deep cervical fascia into an anterior and a posterior sheath. The ligament of Berry tightly attaches the thyroid to the anterior trachea, which causes the thyroid to move with the larynx and trachea while swallowing. The true capsule is made of a thin fibrous layer that sends septae into the gland. Blood is supplied to the thyroid gland by the superior and inferior thyroid arteries. The superior thyroid artery is the first branch of the external carotid artery. The inferior thyroid artery arises from the thyrocervical trunk off the subclavian artery and approaches the gland inferiorly from a posterolateral direction, behind the carotid sheath. A fifth artery, the thyroidea ima, originates directly from the aortic arch, ascends in the midline, and enters the gland inferiorly. Venous drainage of the thyroid is via subcapsular venous plexuses, which converge to form the superior, middle, and inferior thyroid veins. The superior and middle veins drain into the internal jugular veins, while the inferior ones drain into the brachiocephalic trunks. Of special importance for the surgeon is the middle thyroid vein, unaccompanied by an artery, which is the only structure in the region crossing the carotid sheath anteriorly. It can be safely divided over the carotid artery to reflect the thyroid gland before identification of the recurrent laryngeal nerve. Lymphatic drainage of the thyroid gland is racemose, but destined for pretracheal, paratracheal, and jugular lymph nodes (1). The relationship of the thyroid gland to the recurrent laryngeal nerves is extremely important for surgeons. If these nerves are involved in a neoplastic process or injured during surgery, alterations of the voice can occur. The recurrent laryngeal nerves have a different course on the right and left side. After originating from the vagus nerve, the right recurrent laryngeal nerve loops around the subclavian artery and ascends in the tracheoesophageal groove on the posterior aspect of the thyroid. The left recurrent laryngeal nerve loops around the ligamentum arteriosum at the aortic arch after leaving the vagus, and then ascends along the left tracheoesophageal groove. The recurrent laryngeal nerves cross the inferior thyroid artery in the middle-third of the thyroid gland and may course behind the artery (most of the cases), between its branches, or in front of the artery. The inferior parathyroid glands are located anterior to the nerves, at the junction of the recurrent laryngeal nerves and inferior thyroid artery. The recurrent laryngeal nerves may have several trunks (2). The recurrent laryngeal nerve pierces the cricothyroid membrane to innervate all muscles of the larynx except the cricothyroid. It also supplies sensation to the trachea and subglottic region of the larynx. In rare cases, the nerves may not be recurrent and enter the larynx directly. Injury of

medwedi.ru 989

990

Part Seven: The Endocrine System

the recurrent laryngeal nerve on one side leads to ipsilateral vocal cord paralysis, with the cord lacking tension and resting immobile near its midline position. The superior laryngeal nerve originates from the inferior (nodose) ganglion of the vagus, just caudal to the jugular foramen of the skull. At the level of hyoid bone, it splits into an external and an internal branch. The internal branch travels parallel and medial to the superior laryngeal artery, passes beneath the thyrohyoid muscle to pierce the thyrohyoid membrane, and supplies sensation to the pyriform fossa and laryngeal mucosa above the vocal cords. In rare cases, this branch can have an inferior and medial position relative to the superior laryngeal artery (3). The external branch of the superior laryngeal nerve descends lying on the inferior pharyngeal constrictor muscle. It travels with the superior thyroid artery and, before this artery branches to approach the superior pole of the thyroid gland, the external branch of the recurrent laryngeal nerve pierces the cricothyroid muscle. If this branch is injured, the cricothyroid is paralyzed and the vocal cords cannot be tensed. As a consequence, the timbre and volume of the voice are diminished and the voice tires easily.

Histology The thyroid gland is divided by fibrous septae into pseudolobules, which are subdivided into 20 to 40 follicles each. The follicles, spherical in shape, are lined by cuboidal epithelium and have a central core of proteinaceous colloid. In the stroma surrounding thyroid follicles, there are C-cells or parafollicular cells. These cells are more numerous in the upper portions of the thyroid lobes and can be either individual or aggregated in the interfollicular stroma (Fig. 2).

Embryology Development of the thyroid gland begins in the second branchial arch at the base of the tongue, in the region of the foramen cecum. From here, it descends in the anterior region of the neck, between the fusing halves of the hyoid bone and the larynx. The descent occurs along the

thyroglossal duct, a structure that will eventually atrophy in normal individuals. During its descent, the thyroid is invaded by cells from the ultimobranchial body from the fourth branchial pouch to populate the gland with the C-cells, or parafollicular cells, that produce calcitonin.

Anomalies of Development Developmental anomalies may be classified as failure of development, failure of descent, or failure of atrophy of the thyroglossal duct. The failures of development include thyroid agenesis (athyreosis) or hemiagenesis. Although the pathogenesis of these conditions is not known, it is believed that, at least in some cases, genetic factors might be involved (4). Failure of descent of thyroid gland results in thyroid tissue being located anywhere along its tract of descent. Although the most common location is the base of the tongue, ectopic thyroid tissue can be sublingual, thyroglossal, or intralaryngotracheal. The presentation depends on the location, and in rare cases these patients can develop ectopic thyroid carcinoma (5,6). The thyroid gland can also descend more caudally, to an intrathoracic location. When the thyroglossal duct fails to atrophy, the remnants form thyroglossal duct cysts, the most common congenital cervical abnormality. They can be found anywhere in the midline, from the submental region to the suprasternal notch, but are most commonly located in the vicinity of the hyoid bone. These cysts also contain thyroid tissue, which can undergo malignant transformation in 1% of cases (7).

PHYSIOLOGY The two active thyroid hormones are represented by triiodothyronine (T3) and tetraiodothyronine (Thyroxine, T4). Through their secretion, the thyroid gland controls the metabolic rate of most tissues in the body. Regulation of thyroid function is by plasma iodide concentration and hypothalamo-pituitary-thyroid axis.

Iodine Metabolism The synthesis of thyroid hormones depends on the availability and entry of iodine, one of their major constituents, into the thyroid gland. The sources of iodine in the body are exogenous, from alimentation, and endogenous, from the conservation of degraded thyroid hormones. Organic dietary iodine is converted in the stomach and jejunum to iodide, which is easily absorbed through the intestinal mucosa. Iodide is mainly removed from plasma by the thyroid gland (one-third of iodide concentration) and the kidneys (the remaining two-thirds). Kidney clearance depends on glomerular filtration rate and is not influenced by the plasma hormones or iodide levels.

Synthesis and Secretion of Thyroid Hormones

Figure 2 Microanatomy of the thyroid gland.

Synthesis of thyroid hormones is a multistep process, controlled by the secretion of thyroid-stimulating hormone (TSH) from the pituitary gland. This process involves (i) active uptake of iodide into the thyroid cell; (ii) oxidation of iodide to iodine; (iii) efflux of iodine into the follicle and bonding to tyrosine residues in thyroglobulin to form monoiodothyrosines (MIT) and diiodothyrosines (DIT); and (iv) different combinations of MIT and DIT to form active thyroid hormones (T3 and T4).

Chapter 52: The Thyroid Gland

Inorganic iodide is actively transported from plasma into the thyroid follicular cell by a sodium-iodide symporter present in the basolateral plasma membrane. Once inside the cytoplasm, iodide diffuses toward the apical membrane, where it is oxidized under the influence of thyroperoxidase and hydrogen peroxide. It subsequently passes from the thyroid cell into the colloid through a chloride–iodide– transporting protein (8). Here, at the apical membrane, iodine becomes attached to tyrosine residues in the primary sequence of thyroglobulin, a protein produced by the follicular cell and found abundantly in colloid (Fig. 3). Tyrosine iodination gives rise to two molecules, MIT and DIT. Two iodinated tyrosine residues are removed from thyroglobulin and make a dipeptide by a coupling enzyme. MIT and DIT combine to form triiodothyronine (T3). The combination of two molecules of DIT forms tetraiodothyronine (T4). Formation of T3 and T4 is mediated, at their turn, by thyroperoxidase and hydrogen peroxide. The deiodinated tyrosine has the active carboxyl group. Reverse T3 is an inactive hormone and has no metabolic functions. It is formed by DIT and MIT, where the monoiodinated tyrosine has the active carboxyl group (Fig. 4). T3 and T4 are stored in the colloid follicle bound to thyroglobulin, but no longer in the primary sequence. For active hormones to be released into the blood, they must cross the thyroid cell. Colloid is taken up by pinocytosis at the apical membrane and, inside the follicular cell, colloid droplets fuse with the lysosomal vesicles to form phagolysosomes, in which proteases hydrolyze thyroglobulin. Subsequently, free T3 and T4 are released into the blood. Thyroglubulin hydrolyzation also gives rise to MIT and DIT, which are deiodinated in the follicular cell and the iodine is recycled. T4 is the dominant product.

Thyroid Hormone Transport and Metabolism In the blood, thyroid hormone is almost entirely bound to plasma proteins, which act as transporters. Binding proteins include thyroid hormone binding globulin (TBG), thyroid hormone binding prealbumin (TBPA), and albumin. A small quantity of thyroid hormone (0.02%) is unbound and represents the active physiological fraction. Increased TBG levels associated with certain conditions (Table 1) lead to an initial lowering of free hormone concentration.

991

Figure 3 Synthesis of thyroid hormones.

Compensatory mechanisms restore the free hormone levels by raising the total hormone concentration and therefore restoring the euthyroid state. Although the thyroid secretes more T4 than T3 (the T4:T3 ratio in the blood is 10:1 to 20:1), T3 is more active than T4 and it is less tightly bound to plasma proteins; therefore it enters the extracellular fluid space more quickly. T4 converts peripherally to T3, making the thyroid hormone more readily available to the tissues. The peripheral conversion of T4 also gives rise to the inactive form rT3 (Fig. 5).

Figure 4 Chemical reactions leading to formation of thyroid hormones.

medwedi.ru

992

Part Seven: The Endocrine System

Table 1 Circumstances Associated with Increased Concentrations of Thyroglobulin

Table 2 Conditions Associated with Decreased Peripheral Conversion of T4 to T3

Increased TBG

Decreased peripheral conversion of T4 to T3

Pregnancy Newborn state Use of oral contraceptives and other sources of estrogen Use of tamoxifen Infectious and chronic active hepatitis Biliary cirrhosis Acute intermittent porphyria Perphenazine Genetic determination

Physiologic Fetal and early neonatal life Old age Pathologic Fasting Malnutrition Systemic illness Physical trauma Postoperative state Drugs (propylthiouracil, dexamethasone, propranolol, amiodarone) Radiographic contrast agents (ipodate, iopanoate)

Abbreviation: TBG, thyroid hormone–binding globulin.

Thyroid Hormone Action Thyroid hormones are transported into the cell by an adenosine triphosphate–dependent transport mechanism. Inside the cells, T3 is the active hormone and it binds to one or more cytoplasmic receptor complexes, which in turn bind to specific regulatory sites on the chromosomes to influence phenotypic expression. There are two classes of thyroid hormone receptors—a and b—each with two isoforms. They are encoded by genes located on chromosomes 17 and 3, respectively. Expression of T3 receptors is tissue specific, with the liver expressing mostly b receptors, the brain mostly a receptors, and the cardiac muscle both of them. Thyroid hormone affects most organs and systems in the body, being essential for calorigenesis, by increasing the basal metabolic rate and oxygen consumption rate in all tissues except brain, spleen, and testis. Thyroid hormone modulates intermediary metabolism, by stimulating protein synthesis, glycogenolysis, gluconeogenesis, lipolysis, and synthesis and degradation of cholesterol. It increases the heart rate and myocardial contractility and also increases the total body sensitivity to catecholamines and the number of catecholamine receptors in cardiac muscle. Thyroid hormone also increases bone turnover and stimulates erythropoiesis and steroid hormone release. In childhood, thyroid hormone is essential for normal myelination and development of the nervous system. Thyroid hormone is also essential for normal growth and development.

Thyroid Hormone Elimination Once inside the peripheral cells, T3 and T4 undergo a series of reactions that will ultimately lead to their inactivation and excretion. The most important is deiodination, in which iodine atoms are sequentially removed from the thyronine nucleus. Removal of only one iodine atom from

T4 yields T3, and this reaction accounts for almost 80% of T3 present in the body. It is catalyzed by the type 1 izoenzyme in the liver and kidney and by the type 2 izoenzyme in the pituitary, central nervous system, placenta, and brown fat. In certain conditions, the peripheral conversion of T4 to T3 is impaired and may lead to hypothyroidism if a compensatory increase in T4 production does not follow (Table 2). After complete deiodination, the free iodine can be recycled in the thyroid or excreted in the kidneys. T4 and T3 are also conjugated with glucuronate or sulfate in the liver and then excreted in the bile, thus reaching the small intestine. They can be either excreted or reabsorbed, constituting one enterohepatic circulation.

Regulation of Thyroid Function Thyroid function is regulated by suprathyroid and intrathyroid mechanisms. The hypothalamic-pituitarythyroid axis represents the suprathyroid one. TSH is a glycoprotein of 28,000 Da produced by the basophilic cells of the anterior pituitary, and it directly influences thyroid function through multiple mechanisms: (i) thyroid hypertrophy, hyperplasia, and vessel formation; (ii) increased iodine uptake into the follicular cell; (iii) enhanced synthesis of nucleic acids and proteins, including thyroglobulin; and (iv) stimulated synthesis and secretion of thyroid hormones. TSH secretion from the pituitary gland is regulated by three mechanisms. Secretion is stimulated by thyrotropinreleasing hormone (TRH), a tripeptide from the hypothalamus, and inhibited by somatostatin or raised levels of thyroid hormone in the blood. TRH reaches the pituitary via the hypophyseal portal system and exerts its actions

Figure 5 Conversion of thyroxine to triiodothyronine and reverse-triiodothyronine.

Chapter 52: The Thyroid Gland

through hydrolysis of inositol triphosphate, leading to Ca2þ and diacylglycerol activation of protein kinase C. Circulating thyroid hormone also inhibits TRH secretion from the hypothalamus through a feedback loop. Intrathyroid regulation of thyroid function is also important. Organic iodine concentration in the thyroid gland influences the response to TSH stimulation: low levels of iodine enhance TSH effects on the thyroid, while increased levels inhibit its actions. Other factors involved in the regulation of the hypothalamo-hypophyseal-thyroid axis in physiologic conditions or in stress include glucocorticoids, tumor necrosis factor-a (TNF-a), interleukins 1 and 6, and interferon-g (9).

ASSESSMENT OF PATIENTS WITH THYROID DISEASE The most common complaints that make a patient with thyroid disease present to the physician are related to alteration of thyroid function (either hypo- or hyperfunction) or presence of a mass. Mass and the altered function can be present at the same time.

Signs and Symptoms Hyperthyroidism, or thyrotoxicosis, is represented by excess circulating levels of thyroid hormone. The common complaints include weight loss with increased appetite, altered mood, irritability, insomnia, heat intolerance, palpitations, amenorrhea or loss of libido, and increased bowel frequency. Hypothyroidism is characterized by decreased levels of thyroid hormones. Usually, the disease develops progressively and patients seek medical attention late. The symptoms include weight gain, cold intolerance, fatigue, dry skin, menorrhagia, and constipation. If goiter is present, compression symptoms may be due to the mass effect. These include dysphagia, dyspnea, and choking. Superior vena cava syndrome, although uncommon, can be seen in patients with a large intrathoracic goiter. Pain is usually not a common presentation in patients with thyroid disease. If present, its characteristics should be noted. Localized pain may suggest either hemorrhage into a colloid nodule or malignancy, especially medullary thyroid carcinoma. Thyroiditis may sometimes present with pain radiating to the ear. Thyroid disease may present as only a thyroid nodule. Rapid growth of a nodule and changes in the character of the voice are suspicious for malignancy. Voice alteration may occur secondary to vocal cord paralysis due to recurrent laryngeal nerve involvement in a malignant process. However, a benign nodule may grow rapidly after an intralesional hemorrhage, and a benign goiter may stretch the recurrent laryngeal nerve to cause hoarseness.

A family history of benign or malignant diseases of the thyroid is relatively common. This is especially true for medullary carcinoma of the thyroid in multiple endocrine neoplasia (MEN) type II. However, a family history of goiter, thyroiditis, or, rarely, papillary cancer may be encountered. Living in an iodine-deficient area, taking goitrogenic medication, or having relatives with thyroid malformations represent other important factors that may be present in patients with thyroid disease.

Physical Examination The thyroid gland may not be palpable under normal circumstances. However, it usually can be appreciated by bimanual palpation. The examiner stands behind the seated patient, whose neck is slightly extended. With the examiner’s fingers fixed on either side of the trachea, the patient is asked to swallow. The thyroid gland ascends due to its attachments to the trachea. Palpation helps assess thyroid size, thyroid nodules, tenderness, and the consistency of the gland (Fig. 6). Cervical lymph nodes should also be assessed, both along the carotid sheath and in the posterior triangle of the neck. The presence of enlarged lymph nodes adjacent to a thyroid nodule is highly suggestive of cancer. Sometimes a median lymph node (Delphian node) can be palpated between the isthmus and the cricoid cartilage. It is called Delphian because its presence may predict, like the Delphic oracle, the presence of thyroid cancer when the primary lesion is not palpable.

Laboratory Tests A large variety of laboratory tests can assess the function of the thyroid gland. However, most of them are only of historical interest and have little importance in the management of thyroid disease. Ultrasensitive measurement of TSH levels has made this the first-line test for diagnosing hyper- and hypothyroidism (both subclinical and overt), eclipsing all other methods (10). The test, based on nonisotopic immunometric assay, has a sensitivity of 0.02 mIU/L or less. Low TSH implies hyperthyroidism with suppression of the hypothalamopituitary-thyroid axis. High TSH implies hypothyroidism

Patient History Prior exposure to low doses of ionizing radiation (<1 gray) is associated with an increased frequency of benign thyroid nodules, as well as with increased incidence of thyroid and salivary cancer. This type of exposure was historically applied in infants for thymic enlargement, enlarged adenoids, acne, or tinea capitis. Low irradiation doses are more carcinogenic than the much larger doses used in radiation therapy, which are more likely to cause hypothyroidism.

993

Figure 6 Bimanual examination of the thyroid gland.

medwedi.ru

994

Part Seven: The Endocrine System

Table 3 Thyroid Tests Increased Ultrasensitive TSH Antiperoxidase Antithyroglobulin Thyroglobulin Thyrocalcitonin

Hypothyroidism Thyroiditis Graves’ disease Thyroid malignancy Medullary carcinoma

Decreased

there is no palpable disease in the neck. CT or MRI is strongly indicated by elevation of serum levels of tumor markers such as thyroglobulin or thyrocalcitonin (12).

Hyperthyroidism N/A

Fine Needle Aspiration Biopsy Thyroidectomy Thyroidectomy

Abbreviations: TSH, thyroid-stimulating hormone; N/A, not available.

with an appropriate hypothalamo-pituitary response. Ultrasensitive TSH is also the standard way to assess the adequacy of therapeutic thyroid replacement or therapeutic thyroid suppression. Ultrasensitive TSH may miss the rare patient with either secondary (central) hypothyroidism, or hyperthyroidism due to a TSH-secreting pituitary adenoma or thyroid hormone resistance. Moreover, this test can also be misleading when hypothyroidism was induced in the initial treatment of hyperthyroidism, due to delayed recovery of previously suppressed TSH. When there is any doubt, both TSH and free thyroxine levels (FT4) should be measured (11). Thyroid autoantibody tests determine autoimmune thyroiditis. High titers of antithyroid peroxidase antibodies or antithyroglobulin antibodies are encountered in patients with Hashimoto’s thyroiditis or Graves’ disease. Serum thyroglobulin is a tumor marker for differentiated thyroid carcinomas. Because thyroglobulin is secreted only by the follicular cell of the thyroid, increased levels in patients after total thyroidectomy suggests the presence of loco-regional recurrence or distant metastases. Serum calcitonin from C-cells is elevated in medullary carcinoma. If this disease is part of MEN type II, mutations of the RET proto-oncogene may also be detected (Table 3).

Imaging Tests Radionuclide scanning can demonstrate hypo- or hyperfunctional areas within the thyroid gland, including the function of a palpable thyroid nodule, ectopic thyroid tissue, retrosternal goiter, hemiagenesis of the thyroid, and functioning metastases of thyroid carcinoma. The test employs 123 I or sodium [99mTc] pertechnetate and defines areas within the gland as ‘‘cold’’ or ‘‘hot,’’ depending on the concentration of the isotope in that specific area relative to the surrounding tissue. Radionuclide scanning for neoplasm is currently rarely used in clinical practice. Ultrasonography is useful in assessing the size of the thyroid nodules. It can reliably differentiate between cystic and solid masses, but not between benign and malignant nodules. It is also used to verify the presence of nonpalpable thyroid nodules discovered incidentally by other imaging procedures and to detect cervical lymph nodes in followup examination. Ultrasonography may guide the fine needle aspiration biopsy (FNAB). Sequential ultrasonagraphy can assess the progression of a goiter or the regression of the thyroid pathology with resolving inflammation or after medical treatment. Chest X rays may be helpful in diagnosing a substernal goiter. Computed tomography (CT) and magnetic resonance imaging (MRI) of the neck are not useful in the evaluation of thyroid patients, except in the planning of operations for mediastinal goiter or advanced malignancy. They may give important information when recurrence is suspected but

FNAB is a simple and low-risk method used in the assessment of patients with thyroid nodules. Since its introduction into practice in the 1970s, it has become the initial diagnostic test of choice for thyroid nodules. The nodule is pierced with a fine caliber needle and its contents are aspirated into a syringe. The aspirated cells are prepared for cytologic examination. Although the aspiration can be performed by a primary care physician, surgeon, pathologist, or endocrinologist, the accuracy of the test depends on the skills and experience of the cytopathologist. Two techniques are used for performing FNAB and they yield similar results. In the suction technique, a 22- to 25-gauge needle is attached to a 10- or 20-mL syringe that may, or may not be attached to a ‘‘pistol-grip’’ device. Local anesthesia may be used but an injection of lidocaine to numb the skin for another needle puncture seems unnecessary. The patient may either lie supine, with the neck in hyperextension, or sit. The physician immobilizes the nodule with his nondominant hand, while the needle is advanced rapidly into the nodule. Upon penetration, the needle is moved back and forth multiple times while vigorous negative pressure is applied to the syringe, to dislodge cells and draw them into the needle. The pressure in the syringe must rise to atmospheric pressure before removing the needle to avoid splatter of the material into the syringe chamber. The syringe is then detached from the needle, filled with air, and reattached to extrude the contents of the needle onto the cytology slides. It is recommended that both alcohol-fixed and air-dried smears be prepared with the material extracted from the nodule. The needle and syringe barrel may be rinsed with fixatives to prepare a cellblock after centrifugation of the liquid. The nonsuction technique is similar, but the thyroid nodule is punctured with a detached needle, which is moved multiple times back and forth within the mass. The needle is then withdrawn and attached to a syringe filled with air, and the content is blown onto the slides for smear preparation. Either Papanicolaou or hematoxylin and eosin stains may be employed. FNAB is not, however, a substitute for conventional histopathology. Instead, it should be regarded as a component of the diagnostic study of thyroid nodules in combination with clinical, imagistic, and other laboratory data. Rare complications of the FNAB include bleeding and hematoma formation. Pressure at the aspiration site usually is sufficient. Most importantly, FNAB has not been associated with needle tract implantation of tumor cells.

SICK EUTHYROID SYNDROME Sick euthyroid syndrome represents a derangement of the thyroid hormone economy in patients with shock, severe illness, trauma, or psychological stress. The abnormality may involve alterations in the peripheral transport and metabolism of thyroid hormones, inappropriate secretion of TSH, or modifications in the function of the thyroid gland. In the most common variant, the sick euthyroid syndrome is characterized by decreased circulating concentrations of T3 and increased concentrations of rT3, as a result

Chapter 52: The Thyroid Gland

of impaired conversion of T4 to T3 in peripheral tissues. TSH levels in serum are normal, although diminished TSH response to TRH stimulation may be encountered. The abnormalities are of no physiologic importance because the patients are infact euthyroid.

HYPERTHYROIDISM (THYROTOXICOSIS) Thyrotoxicosis is a disorder of metabolism due to excess thyroid hormone. The cause may be excessive intake of exogenous thyroid hormone or increased secretion of thyroid hormones with loss of the normal feedback inhibition. Graves’ disease and toxic multinodular goiter are by far the most common causes of the longer list in Table 4.

Graves’ Disease Graves’ disease was first described by Robert Graves of Dublin in 1835. It is the most common form of thyrotoxicosis and is most commonly seen in young women in the third or fourth decade of life. The ratio of women to men is 13:1 and a family history is obtained in 33% of patients. The evidence of this common endocrine disorder is estimated at 1 in 100 people. Graves’ disease is an autoimmune disease where the offending antibody drives the thyroid gland to an excess of secretion. Hyperthyroidism with diffuse goiter is associated with a specific ophthalmopathy. Other extrathyroidal manifestations may include pretibial myxedema, dermopathy, acropathy, and vitiligo. The thyroid gland is uniformly enlarged, with a smooth consistency and an increased vascularity. Histologically, hyperplasia of the follicular epithelium is present, with columnar appearance and a reduced quantity of colloid. Lymphocytic infiltration with germinal center formation and some regional reactive lymph adenopathy may also be encountered.

Pathogenesis The pathogenesis of the disease involves antibodies against the TSH receptor on the follicular cell. These antibodies have a stimulatory effect on thyrocytes, leading to increased hormone secretion, hypertrophy, and hyperplasia of the thyroid follicles. Although stimulating TSH receptor antibodies (TSHR-Ab) are unique to patients with Graves’ disease, serum of these patients contains a mixture of both

995

blocking and stimulating antibodies (13). These levels of thyroid hormone in patients with Graves’ disease are not directly correlated with the TSHR-Ab levels. Lymphocytic infiltration is common in Graves’ disease and these cells are the major source of antibodies (14). Some other locations responsible for antibody production include bone marrow and cervical lymph nodes. Initiation of antibody production in Graves’ disease is not clearly understood. Probably a lack of suppressor T-cells leads to multiplication of T-helper cells and subsequent stimulation of TSHR-Ab production from B-cell clones. The intrathyroidal inflammatory cells also produce cytokines, such as interleukin-1, TNF-a, and interferon-g, which lead to adhesion and activation of local inflammatory cells. Thyrocytes themselves may synthesize other cytokines, which sustain the intrathyroidal autoimmune process (15). However, thyroid follicular cells are not damaged by the lymphocyte infiltration, as in Hashimoto’s thyroiditis. The follicular cells are not destroyed because the antibody does not fix complement. This cell preservation might also be explained by the regulation of the apoptotic factor Fas, its ligand, FasL, and the antiapoptotic molecule Bcl-2. The balance of these factors in the infiltrating lymphocytes may lead to their own apoptosis, thus impairing their ability to mediate tissue damage. Contrarily, in the follicular cells, the reduced levels of Fas and increased levels of Bcl-2 probably favor thyrocyte survival and hypertrophy associated with TSHR-Ab (16). The ophthalmopathy in Graves’ disease is probably due to recognition by T-cells of an antigen that crossreacts with a TSH receptor-like protein, expressed in the periorbital preadipocyte fibroblasts. Lymphocyte infiltration in the extraocular muscles and orbital connective tissue leads to production of cytokines that activate fibroblasts, which secrete hydrophilic glycosaminoglycans, resulting in an increased osmotic pressure, swelling of the extraocular muscles, fluid accumulation, and eventually fibrosis (15). Predisposition to Graves’ disease is determined by genetic, environmental, and endogenous factors in different proportions. The genetic factor is suggested by the presence of disease in homozygous twins and the increased frequency of specific human leukocyte antigens (HLAs) in different populations with Graves’ disease: HLA-B8 and HLA DR3 in Caucasian populations, HLA-Bw 35 and HLA-A2 in the Japanese, and HLA-Bw 46 in Chinese populations (17). Psychological stress may trigger Graves’ disease. Of the environmental factors, the increased ingestion of iodine seems to play the most important role in initiation of this condition.

Table 4 Diseases Associated with Thyrotoxicosis Causes of hyperthyroidism

Clinical Manifestations

Associated with increased thyroid hormone secretion (hyperthyroidism) Graves’ disease Toxic multinodular goiter Iodine-induced (Jod–Basedow) thyrotoxicosis Hyperfunctioning thyroid adenoma Functioning metastatic thyroid cancer TSH-secreting pituitary tumors Struma ovari Not associated with increased thyroid hormone secretion Subacute thyroiditis Trophoblastic tumor (secretes human chorionic gonadotropin with thyroid-stimulating properties) Thyrotoxicosis factitia (thyroid hormone ingestion) ‘‘Hamburger toxicosis’’ (ingestion of food prepared from animal thyroid)

The clinical features of Graves’ disease can be divided into signs and symptoms of thyrotoxicosis and those specific to Graves’ disease. Common manifestations of hyperthyroidism include hyperactivity, hyper-reflexia, weight loss with increased appetite, irritability, altered mood, insomnia, heat intolerance, increased sweating, warm, moist skin, palpitations, sinus tachycardia, atrial fibrillation, muscle weakness and wasting, oligomenorrhea or amenorrhea, and loss of libido. Diarrhea or increased bowel frequency is the most common abdominal complaint. Specific manifestations of Graves’ disease include goiter, ophthalmopathy, and dermopathy. The goiter is a diffuse enlargement of the thyroid, including the pyramidal lobe, with smooth consistency. Ophthalmopathy includes exophthalmos with proptosis, supraorbital and infraorbital

Abbreviation: TSH, thyroid-stimulating hormone.

medwedi.ru

996

Part Seven: The Endocrine System

swelling, and chemosis. Skin changes include nonpitting edema of the pretibial region with occasional raised, hyperpigmented, violaceous papules. These physical findings, especially in a young woman, plus a low TSH confirm the diagnosis. TSHR-Ab may be helpful.

Treatment The goals of treatment in patients with Graves’ disease are to restore euthyroidism and to obtain a good control of the symptoms. No therapeutic modality is perfect. Graves’ disease is managed by treating the target organ, the thyroid, rather than by addressing the autoimmune process. Treatments include antithyroid drugs, radioiodine, and surgery. The choice of treatment may depend on the age of the patient, the severity of the disease, the size of the goiter and the associated pathology, and regional preferences exist in various parts of the world. For instance, management of Graves’ disease employs the prolonged use of antithyroid drugs in Europe, Asia, New Zealand, Australia, and the former USSR, while radioiodine after antithyroid drugs is preferred in North America (18–22). For failure of medical therapy, surgical ablation is favored in most of the world, while thyroid ablation with radioactive iodine (RAI) is the standard in North America. Initial medical management includes thionamines (antithyroid drugs) in either case. The antithyroid drugs (propylthiouracil and methimazole) are transported into the follicular cells, where they block thyroid hormone synthesis. Propylthiouracil also blocks the peripheral conversion of T4 to T3. Initial dose is 100 to 300 mg propylthiouracil three times a day, or 10 to 30 methimazole three times a day. The dose is dropped when a response is seen, usually in several weeks. Some physicians prefer to add to this regimen 0.05 to 0.1 mg of thyroxine a day, to prevent hypothyroidism (the ‘‘blockreplace’’ regimen). Based on the TSH levels, the dose is decreased as euthyroidism is achieved. Propylthiouracil can be used safely during pregnancy, when radioiodine therapy is contraindicated and surgical treatment is not fully embraced by all physicians. The adverse effects of antithyroid drugs include agranulocytosis, hepatitis, vasculitis, thrombocytopenia, rash, arthralgia, and fever. The length of treatment varies between 12 to 24 months in the majority of cases. However, the likelihood of recurrence after treatment is 60% to 70% (15). Therefore definitive therapy is usually required by thyroid ablation method, like radioiodine or surgery. Surgery is rarely the preferred ablation in the United States, although most authors recommend it for children, very large glands that do not respond well to RAI, those who fail RAI, women in fertility programs likely to conceive in the next year, and those patients who adamantly refuse radiation (23). Ophthalmopathy is not necessarily controlled by operation and mechanistically should not be. Subtotal thyroidectomy is the preferred operation and patients should be euthyroid prior to the operation or at least have a beta-adrenergic blockade. Most patients are euthyroid due to antithyroid drugs. Beta blockade is established prior to operation to prevent thyroid storm. Thyroid storm is marked by exacerbated symptoms of hyperthyroidism, with tachycardia, hyperpyrexia, congestive heart failure, vomiting, diarrhea, and neurological impairment. If untreated, it can progress to coma. Thyroid storm precipitated in hyperthyroid patients by trauma, infection, or iodine ingestion. All manifestations are apparently

mediated by the beta-adrenergic nervous system. If the condition develops, the treatment should take place in an intensive care unit and it employs the use of replacement fluids, antithyroid drugs, beta-blockers, sodium iodate solution or Lugol’s solution, hydrocortisone, and a cooling blanket. If the patient is agitated, sedation is recommended. With preoperative beta blockade, thyroid storm is a preventable complication of surgery for Graves’ disease. To prevent thyroid storm, if patients are not completely euthyroid by antithyroid medication prior to operation, very large doses of propranolol are needed to achieve blockade, which is documented by a normal heart rate. Prior to surgery, beta blockade is far more important for a safe operation than a drug-induced euthyroid state. The euthyroid patient may still have a storm, but the patient with beta blockade is secure in this regard. Potassium iodide is a traditional treatment to suppress the thyroid before operation. This tactic also reduces blood flow and may provide some surgical advantage. In fact, a bruit can commonly be heard over the toxic thyroid, which attenuates or disappears on iodine suppression. However, many patients who take oral iodine have gastric distress that may confound the taking of the beta-blocker. Beta blockade is paramount. Surgical treatment entails subsequent hypothyroidism in about half of patients. Some surgeons prefer total thyroidectomy to avoid recurrence. The operation can be complicated by bleeding, cord paresis, and hypocalcemia. The latter may be due to parathyroid damage or secondary hypoparathyroidism from excess bone metabolism under the influence of thyrotoxicosis. The more common treatment in the United States calls for RAI and requires no beta blockade. A dosee of 5 to 15 mCi 131I is enough to ablate the gland. The advantage of this medical therapy to permanently correct hyperthyroidism is its ease of dosing and lack of complications. Some authors prefer to use it as a first-line treatment in hyperthyroid patients (24), although the more common approach involves the use of antithyroid drugs first, followed by radioiodine ablation. The most important side effect of radioiodine treatment is hypothyroidism, which occurs in more than 50% at 10 years (25). Less common side effects include worsening of ophthalmopathy and radiation thyroiditis. RAI is contraindicated in pregnancy and children.

Toxic Multinodular Goiter (Plummer’s Disease) Toxic multinodular goiter may complicate long-standing simple goiter. One or more nodules inside the thyroid become hyperfunctional and secrete excess thyroid hormone independent of TSH control. Mutations of the TSH receptors are present in almost all these nodules (26). The condition is more commonly found in the elderly and in iodine-deficient areas. The iodine-deficient goiter will in all likelihood become hyperthyroid if iodine is suddenly reintroduced to the diet. The clinical presentation is characterized by milder hyperthyroidism symptoms than in Graves’ disease and the lack of ophthalmopathy. The thyroid gland is enlarged and nodules can be palpated. Compression symptoms like dysphagia or dyspnea may be present. Laboratory tests show decreased TSH and increased levels of thyroid hormone. The treatment of choice is thyroidectomy. Antithyroid drugs and beta-blockers are used to control the symptoms prior to operation. Radioiodine therapy is less effective than in Graves’ disease. The surgical treatment employs subtotal or total thyroidectomy.

Chapter 52: The Thyroid Gland

Hot Nodule Occasionally, thyrotoxicosis is due to a solitary hyperfunctioning nodule. Patients with thyrotoxicosis and a single nodule should have a scan to assess for activity of that nodule. If the single nodule is the cause of thyrotoxicosis, antithyroid drugs and beta-blockers should precede a thyroid lobectomy, which is curative.

HYPOTHYROIDISM Hypothyroidism is characterized by decreased circulating levels of thyroid hormones. A severe form is represented by myxedema, in which mucopolysaccharides are deposited in the dermis and other tissues. The leading cause of hypothyroidism worldwide is iodine deficiency, although in the United States the most common causes are autoimmune thyroiditis and iatrogenic mechanisms. A more complete classification of the causes of hypothyroidism is listed in Table 5. Between 60 and 89 years of age 7% of women and 3% of men are hypothyroid (27). Therefore, screening by ultrasensitive TSH is a reasonable measure at this age for subclinical hypothyroidism (28). Untreated hypothyroidism can progress to myxedema coma, which may be fatal. This condition is associated with hypothermia, stuporous state, respiratory depression, and increased PCO2. Decreased levels of thyroid hormones characterize hypothyroidism. The most useful laboratory test is the measure of ultrasensitive TSH, which is increased in primary hypothyroidism and decreased in secondary hypothyroidism.

Table 5 Causes of Hypothyroidism Primary Autoimmune Hashimoto’s thyroiditis Primary idiopathic myxedema Iatrogenic Thyroidectomy 131 I therapy Antithyroid drugs (aminosalicylic acid, iodides, phenylbutazone, iodoantipyrine, lithium) Congenital (cretinism) Developmental defects Heritable biosynthetic defects Maternally transmitted (iodides, antithyroid agents, circulating antibodies) Inflammatory Subacute thyroiditis Riedel’s thyroiditis Metabolic Iodine deficiency Secondary Pituitary hypothyroidism Panhypopituitarism Isolated TSH deficiency Hypothalamic hypothyroidism Congenital defects Infection (encephalitis) Neoplasm Infiltrative (sarcoidosis) Peripheral resistance to thyroid hormones Abbreviation: TSH, thyroid-stimulating hormone.

997

If autoimmune thyroid disease is present, circulating autoantibodies like antithyroglobulin, antimitochondrial antibodies, or antithyroid-peroxidase may be detected. Patients with hypothyroidism are treated with thyroid hormone replacement. There is large product variability among the oral thyroid drugs. Levothyroxine (T4) replacement is between 50 and 200 mg/day, depending on the age of patients and severity of disease. The treatment is monitored by ultrasensitive TSH levels and the clinical response of the patient. Bone resorbtion may be associated with excess thyroid hormone replacement and may limit compliance to therapy (29,30). The end point for thyroid replacement is a drop in TSH and not an arbitrary value for T4. With this guideline over treatment, metabolic bone disease may be avoided.

THYROIDITIS Inflammatory disease of the thyroid may be due to a variety of conditions. Riedel’s thyroiditis and acute suppurative thyroiditis are rare diseases. Riedel’s thyroiditis is characterized by fibrosis of the thyroid and surrounding structures and is sometimes associated with fibrosis of the mediastinum and retroperitoneum, lacrimal ducts, and bile ducts. Patients are euthyroid and have compression symptoms in most of the cases. Treatment may involve the use of steroids, tamoxifen, thyroxine, or surgery. Acute suppurative thyroiditis is usually preceded by an upper respiratory infection and manifests with tenderness and swelling of the thyroid, localized pain, and general signs of infection. The treatment is represented by intravenous antibiotics and incisional drainage of any abscess, if present. Subacute thyroiditis and Hashimoto’s thyroiditis are more common entities, and their characteristics are described below.

Autoimmune Lymphocytic Thyroiditis (Hashimoto’s Thyroiditis) Hashimoto’s thyroiditis is a chronic inflammatory disease of the thyroid, and the most common cause of hypothyroidism. It is most frequently encountered in middle age women and is the most common cause of sporadic goiter in children. The disease appears to develop as a result of a complex interaction between predisposing genes and environmental factors (31). Autoimmune factors were proven to play an important role in the pathogenesis of Hashimoto’s thyroiditis. The condition may coexist with other autoimmune disease, like pernicious anemia, Sjo¨gren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, adrenal insufficiency, diabetes mellitus, and Graves’ disease. Studies assessing the regulation of apoptosis in endocrine autoimmunity suggest that activation of Fas death receptors and decreased expression of the antiapoptotic molecule Bcl-2 in Hashimoto’s thyroiditis can promote thyrocyte apoptosis and gradual reduction in thyrocyte number, leading to hypothyroidism (16). The clinical manifestations are dominated by the presence of a firm, painless, nontender goiter, which involves symmetrically the entire gland and sometimes also the pyramidal lobe. Compression symptoms, although not common, may be associated. The patients are initially euthyroid, but they become hypothyroid as the disease progresses. This happens due to replacement of thyroid follicles by lymphocytes or fibrous tissue. Thyroid failure is represented by increased levels of TSH and decreased levels of T4.

medwedi.ru

998

Part Seven: The Endocrine System

Antithyroglobulin and antithyroid peroxidase antibodies are present in most of the cases. In some patients, hyperthyroidism can alternate with hypothyroidism, perhaps due to the intermittent presence of thyroid-stimulating antibodies or disruptions of follicles with random hormone release. FNAB can confirm the diagnosis and it is recommended when a nodule suggests malignancy. Typical histopathologic findings in Hashimoto’s thyroiditis include lymphoid follicles with germinal centers, follicular and Hu¨rthle cells (degenerated epithelial cells), low-to-moderate colloid, and lymphocytes and plasma cells infiltrating the epithelium (32). As lymphocytic infiltration extends, the thyroid tissue degenerates and is progressively replaced by fibrous tissue. Treatment usually employs the use of thyroxine, which should be administered in the presence of goiter, even if patients are euthyroid. T4 treatment for six months may reduce the thyroid enlargement by 30% (33). Patients with thyroiditis are atrocious surgical candidates. Surgical treatment is indicated in the presence of compression symptoms or thyroid pain, unresponsiveness to hormonal replacement therapy, or when cancer is associated (34). No surgeon should express enthusiasm for operation in thyroiditis. The angry gland is adherent, is bloody, and resists removal. Any surgical indication (goiter, hyperthyroidism, or nodules) should be regarded with skepticism if thyroiditis is at issue. Any patient with a tender goiter has thyroiditis until proven otherwise.

Subacute Thyroiditis (De Quervain’s, Granulomatous, Giant Cell Thyroiditis) Subacute thyroiditis is an acute, inflammatory disorder of the thyroid, which is believed to be viral in origin. It usually manifests after an upper respiratory infection. The clinical picture is represented by asthenia, malaise, fever, and unilateral or bilateral thyroid pain. Sometimes the pain is referred to the mandible, ear, or occiput. In some patients, symptoms of thyrotoxicosis may be present due to the disruption of the thyroid follicles by the inflammatory process. Palpation of the gland may reveal uni- or bilateral tenderness and nodularity. The laboratory findings are represented by elevated erythrocyte sedimentation rate and neutrophilia. In the initial stages of the disease, serum levels of T3 and T4 are high, due to leakage of hormones from the gland, and consequently TSH levels are low. Later, as glandular hormones are depleted, patients may pass through a hypothyroid phase, with decreased levels of T4 and increased TSH. Usually, the clinical picture and lab tests are enough for establishing the diagnosis. However, if FNAB is performed, the histologic examination shows the presence of noncaseous granulomas comprising colloid, inflammatory cells, and multinucleated giant cells. In the nongranulomatous lesions, the cellular inflammatory infiltration leads to disruption of the basement membrane and rupture of the follicles (35). Treatment employs nonsteroidal anti-inflammatory drugs (NSAIDs), which alleviate the symptoms and allow the disease to run its spontaneous course in an asymptomatic fashion. Beta-blockers may be needed in the initial stages for thyrotoxic patients. In more severe cases, corticosteroids rapidly relieve symptoms in 24 to 48 hours. In rare situations, thyroxine treatment may be used to prevent repeated exacerbations (36). Thyroidectomy, although not part of the routine treatment, should be considered in patients not responsive to the medical treatment or in those with severe dysphagia (37).

Table 6 Types of Thyroid Nodules Cyst Simple cyst Mixed cystic-solid nodule Colloid nodule Adenoma Nonfunctioning or hypofunctioning Functioning (hot) Thyroiditis Dominant nodule in multinodular goiter Carcinoma Primary Metastatic Primary lymphoma

De Quervain’s thyroiditis usually has a one- to sixweek course, after which the symptoms disappear completely. In some cases, the disease lasts longer, with alternating recurrence and remission episodes. Rarely, recurrence may occur years after the initial episode (38). Permanent hypothyroidism may develop in a small number of patients, despite NSAID or corticosteroid therapy (39).

THYROID NODULE Palpable thyroid nodules are found in 4% to 7% of the general population, but ultrasound shows nodules in 19% to 67% of the population (40,41). A solitary thyroid nodule is a discrete mass within a normal size thyroid or a diffusely enlarged goiter. Dominant thyroid nodules are defined as large nodules in a multinodular thyroid. The prevalence of thyroid nodules appears to increase with age, and women are more affected than men. Different thyroid conditions may present as a thyroid nodule (Table 6). The vast majority of thyroid nodules are benign and do not require removal. However, the nodules occurring in children and in the elderly have an increased chance of being malignant and the nodules in males are more suspect than those in females. The challenge for the physician is to assess the risk factors for thyroid cancer and to determine the number of patients who will benefit from surgical intervention. Malignancy accounts for 20% of the palpable solitary thyroid nodules in euthyroid patients. The risk for a solitary or dominant thyroid nodule to be malignant is increased in patients previously exposed to low-dose ionizing radiation of the head and neck or if another family member has thyroid cancer. Moreover, the characteristics of the nodule or the associated symptoms can be highly suggestive of malignancy. Factors associated with an increased risk for thyroid cancer are listed in Table 7. Table 7 Factors Associated with Increased Risk for Thyroid Cancer Older male Exposure to low-dose ionizing radiation Family member with thyroid cancer or MEN type II or type III Rapid growth of nodule Adherence of the nodule to trachea or strap muscles Compression symptoms (dyspnea, dysphagia) Horner’s syndrome Hoarseness Cervical lymphadenopathy adjacent to a thyroid nodule Abbreviation: MEN, multiple endocrine neoplasia.

Chapter 52: The Thyroid Gland

999

Table 8 Diagnostic Groups for Fine Needle Aspiration Biopsy of the Thyroid

Table 9 The Number of New Cases and Deaths Per Year for Several Organ Malignancies

Benign thyroid nodule Scant cells Colloid Indeterminate thyroid nodule Numerous follicular cells, scant colloid Consistent with follicular neoplasm Hu¨rthle cells Malignant thyroid nodule Papillary Follicular Medullary Anaplastic Lymphoma Metastatic

Site

New cases per year

Deaths per year

23,300 30,300 17,000 13,100 20,700

13,900 29,700 13,100 12,600 1300

Ovary Pancreas Brain Esophagus Thyroid

Evaluation of Thyroid Nodules FNAB is the method of choice for evaluating patients with thyroid nodules. The procedure is fast, inexpensive, accurate, minimally invasive, and causes little discomfort to the patient. Since its introduction into clinical practice, FNAB reduced the number of patients who require surgery and increased the percentage of malignant lesions in the excised nodules. The procedure still has limitations, and falsenegative results are encountered in some patients. This is why patients with an initial benign FNAB should be followed up, and the procedure repeated if the nodule persists. Table 8 illustrates the terminology used by most laboratories for reporting the results of the FNAB. Primary malignant nodules are treated surgically. These lesions, which are highly cellular, may represent an adenoma or a malignancy with well-differentiated follicular cells. These patients should be scanned, and if the nodule is cold, it should be treated surgically. If the nodule is clearly benign as in colloid nodule or inflammatory lesions are present, the patient is followed with serial examinations, and FNAB is repeated if suspicion increases. Even benign nodules are appropriately treated by excision if they become symptomatic. Hu¨rthle cells seen alone reflect a worrisome neoplasm. However, Hu¨rthle cells in the company of inflammatory cells are consistent with thyroiditis. Management of a solitary thyroid nodule follows the algorithm in Figure 7.

THYROID CANCER Thyroid cancers have variable histology, patterns of metastasis, and response to therapy. They account for approximately

1.5% of all new malignancies. Thyroid cancer is in the middle rank of malignancies in the United States along with ovarian, pancreatic, brain, or esophageal cancers. However, unlike those other diseases, thyroid cancer is a very rare cause of death as shown in Table 9 (42). Of all thyroid malignancies, 94% are differentiated thyroid carcinomas, that is follicular or papillary carcinomas; 5% are medullary thyroid carcinomas, and 1% are anaplastic (43,44). The chief complaint is usually a palpable solitary nodule, which if properly diagnosed and managed, has a wonderful probability of survival for well-differentiated thyroid cancer. The 10-year survival for thyroid carcinomas is approximately 93% to 98% for the papillary type, 85% to 92% for the follicular carcinomas, 75% to 80% for the medullary, and 13% to 14% for the anaplastic ones (Table 10). These recent reports represent a substantial improvement over statistics from 20 years ago (44,45). The molecular basis and the genetics of thyroid carcinomas are unclear. The familial inheritance is most obvious in medullary thyroid carcinomas, in which a mutation in the tyrosine kinase proto-oncogene RET, located on chromosome 10, is transmitted in an autosomal dominant way and is present in 98% of the affected family members. However, familial aggregation may be also present in 5% of patients with differentiated thyroid carcinoma, or this condition may be inherited as a component of familial adenomatous polyposis, Gardner’s syndrome, or Cowden’s disease (43). Low-dose irradiation of the head or neck for varied conditions favors the development of thyroid carcinomas. The phenomenon was observed after the nuclear accident at Cherbonyl, which led to an increase in the incidence of papillary carcinomas of the thyroid (46,47). RET activation with production of the RET/papillary thyroid carcinoma (PTC) oncogenes is only present in a limited number of patients with papillary carcinomas, and it may also be present in benign thyroid disease (48). Besides the RET/PTC rearrangements, some other mechanisms may be implicated in the etiology of papillary carcinomas. A more complete list of these factors is outlined in Table 11. The RET mutation in MEN may be demonstrated in every cell of the body (germ line), while the mutations in the papillary cancer are limited to the tumor (somatic). One distinction of follicular adenoma from carcinoma is point mutation in the ras oncogenes and deletion of genes from chromosomes 11 and 3, but none of these findings can have a predictive or diagnostic role. Table 10 The Incidence and 10-Year Survival Rates for Different Thyroid Carcinomas

Figure 7 Algorithm for management of patients with a solitary thyroid nodule. Abbreviation: FNA, fine needle aspiration.

Papillary carcinoma Follicular carcinoma Medullary carcinoma Anaplastic carcinoma

medwedi.ru

Incidence (%)

10-year survival rate (%)

80 15 4–5 1–2

93–98 85–92 75–80 13–14

1000

Part Seven: The Endocrine System

Table 11 Factors Associated with the Development of Thyroid Carcinomas

Table 13 Stage Grouping for Differentiated Thyroid Carcinomas

Papillary carcinoma RET rearrangements (chromosome 1)-RET/PTC 1, RET/PTC 3 TRK-A (chromosome 1) overexpression Mitogen-activated protein kinase overexpression c-myc overexpression c-fos overexpression c-ras overexpression c-erb B2/neu overexpression DNA hypermetilation Cell cycle dysregulation Follicular carcinoma Ras mutations Deletions of genes from chromosome 11q Deletion of chromosome 3p Pax8-peroxisome proliferator activated receptor recombination Medullary carcinoma RET mutations Anaplastic carcinoma p53 mutations

I II III IV

Abbreviations: RET, rearranged during transfection; PTC, papillary thyroid carcinoma; TRK, tropomyocin receptor kinase.

As stated before, medullary thyroid carcinomas have a high familial aggregation, and RET mutations are a common finding in all family members with the disease. The mutations are also present in some of the patients with clinically sporadic disease. Mutations of the p53 tumor suppressor gene lead to proliferation of malignant cells and are present in many cancers. Between 60% and 90% of patients with undifferentiated and anaplastic carcinomas also have this mutation (49). Although different staging systems exist for differentiated thyroid carcinoma, the tumor node metastasis (TNM) classification (Table 12) is the most recommended for use and represents the most useful way to predict death from thyroid cancer. However, other staging systems are in common use (Tables 13 and 14).

Stage

Age <45 years

Age >45 years

M0 M1 – –

T1 T2-3 T4 or N1 M1

cytoplasm and intranuclear inclusions, called ‘‘Orphan Annie’’ cells. The name comes from a cartoon strip character of the same name who was depicted with large but featureless blank eyes. The stroma may contain calcium deposits known as psammoma bodies. Although the histology of papillary carcinomas resembles the normal histology of the gland to a lesser degree when compared to follicular carcinoma, the prognosis is better in papillary than in the follicular carcinoma. Unlike most cancers, the papillary carcinomas have a better prognosis if present in younger patients, and are generally more fatal in older patients. In 20% to 30% of cases, the lesion may be multicentric, but this does not affect the prognosis of the disease. Papillary cancer metastasizes by lymphatic spread. However, in advanced forms, papillary tumors may invade neighboring structures or metastasize hematogenously. The presence of metastases in the lymph nodes has little influence on the prognosis, as well. The anomalous features of papillary cancer relative to other malignancies are listed in Table 15. In 1987, clinicians at the Mayo Clinic found four independent variables for well-differentiated thyroid cancer by multivariable analysis, which affects prognosis. Patient age and tumor grade, extent, and size were the four variables and a score could be assigned (50,51). Indeed younger patients fare better and lymph node metastases are not a significant barrier. At one time, those patients at higher risk were thought to be candidates for more radical surgical treatment. However, no additional benefit at 10-year or 25-year survival can be shown with bilateral resections compared to unilateral operations, even for large tumors.

Papillary Carcinoma Papillary carcinoma is the most common form of thyroid cancer. FNAB is usually diagnostic. Papillary carcinomas have pathologic features that make them unique compared with the other forms of thyroid cancer. These include the presence of cuboidal cells with pale and abundant Table 12 The Tumor Node Metastasis Classification for Thyroid Carcinomas Primary tumor (T) TX T0 T1 T2 T3 T4 Nodal involvement (N) NX N0 N1 Distant metastases (M) MX M0 M1

Primary tumor cannot be assessed No evidence of primary tumor 1 cm or less, limited to thyroid 1.1–4 cm More than 4 cm, limited to thyroid Any size, extends beyond thyroid capsule Nodes cannot be assessed No regional nodes involved Regional nodes involved Metastases cannot be assessed No metastases present Distant metastases present

Treatment of Differentiated Thyroid Carcinoma Surgical Treatment Surgery is the treatment of choice for differentiated thyroid carcinoma. The extent of resection varies. Total thyroidectomy is supported by the following facts: 5% to 10% of recurrences of papillary carcinoma after lobectomy occur in the contralateral lobe (50); postoperative radioiodine treatment is more effective if there is no normal tissue competing in affinity for the iodine; and the thyroglobulin monitoring has a higher specificity as a marker of recurrence if total thyroidectomy was performed. Moreover, the incidence of locoregional recurrence is proved to be lower in total versus unilateral thyroidectomy (52), while,

Table 14 Stage Grouping for Medullary Thyroid Carcinomas Stage I II III IV

Characteristic T1 T2-4 N1 M1

Chapter 52: The Thyroid Gland

1001

Table 15 Prognostic Features of Papillary Thyroid Carcinoma That Differentiate It from Most Malignancies

Table 16 Tumor Recurrence 10 Years After Initial Surgery for Different Postoperative Approaches in Patients with Differentiated Thyroid Carcinoma

Anomalous behavior of papillary carcinoma

Type of postoperative treatment

Better prognosis in young patients Better prognosis than follicular cancer, although worse histology Multicentricity does not affect prognosis Presence of lymph node metastases does not affect prognosis

None T4 alone T4 þ RAI remnant ablation

in high-risk patients, mortality is moderately decreased after bilateral operations in some reports (53). A very prudent variant of total thyroidectomy is neartotal thyroidectomy. In this maneuver, an inconsequential 50 mg of thyroid tissue at the tubercle of Zuckerkandl is left intact to avoid a tedious dissection of the recurrent laryngeal nerve near its entry into the cricothyroid membrane. Unilateral thyroidectomy is a highly effective treatment of differentiated thyroid carcinoma. The reasons to support it are the absence of any substantial survival benefits with more extensive procedures, and unaffected prognosis of papillary carcinomas by the multicentricity of the disease. In low-risk patients, the cause-specific mortality and the incidence of distant metastases are not significantly higher if thyroid lobectomy is performed, compared to total thyroidectomy (52). However, leaving one lobe of the thyroid in place has the disadvantage of making the postoperative monitoring with thyroglobulin impossible. All patients receive T4 to deprive any remaining tumor cells of the trophic effects of TSH. Therefore, leaving the contralateral lobe does not provide any thyroid function. The complications of total versus unilateral thyroidectomy are not different (54), especially if a parathyroid autograft is routinely done to prevent hypoparathyroidism (55). Although positive lymph nodes do not have a major influence on the survival rate in papillary carcinoma, removal of palpable nodes is recommended. Radioiodine Ablation of Residual Thyroid Tissue Postoperative iodine ablation is advised in patients with differentiated thyroid carcinoma who had an initial tumor larger than 1.5 cm. This treatment was proved to reduce the recurrence of disease in patients of all ages, and to reduce the risk of death from thyroid carcinoma in patients older than 40 years at the time of diagnosis (56). The effects of therapy are less profound if the initial tumor was less than 1.5 cm, unless there is history of radiation exposure, extrathyroid invasion, or metastasis (57). Postoperative 131I adjuvant therapy in well-differentiated thyroid carcinoma decreases recurrences by elimination of microscopic residual or metastatic disease (44,58,59). Some authors report increased disease-free intervals (60) and prolonged survival with radioiodine therapy (57). Radioiodine is concentrated into the follicular cells, including malignant cells of follicular origin. Once inside the cell, the isotope releases high-energy electrons, which undergo both b and g decay, resulting in high radiation ablation locally. Gamma rays can also be detected in scanning procedures, for diagnostic purposes. The effective radiation doses are 100 mCi for functioning tissue in the thyroid bed, 150 to 175 mCi for cervical node metastases, 175 to 200 mCi for lung metastases, and 200 mCi for skeletal metastases (61). The tissue dose is 250 Gy when 150 mCi are given. In 80% of cases, all residual malignancies or nodal metastases will be ablated by a radiation dose of 30,000 rad delivered to the residual thyroid tissue or 10,000 2000 rad/lymph node (62).

Total recurrences (%) 40 22 8

Abbreviation: RAI, radioactive iodine.

Because TSH stimulates iodine trapping into the follicular cells, TSH should be driven to higher levels prior to 131 I administration (40 pg/mL). Therefore, thyroid hormone replacement therapy should be delayed until after this procedure, and it takes three to four weeks for patients to become profoundly hypothyroid with high TSH. However, T3 (cytomel) can be given until about a week prior to study and the TSH will still rise. Foods with high concentration of iodine should be avoided, because non-RAI trapping into the thyroid tissue would impede the capture of 131I isotope. After TSH is stimulated (3–4 weeks), a total body thyroid scan is performed. If there is an uptake of iodine at any site, 150 mCi of RAI are given. Residual thyroid activity in the neck does not imply metastatic disease. Some 25% of patients after anatomically complete thyroidectomy will have some residual activity in ectopic thyroid tissue. Thus, the near total thyroidectomy leaving 50 mg of thyroid tissue does not have any significant impact or raise any grave concerns when there is a small amount of activity on the total body scan. Thyroid hormone administration is the most important adjunctive measure for differentiated thyroid tumors to reduce local recurrence. This is true if the patient has residual functioning lobe or needs replacement if total thyroidectomy has been done. TSH from the pituitary stimulates the growth of differentiated thyroid carcinoma. Thyroxine (T4) at a dose of 150 mcg/day is preferred to T3 for several reasons. T4has a longer half-life than T3 (1 week, compared to 1 day), allowing a sustained suppression of TSH. Another advantage is that cardiac arrhythmias occur less with T4 than with T3 (54). However, TSH suppression may still have adverse effects, which include acceleration of osteoporosis, provocation of atrial fibrillation, and cardiac hypertrophy and dysfunction (43). The effects of different treatments on the number of total recurrences 10 years following total thyroidectomy for differentiated thyroid carcinoma are summarized in Table 16 (57). Other Therapeutic Options External beam radiotherapy showed little beneficial value in the management of patients with differentiated thyroid carcinoma, because these tumors are not especially radiosensitive. It may be effective if gross extrathyroidal invasion is present, after incomplete resection, or if the tumor does not take up RAI. Chemotherapy is used in patients who do not respond to surgery and radioiodine treatment. Doxorubicin, either alone or in combination with other drugs, may improve the survival rate in this category of patients.

Follow-Up of Patients with Differentiated Thyroid Cancer The long-term follow-up regimen is well established. Thyroglobulin is tested yearly and total body 131I scanning should be performed every three to five years to identify

medwedi.ru

1002

Part Seven: The Endocrine System

recurrences. TSH is measured yearly to assess T4 replacement and suppression. Physical examination yearly helps assess local, nodal, or thyroid bed recurrences.

Follicular Carcinoma Follicular carcinoma is the other type of differentiated carcinoma of the thyroid. It occurs in older age groups than the papillary type, and it is more frequent in iodine-deficient areas. The FNAB cannot always differentiate between follicular adenoma and carcinoma. The lesion is typically unifocal and surrounded by a capsule. Microscopically, the follicles are present but they contain little colloid. Follicular tumors metastasize hematogenously to bone and lung. Lymphatic spread is uncommon. Follicular carcinoma is also less likely than papillary to take up radioiodine. Occasionally, FNAB will show follicular cells, but histology of the specimen shows mixed papillary and follicular carcinoma. These mixed tumors do not show a malignant behavior intermediate between papillary and follicular carcinomas. All tumors with any element of papillary cancer behave in the more favorable pattern of papillary lesions.

Hu¨rthle Cell Carcinoma Hu¨rthle cell carcinoma is considered a variant of follicular cell neoplasm. It is often an aggressive tumor with a worse prognosis than differentiated thyroid carcinoma. Hu¨rthle cell carcinomas originate in the oxyphilic cells of the thyroid, whose function is unknown, and are characterized microscopically by the presence of oxyphilic cells with an increased number of mitochondria. Contrary to follicular cell carcinomas, Hu¨rthle cell carcinomas are more likely to be multifocal and bilateral, they metastasize more often in the regional lymph nodes, and are even less likely to take up radioiodine. Total thyroidectomy with ipsilateral central neck lymphadenectomy and modified radical neck dissection is the procedure of choice when there is evidence of central or lateral node involvement (63). Postoperative radioiodine ablation of any thyroid remnant is advised, although fewer than 10% of these neoplasms take up 131I. All patients with Hu¨rthle cell carcinoma should be administered thyroid hormones, because most of these tumors have TSH receptors. Like differentiated thyroid carcinomas, Hu¨rthle cell carcinomas produce thyroglobulin. Therefore, postoperative follow-up by measuring serum thyroglobulin levels is effective in detecting tumor recurrences.

Anaplastic Carcinoma Anaplastic carcinoma is the worst of all follicular cell malignancies and the most aggressive of all thyroid tumors. It is encountered mainly in the elderly, with a peak incidence in the seventh and eighth decades of life. It is slightly more common in women than in men. The tumor occurs more frequently in iodine deficient areas and is associated with a history of goiter or differentiated thyroid carcinoma. Explosive growth may occur, leading to death within a few months after diagnosis. Microscopically, anaplastic carcinomas are characterized by the presence of different cell populations. Large multinucleated cells or spindle-shaped cells may be encountered. Furthermore, foci of papillary or follicular malignant cells may also be present. Anaplastic carcinomas metastasize very frequently, by local, lymphatic, and hematogenous ways. Local invasion is aggressive, leading to dyspnea, dysphagia, and dysphonia. Cervical lymph nodes are usually palpable at presentation.

Distant metastases may be present in lungs, pleura, bone, and brain (43). There is no effective treatment for patients with anaplastic carcinoma. Several approaches have been tried, including combination of surgery, radiotherapy, and chemotherapy, but the results are not satisfactory. The role of the surgery is palliative and its purpose is to maintain the integrity of the aerodigestive tract for as long as possible.

Medullary Thyroid Carcinoma Medullary thyroid carcinoma arises from the parafollicular (or C) cells of the thyroid. These are neuroectodermal cells derived from the ultimobranchial bodies of the fourth branchial pouch, and more densely populate the superior parts of the thyroid lobes. The condition may occur either as a sporadic form, which accounts for 80% of the cases, or as familial forms. The inherited forms may, in turn, be part of MEN type II and type III syndromes or may occur in a non-MEN setting. MEN type II is characterized by the presence of medullary thyroid carcinoma associated with pheochromocytoma and parathyroid hyperplasia. Hirschsprung’s disease and lichen cutaneous amyloidosis may be associated in rare cases. Patients with MEN type III have medullary thyroid carcinoma, pheochromocytoma, ganglioneuromatosis, and marfanoid habitus. Multicentricity is encountered in 20% to 30% of sporadic cases and in almost all familial ones. Microscopically, medullary thyroid carcinomas have great heterogenicity, with sheets of polygonal or spindle-shaped cells in an amyloid and collagen stroma. Certain staining features make the diagnosis of medullary thyroid carcinoma sure, and these include the presence of amyloid, calcitonin secretory granules, and carcinoembryonic antigen (CEA). The mode of spread may be lymphatic or hematogenous. In 50% of patients, enlarged cervical lymph nodes are noted at initial presentation. The tendency of tumor and the involved lymph nodes to calcify may help in making the diagnosis, when calcification is noted on radiographs of the neck. Medullary thyroid carcinoma is slightly more common in women than in men. The sporadic form has a peak incidence in the fifth or sixth decades of life, although the disease may appear at younger ages in patients with MEN syndromes. The chief complaint at presentation is a neck mass, which may be associated with cervical lymphadenopathy or compression symptoms. Medullary thyroid tumors may secrete a variety of peptides, including calcitonin, calcitonin gene–related peptide, adrenocorticotrophic hormone, CEA, and serotonin. These lead to unusual symptoms, like diarrhea, Cushing’s syndrome, or facial flushing. The diagnosis is usually made by FNAB. Although serum calcitonin is increased in patients with medullary thyroid carcinomas, routine use of this test is not recommended in the assessment of all patients with thyroid nodules, because the test is not cost-effective. Because it is difficult to distinguish between familial and nonfamilial forms of the disease, RET mutations should be assessed in all newly diagnosed patients. Differentiation between the gene line mutations of the sporadic versus familial forms helps the surgeon decide whether preoperative screening for pheochromocytoma is necessary. If RET testing cannot be performed, serum calcium and 24-hour urinary excretion of metanephrines and catecholamines should be measured before the operation, to exclude the MEN syndrome. The treatment of patients with medullary thyroid carcinoma consists of total thyroidectomy with bilateral central neck compartment dissection, because these lymph nodes

Chapter 52: The Thyroid Gland

are involved early in the disease. If central lymph nodes are positive at the time of operation, additional prophylactic ipsilateral radical neck dissection is recommended. If the primary tumor is bilateral, then bilateral radical neck dissection is advised (64). Postoperative external beam irradiation may be useful in patients at high risk for regional recurrences. Because these tumors originate from the C-cells, RAI therapy and TSH suppression have no influence on the outcome. Somatostatin may help alleviate associated symptoms (diarrhea, flushing, weight loss, etc.). Postoperative thyroid hormone replacement is of course necessary after thyroidectomy. The postoperative follow-up is done by measuring the blood levels of calcitonin and CEA. Increased values after the operation alert the surgeon to look for residual disease in the neck and distant metastases. The imaging studies to localize residual or recurrent disease may include ultrasonography, CT, and MRI. Tumor markers may implicate residual disease long before any tumor can be detected by palpation or imaging. In these circumstances, prescriptive ablative surgery offers no advantage over prudent waiting and selective application of surgery or chemotherapy.

SUMMARY The thyroid gland is of significance to the surgeon in two important respects. First, its dysfunction can adversely affect the perioperative management of a patient requiring surgery, making it mandatory that any physiologic aberration is corrected preoperatively. Second, surgery often plays an important role in managing patients with enlarged glands and hyperthyroid states as well as individuals with thyroid lesions that could be potentially malignant. A thorough understanding of these pathologic states and their current management have greatly benefitted individuals who will need thyroid surgery. Except in unusual circumstances, a good-to-excellent outcome can be expected with minimal morbidity and almost no mortality.

REFERENCES 1. Wiseman SM, Hicks WL Jr, Chu QD, Rigual NR. Sentinel lymph node biopsy in staging of differentiated thyroid cancer: a critical review. Surg Oncol 2002; 11(3):137–142. 2. Hisham AN, Lukman MR. Recurrent laryngeal nerve in thyroid surgery: a critical appraisal. ANZ J Surg 2002; 72(12):887–889. 3. Furlan JC, Brandao LG, Ferraz AR, Rodrigues AJ Jr. Surgical anatomy of the extralaryngeal aspect of the superior laryngeal nerve. Arch Otolaryngol Head Neck Surg 2003; 129(1):79–82. 4. Leger J, Marinovic D, Garel C, Bonaiti-Pellie C, Polak M, Czernichow P. Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism. J Clin Endocrinol Metab 2002; 87(2):575. 5. Jimenez OV, Ruiz RR, Davila MA, et al. Intra-laryngeal ectopic thyroid tissue. Report of one case and review of the literature. Acta Otorrinolaringol Esp 2002; 53(1):54–59. 6. Massine RE, Durning SJ, Koroscil TM. Lingual thyroid carcinoma: a case report and review of the literature. Thyroid 2001:1191–1196. 7. Organ GM, Organ CH Jr. Thyroid gland and surgery of the thyroglossal duct: exercise in applied embryology. World J Surg 2000; 24(8):886–890. 8. Nilsson M. Iodide handling by the thyroid epithelial cell. Exp Clin Endocrinol Diab 2001; 109(1):13–17. 9. Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993; 329(17):1246.

1003

10. Demers LM, Spencer CA. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol 2003; 58(2):138–140. 11. Beckett GJ, Toft AD. First-line thyroid function tests—TSH alone is not enough. Clin Endocrinol 2003; 58(1):20–21. 12. Lawrence W Jr, Kaplan BJ. Diagnosis and management of patients with thyroid nodules. J Surg Oncol 2002; 80(3):157–170. 13. Davies T, Marians R, Latif R. The TSH receptor reveals itself. J Clin Invest 2002; 110(2):161–164. 14. Simchen C, Lehmann I, Sittig D, Steinert M, Aust G. Expression and regulation of regulated on activation, normal T cells expressed and secreted in thyroid tissue of patients with Graves’ disease and thyroid autonomy and in thyroid-derived cell populations. J Clin Endocrinol Metab 2000; 85(12):4758. 15. Weetman AP. Graves’ disease. N Engl J Med 2000; 343(17):1236. 16. Salmaso C, Bagnasco M, Pesce G, et al. Regulation of apoptosis in endocrine autoimmunity: insights from Hashimoto’s thyroiditis and Graves’ disease. Ann NY Acad Sci 2002; 966:496–501. 17. Huang M, Wu J, Lee TD, Yang EKL, Shaw K, Yeh C. The association of HLA-A, -B, and -DRB1 genotypes with Graves’ disease in Taiwanese people. Tissue Antigens 2003; 61(2):154–158. 18. Ford HC, Delahunt JW, Feek CM. The management of Graves’ disease in New Zealand: results of a national survey. N Z Med J 1991; 104(914):251–252. 19. Wartofsky L, Glinoer D, Solomon B, Lagasse R. Differences and similarities in the treatment of diffuse goiter in Europe and the United States. Exp Clin Endocrinol 1991; 97(2–3):243–251. 20. Tominaga T, Yokoyama N, Nagataki S, et al. International differences in approaches to 131I therapy for Graves’ disease: case selection and restrictions recommended to patients in Japan, Korea, and China. Thyroid 1997; 7(2):217–220. 21. Gerasimov G, Judenitch O, Zdanova E, et al. The management of hyperthyroidism due to Graves’ disease in the former USSR in 1991: results of a survey. J Endocrinol Invest 1992; 15(7):513–517. 22. Walsh JP. Management of Graves’ disease in Australia. Aust N Z J Med 2000; 30(5):559–566. 23. Alsanea O, Clark OH. Treatment of Graves’ disease: the advantages of surgery. Endocrinol Metab Clin North Am 2000; 29(2):321–337. 24. Solomon B, Glinoer D, Lagasse R, Wartofsky L. Current trends in the management of Graves’ disease. J Clin Endocrinol Metab 1990; 70(6):1518–1524. 25. Ginsberg J. Diagnosis and management of Graves’ disease. CMAJ 2003; 168(5):575. 26. Luft FC. Toxic thyroid adenoma and toxic multinodular goiter. J Mol Med 2001; 78(12):657–660. 27. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging thyroid. Increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA 1979; 242(3):247–250. 28. Woolf SH. Laboratory screening tests. In: Woolf SH, Jonas S, Lawrence RS, eds. Health Promotion and Disease Prevention in Clinical Practice. Williams & Wilkins, 1996:85–142. 29. Coindre JM, David JP, Riviere L, et al. Bone loss in hypothyroidism with hormone replacement. A histomorphometric study. Arch Intern Med 1986; 146(1):48–53. 30. Krolner B, Jorgensen JV, Nielsen SP. Spinal bone mineral content in myxoedema and thyrotoxicosis. Effects of thyroid hormone(s) and antithyroid treatment. Clin Endocrinol (Oxf) 1983; 18(5):439–446. 31. Tomer Y, Barbesino G, Greenberg DA, Concepcion E, Davies TF. Mapping the major susceptibility loci for familial Graves’ and Hashimoto’s diseases: evidence for genetic heterogeneity and gene interactions. J Clin Endocrinol Metab 1999; 84(12): 4656–4664. 32. Kumar N, Ray C, Jain S. Aspiration cytology of Hashimoto’s thyroiditis in an endemic area. Cytopathology 2002; 13(1): 31–39. 33. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996; 335(2):99–107. 34. Gourgiotis L, Al Zubaidi N, Skarulis MC, et al. Successful outcome after surgical management in two cases of the ‘‘painful variant’’ of Hashimoto’s thyroiditis. Endocr Pract 2002; 8(4):259–265.

medwedi.ru

1004

Part Seven: The Endocrine System

35. Kojima M, Nakamura S, Oyama T, Sugihara S, Sakata N, Masawa N. Cellular composition of subacute thyroiditis an immunohistochemical study of six cases. Pathol Res Pract 2002; 198(12):833–837. 36. Volpe R. The management of subacute (DeQuervain’s) thyroiditis. Thyroid 1993; 3(3):253–255. 37. Duininck TM, van Heerden JA, Fatourechi V, et al. de Quervain’s thyroiditis: surgical experience. Endocr Pract 2002; 8(4):255–258. 38. Iitaka M, Momotani N, Ishii J, Ito K. Incidence of subacute thyroiditis recurrences after a prolonged latency: 24-year survey. J Clin Endocrinol Metab 1996; 81(2):466–469. 39. Fatourechi V, Aniszewski JP, Fatourechi GZ, Atkinson EJ, Jacobsen SJ. Clinical features and outcome of subacute thyroiditis in an incidence cohort: olmsted county, Minnesota, study. J Clin Endocrinol Metab 2003; 88(5):2100–2105. 40. Welker MJ, Orlov D. Thyroid nodules. Am Fam Physician 2003; 67(3):559–566. 41. Brander AEE, Viikinkoski VP, Nickels JI, Kivisaari LM. Importance of thyroid abnormalities detected at US screening: a 5-year follow-up. Radiology 2000; 215(3):801. 42. Jemal A, Thomas A, Murray T, Thun M. Cancer Statistics 2002. CA Cancer J Clin 2002; 52(1):23–47. 43. Sherman SI. Thyroid carcinoma. Lancet 2003; 361(9356): 501–511. 44. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer 1998; 83(12):2638–2648. 45. Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973–1991. Cancer 1997; 79(3):564–573. 46. Bandurska-Stankiewicz E, Stankiewicz A, Shaffie D, Wadolowska L. Thyroid cancer morbidity in the Olsztyn region in 1993–1999. Wiad Lek 2001; 54(suppl 1):136–142. 47. Pacini F, Vorontsova T, Molinaro E, et al. Thyroid consequences of the Chernobyl nuclear accident. Acta Paediatr Suppl 1999; 88(433):23–27. 48. Elisei R, Romei C, Vorontsova T, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 2001; 86(7):3211–3216. 49. Haugen BR, Woodmansee WW, McDermott MT. Towards improving the utility of fine-needle aspiration biopsy for the diagnosis of thyroid tumours. Clin Endocrinol (Oxf) 2002; 56(3):281–290. 50. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using

51.

52.

53.

54. 55.

56. 57.

58.

59.

60.

61.

62.

63. 64.

a novel prognostic scoring system. Surgery 1987; 102(6): 1088–1095. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993; 114(6):1050–1057. Hay ID, Grant CS, Bergstralh EJ, Thompson GB, van Heerden JA, Goellner JR. Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 1998; 124(6):958–964. Hay ID, McConahey WM, Goellner JR. Managing patients with papillary thyroid carcinoma: insights gained from the Mayo Clinic’s experience of treating 2,512 consecutive patients during 1940 through 2000. Trans Am Clin Climatol Assoc 2002; 113:241–260. Clark OH. TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 1981; 5(1):39–47. Kikumori T, Imai T, Tanaka Y, Oiwa M, Mase T, Funahashi H. Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma: long-term follow-up of grafted parathyroid function. Surgery 1999; 125(5):504–508. Mazzaferri EL. Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid 1997; 7(2):265–271. Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001; 86(4):1447–1463. Varma VM, Beierwaltes WH, Nofal MM, Nishiyama RH, Copp JE. Treatment of thyroid cancer. Death rates after surgery and after surgery followed by sodium iodide I-131. JAMA 1970; 214(8):1437–1442. Samaan NA, Maheshwari YK, Nader S, et al. Impact of therapy for differentiated carcinoma of the thyroid: an analysis of 706 cases. J Clin Endocrinol Metab 1983; 56(6):1131–1138. Samaan NA, Schultz PN, Hickey RC, et al. The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients. J Clin Endocrinol Metab 1992; 75(3):714–720. Parthasarathy KL, Crawford ES. Treatment of thyroid carcinoma: emphasis on high-dose 131I outpatient therapy. J Nucl Med Technol 2002; 30(4):165–171. Maxon HR, Thomas SR, Samaratunga RC. Dosimetric considerations in the radioiodine treatment of macrometastases and micrometastases from differentiated thyroid cancer. Thyroid 1997; 7(2):183–187. Yutan E, Clark OH. Hu¨rtle cell carcinoma. Curr Treat Options Oncol 2001; 2(4):331–335. Kebebew E, Clark OH. Medullary thyroid cancer. Curr Treat Options Oncol 2000; 1(4):359–367.

53 Endocrine Pancreas Ronald C. Merrell, Giacomo P. Basadonna, and Cristiana Rastellini

INTRODUCTION To coordinate the function of metazoan life forms for mutual, organismal benefit, the cells of the organism must communicate. In simple multicellular organisms, electrical coupling, cell-contact events, and the local diffusion of metabolic and messenger molecules are sufficient. Neighboring cells are informed by mass action, allosteric enzyme interactions, or specific binding to receptors. In a larger organism with a circulatory system, coordinating messages in the form of small molecules may flow through the organism to arrive at tissues possessing specific receptors, with complex postreceptor events. Also, neural fibers arborize across great distances to release communicating molecules to specialized receptors when triggered by propagated depolarization of the neuronal membrane (1). The pancreas demonstrates essentially all the known mechanisms for cellular communication in a metazoan organism. In addition to cell-to-cell interaction among islet cells across gap junctions (Fig. 1), the simplest coordinated function, and complex adrenergic and cholinergic innervation, the pancreas engages in exocrine, paracrine, and endocrine interactions with the remainder of the body (Fig. 2). Exocrine function is described as the release of synthesized products into a nonvascular duct for delivery at another anatomic locus. Paracrine function is the release of a synthesized product into the extracellular space for delivery by diffusion to a target tissue no more than several microns away. Endocrine function is the release of a synthesized product that enters the circulation for transport to a distant target tissue. The intricacy and redundancy of communication pathways for this islet cell mass underscore its crucial role in maintaining glucose homeostasis through the balance of glucose clearance, mediated by insulin, and glucose generation, mediated by glucagon. In 1869, Paul Langerhans demonstrated the unique features of the islets that now bear his name. These structures, originally viewed as islands in the alien sea of the exocrine pancreas, are now more clearly seen as integral rather than accidental features of the pancreas, with extensive interaction with the exocrine portion of the gland. Von Mering and Minkowski (2) provided evidence for an endocrine function of the pancreas in 1889, when they found that total pancreatectomy led not only to the expected exocrine insufficiency but also to diabetes mellitus. Attribution of endocrine function to the islets followed, seeming to culminate with isolation of insulin and its clinical application for type I diabetes mellitus by Banting and Best in 1922 (3). However, the full richness of islet interaction and regulation was only suggested by the recognition of insulin, and new data continue to enhance the importance of the islets in homeostasis. This chapter describes the endocrine community of the islets of Langerhans, their origins and relationships

(both internal and external), and their role in homeostasis and disease states.

ANATOMY AND EMBRYOLOGY OF THE ISLETS The islets of Langerhans individually constitute an endocrine community engaged in active collaboration to secure glucose homeostasis. At least four distinct endocrine cells have been identified: (i) A cells, which secrete glucagon, a catabolic hormone that raises plasma glucose level; (ii) B cells, which produce insulin, an anabolic hormone that lowers plasma glucose level; (iii) D cells, which produce somatostatin, a regulatory hormone for A and B cells;

Figure 1 Gap junctions and tight junctions between islet cells suggest the rich transcellular communication between component cells of islets of Langerhans. This freeze-fracture electron micrograph shows extensive cellular contacts between islet cells. Courtesy: Lelio Orci, Geneva.

medwedi.ru 1005

1006

Part Seven: The Endocrine System

Figure 2 Exocrine delivery of secreted cellular products occurs along ducts that ultimately discharge into the gastrointestinal tract or outside the body. Paracrine secretions reach a target cell solely by diffusion across a short distance (the schematic cell on the left is discharging a substance received by the cell on the right). Endocrine secretions enter the circulation and arrive at a target tissue some distance from the point of origin. (The schematic cell on the left is discharging substance into blood; blood transports the substance to the target cell on the right.)

Figure 3 B cells are centrally located in the islet in close approximation to incoming blood supply, whereas A cells are arrayed as a mantle at the periphery of the islet. D and F cells are interspersed. B cell secretions move through the islet toward the periphery before reentering the circulation. This flow determines the opportunity for paracrine interaction among the component cells. The modest suppression by insulin of A cells may be paracrine, whereas the more substantial stimulation of B cells by glucagon must be endocrine. D and F cells could interact with one another, with A cells, or with B cells.

and (iv) F cells, which secrete pancreatic polypeptide (PP), a 36–amino acid linear polypeptide. Each cell contains and secretes only one endocrine product. The lettering system for these cells stems from special chemical staining properties of the secretory granules. The letter C in the series was reserved for a cell in guinea pig islets, which contained no granules. This cell may have been a degranulated B cell or a precursor cell, but it no longer has any valid stature among its lettered neighbors. Also, the E cell, described only in the opossum, must await further study before inclusion in this endocrine community. The cells were lettered in order of discovery, and the missing C and E cells in the islet serve to remind us of the enormous confusion that preceded our current, meager understanding (4). That understanding is based on staining islets with specific antibodies to the various secretory products and then using a variety of tactics to visualize that bound antibody on the secretory granules of the appropriate cell. This staining by immunocytochemistry forms the basis of our current understanding of islet anatomy. The pancreas arises from foregut endoderm through a dorsal bud, first evident in the 3 mm embryo, and then by a ventral anlage, which is a branch of the liver bud. By clockwise rotation, the ventral structure ultimately fuses with the dorsal structure. The endocrine cells derive from precursors along the pancreatic ductal elements. With immunocytochemistry, A, B, and D cells can be recognized in organized islets by eight weeks of gestation. By 10 to 11 weeks, islets can be identified. The islets organize away from ducts as discrete structures and then grow by cell division throughout fetal life and for the first few years after birth. Islets are not of uniform size in humans, but they average approximately 300 mm (5). The A cells mature first, but at birth the distribution of the cells is the same as in adults: 60% to 70% B cells, 20% to 25% A cells, 10% to 15% D cells, and 5% to 10% F cells (Fig. 3). The distribution of the islets is not completely uniform throughout the pancreas with respect to constituent cells. For example, A and B cells are more numerous in tail islets, and F cells are much more numerous in the pancreatic head. Islets have a direct arterial

blood supply and are so well vascularized that the mass of islets’ capillaries is often described as glomerulus-like. Islets’ serial sections reveal four patterns of islet endocrine cells and capillaries: (i) a single row of cells between two capillaries, (ii) a double row of cells between two capillaries, (iii) a ring of cells around a cross-sectioned capillary, and (iv) a clump of cells between two capillaries. At least two of these patterns are present in any islet section (6). Ultrastructural studies show that in a normal B cell, insulin granules fill the cytoplasm, and no obvious polarity is evident. After degranulation, however, a clear polarity of insulin granules has been demonstrated, with insulin granules clumped at the opposite side of the arbitrarily defined basal face, where the nucleus is closer to one capillary face. All the B cells around a particular cross-sectioned capillary show the same polarity, with the apical side facing the central capillary (6). These findings could signify a topographic separation of an apical secretory surface and a basal sensing surface for the B cell and possibly the other endocrine cells. The origin of islet cells has been the subject of spirited debate for nearly 10 years. The islet cells have metabolic and morphotic features shared by all neuroendocrine cells, including amine precursor uptake and decarboxylase (APUD) and neurone-specific enolase. A common embryologic source for all these cells in the neuroectoderm of the neural crest has been proposed (7). However, careful studies in developmental biology refute this origin for pancreatic islet cells and place them firmly in the same lineage as the exocrine cells. For example, elimination of the neural fold before the three-somite stage does not preclude B cell development in rat embryo explants (8). A great majority of the endocrine system derives from the gastrointestinal epithelium, including the pituitary (Rathke’s pouch), the thyroid (second branchial arch and ultimo branchial body), and the parathyroid glands (branchial pouches III and IV). Nonetheless, the APUD concept has been of enormous value in predicting the properties of endocrine tissue in a site, on the basis of knowledge of other endocrine systems. Also, the behavior of pathologic endocrine tissue can be

Chapter 53: Endocrine Pancreas

Table 1 Insuloacinar Axis Hormone Insulin

Glucagon

Somatostatin Pancreatic polypeptide

Exocrine effect m Uptake of amino acids m Amylase synthesis m Cell division Permits HCO3 release ! Enzyme synthesis ! Enzyme release m HCO3 release ! Pancreatic secretion ! Release of enzymes

anticipated in less well-known tumors on the basis of knowledge of better-characterized tumors. All cells in an organism have the same genome, and the differentiation of transcription during development can be convergent, so after many different branch points in development, two cells serving similar (e.g., endocrine) functions may be more alike than are cells much closer in developmental lineage. It is significant that the islets are in the pancreas and develop with the pancreas, because this relationship suggests that islets function along with the remainder of the pancreas. Indeed, there is an insuloacinar axis, which constitutes a portal system that delivers islet hormones in high concentrations to much of the acinar pancreas (Table 1). Insulin increases amylase synthesis, permits bicarbonate secretion, and is permissive for the action of cholecystokinin (CCK). The pancreas in patients with insulindependent diabetes is much smaller than normal as a result of atrophy, which may be caused by a relative lack of insulin locally or by the inhibitory effects of excess glucagon, which suppresses enzyme synthesis and release, although it stimulates bicarbonate secretion. The inhibitory effects of glucagon are so pronounced experimentally that this hormone was proposed for the treatment of acute pancreatitis; however, clinical results have not been impressive. Somatostatin and PP are also inhibitory to the exocrine pancreas, and they presumably are active in the insuloacinar axis (9).

PHYSIOLOGY OF THE ISLETS Insulin and the B Cell The best studied of the islet cells is the B cell. The nucleus of this cell transcribes messenger RNA (mRNA) for preproinsulin, which is synthesized in the rough endoplasmic reticulum. The amino-terminal signal sequence is cleaved in the lumen of the endoplasmic reticulum, and the 9 kDa product, proinsulin, passes through the Golgi apparatus, where secretory vesicles are assembled. The insulin gene, one of the first human genes to be cloned (10), is 1500 bp long and contains three exons and two introns. The introns can be of variable length: intron 1 varies from 119 bp in chickens to 179 bp in humans, whereas intron 2 can vary from 264 bp in dogs to more than 3500 bp in chickens (786 in humans). The insulin gene exists as a single copy in most species, except in rats and mice, where two copies exist. Interestingly, rat insulin gene I does not have the second intron and exhibits 70% homology with the other copy. In the rat, both genes are present in the same chromosome and appear to be transcribed in equal portions. In mice, the genes are in different chromosomes, but this seems to have no effect on the relatively identical rates of transcription. The location of the insulin gene in humans is on band p15 of the short arm of chromosome 11 (11). Glucose stimulates insulin biosynthesis as well as secretion. Glucose does indeed regulate insulin biosynthesis

1007

at both translational and transcriptional levels, but there is a time shift in these effects. Thus, transcriptional effects are long term, whereas the translational effects occur in the short term. Some evidence to support this conclusion is that the glucose-stimulated increase in the amount of preproinsulin mRNA is not observed until two hours after glucose administration, and it is then maintained for about 24 hours. On the other hand, after one hour, there is an increase in insulin biosynthesis without a change in the mRNA levels. Glucose also stimulates preproinsulin mRNA levels as well as secretion in human islets (12). The effects of glucose on preproinsulin mRNA levels occur in two phases: an initial short-term phase involving posttranscriptional control, and a longterm regulation under transcriptional control. The insulin vesicles are stored in the cytoplasm in the webbing of the cytoskeleton and, under secretory stimuli, move to the plasma membrane, where the vesicle and plasma membranes fuse to release equimolar concentrations of insulin and C-peptide into the extracellular space. In the storage vesicles, the single chain of proinsulin is doubly cleaved to give the A and B chains of insulin (molecular weight 6 kDa), bonded together by two disulfide bridges and the connecting chain, C-peptide. A third disulfide bond determines the shape of the A chain. In the vesicles, insulin is a hexamer coordinated by two Zn2þ ions. During release and dilution, the hexamer dissociates to the active monomeric form (13). Stored insulin is abundant, and the number of B cells in the normal pancreas far exceeds the number required for insulin release. Even when insulin release is maximally stimulated, the release of more than 5% of the total insulin available is rare. As much as 95% of the normal pancreas can be resected without inducing insulin insufficiency or carbohydrate intolerance. The intracellular signals for the release of insulin are prompted by a movement of Ca2þ into the B cell and by the accumulation of the cyclic adenosine monophosphate (cAMP). Glucose enhances Ca2þ uptake from extracellular medium, as well as other secretagogues such as glyceraldehyde and sulfonylurea. Glucose may also cause a transient decrease in Ca2þ efflux and the closure of Kþ channels, which could cause the opening of Ca2þ channels (14). At high glucose concentrations, insulin secretion agonists such as glucagon induce secretion by increasing cAMP concentration through protein phosphorylation. It is convenient to view Ca2þ and cAMP as the final events necessary for access to the insulin pool. Access to the Ca2þ and cAMP pools, in turn, can be achieved through a variety of routes, either receptor mediated or connected to the metabolism of the B cell (Fig. 4) (15). Pluralistic access to the insulin pool is important to explain even partially the wide range of secretagogues and inhibitors for the release of this crucial hormone. Glucose is one of the most important extracellular signals for insulin release (Table 2). On the other hand, after a normal mixed meal, plasma glucose levels reach only low peak values (6–7 mmol/L). These concentrations of extracellular glucose are usually able to elicit a very weak insulin response. Nevertheless, after ingestion of a mixed meal, a significant insulin response is obtained through different patterns, releasing acetylcholine at parasympathetic synapses of vagal efferents on B cells, and secreting CCK through the neurons that innervate the B cells. CCK, glucagon-like peptide 1, and gastric-inhibitory peptide (GIP) all act on the B cell through the bloodstream. GIP and glucagon-like peptide 1 stimulate adenylate cyclase. Acetylcholine and CCK act on phosphoinositide-specific phospholipase C, causing an increase in both phosphoinositide hydrolysis and the Ca2þ concentration.

medwedi.ru

1008

Part Seven: The Endocrine System

Figure 4 The release of insulin from B cells is controlled at least by intracellular cAMP and Ca2þ. Although glucose is the predominant secretagogue for insulin, many other metabolic or receptor-mediated events also modulate insulin secretion. Proinsulin is packaged from the endoplasmic reticulum after synthesis and moves through the Golgi body. Proinsulin is cleaved in the secretory or storage vesicles to yield C-peptide and insulin, which are released in equimolar quantities by exocytosis. Abbreviation: cAMP, cyclic adenosine monophosphate.

The B cells are generally concentrated at the center of an islet, in close apposition to the arteriole that penetrates the islet to deliver blood initially to its interior (Fig. 3). These cells are coupled electrically to surrounding cells and have rich gap–junction contacts, transmitting sizable molecules among B cells and other adjacent endocrine cells (16). Table 2 outlines the major secretagogues and inhibitors of insulin release. The insulin leaving the islets, like all islet hormones, reaches the liver through the portal vein. Approximately 50% of insulin is removed on the first pass through the liver, which may be considered the major site of action for insulin. Table 2 Insulin Release Secretagogs Metabolic Glucose Other hexoses (potentiate) Hexosamines (potentiate) Glycolytic products (potentiate) Amino acids Fatty acids Ca2þ(ionic) Calcium ionophores Islet-activating protein Receptor-mediated Glucagon GIP b-Endorphin b-Adrenergic agonists Acetylcholine Sulfonylurea Gastrin Secretin CCK Coristol

Suppressors Metabolic D-Manno-heptulose 2-Deoxy-D-glucose Diazoxide

The least understood of the mechanisms for insulin release are the metabolic pathways. Clearly, flow of oxygen through the mitochondrial respiratory chain is critical, and lipoxygenase has been implicated (17). It is possible that glucose has a membrane receptor that prompts release in addition to metabolic regulation. Although many hexoses and intermediates are secretagogues or facilitate glucosemediated insulin release, galactose and 3-O-methylglucose participate in glycolysis but do not promote insulin secretion. Also, some agents that block glycolysis do not block glucose-stimulated insulin release. Therefore, a glucose receptor has been suggested (18). However, the nature of a receptor that responds in a concentration range of 5 103 to 15 103 mol/L for glucose is obscure at best. The dissociation constant for hormone receptors favors regulatory interaction at 108 to 109 mol/L. The high molecular concentration of glucose that affects insulin regulation is more consistent with allosteric interaction with an enzyme than with cell-surface or cytosolic receptor kinetics. It is clear that glucose metabolites promote insulin exocytosis, which maybe via inhibition of specific protein phosphatases (18a). In general, three routes of stimulation may be distinguished: metabolic, typified by glucose and amino acids; receptor mediated, typified by acetylcholine; and ionic, as in Ca2þ ionophores. Vagal stimulatory effects on insulin secretion are dramatic and may induce hypoglycemia with only the sight and smell of food. However, B cells can generally function in glucose homeostasis with or without this extraordinary amount of input. The checks and balances of insulin release are so numerous that failure of the B cell mass with glucose intolerance represents the collapse of a long series of protective endocrine and metabolic mechanisms. The basal release of insulin averages 4 mU/min (19). This level is biologically quite active. Therefore, insulin is important in basal metabolism and does not simply reduce excursions in the glucose concentration. When an appropriate stimulus is given, insulin is released in two phases. There is an initial or first-phase peak, which reaches about five times the basal insulin within three to five minutes. This phase deteriorates and a second, sustained phase of insulin release continues for 60 to 70 minutes. This second phase is quantitatively much more substantial (20). The biphasic contour (Fig. 5) suggests that insulin is stored in

Receptor-mediated Somatostain a-Adrenergic agonists Suppression of Electrical Activity Cytoskeleton blockade Diphanylhydantoin Colchicine

Abbreviations: GIP, gastric-inhibitory peptide; CCK, cholecystokinin.

Figure 5 Biphasic release of insulin after glucose stimulation is seen either from isolated islets of Langerhans, as in this figure, or from the in situ pancreas when pulsed with glucose. The initial sharp peak of insulin release at three minutes is followed by sustained insulin release, which peaks at 30 to 60 minutes. The significance of the biphasic nature of insulin secretion is probably great but is poorly understood. Multiple insulin pools have been proposed to explain the discontinuity of insulin release.

Chapter 53: Endocrine Pancreas

at least two compartments under somewhat different controls. Insulin release returns to the basal level after either restoration of ambient glucose to normal levels or exhaustion of the B cell. Physiologic inhibitors do indeed modulate insulin release, but they are not important in a feedback loop. Insulin itself may not be directly involved in feedback, because infused insulin in vivo (21) can reduce insulin output, but no such effect can be demonstrated with isolated islets in vitro (22). All the modulators of insulin release are of modest importance compared with the primacy of glucose as the major regulator of B cell function. Insulin lowers plasma glucose level principally by facilitating the diffusion of glucose into tissues that have insulin receptors. After interaction with its receptors, a number of protein phosphorylations occur, and the entry of glucose as glucose-6-phosphate is greatly accelerated (23). The hormone promotes glycogen synthesis by reducing cAMP effects on glycogenolysis. Insulin also promotes amino acid uptake and protein synthesis and inhibits protein degradation. Fat synthesis is promoted by means of pyruvate dehydrogenase, and lipolysis is inhibited (24). Insulin promotes the entry of Kþ and Mg2þ into cells, even in the absence of glucose (Table 2). The hormone generally supports cell growth and division by metabolic enhancement. Insulin is similar in primary structure to nerve growth factor, other growth factors, and relaxin. The wide array of insulin effects apparently does not have a common postreceptor second messenger. Rather, insulin has multiple intracellular actions after initial binding and internalization of the insulin–receptor complex. Insulin is also associated with a reduction in intracellular cAMP. Insulin is so critical to the existence of life forms with a circulatory system, and therefore with endocrine relationships, that its primary sequence is conserved with exquisite precision through speciation. Among mammals, there is significant variation only at amino acid residue numbers 8, 9, and 10 of the A chain (25). Human and porcine insulins differ by only one amino acid. Insulin from fishes has significant biologic activity in humans (Fig. 6). Although most tissues need insulin to modulate the metabolism of glucose, this hormone is not needed by the central nervous system. In fact, insulin does not readily pass the blood–brain barrier. Muscle tissue that has been physically conditioned by exercise has a great reduction in the need for insulin to transport glucose. Quantitatively, the most important site for insulin activity in metabolism is the liver, and the most important site for rapid reduction of plasma glucose is the fat cell mass.

Figure 6 The structure of insulin in all species is quite similar to human insulin, which is shown here. Sequence variation among various species is most prominent at residues 8, 9, and 10 of the A chain. Both A and B chains are derived from the same proinsulin molecule by proteolytic removal of the C-peptide. The three sulfhydryl bridges coordinate the tertiary structure of the molecule.

1009

Glucagon and the A Cell The complementary hormone to insulin is glucagon, which is secreted by A cells and acts to raise plasma glucose level. Glucagon is a single peptide of 3.485 kDa, which has sequence homology with secretin, vasoactive intestinal peptide (VIP), GIP, growth hormone–releasing factor, and placental lactogen (26). A prohormone is synthesized, which yields glucagon in the secretory granules after proteolytic cleavage. In health, glucagon is clearly as important as insulin, but because it is not of primary importance in any common disease states, its discovery in 1923 received little notice (27). This crucial hormone has until recently been viewed as a probe to the primacy of insulin. However, glucagon in stress is so preponderant in driving catabolic metabolism that new knowledge concerning its actions and properties is received with great anticipation by those wishing to better understand stress physiology. The principal stimulus for glucagon release is hypoglycemia. The mechanisms of release are probably similar to those of insulin but have been much less studied. Amino acids stimulate the release of both glucagon and insulin. The only gastrointestinal peptide known to stimulate glucagon secretion is CCK. Glucagon release is also prompted by epinephrine by means of a-adrenergic effects. Cortisol, growth hormone, and b-endorphin all promote glucagon release. Glucagon release is suppressed by hyperglycemia, somatostatin, secretin, and insulin. It also exercises feedback inhibition on its own secretion (28). After a glucose challenge, the suppression of baseline glucagon release closely parallels insulin stimulation. The magnitude of the suppression is much greater after oral glucose intake than after intravenous delivery. The mirror image of insulin response is clear. 1.

2.

Secretagogues a. Hypoglycemia b. Amino acids c. CCK d. a-Adrenergic agonists e. Cortisol f. Growth hormone g. b-Endorphin Suppressors a. Hyperglycemia b. Insulin c. Secretin d. Somatostatin

Basal glucagon level is of great importance in countervailing the effects of insulin. At steady state glucose level, basal insulin release describes an oscillation easily measured in portal venous blood. The period of the oscillation is about 10 minutes. Basal glucagon release follows a similar sinewave variation, 180 out of phase with that of insulin. The oscillatory delivery of insulin and glucagon to the liver cannot be explained on the basis of variable glucose delivery to the islets. Rather, an internal rhythm must be presumed in the islets themselves, one that does not require the circulatory system (29). Despite the extensive communication among the cells within an islet, there is no evidence for linkage among individual islets. However, rhythmic basal insulin release can be seen in cultured islets in vitro. The mechanism for this biologic clock is not known. Approximately 25% of the portal venous glucagon remains in the liver after one pass. The liver is the most important target tissue for this hormone; in the liver, specific receptors recognize portal venous glucagon and promote a

medwedi.ru

1010

Part Seven: The Endocrine System

Table 3 Glucagon Effects Enhances Glycogenolysis Lipolysis Gluconeogenesis cAMP

Inhibits Glycogen synthesis Lipogenesis

Abbreviation: cAMP; cyclic adenosine monophosphate.

rise in intracellular cAMP level. Glycogenolysis follows by enzyme activation by means of protein kinases. On a molar basis, glucagon is 20 to 30 times more potent than epinephrine in stimulating glycogenolysis. Gluconeogenesis is enhanced, whereas lipolysis in both the liver and the periphery is stimulated by this hormone. Glucagon is not as pervasive in its cell membrane effects as insulin. There are, for example, no important ion movements associated with glucagon, and it does not stimulate cell division. In addition to its metabolic effects, however, glucagon is a powerful suppressor of pancreatic exocrine activity and a powerful smooth muscle antagonist in the gastrointestinal tract (Table 3). This property is used mostly in endoscopy and radiology, to temporarily paralyze the gut.

Somatostatin and PP Somatostatin is released by islet D cells that lie in juxtaposition to, and often between, A and B cells. It was first recognized in the brain as a suppressor of growth hormone release. Somatostatin modulates insulin and glucagon release by inhibiting both. Its regulatory action in the islets may be more paracrine than endocrine. One pathway to the inhibition of insulin release may be by means of somatostatin. The release of somatostatin is prompted by glucose, arginine, leucine, and glucagon (30). PP is a hormone with a single peptide chain weighing 4.240 kDa and is secreted by the F cells of the islets. PP bears sequence homology to glucagon and secretin. Its potency to promote hepatic glycogenolysis rivals that of glucagon. It also causes gallbladder relaxation, decreases intestinal motility, and suppresses gastric acid secretion. This intriguing peptide, described first in 1968 (31), does not have a clear place in metabolic regulation and gastrointestinal physiology. Assignment of importance or consignment to obscurity must await further investigation.

ISLETS IN HEALTH AND DISEASE As reviewed in the previous section, the islets of Langerhans regulate metabolism with the object of maintaining plasma glucose level. The principal site for insulin and glucagon to accomplish this mission is the liver. At rest between meals, insulin and glucagon have a balanced, almost harmonic effect. After meals, the hormonal balance shifts according to the chemical nature of the meal to distribute the calorigenic nutrients for efficient use and storage. In prolonged fasting, glucagon is more important to support glucose synthesis from protein by gluconeogenesis and by hydrolysis of glycogen. Glucagon also permits use of the lipid stores. The glucose requirement in fasting is modest, and its provision generates little detriment to body protein. In times of severe stress or injury, glucagon is again important to provide the extra glucose synthesis needed for caloric consumption from protein by gluconeogenesis and by hydrolysis of glycogen. Therefore, the islet cell mass

responds to disease states and metabolic derangements by ensuring a hormonal balance through insulin or glucagon release, which promotes the generation of endogenous fuel substrates. The disease states of the endocrine pancreas are small in number, although they are significant in terms of medical consequence. There are states of deficiency and neoplasia. The only spontaneous deficiency involves the B cells. No natural deficiency diseases are recognized for glucagon, somatostatin, or PP. However, each cell of the islet may become neoplastic as a benign or malignant tumor, secreting isotopic (entopic) hormone, ectopic hormone, or no hormone.

Diabetes Mellitus The B cells may be nearly eliminated, as occurs in type I insulinopenic diabetes mellitus, or may be functionally inadequate, as occurs in type II diabetes mellitus. In the latter condition, plasma insulin level may be normal or high, but insulin insensitivity in target tissues hampers glucose clearance, and hyperglycemia develops. Type I or insulinopenic diabetes mellitus results from the loss of B cells in childhood or early adult life. There is a strong familial tendency in the autosomal recessive mode with variable penetrance. Approximately 25% of patients with diabetes have one or more first-order relatives with the disease. Children whose fathers have diabetes have a 6.1% likelihood of acquiring the disease; offspring of mothers with diabetes have a diabetic incidence of only 1.3%. This disparity is not explained (32). A close association with the antigens HLA-DR3 and HLA-DR4 has been noted. In families at risk for diabetes, the clinical disease is heralded for as long as a year by circulating autoantibodies to islet cells (33), which are frequent in 65% to 85% of patients with diabetes. Although the detection of anti-islet antibodies is useful for disease prediction, the consensus among investigators is that beta-cell destruction is mediated by T-cells, and not by autoantibodies. Islet-specific T-cell clones have been isolated from the spleen, lymph node, and islets of Langerhans of nonobese diabetic (NOD) mice, and such isletspecific T-cells are capable of inducing diabetes after adoptive transfer into young NOD mice. Evidence of disease ‘‘transfer’’ in human patients is also available with the recurrence of islet beta-cell destruction in pancreas transplanted from a nondiabetic identical twin into a twin with long-term diabetes. The development of frank diabetes is also prefaced by a progressive decline in the first phase of insulin release. In a bold experiment, children with recently diagnosed diabetes were immunosuppressed with cyclosporine. After one year, a startling one-half of those children were in remission and required no insulin (34). These newer data conflict with the previous picture of diabetes developing as an acute illness, with perhaps a viral cause. There are, in fact, viruses that selectively destroy B cells in animals, and there are numerous B cell–specific toxins. Patients with familial diabetes may not accurately represent the larger number (50–75%) of spontaneous diabetes cases. The final common pathway to the disease is loss of B cells, and a variety of approaches to this path can be imagined. However, among the diabetes-prone families, the recognition of prediabetes as an autoimmune event offers the prospect of immune suppression to delay or eliminate the emergence of overt diabetes. In some patients newly diagnosed with type 1A diabetes, initial insulin therapy may be accompanied by a brief metabolic remission,

Chapter 53: Endocrine Pancreas

termed the ‘‘honeymoon phase.’’ During this time, low doses of insulin are sufficient to achieve glycemic control. This brief metabolic remission usually lasts for less than one year, and it probably reflects decreased insulin resistance after treatment of severe hyperglycemia. With the discovery of two spontaneous animal models of type 1A diabetes, the NOD mouse and the biobreeding (BB) rat, studies of animal T-cells have contributed to our understanding of the immunopathogenesis of this disease. The development of diabetes in the transplanted pancreas was remarkable in that diabetes recurred within a matter of weeks after organ transplantation. This finding suggests that the immune process that leads to type 1A diabetes remains intact for years after the development of diabetes. In contrast, the development of diabetes usually occurs over years. In human patients, not only is there progressive loss of insulin secretion after intravenous glucose before the diagnosis of diabetes, but also, after the diagnosis of diabetes, C-peptide secretion is progressively lost. Although insulin deficiency results in diabetes mellitus, several mutant insulins have been characterized. Both [LeuB25] and [SerB24] insulin have been found in patients with diabetes; the latter results in a milder form of the disease (35). Another important process in the development of type 1 diabetes is the balance between B cell mass destruction through different temporal courses in different patients. In vitro and in vivo data prove that B cells are able to repair themselves after damage. Islets from nonobese diabetic mice, isolated in the prediabetic period, can restore a normal insulin-release pattern in tissue culture. Glucose, nicotinamide, and branched-chain amino acids can enhance B cell ability to repair damage after toxic assault. Better understanding of this process and possible intervention in this delicate mechanism of B cell repair could change the development of type 1 diabetes (36). Insulinopenic type I diabetes, also called juvenile-onset diabetes, accounts for about 10% of the 200,000 new cases of diabetes diagnosed in the United States each year. Before the use of insulin, this acute illness was usually fatal, and the gene pool for diabetic propensity remained small. In the last 60 years, however, the gene pool has enlarged considerably as patients treated for diabetes have more consistently achieved reproductive maturity. What had been a devastating acute illness has now become an important chronic illness. When all patients with diabetes are grouped together, they represent 1% to 5% of the U.S. population. Diabetes is the leading cause of blindness in young Americans, and it is the most frequently reported diagnosis for patients beginning long-term dialysis for renal failure. The clinical ramifications of this disease are so extensive that it is appropriate to consider the condition as a syndrome rather than a single disease. The most obvious effect of diabetes is hyperglycemia, which reflects the reduced capacity of glucose to enter cells that rely on insulin–receptor occupation for facilitated glucose diffusion. Renal tubular capacity to reabsorb glucose is exceeded at 180 to 200 mg/dL (10 mmol/L), and glycosuria follows. Glucose is osmotically important and causes osmotic diuresis. Hemoconcentration and dehydration follow because of the diuresis. Hyperosmolar effects are significant when the plasma glucose level exceeds 540 mg/dL, where the 30 mmol/L glucose contributes 30 mOsm/L to the plasma osmolarity. Hyperosmolarity leads to coma, and the volume loss caused by osmotic diuresis leads to vascular collapse. Without treatment, hyperglycemia is fatal (Fig. 7).

1011

Figure 7 Effects of hyperglycemia.

The metabolic response to reduced glucose movement into cells is prompt, damaging, and potentially fatal (Fig. 8). Intracellular metabolic compartments perceive the massaction message of insufficient glucose. Therefore, protein catabolism is accelerated to support gluconeogenesis. Nitrogen loss is massive and is accompanied by substantial loss of potassium. The extra glucose leads to further increases in plasma glucose level. It is important to realize that the potentially fatal glucose level in the plasma of patients with uncontrolled diabetes does not represent ingested carbohydrate that arrives in the circulation directly from the jejunum. Rather, the source of the enormous glucose compartment in the plasma is endogenous, either glycogen or gluconeogenesis. The decrease in intracellular energy substrate also prompts lipolysis. The liberated glycerol participates in gluconeogenesis. Free fatty acids go to the liver, where b-oxidation in the mitochondria is associated with the release of acetoacetate and beta-hydroxybutyrate (ketogenic events). The generation of ketones involves acidic reactions sufficient to produce metabolic acidosis. There are no renal mechanisms to reabsorb these short carbon chains; therefore, ketonuria develops. Also, the ketones are volatile and may escape in expired air, lending a fruity odor to the breath. The released ketones are available for metabolism and energy generation. b-Oxidation is the only event in the diabetic adaptation, which helps to increase the generation of highenergy phosphate bonds. The respiratory response to the metabolic acidosis is hyperventilation in the form of air hunger called Kussmaul–Kien respiration. The clinical picture of diabetic ketoacidosis is now complete, with hyperglycemia, dehydration, ketoacidosis, ketonuria, polyuria, and Kussmaul– Kien respiration. If this metabolic nightmare is not corrected by insulin, coma, vascular collapse, and death follow.

Figure 8 When insulin levels are low, insulin mediation of glucose uptake in responsive tissues is greatly reduced, leading to a deficiency of intracellular glucose. The response to diminished intracellular carbohydrate is to increase the export of glucose from the liver by gluconeogenesis or glycogenolysis. In response to meager intracellular energy, substrate lipolysis is encouraged, with export of ketone bodies, acetoacetate, and b-hydroxybutyrate from the liver. Pathologically elevated plasma glucose level, abundant plasma ketones with ketonuria, and the metabolic acidosis that attends ketogenesis is defined as hyperglycemic ketoacidosis.

medwedi.ru

1012

Part Seven: The Endocrine System

Type II noninsulin-dependent diabetes mellitus is also called adult-onset diabetes mellitus or nonketogenic diabetes. This disease is quite distinct from type I diabetes and shares only the common feature of derangement of carbohydrate metabolism tending toward hyperglycemia. The consequences of the hyperglycemia in terms of vascular complications are quite similar in the two diseases. Whereas type I diabetes is marked by profound insulinopenia, type II diabetes is a condition in which the circulating insulin levels may be normal, or even greater than normal. The impact of circulating insulin in regulating total body carbohydrate metabolism is greatly diminished, however, and hyperglycemia develops. The presence of amyloid deposits, one of the common pathologic features of the islets of patients with type II diabetes, was originally described in 1901 (37). The major component of this amyloid tissue is a protein termed islet amyloid polypeptide, which represents a new B cell secretory product whose activities are unknown. The production of the islet amyloid polypeptide is not necessarily the cause of the type II diabetes, but it may be the consequence of a derailed behavior of B cells. Studies seeking a deeper knowledge of this protein are underway (38). The sensitivity of peripheral tissue receptors for insulin seems greatly diminished in patients with type II diabetes, and there has been considerable confusion regarding whether this disease arises because of any real pathology of the B cells of the islets of Langerhans or whether it indeed represents a receptor problem at the periphery. Although defects in the insulin receptor may cause insulin resistance, the primary cause of insulin resistance in patients with type II diabetes is believed to be in one of the fastreceptor sites, such as the glucose transport system, which is characterized by decreased activity and decreased number of transporters in cases of insulin resistance. Recent studies have shown that an abnormal regulation and expression of a specific glucose transporter isoform, GLUT4, which mediates insulin-stimulated glucose transport in adipose and muscle cells, is responsible for insulin resistance in adipose tissue and possibly muscle tissue as well (39,40). Because insulin secretion and reception are so tightly linked, it is difficult to divorce the two events to obtain a better, if arbitrary, distinction between type I and type II diabetes. Type II diabetes, though, does occur in older patients, with a striking propensity for obese patients. The hyperglycemia and hyperinsulinemia can be resolved in many obese patients simply by lowering the fat stores through a reducing diet. There is a familial tendency in adult-onset diabetes, but it more closely parallels the familial incidence of obesity. Control of hyperglycemia may require supplemental insulin in patients with type II diabetes mellitus, but the use of insulin still should not cause confusion between this illness and the type I variant. In type II diabetes, the insulin is not required to sustain life but merely to better regulate plasma glucose level. Therefore, the term noninsulin-dependent diabetes mellitus is still applicable to type II diabetes. The principal feature of type II diabetes that causes clinical trouble is hyperglycemia. This can be associated with a striking and life-threatening syndrome of hyperosmolar coma when the blood sugar level exceeds 800 mg/dL. The increase in blood glucose level is osmotically quite important and can literally draw water out of the brain cells, resulting in a comatose state. However, ketosis is not associated with this drastic derangement in carbohydrate metabolism in which glucose clearance is so inadequate as to potentially lead to hyperosmolar death.

This lack of ketosis is not completely understood. The dehydration that is associated with the polyuria of hyperosmolar coma has been implicated. It is more likely that the hyperglycemic crisis in type II diabetes is unique because insulin is indeed present in substantial quantities, unlike the situation in the hyperglycemic crisis of type I diabetes. The impact of insulin in diminishing lipolysis is preserved in larger measure in type II diabetes. The adipocytes are 20 to 30 times more sensitive to the antilipolytic effects of insulin than to the facilitated entry of glucose under the influence of insulin. It is therefore likely that, although a hyperglycemic crisis has followed because of poor insulin effect in type II diabetes, lipolysis and thus ketogenesis cannot occur. The treatment of nonketotic, hyperosmolar coma in type II diabetes is directed toward fluid resuscitation and providing sufficient insulin to clear the extracellular compartment of the extraordinary concentrations of free glucose.

Complications of Diabetes Diabetes is a truly devastating disease in terms of curtailment of longevity and quality of life, as a consequence of its complications, and not as a consequence of its more dramatic metabolic manifestations such as ketoacidosis or nonketotic hyperosmolar coma. It is the leading cause of blindness in young Americans and may soon become the most common diagnosis in patients subject to long-term dialysis programs for end-stage renal disease. Although diabetes affects less than 10% of the population of the United States, it is the eighth leading cause of death. About half of patients with diabetes die of coronary disease, whereas most patients with juvenile-onset diabetes die of ramifications of renal failure. The complications are not inherently different in type I and type II diabetes and may be considered to be neural, vascular, or infectious. These three categories are interrelated but probably independent in their genesis. Nonetheless, they are all related to abnormal glucose metabolism. Neuropathy is manifested by autonomic motor and sensory problems. The autonomic problems include gastroparesis, impotence, orthostatic hypotension, and diarrhea. Sensory deficits include position sense and pinprick sensation. Radiculopathy is seen, and the pain can be disabling. The sensory deficit problems contribute to lower extremity injury, which does not heal because of poor blood supply. Such extremities tend to become infected because of poor response to bacteria, with consequent limb loss. The cause of the neuropathy is not well understood and tends to parallel the vascular complications in the course of the natural history of diabetes. However, recent work implicates abnormal metabolism of sugar alcohols through the enzyme aldose reductase. This activity of this enzyme is the rate-limiting step in the pathway to sugar alcohols, and that pathway is confined to Schwann cells, spinal roots, and the lens epithelium. The enzyme is probably not abnormal in patients with diabetes, but massaction events in hyperglycemia and intracellular glucoprevia activate this otherwise exotic pathway. The nature of the toxicity of sugar alcohols in these tissues has not been elucidated, but inhibition of aldose reductase has been clinically useful in improving autonomic function and in relieving the pain that can be a manifestation of sensory neuropathy (41). The vascular lesions of diabetes are numerous and perhaps distinct in development. There is an acceleration of atherosclerosis in patients with diabetes along lines that

Chapter 53: Endocrine Pancreas

are indistinguishable from the peripheral vascular lesions seen in patients without carbohydrate intolerance. These lesions are associated with the hyperlipemia that accompanies diabetic metabolism. However, disease of small vessels develops along lines that are distinctive to diabetes (42). Capillary basement membranes thicken through the course of diabetes. Although this thickening may be something of an exaggeration of normal aging, its implications for the patient with diabetes are important. If the capillary basal lamina is considered to be the framework for wound healing and the gate that must be passed in the diapedesis of inflammatory cells, the stiff, thickened layer may be seen as a significant part of other diabetic problems. The glycopeptides of basal lamina have not been exclusively studied in diabetes, but the opportunity for abnormal glycosylation is certainly great in hyperglycemia and has been observed in patients with this disease. The covalent addition of glucose molecules to protein normally requires a glycosyl transferase. However, enzymatic glycosylation, like all enzymatically catalyzed reactions, favors through catalysis a reaction that would normally occur without the enzyme, although at a much slower rate. In the presence of persistently high ambient glucose concentrations, glucose molecules apparently can be added to the amino acid backbone of many peptides to create new and potentially pathologic glycopeptides. The glycosylated hemoglobin, hemoglobin A-1-c (HbA1c), is easily measured, and the concentration of this substance in the blood of a patient with diabetes has a direct correlation with the degree of ambient hyperglycemia in recent weeks (43). Therefore, a high HbA1c level means that control of hyperglycemia has been poor not just on the day of blood sampling but in preceding weeks as well. Although HbA1c has not by itself been associated with any malfunction of hemoglobin, the potential importance of glycosylation of other peptides in the evolution of diabetic pathology has been suggested. This glycosylated product can be measured readily and reflects the degree of hyperglycemia and thus the degree of diabetic control in recent weeks. The ultimate significance of glycosylation in diabetic pathology remains to be determined. Angiopathy in the retina takes the form of microaneurysms of capillaries. These lesions can rupture, with escape of blood and opacification of the eye. Great progress has been made in controlling these lesions by photocoagulating aneurysms with lasers to thrombose them before they burst. Cataract formation is also prevalent in patients with diabetes as a consequence of either derangement of carbohydrate metabolism or accelerated aging. The renal vasculopathy seen in diabetics was first described by Kimmelstiel and Wilson in 1936. Accumulation of basement membrane material in the mesangium of the glomerulus may be either nodular or diffuse. This glomerulosclerosis leads to proteinuria and eventually to azotemia. All patients with insulin-dependent diabetes who have survived 20 years or longer manifest the microscopic lesion, and half of the patients have significant renal impairment. The kidney may also be affected by hypertension, atherosclerosis, and infection in patients with diabetes. End-stage renal disease in patients with diabetes is treated with dialysis and renal transplantation.

Diagnosis and Treatment of Diabetes The diagnosis of diabetes is precise and easily accomplished. Patients with polyuria, polydipsia, and weight loss, and especially those with visual disturbances or frequent

1013

pyogenic infections, should be evaluated for hyperglycemia. A fasting blood sugar level 140 mg/dL on more than one occasion defines carbohydrate intolerance and mandates its evaluation by oral glucose-tolerance testing. After an overnight fast by a patient who has previously had unrestricted calories and unrestricted exercise, 75 g glucose is given by mouth, and the blood glucose level is measured periodically for the next two hours. A value of 200 mg/dL or greater at two hours and at one previous time point defines diabetes mellitus. The test is invalidated by stress from infection, surgery, or trauma; prolonged fasting, prolonged physical inactivity, and glucocorticoid or thiazide administration. Therefore, testing of hospitalized patients as a group is inappropriate. Furthermore, the benefit of diagnosing mild diabetes mellitus in truly symptom-free patients is meager in that no treatment is indicated. Oral glucose-tolerance testing is therefore not a routine screening test (44). The goal of diabetes management is to keep blood glucose levels as close to the normal range as safely possible. A major study, the Diabetes Control and Complications Trial (DCCT), sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, showed that keeping blood glucose levels as close to normal as safely possible reduces the risk of developing major complications of type 1 diabetes. The 10-year study, completed in 1993, included 1441 people with type 1 diabetes. The study compared the effect of two treatment approaches—intensive management and standard management—on the development and progression of eye, kidney, and nerve complications of diabetes. Intensive treatment aimed at keeping HbA1c as close to normal (6%) as possible. HbA1c reflects average blood sugar over a two- to three-month period. Researchers found that study participants who maintained lower levels of blood glucose through intensive management had significantly lower rates of these complications. More recently, a followup study of DCCT participants showed that the ability of intensive control to lower the complications of diabetes persists up to four years after the trial ended. The treatment of type II adult-onset diabetes mellitus in many, if not most, cases involves caloric restriction and weight loss to restore carbohydrate tolerance. If insulin is required, the goals and considerations for treatment become the same as for type I diabetes. The use of oral hypoglycemic agents (e.g., tolbutamide) has been less important recently, because the benefit to patients in the long term has been difficult to document and there has been more than a suggestion that vascular complications are made worse (45). Perhaps oral agents were misused by patients as an apparently simple alternative to the rigors of dieting. Therefore, patients receiving oral agents may have represented a rather noncompliant population. At any rate, when dietary measures fail to control type II diabetes, the use of insulin to manage hyperglycemia is becoming more commonplace. The goals of diabetic management are to keep blood glucose levels normal, to recognize and treat complications promptly, and to enhance the lifestyle of patients having this disease. A significant advance has been realized in recent years by improved monitoring of plasma glucose levels. Traditionally, patients with diabetes estimated blood glucose control by monitoring the presence of glucose in the urine with test strips impregnated with glucose oxidase or tubules that tested for glucose as a reducing substance. When the plasma glucose level exceeded the maximum

medwedi.ru

1014

Part Seven: The Endocrine System

for renal tubular reabsorption (180 mg/dL or 10 mmol/L), glucose spill in the urine occurred. The greater the plasma glucose level, the greater was the renal loss. Therefore, the more intense the glucose reaction in urine, the greater was the need for insulin administration. Despite the usefulness of glycosuria monitoring to determine insulin needs in most patients with diabetes, it must be emphasized that its correlation with the status of glucose intolerance is generally unreliable in renal disease, pregnancy, and unstable or brittle diabetes. Although measurement of urinary glucose is preferred in monitoring patients who do not require insulin, blood glucose measurement at home is becoming the recommended parameter for insulin administration. Capillary blood obtained by finger stick is made to react with glucose oxidase on paper strips and is read by a color chart or in a reflectance meter. Plasma glucose level is usually about 15% higher than these whole-blood measurements. Home blood glucose monitoring offers precise monitoring for extremely close glucose control. Another tactic to quantitate the precision of glucose control is the measurement of HbA1c. As previously indicated, this glycosylated hemoglobulin is generated by nonenzymatic means, has a relatively long half-life, and is directly proportional to the average ambient glucose level. Chromatographic analysis of HbA1c reflects the accumulation of the glycoprotein in recent weeks above the customary 4% of total hemoglobin. The accumulation of HbA1c is an excellent parameter of glucose control through time. The use of home glucose monitoring and precise review of management by measuring HbA1c are only appropriate in highly trained patients with diabetes. The training of patients with diabetes to become actively involved in the management of their disease has been greatly promoted and advanced by the American Diabetes Association. From a very early age, the patient is an active participant in therapy, recognition of complications, general health maintenance, and formulating life goals. There are instructional peer group camps for children, instructional programs for all ages, mutual support groups, and active encouragement for patients to understand and question the scientific progress being made in the area of diabetes. Dietary measures to limit disposable glucose have recently been greatly liberalized to permit the patient with diabetes more freedom. The effect has been to generally improve adherence by better-trained patients to a more acceptable dietary regimen. Carbohydrates constitute 45% to 60% of daily calories, fat provides 30% to 35%, and protein yields 12% to 20%. Total calories are carefully prescribed on the basis of physical activity. Appropriate insulin therapy necessitates a familiarity with the various forms available. Insulin is purified from beef or pork pancreas and exists in several modifications. When given subcutaneously, regular, crystalline insulin has its onset of action at 30 to 60 minutes, peaks at three to six hours, and has a duration of action of 6 to 10 hours. Neutral protamine Hagedorn (NPH) insulin is complexed for slower absorption and has its onset of action at 1.5 to 3 hours, peaks at 6 to 12 hours, and has a duration of action of 18 to 24 hours. Other forms are available for special purposes, but regular and NPH insulin form the basis for most diabetic management. Some patients acquire allergies to the protein sequence of animal insulin. Porcine insulin differs by only one amino acid from human insulin, but standard preparations are contaminated with proinsulin, which is antigenically quite distinct in the C-peptide region. Porcine insulin can be more

highly purified for allergic patients. Recombinant DNA technology now offers human insulin for therapy in patients with significant allergy to animal insulins. Maintenance insulin is administered to keep the plasma glucose level below 150 mg/dL and above 80 mg/dL. Insulin is usually administered subcutaneously as a single morning dose, with a supplemental evening dose, as needed. The dosage in type I diabetes varies from 15 to 90 NPH U/day. For the patient without a pancreas, who lacks the countervailing effects of glucagon, 15 to 20 U/day is generally sufficient. The management of ketoacidosis is a special case for insulin administration. The acidosis diminishes tissue sensitivity to insulin. Therefore, extremely large amounts of insulin are required. The objectives in treating ketoacidosis are rehydration, restoration of normal plasma pH, reduction in plasma glucose level, and replacement of glycolytic pathways with ketogenic pathways by moving glucose into cells. Rehydration is commenced with normal saline solution at 1 L/hr until the heart rate, blood pressure, and urinary output suggest an improvement in the volume status. In adults, 2 to 3 L is commonly needed. Hypotonic saline solution (0.45%) is given at a rate of 1 L every two to four hours to resuscitate and reduce the hyperosmolarity that follows the osmotic diuresis and high glucose levels. When plasma glucose level falls to 300 mg/dL, glucose should be added to the intravenous infusion. If the arterial pH is less than 7.1, buffering with intravenous bicarbonate is indicated. As the plasma glucose moves into cells under the influence of insulin, potassium is shifted also. Therefore, vigorous potassium replacement is necessary. The regimen for insulin administration in ketoacidosis is disputed among clinicians. Basically, the glucose level must be lowered in a patient with rapidly changing insulin sensitivity, but without inducing an overshoot and potentially fatal hypoglycemia. A safe approach calls for 20 U of regular insulin administered intravenously, followed by an insulin drip (100 U in 500 mL of 0.45% saline solution) at 50 to 75 mL/hr. The blood glucose level must be measured every 30 to 60 minutes until the insulin infusion rate stabilizes. The fatal components of ketoacidosis are dehydration and acidosis. There is no need to cause the glucose level to plummet in a short time. In fact, rapid reduction can lead to fluid shifts, resulting in cerebral edema or fatal hypoglycemia. Insulin administration in the patient with diabetes who is undergoing surgery varies, depending on the complexity of the operation and the time it takes to perform. If the procedure is minor and the operation is performed early in the morning, the insulin dose is delayed until the procedure is completed. For major procedures involving a general anesthetic, a highly workable regimen calls for half the usual morning dose to be given subcutaneously as NPH, continuous 5% dextrose intravenous infusion, and monitoring of the plasma glucose every six hours. Insulin is given to keep the glucose level between 150 and 250 mg/dL. After surgery, insulin dosages according to urinary glucose are not as precise as the dosages administered according to the plasma glucose level. Continuous insulin infusion along with 5% dextrose infusion is appropriate in monitored environments and may replace intermittent insulin administration just before and after the operation. Surgical patients undergoing prolonged operations or undue stress may require 25% or 50% more insulin than usual. To attain a constancy of plasma glucose level, which is impossible with bolus injection, continuous subcutaneous insulin infusion was recently developed. A programmable pump delivers short-acting regular insulin by means of a subcutaneous cannula. The baseline delivery rate can be

Chapter 53: Endocrine Pancreas

increased to cover for the increased carbohydrate absorption after meals. Continuous subcutaneous insulin infusion and home glucose monitoring offer the greatest precision in control of ambient glucose. The precision can be documented by tracking HbA1c levels. However, the impact of this precision on preventing or slowing the development of diabetic complications has not been particularly gratifying (46). An unstated belief has long prevailed in the management of diabetes that the complications associated with this disease are the consequence of inferior compliance by the patient and therefore of inadequate control of blood glucose level. By implication, perfect control of glucose levels with supplemental insulin should eliminate complications. Although there is some basis for this belief, it cannot be absolutely true. Vascular and retinal complications progress even in patients treated with infusion pumps. To explain the syndrome of diabetes mellitus, there is no reason to propose that the loss of B cells leads to a deficiency of any hormone other than insulin. However, the exquisite balance between insulin and glucagon metabolism that occurs in the patient without diabetes has not been achieved by exogenous insulin delivery. Plasma glucose level is merely a crude approximation of the profound coordination that exists between insulin and glucagon release and its effects on the body’s metabolic compartments and the movement of substrate through those compartments. Until the interaction of A and B cells is more completely understood and mechanically reproducible, transplantation of islets of Langerhans may offer an option for normal glucose homeostasis in patients with diabetes. In rodent models of diabetes caused by streptozocin, syngeneic islets purified from the pancreas of a healthy animal can be transplanted into the liver through the portal vein. Treated animals are permanently replenished and normoglycemic (47,48). Apparently, loss of innervation, acinar relationships, and the introduction of heterotopic relationships do not affect the capacity of the transplanted islets to serve the endocrine needs of affected animals. However, the animals with transplants have a distinct advantage with respect to diabetic rats treated with exogenous insulin. Rats with streptozocin-induced diabetes maintained on a regimen of insulin eventually show retinal and renal changes that resemble those seen in humans. Transplantation of islets of Langerhans can arrest and even reverse these changes (49,50). Therefore, the prospect looms for controlling the diabetic syndrome in its entirety, rather than controlling only the gross excursions of plasma glucose level. The rodent experience with transplantation has been extended to autografts in dogs, but not yet successfully to humans. Pancreatic islet transplantation is a relatively innovative approach for the treatment of diabetes. This offers the promise of cure in type 1 diabetes mellitus by a simple injection of cellular graft into the liver, with consequent freedom from administration of exogenous insulin, glucose monitoring, and dietary restriction. Furthermore, this approach may prevent, stabilize, or even reverse secondary diabetic complications if applied sufficiently early in the course of the disease (51,52). There has been increased research activity in the field of pancreatic islet transplantation during the last decade (1990–2000). Major experimental findings have been promptly applied to the clinical setting, reporting sporadic successes and relevant information. During the last decade, a drastic increase in clinical islet transplantation cases was observed, with 35 centers worldwide performing 267 allotransplants.

1015

Prevention of surgically induced diabetes in patients undergoing total or partial pancreatectomy, performing an autoinfusion of islets (first reported in 1972 by Najarian and colleagues) demonstrated the feasibility of the procedure in replacing the endocrine function of the pancreas and controlling the glucose homeostasis. Whereas the autotransplants performed achieved an elevated rate of success (53), the treatment of autoimmune diabetes with pancreatic islet transplantation has been unsatisfactory and inconsistent up to 1999 (54,55). Major limitations and the possible interconnection of multiple factors seem to yield this poor result. Reduced mass of islets engrafting, high metabolic demand, immunological graft loss, and diabetogenicity of the immunosuppressive drugs are the crucial aforementioned variables involved and have been responsible for the final outcome. On comparing the data from auto- and allotransplantation cases, it is clear that the immunological component plays the major role in the failure of establishment and maintenance of insulin independence (53,55). Based on a retrospective analysis, we can extrapolate that in an alloenvironment, a certain critical mass of more than 10,000 fresh islets/kg must be infused into the recipient to potentially achieve normoglycemia. Presumably, the transplanted mass per se is not responsible for graft failure but rather the environmental factors that involve any single injected islet, from the inflammatory response to the systemic insulin resistance of long-term diabetic patient and the specifically toxic effect of the immunosuppression, determine the requirement of a larger amount of cells. The toxic effects of cyclosporine, tacrolimus, and steroids, the regimen followed up to 1999 to protect grafts from rejecting, have been extensively demonstrated in experimental and clinical settings (56–60). Moreover, a dose-related toxicity has been observed in experimental and clinical solid organ and cell transplantation (61–64). The simultaneous transplantation of pancreatic islets and either kidney or liver performed in humans (majority of the total number of allo-islet transplants performed between 1990 and 2000) has always implied a consistently elevated level of immunosuppression to insure the solid organ engraftment and protection. While strategies of minimally toxic nonspecific immunosuppression have been proposed, new specific modulations of the immune system without a diabetogenic effect have been conducted in animal models leading to innovative approaches now available for clinical investigation. Because of the aforementioned limitations, up to 1999, the promise of islet transplant as a cure for diabetes has been difficult to sustain in worldwide trials, and of the 267 allografts performed over the most recent decade, only 12.4% achieved insulin independence for longer than one week, and only 8.2% beyond one year (65). Improvements in the separation of viable insulin-producing and -secreting cells have permitted renewed attempts at islet cell replacement (66,67). The exponential increase in availability of new and more potent immunosuppressive agents within the past five years offered potential for development of specifically tailored strategies to meet the unique needs of islet transplantation, providing greater immunological protection without diabetogenic side effects (68,69). Several factors seem to limit insulin independence after islet transplantation (55): (i) an inadequate B cell reserve due to a limited islet engraftment mass and immediate cellular loss through apoptotic and other nonimmune inflammatory pathways (70–72), (ii) immunological graft loss through both alloimmune and autoimmune pathways as a result of ineffective immunosuppression (73), and exacerbated by the lack of available

medwedi.ru

1016

Part Seven: The Endocrine System

tools for early diagnosis of rejection (68,69,74), and (iii) a high islet metabolic demand from preexisting insulin resistance and further compounded by the use of highly diabetogenic immunosuppressive drugs including synergistic toxicity from calcineurin inhibitors and steroids in combination (59,68,69,75). Recent data from the Edmonton Group have shown 100% success in achievement of sustained insulin independence in 12 consecutive, brittle type 1 diabetic patients receiving solitary islet grafts in conjunction with a novel steroid-free immunosuppressive regimen (76,77). This study has clearly demonstrated that by optimizing all aspects of islet preparation, transplantation, immunosuppression, and posttransplant care, solitary islet transplantation offers minimal risk and now provides good metabolic control with normalization of HbA1c and sustained freedom from exogenous insulin. The immunosuppressive strategy utilized induction with the humanized anti-IL2 receptor monoclonal antibody daclizumab, and a combination of sirolimus and low-dose tacrolimus. This is the first trial where consecutive diabetic patients are cured from diabetes using a pancreatic islet infusion. Furthermore, these results are providing, following sporadic cases reported by various investigators (54), the consistent result of the autotransplant cases that transplanted pancreatic islets could effectively replace the missing endocrine function. Islet recipients represent the most attractive patient source for subsequent trials, because the consequences of graft failure will result in the patient’s return to insulin injections, rather than the loss of a life-sustaining solid organ graft. Immunomodulatory procedures could be investigated in islet recipient patients because (i) the procedural risk of islet transplantation is minimal, (ii) graft failure is not life threatening, (iii) conventional immunosuppressive drugs are diabetogenic, and, most importantly, (iv) tolerogenic protocols have shown promise in preclinical NOD and nonhuman primate islet transplant models. Moreover, unique options exist for tolerance induction in islet transplantation, because isolated islets can be pretreated in culture, transplanted to immunoprivileged sites, and potentially transplanted after a delay to permit recipient pretreatment and conditioning with donor antigen. Unparalleled progress made over the past few years in the conceptual understanding of the mechanisms operative in the induction of allotolerance and restoration of self-tolerance has led to the development of unique and selective immunomodulatory strategies. Prime examples of progress made include: (i) the demonstration of long-term islet allograft survival in nonhuman primates receiving anti-CD40L antibody monotherapy (78), (ii) the induction of robust tolerance to murine islet allografts by alloantigen pretreatment under the cover of short-term anti-CD40L therapy (79), and (iii) the restoration of self-tolerance to B cell autoantigens in overtly diabetic NOD mice by FcR nonbinding anti-CD3 antibodies (80,81). Moreover, blockade of the CD40L/CD40 costimulatory pathway has been shown to prevent inflammatory responses such as cell extravasation, production of inflammatory and chemotactic cytokines, and activation of macrophage effector function (82). Pancreatic transplantation remains the best method available today to successfully substitute the endocrine pancreas and reverse the diabetic condition to a normal glucose metabolism. Pancreatic transplantation was originally reported in 1967 at the University of Minnesota. Since then,

and especially during the past 10 years, more than 15,000 cases have been reported worldwide. Pancreatic transplantation today carries a five-year patient survival greater than 80%, and a graft survival greater than 70%. Recipients of a pancreas graft for diabetes are insulin free, and recent research shows a positive impact of the new pancreas on the secondary complications of type I diabetes, in particular neuropathy and microangiopathy (83,84). Pancreatic transplantation is currently offered to patients with uremic diabetes in need of a renal transplant or who received a kidney graft in the past. In some selected nonuremic patients with diabetes, affected especially by extremely brittle glucose control, frequent hypoglycemia, and severe neuropathy manifesting as hypoglycemia unawareness, pancreatic transplantation remains the only logical therapeutic alternative. New options in the fight to cure diabetes, such as gene therapy, continue to be aggressively pursued and could become available to prevent the disease entirely in the future.

ENDOCRINE TUMORS OF THE PANCREAS The rich endocrine resources found within the pancreas can generate a wide variety of syndromes and clinical conundrums when one or more of the cell lines becomes neoplastic (Table 4). The resulting tumors may secrete hormones not normally released from the endocrine pancreas, in which case the secretions are ectopic. Although endocrine tumors of the pancreas are rare, they have taught us a great deal about the nature of endocrinology in health and disease. For example, hypergastrinemia, first described by Zollinger and Ellison in 1955 (85), has, despite its rarity, greatly advanced our understanding of acid-peptic ulceration of the stomach. Proinsulin was first discovered in secretions of an insulinoma and introduced the concept of largemolecular-weight gene products that are subsequently tailored before secretion (4). Our understanding of the nature of endocrine tumors has been greatly advanced by the APUD concept of Pearse and Polak (86). The capacity to diagnose these tumors has been profoundly enhanced by the availability of radioimmunoassays for the measurement of the endocrine products. Localization of endocrine tumors has been tremendously aided by selective venous catheterization coupled with radioimmunoassay to identify the source of the abnormal concentrations of the hormones found in circulating blood. Localization and logistics for removal of endocrine tumors have been aided considerably by precise arteriography, ultrasonography, and computed tomographic imaging of the pancreas (87). Unfortunately, a significant number of pancreatic endocrine tumors are malignant, with a propensity toward early metastasis. Medical oncology sees islet cell tumors in ways not incompatible with surgeons challenged to ablate or palliate. The reviews in Surgical Clinics of North America (June 2001) provide much details about these challenging tumors (88,89).

Types of Pancreatic Endocrine Tumors Insulinoma Insulinomas, the most common of the pancreatic endocrine tumors, arise from the B cells of the islets. Approximately 80% are solitary and benign; the incidence of malignancy is about 10%. The remainder are either multiple benign adenomas or islet cell hyperplasia causing hyperinsulinism.

Chapter 53: Endocrine Pancreas

1017

Table 4 Pancreatic Endocrine Neoplasia Syndrome/cell of origin

Pathology

B

Adenoma Carcinoma (10%) Hyperplasia

A

Carcinoma (70%) Hyperplasia

D

Carcinoma Adenoma

F ? Zollinger–Ellison

Adenoma Carcinoma (80%) Adenoma Hyperplasia Carcinoma (50%) Adenoma

? Verner–Morrison

Metabolic change Hypoglycemia Glycogenesis Gluconeogenesis Lipolysis Ketogenesis Hyperglycemia Glycogenolysis Lipolysis Ketogenesis Gastrointestinal motor changes Mixed, mild glucose Biliary Pancreatic exocrine ? Hþ secretion

Intestinal secretion Gastric secretion Hypokalemia

Hormone

Symptoms

Insulin Proinsulin

Those of hypoglycemia

Glucagon Enteroglucagon

Dermatitis Ileus Constipation

Somatostatin Insulin Glucagon PP Gastrin

Cholelithiasis Steatorrhea Dyspepsia None Acid-peptic ulceration Diarrhea

VIP

Diarrhea Hypochlorhydria

Abbreviations: PP, pancreatic polypeptide; VIP, vasoactive intestinal peptide.

In infants, hyperinsulinism is usually a result of adenomatous hyperplasia of B cells (nesidioblastosis). Insulinomas are small; about 40% are 1 cm or less in diameter. Tumors are distributed in almost equal numbers throughout the head, body, and tail of the pancreas. Only 1% or fewer of all insulinomas are ectopic, and these are found close to the pancreas in most instances. Multiple endocrine neoplasia type I syndrome occurs in 10% of patients with insulinomas (see Chapter 51). The major signs and symptoms of insulinoma are a result of the effects of hypoglycemia (from the hyperinsulinemia) on the central nervous system. These include apathy, sluggishness, irritability, excitement, changes in behavior, and occasionally convulsions and coma. Hypoglycemia also induces a release of epinephrine, which causes sweating, nervousness, tremor, palpitation, hunger, and pallor. The classic diagnostic criteria (Whipple’s triad) are still valid. Whipple’s triad includes central nervous system symptoms brought on by fasting, a fasting blood glucose level less than 50 mg/dL, and complete reversal of all symptoms by intravenous infusion of glucose. Insulin levels are high relative to the blood glucose concentration. The insulin-to-glucose ratio is normally less than 0.4, but in patients with insulinoma the ratio is often close to 1 or even greater. The measurement of elevated plasma proinsulin levels is also helpful in the diagnosis of insulinoma. Furthermore, malignant tumors can be differentiated from benign islet cell lesions by documenting the greater percentage of proinsulin in the total insulin immunoactivity typically seen in patients with malignant lesions. The traditional diagnostic test for insulinoma is the demonstration of fasting hypoglycemia (less than 50 mg/dL). Fasting is continued for 72 hours, or until hypoglycemic symptoms appear. Hypoglycemia occurs in two-thirds of patients by 24 hours and in 95% by 48 hours. During fasting, insulin levels remain elevated in patients with insulinoma because of the autonomous nature of the insulin secretion. Provocation tests for insulin release (e.g., tolbutamide, glucagon, leucine, and arginine) have been used to make the diagnosis of insulinoma but are thought to be of little

value, because serum insulin levels can be measured directly. The infusion of secretagogues in healthy patients should not result in pathologically low blood glucose levels. However, secretagogues may provoke an insulinoma to release profoundly pathologic amounts of insulin, with consequent hypoglycemia. Selective angiography with subtraction and magnification techniques is the best method of preoperative localization of an insulinoma. The success rate of localizing these tumors approaches 90%. Selective pancreatic vein catheterization and venous sampling for insulin assay have also been used, with considerable success, to diagnose and localize the site of insulinomas. Ultrasonography and computed tomography have been used to localize these lesions, but in comparison with the other diagnostic modalities available, they are of limited usefulness. Localization of the small, usually single, benign insulinoma continues to be an issue. When computed tomography fails to find the lesion, percutaneous transhepatic portal catheterization may give very sensitive clues to the site of the tumor. The most useful information comes from intraoperative ultrasound (90). Endoscopic ultrasound has limited ability to localize and characterize insulinomas (91). Localization of metastatic neuroendocrine tumors, suspected by assayable endocrine activity, can be facilitated by single photon emission computed tomography nuclear imaging with 111 Inpentetreotide, a somatostatin analog (92). Because they are predominantly benign, insulinomas are the only pancreatic endocrine tumors that can frequently be cured by surgery. Depending on location, enucleation or distal pancreatectomy is the treatment of choice. It is rarely necessary to perform a pancreaticoduodenectomy as the initial procedure for a small tumor of the head of the pancreas. Laparoscopic resection of benign insulinoma has been described and almost certainly has merit, although the technical aspects are formidable (93–97). Other endocrine tumors are also amenable to laparoscopic resection, especially if they are small and benign (95,97). Even more aggressive pancreatic resection seems feasible (98). The adjunctive therapeutic agent of choice in patients with

medwedi.ru

1018

Part Seven: The Endocrine System

metastases is streptozocin, with a response rate approaching 50%. In patients in whom persistent hypoglycemia poses a problem after presumably successful removal of insulinoma, and in patients with metastases, diazoxide is frequently effective in suppressing insulin release.

Gastrinoma and Malignant Islet Tumors (Zollinger–Ellison Syndrome) The first of the endocrine tumor syndromes identified in pancreatic islets was reported by Zollinger and Ellison in 1955 (85). The tumors responsible for this syndrome (gastrinomas) not only occur in pancreatic islets but also may be found as isolated lesions within the proximal duodenum or in its vicinity. The cell that gives rise to gastrinoma has not been identified. Gastrin is not a normal product of the islets of Langerhans. The gastrinoma syndrome results from excessive quantities of gastrin released from these tumors and is usually manifested clinically by virulent acid-peptic ulceration of the upper gastrointestinal tract. Such ulceration may be found in the first portion of the duodenum, where other forms of acid-peptic disease commonly occur; not infrequently, however, ulcers may occur in aberrant regions, such as the distal duodenum and jejunum (98). These ulcers are usually single, but they may be multicentric occasionally. Generally, the ulcer precedes identification of the tumor by three to five years; occasionally, the ulcer itself is totally asymptomatic and is discovered accidentally. In approximately 20% of patients, diarrhea with steatorrhea is the only clinical symptom of the syndrome; this presumably occurs because of excessive acid production of the stomach, which inactivates pancreatic enzymes and thereby inhibits fat digestion and absorption by the duodenum and jejunum. Approximately one-third of patients with hypergastrinemia caused by gastrinoma have relatives with endocrinopathies. This condition is commonly suspected because of refractory or recurrent acid-peptic disease. Upper gastrointestinal X-ray films frequently show a suspicious multiplicity of ulcers throughout the duodenum and even the proximal jejunum. Hypertrophic mucosal folds are evident in the stomach as a result of the hypergastrinemia. Before the availability of radioimmunoassays that enable measurement of serum gastrin levels, the clinical diagnosis of gastrinoma was made on the basis of gastric analysis. The high volume of gastric secretion in patients with gastrinoma displayed an acid output that approached the physiologic maximum elicited by histamine derivatives. Currently, the diagnosis is made on the basis of the demonstration of hypergastrinemia under fasting conditions. A serum gastrin level in excess of 200 pg/mL is suggestive of this syndrome. When gastrin levels exceed 100,000 pg/mL, extensive tumoral involvement, including hepatic metastasis, is highly probable. For equivocal fasting gastrin levels, provocative testing with secretin has been useful. A rise of at least 100 pg/mL from a fasting baseline following the administration of an intravenous bolus of 2 U/kg secretin is diagnostic of the disease. Gastrin levels may also be elevated in some patients with hyperplasia of the G cells in the antrum. In this circumstance, however, serum gastrin does not change during secretin provocation (99). Islet tumors of the pancreatic head, which are large and/or malignant, may require pancreaticoduodenectomy for oncologic thoroughness, and long-term survival may follow. However, small benign tumors do not qualify for this radical and complication prone operation. Enucleation can

be curative (100). When islet tumors do not secrete enough hormone to produce an endocrine syndrome, they may grow silently to considerable size even if malignant. Extensive surgical resection is appropriate and may lead to long-term survival (101). When malignant islet tumors metastasize to the liver, patients may have a rather long course of treatment made more difficult because of endocrine issues than oncologic issues. However, a hepatic resection of even concurrent hepatic metastases may significantly prolong life, with prompt and durable oblation of the endocrine syndrome (102). Even hepatic debulking seems to offer benefit in terms of the endocrine syndromes and life extension (103). Hepatic metastases of endocrine tumors are also amenable to radiofrequency ablation when resection is not feasible (104). The most pressing issue in the management of gastrinomas is the acid secretion. When medical management is sought, pantoprazole or other proton pump inhibitors are highly effective as a maintenance therapy (105). The ulcerogenic gastrinoma may be localized in approximately one-third of cases by means of angiography (106). Computed tomography often demonstrates pancreatic tumors if they are larger than 2 cm. Successful localization of pancreatic tumors by computed tomography approaches 32% for primary pancreatic tumors (107). Noninvasive preoperative ultrasonography in the intact patient has not been as successful as desired; however, intraoperative ultrasonography has been successful in identifying lesions otherwise not obvious. Percutaneous transhepatic portal and pancreatic venous sampling for gastrin can also localize the source of systemic hypergastrinemia (108). Hypergastrinemia caused by gastrinoma is ideally treated by complete resection of the gastrinoma. Unfortunately, this is possible in only approximately 20% of cases, because the gastrinomas may be multiple or metastatic at diagnosis. Until recently, total gastrectomy was uniformly accepted as the treatment of choice to control the acid-peptic disease in patients for whom complete tumor excision was not possible. The concept of end-organ ablation by surgical removal has been challenged with the development of H2-receptor antagonist therapy and completely repudiated by the introduction of proton pump inhibitors (109). Parietal cell vagotomy can improve the effectiveness of cimetidine therapy (110), but tumor plus end-organ ablation appears to be the only secure procedure to restore serum gastrin levels to normal. Of interest, an effect of the stomach on enhancing tumor growth has been proposed (111); if the stomach is removed, tumor growth is slowed. Because 80% of gastrinomas are malignant, metastatic disease is not uncommon. Palliation with streptozocin has produced a positive response in about half of the patients with metastatic gastrinoma and other malignant islet tumors so treated. When chemotherapy is invoked for metastatic islet cell tumors, streptozotocin with 5-fluorouracil has been the first-choice drug regimen (112). Somatostain also offers a suppressive effect only on endocrine secretion from islet tumors and also the growth of metastases (113).

Glucagonoma In glucagonoma, a neoplastic condition of the A cells of the islets of Langerhans, the entopic hormone glucagon is released. These tumors are malignant, approximately, twothirds of the time, with early metastases to regional lymph nodes or the liver. Distant metastases are uncommon. The tumors are more frequently found in the tail of the pancreas, where there is the largest representation of A cells.

Chapter 53: Endocrine Pancreas

Glucagonoma causes a striking clinical syndrome manifested biochemically by hyperglycemia as a result of hyperglucagonemia. Patients with the syndrome sustain marked weight loss and demonstrate glossitis, frequent venous thrombosis, depression, and diarrhea. The most striking feature of this syndrome is called necrolytic migratory erythema (114). This skin lesion consists of erythematous macules and pustules together with flaccid bullae. The necrolytic pattern is present on portions of the skin that are easily traumatized. Histologically, there is superficial epidermal necrolysis and severe inflammation of the dermis with cellular infiltration. There is no explanation for this dermatologic phenomenon, which resolves after resection of the glucagonoma. The patients also demonstrate a normochromic, normocytic anemia. The hyperglycemia is not usually particularly severe. The metabolic consequences of hyperglucagonemia include rapid movement of the plasma amino acids into glucoenogenic pathways in the hepatic cytosol. The consumption of amino acids for gluconeogenesis depletes the circulating pool of amino acids and results in hypoaminoacidemia. This pool is not rapidly replenished by a complementary catabolism of muscle protein. The degree of hyperglucagonemia would be expected to cause a much sharper rise in blood glucose level, but this is partially compensated for by a slight hyperinsulinism that arises because of the hyperglycemia, and also because glucagon is a secretagogue for insulin. Although glucagon does not directly promote loss of muscle protein into the amino acid pool, the brisk gluconeogenesis deprives skeletal muscle of circulating amino acids that might be applied to muscle anabolism. Therefore, muscle wasting and weakness are quite prominent. In many ways, patients with glucagonoma resemble chronically stressed patients who have received inadequate nutritional support. When the disease is suspected, diagnosis is established by radioimmunoassay for glucagon (115). In cases of a marginal elevation of glucagon level, pathologic overresponse to arginine can be demonstrated. Intravenous tolbutamide similarly causes a spectacular rise in the glucagon level in patients with glucagonoma. Once glucagonoma has been diagnosed, anatomic localization by computed axial tomography has been useful, because the tumors are frequently rather large in their position in the body and tail of the pancreas. Percutaneous transhepatic venous sampling has not been particularly helpful as a diagnostic aid because of the delicate nature of the glucagon assay and the large number of samples needed for adequate localization. Ultrasonography demonstrates these tumors only when they are large and bulky. Radical surgical resection of the tumor is clearly the most satisfactory treatment for glucagonoma. Unfortunately, surgical resection is frequently palliative because of the presence of hepatic metastases. For unresectable or metastatic glucagonoma, streptozocin can be useful in reducing the size of the tumors, slowing the growth of metastases, and reducing the circulating levels of glucagon (116). The clinical symptoms, such as skin lesions and anemia, are ameliorated by streptozocin; however, the carbohydrate intolerance does not undergo remission, probably because of toxicity of the streptozocin on the B cells of the healthy islets of Langerhans.

Vipoma Verner–Morrison syndrome was described in 1958 as the third islet-associated syndrome, after insulinoma and the

1019

Zollinger–Ellison syndrome (117). These islet cell tumors, called vipomas, secrete VIP. It is not clear as to which cell in the normal islet gives rise to this tumor. The secreted product is clearly ectopic, and the 28–amino acid peptide causes watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria. Only about 100 cases have been described, and in approximately 80% of these, a single tumor of the endocrine pancreas was held responsible for the syndrome. In the remaining 20%, hyperplasia of an uncertain member of the islet cell community was implicated. Ductal proliferation and an increase in the number of cells in the islets have been described in patients with this syndrome. Approximately half of the tumors are benign. The VIP released by these tumors causes diarrhea, with volume losses in the range of 2 to 10 L/day. Associated potassium wasting, leading to hypokalemia, is observed. Not infrequently, the hypokalemia gives rise to flaccid paralysis and a nephropathy that can lead to renal failure. Hypomagnesemia and mild hypercalcemia have also been described in patients with this syndrome. The clinical effects of excessive VIP secretion are anticipated rather easily because of its known biologic action. VIP has specific receptors on the small-bowel mucosa, and binding of the peptide causes a sharp rise in cAMP, causing the effect of VIP to be similar to that of cholera toxin. The fluid losses are quite similar to those expected in cholera, and Verner–Morrison syndrome has therefore been called pancreatic cholera. VIP has substantial sequence homology with other gastrointestinal hormones such as secretin, glucagon, and GIP. Tumors secreting this peptide therefore may (i) enhance the secretion of alkaline fluid by the pancreas, which suggests secretin overactivity; (ii) induce hyperglycemia, which suggests a glucagon effect; and (iii) strikingly suppress gastric acid secretion, like an infusion of GIP. The release of VIP from these tumors can occur in paroxysms, to give pictures of flushing caused by the vasodilatory reaction of VIP, which may lead to some confusion with the carcinoid syndrome. Diagnosis of the Verner–Morrison syndrome is not easily accomplished, because radioimmunoassay for VIP is not universally available. Further, an extremely similar syndrome is caused by tumors that release prostaglandin E2. Generally, when the clinical picture of the Verner– Morrison syndrome is encountered, the pancreas is studied by computed tomography, angiography, or ultrasonography for evidence of a pancreatic mass lesion. If a tumor is identified, the preferred treatment is by surgical resection. In the presence of hepatic metastases, high-dose steroids and streptozocin have offered reasonable palliation (7).

PPoma A few tumors of the endocrine pancreas have been described that apparently secrete only PP. The importance of this is uncertain, because there is no specific metabolic or clinical manifestation of these tumors, called PPomas. PP is released in abnormally large amounts by patients who harbor other kinds of non–B islet cell tumors. Therefore, PP has been suggested as a marker for other pancreatic endocrine tumors, especially in families with a propensity toward development of these lesions. Approximately half of all patients with other pancreatic endocrine tumors have an elevation in the PP level. Furthermore, approximately 50% of patients with carcinoid tumors, regardless of site, demonstrate an elevation in the PP level. When they are present, PP-secreting tumors are detected clinically because of the effect of the mass in the pancreas or because of

medwedi.ru

1020

Part Seven: The Endocrine System

metastases. Therefore, the syndrome of PP-secreting tumors is not necessarily an endocrine syndrome, but one more related to neoplasia. In patients with islet cell tumors, PP is frequently secreted in high concentration in addition to the primary or symptom-producing hormone. Also, the PP level is quite often elevated in the plasma of patients with asymptomatic tumors. Therefore, PP measurement can be used as a tumor marker to screen patients with multiple endocrine neoplasia type 1 syndrome, for the preclinical appearance of an islet cell tumor.

Somatostatinoma The first case report of a somatostatin-secreting tumor was published in 1977. Approximately 20 cases have now been described (118). These tumors are usually malignant and accompanied by hepatic metastases. Somatostatinomas may be located in the pancreas or duodenum. Metabolically, somatostatin inhibits numerous endocrine and exocrine secretory functions. Dyspepsia, mild diabetes, and cholelithiasis with steatorrhea constitute the expected pathophysiologic constellation for this endocrine condition. These effects are easily attributable to the inhibitory effects of somatostatin on a wide array of smooth muscle and endocrine secretory events. Somatostatin is inhibitory for essentially all gastrointestinal hormones, including insulin, PP, glucagon, gastrin, secretin, motilin, and GIP. The mild diabetes is directly attributable to inhibition of insulin secretion, whereas diarrhea and steatorrhea are attributable to deficient secretion of pancreatic enzymes. The dyspepsia may be more a motor disturbance in smooth muscle function, because hypochlorhydria is observed when gastric acid studies are performed in patients with somatostatinoma. The reduced muscular tone of the gallbladder presumably leads to gallbladder stasis and the formation of stones. Patients with somatostatinoma also uniformly lose weight, which may be attributable to neoplastic effects or malabsorption. Somatostatinoma may be identified by elevated levels of somatostatin in the blood. Excessive secretion of somatostatin by these tumors can be induced in response to intravenous tolbutamide. These tumors are identified on computed tomography and angiography; if they have not metastasized, the ideal treatment is complete excision.

Other Islet Cell Tumors Pancreatic islet cell tumors yielding a syndrome related to hypercalcemia have been described. These tumors have undetectable parathyroid hormone levels, so a parathyroid hormone-like substance has been implicated as the causative agent (119). Many of the features of hyperparathyroidism are present, including bone resorption, nephrocalcinosis, nephrolithiasis, peptic ulcer, and psychoneurologic symptoms. Unless the tumor is extirpated, conventional treatment of hypercalcemia is futile, and the patient eventually dies. Adrenocorticotropinomas of the pancreas have been described, and most have produced a clinical Cushing’s syndrome (120). Plasma cortisol and urinary 17-hydroxycorticosteroid levels have not been suppressible by the dexamethasone suppression test. Several cases of tumors of the pancreas secreting growth hormone–releasing factor and causing acromegalic symptoms have been described. Acromegaly may regress after tumor extirpation without hypophysectomy (121). In addition, a variety of non–B islet cell tumors apparently have no secretory products that can be identified. They

generate no endocrine syndrome to lead to their diagnosis, even though they constitute approximately 20% of all islet cell tumors and are most commonly discovered by computed tomography or angiography as incidental structures or as the explanation for a larger intra-abdominal mass. These tumors can affect the biliary tree by obstruction, which leads to their discovery in approximately half of affected patients. A tumor marker for these lesions is plasma neurone-specific enolase, a neural isomer of the glycolytic enzyme enolase. The glycolytic pathway in neural tissue could be adversely affected by the lowered pH in neural cells, which is the consequence of intense metabolic activity. The enolase found in other tissues is an allosteric subunit enzyme that dissociates in the cytosolic pH found in neural cells. Neurone-specific enolase is stable in its allosteric confirmation at the pH range associated with neural tissue. This enzyme is common to all APUD and neural cells. In fact, the enzyme is released into the plasma of patients with APUD tumors and can be used as a marker for all APUD tumors (19). In as many as 80% of patients with nonfunctioning islet cell tumors, histologic examination reveals evidence of malignancy; however, these tumors grow slowly, and even patients with hepatic metastases may have prolonged survival. Surgical removal is generally the preferred treatment; medical therapy with streptozocin yields a good response in patients with metastases. The endocrine tumors of the pancreas present a challenge to the endocrinologist and surgeon, with the prospect for occasional cure and frequent long-term palliation. Recently, substantial endocrine palliation has been achieved with almost all of the endocrine syndromes by administering long-acting somatostatin to suppress hormone release. Somatostatin is not a chemotherapeutic agent, and no tumor remission has been seen. However, control of the endocrine syndrome in Zollinger–Ellison syndrome, insulinoma, Verner–Morrison syndrome, and glucagonoma represents a spectacular improvement in the treatment of these unfortunate patients. A knowledge of the islet cell tumors of the pancreas is important to anyone treating pancreatic neoplasia. In fact, all masses in the pancreas are not evidence of hopeless adenocarcinoma of the pancreas. Indeed, pancreatic masses, even those that occlude the common bile duct, deserve careful attention. The identification of a resectable islet cell tumor may indeed be the happy conclusion of a diagnostic workup in which the islet cell tumor was not the leading possibility at the outset of the investigation.

SUMMARY The endocrine pancreas controls the movement of glucose through the extracellular fluid by regulating the generation of glucose and the facilitated diffusion of glucose into most cells. The islets of Langerhans that comprise the endocrine pancreas constitute a community of at least four cell types that interact in the islets for the purpose of regulating conflicting secretions that either raise or lower the plasma glucose level. The A (glucagon), B (insulin), D (somatostatin), and F (PP) cells respond to a vast number of secretagogues and antagonists to support a hormonal output compatible with an appropriate hormonal presentation, especially to the liver, to guarantee the movement of glucose in response to substrate demand. These cells join a larger number of others strewn along the gastrointestinal tract to secrete the hormonally active gut peptides.

Chapter 53: Endocrine Pancreas

This chapter has outlined the anatomy, embryology, and physiology of the islets. The only known spontaneous deficiency disease of the endocrine pancreas, diabetes mellitus, has been discussed in some detail. The pathophysiology of the functioning neoplasms of these endocrine cells has also been discussed. Although the endocrine neoplasms are quite rare, the metabolic and pathologic sequelae of excess states of these critical hormones serve to reinforce our understanding of metabolism and its hormonal regulation.

REFERENCES 1. Merrell RC. Cell-cell recognition in neuroembryology. In: Bradshaw RA, Schneider DM, eds. Proteins of the Nervous System. New York: Raven Press, 1980. 2. Von Mering J, Minkowski O. Diabetes mellitus nach pancreas extirpation. Arch Exp Pathol Pharmacol 1889; 26:371. 3. Banting FG, Best CHL. The internal secretion of the pancreas. J Lab Clin Med 1922; 7:251. 4. Oyer P et al. Studies on human proinsulin. J Biol Chem 1971; 246:1375. 5. Goldman H, Wong I, Patel YC. A study of the structural and biochemical development of human fetal islets of Langerhans. Diabetes 1982; 31:897. 6. Bonner-Weir S. Morphological evidence for pancreatic polarity of 3-cell within the islets of Langerhans. Diabetes 1988; 37:616. 7. Pignal F et al. Streptozotocin treatment in pancreatic cholera (Verner-Morrison) syndrome. Digestion 1982; 24:176. 8. Rutter WJ et al. An analysis of pancreatic development. In: Papoconstautinoi J, Rutter WJ, eds. Molecule Control of Proliferation and Differentiation. New York: Academic Press, 1978. 9. Henderson JR, Daniel PM, Fraser PA. The pancreas as a single organ: the influence of the endocrine upon the exocrine part of the gland. Gut 1981; 22:158. 10. Bell GI et al. Sequence of the human insulin gene. Nature 1980; 284:26. 11. Espinal J. Understanding Insulin Action. West Sussex (UK): Ellis Horwood, 1989. 12. Hammonds P et al. Regulation and specificity of glucosestimulated insulin gene expression in human islets of Langerhans. FEBS Lett 1987; 223:131. 13. Farnby B, Schmid-Farmby F, Grodsky GM. Relationship between insulin release and 65zinc efflux from rat pancreatic islets maintained in tissue culture. Diabetes 1984; 33:229. 14. Ashcroft FM et al. Glucose induces closure of single potassium channels in isolated rat pancreatic B-cells. Nature 1984; 312:446. 15. Malaisse WJ, Senor A, Malaisse-Lagae F. Insulin release: reconciliation of the receptor and metabolic hypothesis. Mol Cell Biochem 1981; 37:157. 16. Meda P, Perrelet A, Orci L. Increase of gap junctions between pancreatic B-cells during stimulation of insulin secretion. J Cell Biol 1979; 82:441. 17. Metz SA, Fujimoto WY, Robertson RP. Lipoxygenation of arachidonic acid: a pivotal step in stimulus secretion coupling in the pancreatic beta cell. Endocrinology 1982; 111:2141. 18. Matschinksy FM et al. Glucoreceptor mechanisms in islets of Langerhans. Diabetes 1972; 21:555. 18a. Sjoholm A, Lehtihet M, et al. Glucose inhibit protein phosphatases and directly promote insulin exocytosis in pancreatic b-cells. Endocrinology 2002; 143(2):4592–4598. 19. Prinz RA et al. Serum markers for pancreatic islet cell and intestinal carcinoid tumors. Surgery 1983; 94:1019. 20. Reaven E et al. Effect of age and environmental factors on insulin release from the perfused pancreas of the rat. J Clin Invest 1983; 71:345. 21. Klines I et al. Normal insulin sensitivity of the islets of Langerhans in obese subjects with resistance to its glucoregulatory actions. Diabetes 1984; 33:305.

1021

22. Marincola F et al. The independence of insulin release and ambient insulin in vitro. Diabetes 1983; 32:1162. 23. Tepperman J. Metabolic and Endocrine Physiology. 3rd. Chicago: Year Book Publishers, 1973. 24. McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Am Rev Biochem 1980; 49:395. 25. Dayoff MO. Atlas of Protein Sequence and Structure. Silver Spring, MD: National Biomedical Research Foundation, 1969. 26. Pandol SJ et al. Growth hormone-releasing factor stimulates pancreatic enzyme secretion. Science 1984; 225:326. 27. Kimball CP, Murlin JR. Aqueous extracts of pancreas. III. Some precipitation reactions of insulin. J Biol Chem 1923; 58:337. 28. Itoh M et al. Secretion of glucagon. In: Cooperstein SJ, Watkins D, eds. The Islets of Langerhans. New York: Academic Press, 1981. 29. Goodner CJ, Hom FG, Koercker DJ. Hepatic glucose production oscillates in synchronic with the islet secretory cycle in fasting rhesus monkeys. Science 1982; 215:1257. 30. Efendic S, Luft R. Somatostatin and its role in insulin and glucagon secretion. In: Cooperstein SJ, Watkins D, eds. The Islets of Langerhans. New York: Academic Press, 1981. 31. Kimmell JR, Pollack HG, Hazelwood RL. Isolation and characterization of chicken insulin. Endocrinology 1968; 83: 1323. 32. Warren JH et al. Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. N Engl J Med 1984; 311:149. 33. Srikanta S et al. Pre-type I diabetes: identical endocrinological course dependent of HLA DR types or presence of cytoplasmic anti-islet antibodies. Diabetes 1984; 33:10A. 34. Stiller CR et al. Effects of cyclosporine-type I diabetes: clinical course and immune response. Diabetes 1984; 33:13A. 35. Tager HS. Abnormal products of the human insulin glue. Diabetes 1984; 33:693. 36. Eizirick DL et al. Repair of pancreatic b-cells. Diabetes 1993; 42:1383. 37. Opie EL. The relation of diabetes mellitus to lesion of the pancreas: hyaline degeneration of the islands of Langerhans. J Exp Med 1901; 5:527. 38. Bell RH et al. Molecular defects in diabetes mellitus. Diabetes 1991; 40:413. 39. James DE et al. Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature 1989; 338:83. 40. Birnbaum MJ. Identification of a novel gene encoding an insulin-responsive glucose transporter protein. Cell 1989; 57:305. 41. Jaspan J et al. Treatment of severely painful diabetic neuropathy with an aldose reductose inhibitor: relief of pain and improved somatic and autonomic nerve function. Lancet 1983; 2:758. 42. Siperstein MD, Unger RH, Madison LL. Studies of muscle capillary basement membranes in normal subjects, diabetic and pre-diabetic patients. J Clin Invest 1968; 47:1973. 43. Koenig RJ, Cerami A. Hemoglobin A, C, and diabetes mellitus. Annu Rev Med 1980; 31:29. 44. Clutter WE. Diabetes mellitus and hyperlipidemia. In: Campbell JW, Frisse M, eds. Manual of Medical Therapeutics. Boston: Little, Brown, 1983. 45. Cornfield J. The university group diabetes program: a further statistical analysis of the mortality findings. JAMA 1971; 217(12):1676–1687. 46. Lauritzen T et al. Effect of one year of near-normal blood glucose levels on retinopathy in insulin-dependent diabetics. Lancet 1983; 1:200. 47. Ballinger WF, Lacy PE. Transplantation of intact pancreatic islets in rats. Surgery 1972; 72:175. 48. Cobb L, Merrell R. Intrasplenic islet autografts: insulin response to IV glucose challenge. Curr Surg 1983; 40:36. 49. Bell RH et al. Prevention by whole pancreas transplantation of glomerular basement membrane thickening in alloxan diabetes. Surgery 1980; 88:31.

medwedi.ru

1022

Part Seven: The Endocrine System

50. Gray BN, Watkins E. Prevention of vascular complications of diabetes by pancreatic islet transplantation. Arch Surg 1976; 111:254. 51. Tyden G, Bolinder J, Solders G, Brattstrom C, Tibell A, Groth CG. Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 1999; 67(5):645–648. 52. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339(2):69–75. 53. Rastellini C, Shapiro R, Corry R, Fung JJ, Starzl TE, Rao AS. Treatment of isolated pancreatic islets to reverse pancreatectomy-induced and insulin-dependent type I diabetes in humans: a 6-year experience. Transplant Proc 1997; 29(1–2): 746–747. 54. IPTR Annual Report of the International Pancreas Transplant Registry. IPTR Newslett 1998; 10(1):1–12. 55. Hering BJ, Ricordi C. Islet transplantation for patients with type I diabetes. Graft 1999; 2(1):12–27. 56. Gunnarsson R, Klintmalm G, Lundgren G, et al. Deterioration in glucose metabolism in pancreatic transplant recipients after conversion from azathioprine to cyclosporine. Transplant Proc 1984; 16(3):709–712. 57. Friedman EA, Shyh TP, Beyer MM, Manis T, Butt KMH. Posttransplant diabetes in kidney transplant recipients. Am J Nephrol 1985; 5(3):196–202. 58. Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients. Transplantation 1987; 44(3):376–381. 59. Jindal RM. Posttransplant diabetes mellitus—a review. Transplantation 1994; 58(12):1289–1298. 60. Jindal RM, Popsecu I, Schwartz ME, et al. Diabetogenicity of FK506 versus cyclosporine in liver transplant recipients. Transplantation 1994; 58(3):370–372. 61. McGeown MG, Douglas JF, Brown WA, et al. Advantages of low dose steroid from the day after renal transplantation. Transplantation 1980; 29:287. 62. Arner P, Gunnarsson R, Blomdahl S, et al. Some characteristics of steroid diabetes: a study in renal transplant recipients receiving high dose corticosteroid therapy. Diabetes Care 1983; 6(1):23–25. 63. Ricordi C, Zeng Y, Alejandro R, et al. In vivo effect of FK506 on human pancreatic islets. Transplantation 1991; 52(3):519. 64. Rilo HLR, Zeng Y, Alejandro R, et al. Effect of FK506 on function of human islets of Langerhans. Transplant Proc 1991; 23:3164. 65. Brendel M, Hering B, Schulz A, Bretzel R. International Islet Transplant Registry Report. Germany: University of Giessen, 1999:1–20. 66. Linetsky E, Bottino R, Lehmann R, Alejandro R, Inverardi L, Ricordi C. Improved human islet isolation using a new enzyme blend, liberase. Diabetes 1997; 46(7):1120–1123. 67. Lakey JR, Warnock GL, Shapiro AM, et al. Intraductal collagenase delivery into the human pancreas using syringe loading or controlled perfusion. Cell Transplant 1999; 46(7):1120–1123. 68. Shapiro AM, Hao E, Lakey JR, Finegood D, Rajotte RV, Kneteman NM. Diabetogenic synergism in canine islet autografts from cyclosporine and steroids in combination. Transplant Proc 1998; 30(2):527. 69. Shapiro AM, Hao E, Lakey JR, Elliot JF, Rajotte RV, Kneteman NM. Development of diagnostic markers for islet allograft rejection. Transplant Proc 1998; 30(2):647. 70. Kaufman DB, Gores PF, Field MJ, et al. Effect of 15-deoxyspergualin on immediate function and long-term survival of transplanted islets in murine recipients of marginal islet mass. Diabetes 1994; 43(6):778–783. 71. Rosenberg L, Wang R, Paraskevas S, Maysinger D. Structural and functional changes resulting from islet isolation lead to islet cell death. Surgery 1999; 126(2):393–398. 72. Bennet W, Sundberg B, Groth CG, et al. Incompatibility between human blood and isolated islets of Langerhans: a

73.

74.

75.

76.

77.

78.

79.

80.

81.

82. 83. 84.

85.

86.

87.

88.

89.

90.

91. 92.

93.

94.

finding with implications for clinical intraportal islet transplantation? Diabetes 1999; 48(10):1907–1914. Kenyon NS, Ranuncoli A, Massetti M, Chatzipetrou M, Ricordi C. Islet transplantation: present and future perspectives. Diabetes Metab Rev 1998; 14(4):303–313. Swift SM, Clayton HA, London NJ, James RF. The potential contribution of rejection to survival of transplanted human islets. Cell Transplant 1998; 7(6):599–606. Drachenberg CB, Klassen DK, Weir MR, et al. Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 1999; 68(3):396–402. Shapiro A, Lakey J, Ryan E, et al. Islet transplant in seven patients with type 1 diabetes mellitus patients using a glucocorticoid free immunosuppressive regimen. N Engl J Med 2000; 343:230–238. Ryan E, Lakey J, Rajotte R, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 2001; 50(4):710–719. Kenyon NS, Chatzipetrou M, Masetti M, et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CDD154. Proc Natl Acad Sci USA 1999; 96(14):8132–8137. Zheng XX, Markees TG, Hancock WW, et al. CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment. J Immunol 1999; 162(8):4983–4990. Chatenoud L, Primo J, Back JF. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 1997; 158(6):2947–2954. Chatenoud L, Thervet E, Primo J, Back JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 1994; 91(1): 123–127. Grewal IS, Flavell RA. The CD40 ligand. At the center of the immune universe? Immunol Res 1997; 16(1):59–70. Sutherland DER. Pancreas and islet transplantation: an update. Transplant Rev 1994; 8:185. Basadonna GP et al. Morbidity, mortality and long-term allograft function in kidney transplantation alone and simultaneous pancreas/kidney transplantation in diabetic patients. Transplant Proc 1993; 25:1321. Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 1955; 142:709. Pearse AGE, Polak MJ. Endocrine tumours of neural crest origin: neurolophomas apudomas and the APUD concept. Med Biol 1974; 52:3. Stark DD et al. Computed tomography and nuclear magnetic resonance imaging of pancreatic islet cell tumors. Surgery 1983; 94:1024. Brentjens R, Saltz L. Islet cell tumors of the pancrease: the Medical Oncologist’s Perspective. Surg Clin North Am 2001; 81(3):527–542. Azimuddin K, Chamberlain RS. The surgical management of pancreatic neuroendocrine tumors. Surg Clin North Am 2001; 81(3):511–525. Suzuki K, Takahashi S, Airua K, et al. Evaluation of the usefulness of percutaneous transhepatic portal catherization for preoperative diagnosing the localization of insulinomas. Pancreas 2002; 24(1):96–102. Richards ML, Gauger PG, Thompson NW, et al. Pitfalls in the surgical treatment of insulinoma. Surgery 2002; 132:1040–1049. Lebtahi R, Le Cloirec J, Houzard C, et al. Detection of neuroendocrine tumors: 99mTc-P829 scintigraphy compared with 111 In-pentetreotide scintigraphy. J Nucl Med 2002; 43:889–895. Gramatica L Jr, Herrera MF, Mercardo-Luna A, et al. Videolaparoscopic resection of insulinomas: experience in two institutions. World J Surg 2002; 26(10):297–300. Pietrabissa A, Shimi SM, Vaander Velpen G, et al. Localization of insulinoma by laparoscopic infragastric inspection of the pancreas and contact ultrasonography. Surg Oncol 1993; 2(1):83–86.

Chapter 53: Endocrine Pancreas 95. Gagner M, Pomp A, Herrera MF. Early experience with laparoscopic resections of islet cell tumors. Surgery 1996; 120(6):1051–1054. 96. Sussman LA, Christie R, Whittle DE. Laparoscopic excision of distal pancreas including insulinoma. Aust N Z J Surg 1996; 66(6):414–416. 97. Cuschieri A. Laparoscopic pancreatic resections. Semin Laparosc Surg 1996; 3(1):15–20. 98. Lomsky R, Langr F, Vortel V. Demonstration of glucagon in islet cell adenomas of the pancreas by immunofluorescent technic. Am J Clin Pathol 1969; 51:245. 99. Zollinger RM. The ulcerogenic syndrome. In: Friesen SR, ed. Surgical Endocrinology. Philadelphia: JB Lippincott, 1978. 100. Sarmiento JM, Farnell MB, Que FG, et al. Pancreaticoduodenectomy for islet cell tumors of the head of the pancreas: long-term survival analysis. World J Surg 2002; 26(10):1267–1271. 101. Matthews BD, Heniford BT, Reardon PR, et al. Surgical experience with nonfunctioning neuroendocrine tumors of the pancreas. Am Surg 2000; 66(12):1116–1123. 102. Sarmiento JM, Que FG, Grant CS, et al. Concurrent resections of pancreatic islet cell cancers with synchronous hepatic metastases: outcomes of an aggressive approach. Surgery 2002; 132(6):976–983. 103. Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroendocrine metastaes to the liver: a plea for resection to increase survival. J Am Coll Surg 2003; 197(1):29–37. 104. Hellman P, Ladjevardi S, Skogsedi B, et al. Radiofrequency tissue ablation using cooled tip for liver metastases of endocrine tumors. World J Surg 2002; 26(8):1052–1056. 105. Metz DC, Soffer E, Forsmark CE, et al. Maintenance oral pantopyrazole therapy is effective for patients with ZollingerEllison syndrome and idiopathic hypersecretion. Am J Gastroenterol 2003; 98(2):301–307. 106. Giacobazzi D, Passaro E. Preoperative angiography in the Zollinger-Ellison syndrome. Am J Surg 1973; 126:74. 107. Dunnick NR et al. Computed tomographic detections of nonbeta pancreatic islet cell tumors. Radiology 1980; 135:117. 108. Ingemausson S et al. Pancreatic vein catheterization with gastrin assay in normal patients and in patients with ZollingerEllison syndrome. Am J Surg 1977; 134:558.

1023

109. Friesen SR et al. Cimetidine in the management of synchronous crises of MEAI. World J Surg 1980; 4:123. 110. Richardson CT et al. Effect of vagotomy in Zollinger-Ellison syndrome. Gastroenterology 1979; 77:681. 111. Friesen SR. Treatment of the Zollinger-Ellison syndrome. Am J Surg 1982; 143:331. 112. Ramanathan RK, Cnaan A, Hahn RG, et al. Phase II trial of dacarbazine (DTIC) in advanced pancreatic iselt cell carcinoma. Study of the Eastern Cooperative Oncology GroupE6282. Ann Oncol 2001; 12:1139–1143. 113. Fjallsko ML, Sundin A, Westlin JE, et al. Treatment of malignant endocrine pancreatic tumors with a combination of a-interferon and somatostatin analogs. Med Oncol 2002; 19(1): 35–42. 114. Pedersen NB, Jonsson L, Holst JJ. Necrolytic migratory erythema and glucagon cell tumour of the pancreas: the glucagonoma syndrome. Acta Derm Venereol (Stockh) 1976; 56:391. 115. Belchetz PE et al. ACTH, glucagon and gastrin production by a pancreatic islet cell carcinoma and its treatment. Clin Endocrinol 1973; 2:307. 116. Danforth DN et al. Elevated plasma proglucagon-like component with glucagon-secreting tumor: effect of streptozotocin. N Engl J Med 1976; 295:242. 117. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med 1958; 25:374. 118. Pipeleers D et al. Five cases of somatostatinoma clinical heterogeneity and diagnostic usefulness of basal and tolbutamide induced hypersomatostatinemia. J Clin Endocrinol Metab 1983; 56:1236. 119. Rasbach D et al. Pancreatic islet cell carcinoma with hypercalcemia. Am J Med 1985; 78:337. 120. Abe K et al. Production of calcitonin, adrenocorticotropic hormone, and B-melanocyte-stimulating hormone in tumors derived from amine precursor uptake and decarboxylation cells. Cancer Res 1977; 37:4190. 121. Rosch J et al. Functional endocrine tumors of the pancreas: clinical presentation, diagnosis, and treatment. Curr Probl Surg 1990; 26:309.

medwedi.ru

54 Multiple Endocrine Neoplasia: Types 1 and 2 Frank J. Quayle and Jeffrey F. Moley

INTRODUCTION Most tumors of the endocrine system are sporadic and arise within a single gland. However, the multiple endocrine neoplasia (MEN) syndromes are characterized by a predisposition to develop neoplasms in multiple endocrine glands. As in other heritable cancer syndromes, the tumors may be multifocal and bilateral, synchronous or metachronous, and tumor histology varies from hyperplasia to invasive, metastasizing carcinoma. The MEN syndromes have distinct patterns of clinical expression, and each is associated with germline mutations within specific genes. MEN type 1 (MEN 1) is characterized by parathyroid hyperplasia, pancreatic and duodenal neuroendocrine tumors, and pituitary adenomas. It is associated with mutations in the MEN 1 gene. MEN type 2A (MEN 2A) is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia, while MEN 2B is distinguished by MTC, pheochromocytoma, mucosal neuromas, and a distinctive marfanoid habitus. MEN 2A and 2B are associated with mutations in the rearranged during transfection (RET) proto-oncogene. In each of these disorders, derangements of normal endocrine physiology manifest clinical symptoms and lead to laboratory abnormalities that can be used to diagnose and follow the underlying disease.

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 History, Molecular Genetics, and Pathogenesis The presence of parathyroid, islet cell, and pituitary tumors in the same individual was described as a syndrome by Wermer in 1954 (1). Subsequently, MEN 1 was demonstrated to be heritable, highly penetrant, and to have variable clinical manifestations. The pattern of inheritance is autosomal dominant. A combination of genetic-linkage analysis and tumordeletion mapping localized the MEN 1 gene to chromosome 11q13 (2). The frequent loss of heterozygosity seen in MEN 1–associated tumors is consistent with the Knudson two-hit model of oncogenesis, suggesting that the mutant protein is a tumor suppressor (3). In this model, both copies of a tumor-suppressor gene must sustain a mutation before neoplastic transformation occurs. The first mutation is inherited in the germline in affected families and leads to susceptibility within involved tissues. The second occurs as a somatic event, after which the regulatory tumor-suppressor function is lost and clonal expansion and cancer development occur. Conceptually, the multifocal occurrence of tumors in affected endocrine glands is explained by multiple second hits within target tissues.

The MEN 1 gene consists of 10 exons encoding a 2.8 kb transcript, and the 610–amino acid protein product is called ‘‘menin’’ (4). This highly conserved protein is expressed during development and in adults across a variety of tissues. Menin is known to localize to the nucleus and has been demonstrated to bind to the transcription factor JunD, suggesting that its tumor-suppressor function is mediated through inhibition of JunD-activated transcription (5). Mutations implicated in MEN 1 vary widely and include missense, nonsense, frameshift, and splicing defects found across the MEN 1 gene (6,7). No specific genotype– phenotype correlations have been established, although some evidence suggests that mutations associated with MEN 1 tend to cluster in the codons corresponding to domains in the menin protein that interact with JunD (8).

Clinical Features and Management Patients with MEN 1 generally develop signs and symptoms in the third or fourth decade of life, and onset in the first decade is rare. MEN 1 is highly penetrant, with 52% of patients demonstrating some aspect of the disease by the age of 20, and 99% by the age of 50 (7). Histologic evidence of hyperplasia or neoplasia can be found in multiple endocrine tissues in nearly all patients with MEN 1 (9). Men and women are affected nearly equally, and no racial predilection has been identified. Despite high penetrance, MEN 1 demonstrates a wide variability of phenotypic expression, including inconsistent tissue involvement, clinical presentation, clinical course, and prognosis. The most common abnormality is hyperparathyroidism (HPT), found in up to 95% of patients. Pancreatic or duodenal endocrinopathies are found in approximately half of patients, and pituitary adenomas are found in approximately a third, depending on the population studied (Table 1) (10). Less common tumors associated with MEN 1 include adrenocortical adenomas, lipomas, and foregut carcinoid tumors. Each of these tumor types may be present in different combinations, present in different order, and have a different prognosis. Nonetheless, as noted, specific patterns of expression are common within families. The high degree of variability precludes strict definitions of MEN 1. The current working definition of MEN 1 is tumors in two of the three primary sites (i.e., parathyroid, pancreaticoduodenal, and pituitary). Familial MEN 1 is defined by an index MEN 1 case with one or more relatives having tumors in one or more primary sites (11). The clinical manifestations of disease depend upon the specific tissue involved and hormones produced. Classically, the most common presenting problem was peptic ulcer disease, followed by hypoglycemia (12). In the current era, a large proportion of patients continue to present with

medwedi.ru 1025

1026

Part Seven: The Endocrine System

Table 1 Characteristics of Multiple Endocrine Neoplasia Type 1 (MEN 1) Pituitary tumors Prolactinomas ACTH-secreting tumors Growth hormone–secreting tumors Nonfunctional tumors HPT Pancreatic islet cell tumors Most common Gastrinoma Insulinoma Less common VIP-oma Glucagonoma Somatostatinoma Ppoma Nonfunctional tumors Abbreviations: ACTH, adrenocorticotrophic hormone; HPT, hyperparathyroidism; VIP, vasoactive intestinal peptide.

evidence of islet cell tumors, although today the most common presenting problem is HPT. The important principle is that clinical symptoms do not always reflect the degree of underlying involved tissues.

Parathyroid Glands The most common endocrinopathy in MEN 1 is HPT. Unlike most patients with sporadic HPT, who generally have discrete parathyroid adenomas, the distinguishing feature of HPT in MEN 1 patients is four-gland hyperplasia. This distinction has important ramifications for clinical management. The histologic abnormality is diffuse chief cell hyperplasia. Elevated serum calcium is commonly the first biochemical abnormality detected in MEN 1. As with sporadic HPT, elevated serum parathyroid hormone (PTH) confirms the diagnosis of HPT. Clinical features of HPT in the setting of MEN 1 are similar to those associated with sporadic disease, including renal lithiasis, bone disease, anorexia, generalized muscle weakness, and gastrointestinal (GI) complaints. In general, patients with MEN 1 have an earlier onset of disease and milder hypercalcemia than those with sporadic HPT. The challenge in the surgical treatment of HPT in the setting of MEN 1 is balancing the risk of hypoparathyroidism with the risk of recurrent hypercalcemia. Two major strategies have emerged to address this problem (13,14). The first is three and one-half gland parathyroidectomy leaving the remaining half-gland in situ in the neck. This is marked with a clip or nonabsorbable suture to aid in identification in the event of recurrent hypercalcemia. The other option is total four-gland parathyroidectomy with intramuscular autotransplantation of parathyroid tissue into the forearm muscle. In both strategies, parathyroidectomy should include a transcervical thymectomy to remove potential supernumary glands and rests within the cranial horns of the thymus. Residual parathyroid tissue should be cryopreserved to enable a subsequent autotransplant in the event of hypoparathyroidism. The advantages of the four gland/autotransplant approach are twofold. First, in the event of recurrent or persistent HPT, the source is more easily localized if the glands were transplanted into the forearm. PTH levels drawn from right and left antecubital veins will show if the source of

excess PTH is the grafts, or if the source is elsewhere, which would include the neck and mediastinum. Second, if the source of recurrent HPT is the grafts, this can be managed by excising a portion of grafted tissue under local anesthesia, thereby avoiding the complications of reoperative neck surgery. Given the diffuse parathyroid involvement, preoperative imaging studies such as sestamibi scanning or ultrasound are not generally helpful. However, these studies are useful for localization in the event of recurrence. Recurrent hypercalcemia occurs in 20% to 33% of patients with MEN 1, a much higher rate than that seen after surgical management of sporadic disease (13,14). This reflects the diffuse glandular involvement seen in MEN 1 patients. Due to the association of MEN 1 with diffuse parathyroid hyperplasia, patients discovered to have four-gland HPT should undergo screening for other elements of the syndrome. When MEN 1 patients have concurrent HPT and gastrinoma, the former should be addressed first. Hypercalcemia exacerbates hypergastrinemia, and normalization of serum calcium often helps control gastric acid hypersecretion (14).

Pancreas and Duodenum Neuroendocrine tumors of the pancreas and duodenum are the second most common feature of MEN 1, ultimately found in 50% or more of patients. These tumors can be hormonally active or silent and can be benign or malignant. Gastrin, insulin, glucagon, vasoactive intestinal peptide (VIP), and pancreatic polypeptide (PP) may be secreted. Nonfunctioning tumors or those that secrete PP are the most prevalent (15). Histologically, the most common findings are multifocal microadenomas or diffuse islet cell hyperplasia throughout the pancreas rather than large isolated tumors. Enteropancreatic tumors become clinically significant either due to mass effect or more commonly due to active hormone oversecretion. Gastrinomas are the most common clinically functional pancreaticoduodenal tumors in patients with MEN 1 (16). The features of gastrinoma, known as the Zollinger–Ellison syndrome (ZES), include hypergastrinemia, massive gastric acid output, and secondary ulcer disease. The clinical characteristics include epigastric pain, peptic ulcer disease, reflux esophagitis, and secretory diarrhea. In this era, severe ulcer diathesis or secondary complications such as esophageal stricture or perforation are less common. Gastrinomas associated with MEN 1 account for approximately 20% of ZES. The diagnosis of gastrinoma is defined by concurrent demonstration of gastric acid hypersecretion and elevated fasting serum gastrin levels. Levels greater than 15 mEq/L in patients without prior surgery or greater than 5 mEq/L in patients with a history of ulcer surgery constitutes gastric acid hypersecretion, while levels greater than 100 pg/cc constitute an elevated fasting serum gastrin. If results are equivocal, an abnormal secretin test can confirm the diagnosis, defined as an increase of 200 pg/cc in serum gastrin levels after provocative administration of 2 U/kg of secretin. The goal of medical management of ZES is limiting secondary complications through control of acid hypersecretion. This is achieved either with histamine 2–receptor antagonists or preferably proton-pump inhibitors. In general, proton-pump inhibitors effectively control the clinical manifestations of ZES. With these medical therapies, secondary complications of ZES and the need for gastric resection for acid reduction in patients with ZES have been nearly eliminated.

Chapter 54: Multiple Endocrine Neoplasia: Types 1 and 2

The surgical management of gastrinoma in MEN 1 remains a controversial issue. The debate revolves around the efficacy of medical management, the frequency of metastatic disease, and the reduced likelihood of surgical cure. In MEN 1, it is recognized that gastrinomas occur frequently within the wall of the duodenum as multiple microadenomas (17,18), and gastrinomas in the setting of MEN 1 are often malignant with evidence of regional lymph node or hepatic metastases in 50% or greater (19). These suggest that more extensive lymphadentectomy or even pancreaticoduodenectomy might improve the success rate of surgery for ZES in MEN 1. Nonetheless, patients with gastrinoma in the setting of MEN 1 are rarely cured by surgery (20,21). The largest series of these patients demonstrated biochemical evidence of recurrence in 96% within three years and 100% within 10 years (20). Still, 5- and 10-year survival in these patients are 100% and 86%, respectively, illustrating the indolent nature of this disease. Insulinoma is the second most common clinically evident pancreaticoduodenal tumor in MEN 1, occurring in approximately 10% of patients. The clinical symptoms can be incapacitating and are secondary to neuroglycopenia. These include episodic sweating, dizziness, confusion, or syncope, occurring after fasting periods or exercise. A provocative supervised 72-hour fast will elicit symptomatic hypoglycemia with elevated insulin and C-peptide levels and thus establish the diagnosis. Factitious hypoglycemia due to exogenous insulin administration is the other common cause of episodic hypoglycemia and must be ruled out with assessment of C-peptide levels. In contrast to gastrinomas, functioning insulinomas in MEN 1 are more amenable to surgery. They are more often single, large enough to be identified, and located within the pancreatic parenchyma. They are less often malignant, and they do not have an ideal medical therapy. Medical therapy consists of diazoxide or octreotide for control of hypoglycemia. However, the preferred treatment of insulinoma in MEN 1 is preoperative localization followed by surgical resection. Conventional imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound may localize an insulinoma in these patients. Somatostatin receptor scintigraphy has been reported to successfully identify pancreatic neuroendocrine tumors not visualized using traditional modalities (22). Selective arteriography with injection of calcium gluconate stimulates insulin secretion, and differential insulin concentration within the hepatic veins can be used for regional localization (23). Lastly, endoscopic ultrasound (EUS) is a sensitive imaging modality for small pancreatic endocrine tumors, when performed by an experienced ultrasonographer. This technique may image tumors as small as 0.6 cm within the pancreatic parenchyma (24). With or without successful preoperative localization, surgical exploration is indicated for insulinoma in MEN 1. The surgical approach includes complete mobilization of the pancreas, careful inspection and palpation of the gland, and intraoperative ultrasound if the tumor cannot be identified. Small insulinomas are often amenable to enucleation, while larger or multifocal lesions may require partial pancreatectomy. If an insulinoma is not evident despite an exhaustive intraoperative search, blind subtotal pancreatectomy is not recommended. Other functional pancreatic neuroendocrine tumors include glucagonoma, VIP-oma, and somatostatinoma. Glucagonoma is associated with weight loss, glucose intolerance, migratory necrolytic erythema, hypoaminoacidemia,

1027

and normochromic, normocytic anemia. VIP-omas cause profuse diarrhea in the setting of low gastric acid (distinguishing them from gastrinomas). Somatostatinomas have a subtler range of symptoms including mild diabetes, gallbladder disease, weight loss, anemia, steatorrhea, and hypochlorhydria. These tumors are often large at presentation and commonly are malignant. There is little consensus on the role of surgery for enteropancreatic disease in MEN 1. Exploration is clearly indicated for insulinoma. For other tumors, however, recommendations vary widely. Some groups recommend intervening on tumors larger than 3 cm, based on the higher likelihood of metastatic disease in larger tumors (25). Others recommend intervening for tumors of 1 cm, generally the limit of visualization using conventional techniques (26). Based upon the high malignant potential of these tumors, and the advent of more sensitive imaging techniques like EUS, still others are recommending intervention based solely on clear biochemical evidence of enteropancreatic disease (27). As always, the decision to operate must be based upon weighing the risks to the patient and a reasonable likelihood of benefit.

Pituitary Pituitary tumors occur in 15% to 50% of patients with MEN 1. They cause symptoms either by local mass effect or through secretion of hormones. Approximately two thirds are microadenomas. Larger adenomas can cause visual disturbances through compression of the optic chiasm, or even hypopituitarism by displacement of the normal pituitary. The most common functional tumor is a prolactinoma that may cause amenorrhea and galactorrhea in women and hypogonadism in men (28). Bromocriptine is the medical treatment for prolactinoma. Growth hormone–producing tumors result in acromegaly. Much rarer are adrenocorticotrophic hormone (ACTH)-secreting tumors causing Cushing’s disease. Treatment of pituitary tumors associated with MEN 1 is similar to treatment of sporadic pituitary tumors, which can include medical control of functional tumors, surgery, or radiation. When surgery is performed, a trans-sphenoidal approach is usually employed.

Other Tumors in MEN 1 Foregut carcinoids occur occasionally in the setting of MEN 1. They are often clinically silent until a late stage, are rarely biochemically active, and seem to be more aggressive than their sporadic counterparts. The possibility of removing an occult carcinoid or at-risk tissue is an additional reason for transcervical thymectomy at the time of parathyroid exploration. Aside from this, there are no specific recommendations for managing or screening for MEN 1–related carcinoids. In general, recommendations for resection would be limited to controlling symptomatic disease. Adrenal cortical lesions are common in MEN 1, but their clinical significance is variable. Most are hyperplastic and nonfunctional, but carcinoma has been described. In general, adrenal lesions in MEN 1 exhibit an indolent course, and it is not clear whether their management should be different from sporadic adrenal masses.

Screening Screening in MEN 1 involves both genetic testing and biochemical screening for markers of disease. A recent international, multidisciplinary consensus statement addresses both of these issues (11).

medwedi.ru

1028

Part Seven: The Endocrine System

Genetic testing is performed through sequence analysis of the MEN 1 gene in an index case to discover the specific mutation. Once a mutation is identified, other members of the kindred can be tested for it. Sequence analysis is successful in 80% to 90% of kindreds (7). Other methods of genetic testing can include linkage and haplotype analysis if sequence analysis is uninformative. Testing can be offered to index cases and their relatives. However, it is important to emphasize that genetic testing is an informative tool only, and families should be educated about the implications, risks, and benefits of test results by an experienced genetic counselor. Periodic screening of tumor expression in MEN 1 is directed toward early identification of the principal tumor types. This includes evaluating clinical symptoms, biochemical markers, and imaging studies. Based on age-related penetrance, screening should begin in early childhood. Biochemical assays should be performed annually, while imaging studies should be performed every several years.

MEN 2 is caused by ‘‘gain of function’’ mutations in RET. Unlike the tumor suppressor MEN 1, RET is a protooncogene in which activating mutations are dominant in the development of neoplasia. In vitro experiments demonstrated the transforming effect of these mutations in NIH 3T3 cells through constitutive activation of the RET tyrosine kinase. RET mutations associated with MEN 2A lead to constitutive dimerization, while those associated with MEN 2B change the tyrosine kinase substrate specificity (41). Familial Hirschsprung’s disease (HSCR) has also been associated with mutations in the RET gene. The implicated mutations have been frameshift or nonsense, leading to gene inactivation or abrogation of the functional RET product (42,43). However, a small subset of MEN 2A families have associated HSCR. These kindreds have associated missense mutations in codons 618 or 620 (44). Thus, HSCR can be associated with either loss-of-function or gain-of-function mutations in the RET gene.

Clinical Features and Management MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 History, Molecular Genetics, and Pathogenesis Coincident thyroid cancer and pheochromocytoma was first described in 1932 (29), but the association between the two was not recognized until the early 1960s (30), and the heritable syndrome was not characterized until the late sixties (31). Also in the late sixties, a variant was described, which included mucosal neuromas and a distinct facies (32). Today MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC) form a constellation of related syndromes whose hallmark is MTC. The development of a radioimmunoassay for calcitonin in 1970 (33) was pivotal for the study of MTC and MEN 2, because MTC is a cancer of calcitonin-secreting C-cells of the thyroid. Basal and stimulated calcitonin levels are useful markers for the diagnosis and surveillance of MTC. Linkage analysis localized the predisposition gene for the MEN 2 syndromes to the pericentromeric region of chromosome 10 (34,35). Subsequently, mutations in the RET proto-oncogene at that locus were identified in patients with MEN 2A, FMTC (36), and MEN 2B (37). The majority of mutations in MEN 2A are missense involving one of five cysteine residues in the extracellular domain of the RET protein. Almost all cases of MEN 2B demonstrate a methionine to threonine missense mutation in codon 918. The RET gene consists of at least 20 exons and is expressed as five major mRNA species. In adults, RET is only expressed in a limited number of tissues including the C-cells of the thyroid, the adrenal medulla, and the central nervous system. The RET protein is a cell-membrane receptor tyrosine kinase. It has three domains: a cysteinerich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. Experiments in knockout mice suggest a critical role for RET in the developing enteric nervous system and the kidneys (38). Its ligands are now known to include glial-derived growth factor and neurturin (39,40). Ligand binding causes RET dimerization, which in turn leads to phosphorylation and activation of the tyrosine kinase domain, and ultimately downstream signaling. It appears that RET regulates cellular growth and proliferation in cells derived from the neural crest. It is highly expressed in MTC, pheochromocytoma, and neuroblastoma. In contrast to MEN 1, there is no evidence of consistent loss of heterozygosity at the RET locus in MEN 2 tumors.

The hallmark of MEN 2A, FMTC, and MEN 2B is MTC. MTC occurs in nearly all affected persons. Pheochromocytoma occurs in approximately half of MEN 2A and MEN 2B patients. HPT occurs in approximately one quarter of MEN 2A patients, and does not occur in patients with MEN 2B and FMTC (Table 2) (45). The rarer MEN 2B syndrome includes MTC, pheochromocytoma, mucosal neuromas, diffuse ganglioneuromas of the GI tract, skeletal abnormalities, megacolon, and a ‘‘marfanoid’’ habitus. These syndromes demonstrate an autosomal-dominant pattern of heritability; however, both variants may occur de novo in an index patient to affect subsequent generations. MTC is usually the first expression of MEN 2, and management is directed toward early diagnosis, preventive therapy, or control of advanced disease. In MEN 2A, the peak incidence of MTC occurs in the second or third decade of life, and many cases present earlier. MTC in MEN 2B occurs at a younger age (often in infancy) and is more aggressive than MTC in MEN 2A. Due to the aggressive nature of the disease, MEN 2B kindreds are characteristically small, encompassing only two or three generations. The early age of onset necessitates intervention as soon as the genetic testing reveals the presence of an MEN 2B mutation in the RET gene. Thyroidectomy should be performed as soon as the diagnosis is made, during infancy if possible. Because of the narrower scope of clinical expression and the reliability of current mutation-analysis techniques, MEN 2 and its related syndromes do not have the same difficulty of classification as MEN 1. A recent international consensus statement points out that criteria for FMTC Table 2 Characteristics of Multiple Endocrine Neoplasia Type 2 (MEN 2) MEN 2A Medullary carcinoma of the thyroid Pheochromocytoma HPT MEN 2B Medullary carcinoma of the thyroid Pheochromocytoma Mucosal neuromas Marfanoid habitus Typical facies Ganglioneuromas of oropharynx and intestinal tract Abbreviation: HPT, hyperparathyroidism.

Chapter 54: Multiple Endocrine Neoplasia: Types 1 and 2

should be rigorous enough to exclude MEN 2 with late presentation of secondary tumors. These criteria include more than 10 carriers within a kindred, multiple carriers or affected members over the age of 50, and an adequate medical history (11). These rigorous standards should prevent inaccurately designating a true MEN 2 kindred as FMTC and thereby missing a pheochromocytoma. Screening of at-risk MEN 2 and FMTC family members by measurement of serum calcitonin or, preferably, by genetic testing for the presence of RET mutations, identifies affected individuals who are offered preventative thyroidectomy. In patients who present with advanced MTC, management is directed toward control of symptoms and bulky disease. Occasionally, patients will present with episodic headache, dizziness, or other symptoms to suggest pheochromocytoma, and symptoms of HPT are unusual presenting findings in the MEN 2 syndromes.

Medullary Thyroid Carcinoma MTC, overall, is a rare malignancy, comprising 5% to 10% of all thyroid malignancies. Nearly 75% of cases are sporadic, while MEN 2A, MEN 2B, and FMTC constitute the remaining 25% in decreasing order of frequency. MTC is usually the earliest clinical abnormality in MEN 2, diagnosed before or concurrently with pheochromocytoma. Sporadic MTC is nearly always unilateral, while in patients with MEN 2 or FMTC, it is almost always bilateral and multifocal. The characteristic distribution is multicentric foci of tumor in the middle and upper portions of each thyroid lobe. A diffuse proliferation of C-cells known as C-cell hyperplasia is seen in patients with MEN 2 and FMTC, and is thought to be a malignant precursor to MTC. Parafollicular clusters of increased numbers of C-cells represent the early manifestation of hyperplasia or microinvasive carcinoma that ultimately progresses to multifocal MTC. The presence of bilateral MTC or C-cell hyperplasia strongly suggests the presence of familial disease. MTC appears grossly as a circumscribed, gritty, whitish-tan nodule. Histologically, it appears as sheets or nests of uniform cells separated by variable amounts of stroma (46). An amyloid-like material is frequently present in the stroma of MTC, and consists of accumulated calcitonin prohormone secreted by tumor cells (47). The presence of this material is a distinctive feature of MTC, but is not uniformly present. Immunohistochemical staining for calcitonin within tumor cells is diagnostic of MTC. MTC cells are capable of diverse biosynthetic activity and have been reported to secrete (in addition to calcitonin) corticotropin, prostaglandins, melanin, and serotonin. Although rare, paraneoplastic syndromes have been reported with MTC, including Cushing’s syndrome and the carcinoid syndrome. The most significant biologically active product of MTC is calcitonin. Clinically, this causes diarrhea in up to 30% of patients, attributed to increased jejunal water and electrolyte secretion secondary to high plasma calcitonin levels. More often, calcitonin secretion is clinically silent. However, it is a reliable tumor marker for the presence of MTC, whether in preoperative screening or postoperative evaluation, and serum levels correspond to burden of disease and response to therapy (48). Clinically evident MTC most often presents as a palpable thyroid nodule or multinodular thyroid gland. Metastatic disease is suggested by palpable cervical lymph nodes. Fine needle aspiration of thyroid or cervical nodal disease in combination with serum calcitonin makes the

1029

diagnosis. Symptoms such as hoarseness, respiratory difficulty, or dysphagia suggest invasion of adjacent structures and imply locally advanced disease. The pattern of metastatic spread is first to local–regional lymph nodes and then to distant organs. The most commonly involved sites of distant metastases are liver, lung, and bone. Metastasis of MTC in MEN 2 commonly occurs in a miliary pattern of diffuse fine deposits, in contrast to sporadic MTC where metastases more often are larger and fewer in number. Once MTC is clinically evident, the frequency of metastatic disease is high. Patients with a palpable neck mass have an alarmingly high rate of cervical lymph node metastases. In our series, patients with unilateral palpable MTC had nodal metastases in 81% of central nodal compartments, 81% of ipsilateral levels II to V compartments, and 44% of contralateral levels II to V nodes. Patients with bilateral MTC had metastases in 78% of central nodal compartments, 71% of levels II to V nodes ipsilateral to the largest intrathyroid tumor, and 49% of levels II to V nodes contralateral to the largest intrathyroid tumor (49). Historically, measurement of serum calcitonin levels was used to diagnose occult MTC in MEN 2 patients. This was demonstrated by Melvin et al. who showed that patients with clinically occult MTC had either minimally elevated calcitonin levels, or normal basal calcitonin levels that dramatically increased after calcium infusion (50). Later, pentagastrin infusion alone (0.5 mg/kg over 5 sec) (51), and then calcium followed by pentagastrin infusions (2 mg/kg of calcium gluconate over 1 min followed by 0.5 mg/kg of pentagastrin over 5 sec) (52), were demonstrated to be more potent calcitonin secretagogues. Stimulated plasma calcitonin levels above 300 pg/mL are highly suggestive of MTC, and the diagnosis is virtually assured in patients with stimulated plasma calcitonin levels exceeding 1000 pg/cc. Although sensitive and specific, provocative testing is expensive and labor intensive and is associated with side effects that affect compliance with annual testing. Identification of RET mutations has enabled direct genetic testing, which can be performed at any age and requires only the collection of a single peripheral blood sample. Clinical data suggest that DNA testing is more accurate for the diagnosis of early MTC. Various groups have reported that patients with RET mutations but normal provocative calcitonin assays often have microscopic MTC (53–57). Today, genetic testing has supplanted stimulated calcitonin assay for the screening of potential MEN 2 carriers, and enables the earliest intervention before the occurrence of MTC. The operative treatment of MTC is total thyroidectomy. Meticulous removal of all thyroid tissue should be done at the initial operation, because MTC in the setting of MEN 2 is nearly always multifocal and bilateral, and all C-cell containing tissue is at risk for subsequent malignancy. Because MTC develops in essentially all patients with MEN 2 and because thyroidectomy is well tolerated, it can be argued that patients become candidates for thyroidectomy as soon as a RET mutation is identified, regardless of age. Although long-term data are still pending, early thyroidectomy has proven an effective management strategy to prevent metastatic MTC and improve outcomes in patients with MEN 2. An older series of patients undergoing early thyroidectomy reported no evidence of disease in 19 of 22 patients at a mean of 11 years of follow-up (54). A more recent European series reported persistent or recurrent disease at four years of follow-up in only 6 of 71 patients with germline mutations undergoing early thyroidectomy (55).

medwedi.ru

1030

Part Seven: The Endocrine System

The treatment failures in both of these studies can be attributed to later operations after biochemical evidence of MTC. In 22 patients with RET mutations but no biochemical evidence of MTC, undergoing prophylactic thyroidectomy, C-cell hyperplasia was discovered in 7, intrathyroidal MTC in 14, and lymph node metastases in 1 (56). These results suggest that early prophylactic thyroidectomy can be curative or preventive in almost all MEN 2 patients. The recent Consensus Conference on MEN offers stratified guidelines for the timing and specific thyroid management of MEN 2 patients based upon specific codon mutations (11). These reflect genotype–phenotype associations for certain mutations. Codon 883, 918 or 922 mutations (those associated with MEN 2B) are designated as level 3 risks and thyroidectomy with central node dissection is recommended within the first six months of life. Patients with codon 611, 618, 620 or 634 mutations are stratified as level 2 and thyroidectomy with or without central node dissection is recommended before the age of five. Patients with codon 609, 768, 790, 791, 804 or 891 mutations are stratified as level 1 and thyroidectomy is recommended for these patients before the age of 5 or 10 years (little consensus was reached for the management of these patients) (11). Patients with palpable or clinically evident MTC should undergo central neck dissection (right and left levels VI and VII nodes), and ipsi- or bilateral functional neck dissections with removal of levels II to V nodes (49). The goal of this operation is removal of all nodal tissue from the level of the hyoid bone superiorly to the innominate vessels inferiorly. Management of the parathyroid glands is controversial. Some experts, including the authors, recommend four-gland parathyroidectomy with autotransplantation (58), arguing that central node dissection is extremely difficult if the parathyroid glands are left in place with an adequate blood supply. Other experts recommend leaving the parathyroid glands in situ (57). The unreliability of intraoperative assessment to distinguish involved nodes underscores the importance of removing all central nodal tissue. In our series of 73 neck dissections for palpable MTC, intraoperative palpation of lymph nodes had a sensitivity of 64% and a specificity of 71% for identifying metastatic disease. Thus intraoperative assessment would miss involved nodes 36% of the time (49). After the initial operation, patients are followed with serial serum calcitonin levels. This and calcium–pentagastrin stimulation readily detect residual or recurrent disease. More than 50% of patients with MTC develop persistent or recurrent disease after primary surgical resection, forming a difficult population to manage. Radioactive iodine and radiation therapy have not been demonstrated to be effective treatment options (59–61). Chemotherapeutic combinations have been ascribed only limited success in case reports (62–64). Currently, there is no accepted systemic therapy for recurrent or metastatic MTC. MTC often has an indolent biological course, and although early metastases to the cervical lymph nodes may occur, it may remain confined to the neck for many months or years. Some groups have demonstrated biochemical cure of patients with persistent disease after their initial operation, through neck reoperation and meticulous lymph node dissection in approximately one third of cases (65,66). Before neck reoperation is attempted, distant metastatic spread should be assessed. Traditionally, this has been done by CT or MRI scanning of the chest, abdomen, and pelvis. However, a trial involving 41 patients who had persistent or recurrent MTC and who underwent laparoscopic or open

liver examination and biopsy discovered metastatic liver deposits in seven patients with normal CT or MRI examinations (67). Our continued experience has supported these findings, and we currently employ diagnostic laparoscopy in patients being considered for neck reoperation for persistent or recurrent MTC. Cases with distant metastatic disease should be considered individually. In general, we recommend resection of bulky or symptomatic disease. The prognosis of MEN 2A and 2B is essentially that of the thyroid lesion (68). MTC generally has an intermediate grade of malignancy compared with the more aggressive anaplastic thyroid carcinomas or the more benign papillary or follicular carcinomas. However, MTC exhibits variable biological aggressiveness within the different MEN 2 syndromes and varies, sometimes, from kindred to kindred. Most important, the MTC associated with MEN 2B is very aggressive and patients may die at a young age. MTC in the setting of MEN 2A is more frequently indolent and progresses slowly.

Pheochromocytoma Pheochromocytomas in patients with MEN 2A and 2B appear in the second or third decade of life. In contrast to sporadic pheochromocytoma where bilateral pheochromocytoma is unusual, approximately 60% of pheochromocytomas in the setting of MEN 2 are bilateral. Most tumors present after or concurrent with the diagnosis of MTC, and are infrequently the initial presenting feature. Historically, sudden death from pheochromocytoma was a frequent occurrence in 2 families, perhaps equaling the mortality from MTC. Today, accurate characterization of the syndrome and identification of carriers, along with improved management of pheochromocytoma have decreased morbidity associated with this aspect of the disease. The spectrum of clinical symptoms ranges from silent disease to dramatic symptoms including headache, episodic diaphoresis, palpitations, and anxiety. Pheochromocytoma in MEN 2 is nearly always limited to the adrenal medulla and is nearly always benign. Histologically, MEN 2–associated pheochromocytomas have an identical appearance as sporadic pheochromocytoma. However, patients with MEN 2 develop hyperplasia of the adrenal medulla, which may be a precursor of pheochromocytoma. A spectrum of diseases, including nodular or asymmetrical hyperplasia, multiple small pheochromocytomas, or a diffuse thickening of all adrenal medullary tissue, may be observed. This pattern of adrenal involvement is comparable to C-cell hyperplasia within the thyroid gland of patients with MEN 2. The diagnosis of pheochromocytoma in patients with MEN 2 is made biochemically, as for sporadic pheochromocytoma. This is accomplished by measuring urinary excretion of catecholamines and catecholamine metabolites. A 24-hour collection is obtained for measurement of total urinary catecholamines, epinephrine, norepinephrine, metanephrines, and vanillylmandelic acid. Measurement of serum metanephrines is also an acceptable test. High catecholamine or metanephrine levels warrant a CT or MRI to evaluate the adrenal glands. If anatomic imaging is uninformative or equivocal, 131I-metaiodobenzylguanidine scintigraphy may be performed. This study has been shown to have 90% sensitivity and 95% specificity for pheochromocytoma (69). Elevated catecholamine levels in MEN 2 patients may, however, be due to the presence of adrenal medullary hyperplasia, and imaging may not demonstrate a discreet

Chapter 54: Multiple Endocrine Neoplasia: Types 1 and 2

lesion. In these instances, observation with interval imaging is frequently recommended. As in sporadic cases, all patients with MEN 2 and pheochromocytoma must receive adequate alpha-adrenergic blockade prior to adrenal surgery to prevent intraoperative adrenergic crisis. Alpha-blockade consists of phenoxybenzamine administered to the point of postural hypotension. Beta-adrenergic blockade can be added to treat secondary tachycardia or arrhythmia, but should not be administered alone to avoid unopposed vasoconstriction. The definitive treatment of pheochromocytoma is surgical excision. For unilateral disease in the setting of MEN 2, we recommend unilateral adrenalectomy. Proponents of bilateral adrenalectomy argue that adrenal medullary hyperplasia in MEN 2 is almost universally bilateral, there is a substantial risk of subsequent development of pheochromocytoma following unilateral adrenalectomy, and the risk of complications of the anadrenal state should be low. We have found that pheochromocytoma develops in approximately half of the patients with MEN 2 following unilateral adrenalectomy after a mean interval of 12 years. Conversely, we have found that approximately one quarter of patients undergoing bilateral adrenalectomy develop at least one addisonian crisis (70). Our group advocates unilateral adrenalectomy for patients with MEN 2 and a unilateral pheochromocytoma based on the 50% rate of recurrence over a prolonged duration of time, the rarity of malignant pheochromocytoma, effective screening regimens, and the substantial morbidity and mortality associated with the addisonian state. These patients continue to be monitored yearly for the development of a contralateral pheochromocytoma. Intraoperative considerations include avoidance of hyper or hypotension, early ligation of the adrenal vein, and minimal manipulation of the tumor. Laparoscopic adrenalectomy has become the preferred option for experienced laparoscopic surgeons and patients with well-localized unilateral disease. Comparable or even superior results, with regard to operative time, complication rates, hospital stay, and mortality, have been reported for laparoscopic versus open resection (71,72). Cortical-sparing adrenalectomy, both laparoscopic and open, is a new technique that has been described and advocated for bilateral pheochromocytoma (73,72). This approach is frequently not possible in patients with MEN 2 because of the location of the primary tumor, and the presence of a diffusely thickened gland secondary to hyperplasia. It is imperative that patients with known or suspected MEN 2 have pheochromocytoma excluded before undergoing any operation, including thyroidectomy for MTC. This is particularly important because the pheochromocytoma may be silent clinically but may place the patient at a severe operative risk. If a patient is found to have concurrent pheochromocytoma and MTC, adrenalectomy should be performed after adequate alpha-adrenergic blockade, followed by thyroidectomy in the next several weeks.

Parathyroid Glands HPT is the most variable component of the MEN 2A syndrome, occurring in 20% to 30% of patients. It is associated with certain RET mutations, particularly with mutations in codon 634 (74). In general, it is milder in patients with MEN 2A than in those with either sporadic disease or MEN 1. Many patients are asymptomatic and recognition of HPT may stem from the finding of hypercalcemia during routine laboratory studies, or finding one or more enlarged

1031

parathyroid glands at the time of thyroidectomy for MTC in a patient who is normocalcemic. The most common sign of HPT in patients with MEN 2A is the presence of asymptomatic or symptomatic renal stones and more advanced signs, such as osteitis fibrosa cystica or nephrocalcinosis, are unusual. The parathyroid lesions in MEN 2A consist primarily of generalized chief cell hyperplasia. Still, multiple parathyroid gland enlargements may occur, and it is not infrequent to encounter a single ‘‘adenoma.’’ As in sporadic cases or patients with MEN 1, an elevated PTH level confirms the diagnosis. Surgical management of HPT in MEN 2A is somewhat controversial. Options include selective parathyroidectomy (excision of grossly enlarged glands only), subtotal (three and one-half) parathyroidectomy, or total parathyroidectomy with heterotopic autotransplantation of parathyroid tissue into the forearm. The principal arguments against total parathyroidectomy with autotransplantation are that it is associated with unacceptable rates of postoperative hypoparathyroidism and that cure rates for patients with MEN 2A and HPT are excellent with lesser procedures (75,76). In experienced hands, however, autotransplantation is highly successful. The importance of removing all thyroid tissue for the management of MTC in MEN 2A and the attendant difficulty of doing so while keeping the parathyroid blood supply intact argue in favor of total parathyroidectomy. Additionally, HPT in MEN 2A tends to be a multiglandular disease with an increased risk of persistent or recurrent HPT after any procedure. As discussed, recurrent HPT in patients with parathyroid tissue left in situ require neck reexploration and its associated risks. For these reasons, we advocate four-gland parathyroidectomy with heterotopic forearm autotransplantation.

Nonendocrine Manifestations of MEN 2A and 2B MEN 2A and 2B both have distinct nonendocrine features, evidence of the systemic effects of abnormal RET function. As noted, some families with MEN 2A have associated HSCR, a phenotype that is associated with specific RET mutations (44). HSCR, in this setting, presents in a similar manner to sporadic disease and requires early surgical intervention to manage the distal GI obstruction. Several families with MEN 2A have been described, which feature intercapsular lesions of cutaneous lichen amyloidosis (77). This finding is particularly associated with RET codon 634 mutations (78). These lesions are not malignant, but are associated with pruritis in affected areas. Patients with MEN 2B develop several striking abnormalities of the musculoskeletal and nervous systems. Unlike patients with MEN 1 or 2A, these patients have a characteristic phenotype, including a tall, thin ‘‘marfanoid’’ body habitus. Patients develop diffuse ganglioneuromatosis of the GI tract. Externally, multiple neuromas are visible on the lips, tongue, and oral mucosa (Fig. 1). Histologically, GI tract ganglioneuromas demonstrate hypertrophy and nerve fiber disarray of the myenteric and submucosal plexuses. Almost all of these patients will demonstrate some degree of GI symptoms, which can include excessive flatulence, abdominal distention, abdominal pain, constipation or diarrhea, difficulty swallowing, and vomiting. Imaging commonly reveals chronic megacolon, and a significant proportion of them require abdominal surgery (79). MEN 2B patients also demonstrate other evidence of neurologic abnormalities, including hypertrophied corneal nerves on slit-lamp examination of the eyes.

medwedi.ru

1032

Part Seven: The Endocrine System

patients should have regular measurement of calcitonin levels to screen for MTC or recurrence. Additionally, serum metanephrine levels screen for pheochromocytoma, and calcium and PTH levels screen for HPT.

SUMMARY

Figure 1 Patient with MEN 2b. Note the small tumors on the tongue and the puffy lips.

Screening Because MEN 2 is associated with only a limited number of specific activating RET mutations, genetic testing for MEN 2 through DNA sequencing is generally informative. Over 95% of MEN 2 index cases have an identified RET mutation, and the RET locus has not been excluded in any MEN 2 family. Described mutations fall within exons 10, 11, 13, 14, and 15, and so only these exons must be sequenced routinely. Sequencing of the remainder of the gene, haplotype, or genetic-linkage analysis is reserved for families in which initial sequencing is uninformative. Early intervention in MEN 2 and FMTC dramatically affects outcome, and so mutation analysis is mandated for suspected cases. Any patient with early onset MTC, multifocal MTC, or C-cell hyperplasia should undergo mutation analysis. The same holds true for multifocal pheochromocytoma or adrenal medullary hyperplasia. Some have even advocated more aggressive screening of any patient with MTC or pheochromocytoma. The likelihood of a germline RET mutation in cases of apparently sporadic MTC is 1% to 7% (80), while the likelihood of an underlying hereditary syndrome [MEN 2, von Hippel Lindau (VHL) disease, neurofibromatosis type 1 (NF1), or hereditary pheochromocytoma] in cases of apparently sporadic pheochromocytoma is at least 20% (81). These modest but significant likelihoods form the basis for recommendations that all cases of apparently sporadic MTC undergo RET-mutation analysis, and that all cases of apparently sporadic pheochromocytoma undergo RET, VHL, and NF1 analysis and other screening studies for MEN 2 or VHL. At risk family members within MEN 2 kindreds must undergo RET-mutation analysis. Before this, family members should speak with a genetic counselor about the implications of genetic testing. Specifically, they should be educated about forms of inheritance, the likelihood of inheriting an autosomal-dominant disorder, risks and benefits associated with genetic testing, and the implications for treatment, including the need for prophylactic thyroidectomy. These sensitive issues are complicated by the fact that many of these patients are children and intervention is necessary at a young age. For rare patients whose carrier status is in question, or those known carriers who have undergone thyroidectomy, biochemical testing forms the mainstay of screening. These

While most tumors of the endocrine system arise sporadically and involve a single gland, a subset of patients present with neoplastic disease involving multiple endocrine tissues. Two clinical syndromes are now well established and develop familiarly in an autosomal-dominant pattern. MEN 1 is characterized by the familial association of tumors involving the pituitary gland, parathyroid glands, and the pancreatic islets. The familial association of MTC and pheochromocytoma has been designated MEN 2. Two variants of MEN 2 are now known to exist. MEN 2A is characterized by the concurrence of MTC, pheochromocytoma, and hyperparathyroidism. The less common but more lethal MEN 2B is characterized by the association of MTC and pheochromocytoma in concurrence with mucosal neuromas, oropharyngeal and intestinal ganglioneuromatosis, and a marfanoid habitus. Because the genetics of these two syndromes have become better classified and various biochemical markers have become available, patients at risk can now be diagnosed earlier allowing less extensive surgical procedures to be employed for management. The lethal outcomes that previously were associated with these syndromes are now exceedingly uncommon, and the focused and expeditious treatment that is now possible has allowed patients with these conditions to enjoy long and productive lives.

REFERENCES 1. Wermer P. Genetic aspects of adenomatosis endocrine glands. Am J Med 1954; 16:363. 2. Larsson C, Skogseid B, Oberg K, et al. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988; 332:85. 3. Knudson AG, Hethcote HW, Brown BW. Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc Natl Acad Sci USA 1975; 72:5116. 4. Chandrasekhrappa SC, Guru SC, Manickamp P, et al. Positional cloning of the gene for multiple endocrine neoplasiatype 1. Science 1997; 276:404. 5. Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 1999; 96:143. 6. Agarwal SK, Kester MB, Debelenko LV, et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997; 6(7):1169–1175. 7. Bassett JH, Forbes SA, Pannett AA, et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 1998; 62(2):232. 8. Wautot V, Vercherat C, Lespinasse J, et al. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat 2002; 20(1):35. 9. Majewski JT, Wilson SD. The MEA I syndrome: an all or none phenomenon? Surgery 1979; 86:475. 10. Glascock MJ, Carty SE. Multiple endocrine neoplasia type 1: fresh perspective on clinical features and penetrance. Surg Oncol 2002; 11(3):143. 11. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocr Metab 2001; 86:5658.

Chapter 54: Multiple Endocrine Neoplasia: Types 1 and 2 12. Ballard HS, Frame B, Hartsock RJ. Familial endocrine adenoma-peptic ulcer complex. Medicine 1964; 43:481. 13. Wells SA, Farndon JR, Dale JK, et al. Long term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980; 192:451. 14. Norton JA, Cromack DT, Shawker TH, et al. Effect of parathyroidectomy in patients with hyperparathyroidism and multiple endocrine neoplasia type I. Surgery 1987; 102:958. 15. Mutch MG, Frisella MM, DeBenedetti MK, et al. Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type I. Surgery 1997; 122:1012. 16. Vieto RJ, Hickey RC, Samaan NA. Type 1 multiple endocrine neoplasias. Curr Probl Cancer 1982; 7:1. 17. Thompson NW, Vinik AI, Eckhuaser FE. Microgastrinomas of the duodenum. Ann Surg 1989; 209:396. 18. Delcore RJ, Cheung LY, Freisen SR. Characteristics of duodenal wall gastrinomas. Am J Surg 1990; 160:621. 19. Norton JA, Doppman JL, Jensen RT. Curative resection in Zollinger-Ellison syndrome: results of a 10 year prospective study. Ann Surg 1992; 215:8. 20. Norton JA, Fraker DL, Alexander HR, et al. Surgery to Cure the Zollinger-Ellison Syndrom. N Engl J Med 1999; 341(9):635. 21. Van Heerden Ja, Smith SL, Miller LJ. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. Surgery 1986; 100:971. 22. Yim JH, Siegel BA, DeBenedetti MK, et al. Prospective study of the utility of somatostatin receptor scintigraphy in the evaluation of patients with multiple endocrine neoplasia type 1. Surgery 1998: 124:1037. 23. Cohen MS, Picus D, Lairmore TC, et al. Prospective study of provocative angiograms to localize functional islet cell tumors of the pancreas. Surgery 1997; 122:1091. 24. Gauger PG, Scheiman JM, Wamsteker EJ, et al. Role of endoscopic ultrasonography in screening and treatment of pancreatic endocrine tumors in asymptomatic patients with multiple endocrine neoplasia type 1. Br J Surg 2003; 90:748. 25. Cadiot G, Vuagnat A, Doukhan I, et al. Prognostic factors in patients with multiple endocrine neoplasia type 1. Gastroenterology 1999; 116:286. 26. Wiedenman B, Jensen RT, Mignon M, et al. Preoperative diagnosis and surgical management of neuroendocrine gastroenteropancreatic tumors: general recommendations by a consensus workshop. World J Surg 1998; 22:309. 27. Doherty GM, Thompson NW. Multiple endocrine neoplasia type 1: duodenopancreatic tumors. J Int Med 2003; 253:590. 28. Carty SE, Helm AK, Amico JA, et al. The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 1998; 124:1106. 29. Eisenberg AA, Wallerstein H. Pheochromocytoma of the suprarenal medulla (paraganglioma): a clinicopathologic study. Arch Pathol 1932; 14:818. 30. Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961; 31:163. 31. Williams ED. A review of 17 cases of carcinoma of the thyroid and pheochromocytoma. J Clin Pathol 1965; 18:288. 32. Williams ED, Pollock DJ. Multiple mucosal neuromata with endocrine tumors: a syndrome allied to von Recklinghausen’s disease. J Path Bacteriol 1966; 91:71. 33. Tashijian AH, Howland BG, Melvin KEW, et al. Immunoassay of human calcitonin: clinical measurement, relation to serum calcium and studies in patients with medullary carcinoma. N Engl J Med 1970; 283:890. 34. Simpson NE, Kidd KK, Goodfellow PJ, et al. Assignment of multiple endocrine neoplasia type 2a to chromosome 10 by linkage. Nature 1987; 328:528. 35. Norum RA, Lafreniere R, O’Neal LW, et al. Linkage between MEN 2B and chromosome 10 markers linked to MEN 2A. Genomics 1990; 8:313. 36. Mulligan LM, Eng C, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993; 363:458.

1033

37. Hofstra RMW, Ladsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367:375. 38. Schuchardt A, D’Agati V, Larsson-Blomber L, et al. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor RET. Nature 1994; 367:380. 39. Durbec P, Macos-Gutierrez CV, Kilkenny C, et al. GDNF signaling through the Ret receptor tyrosine kinase. Nature 1996; 381:789. 40. Kotzbauer PT, Lampe PA, et al. Neurturin, a relative of glialcell-line-derived neurotrophic factor. Nature 1996; 384:467. 41. Santoro M, Carlomagno F, Romano A, et al. Activation of RET as a dominantly transforming gene by germline mutations of MEN2A and MEN2B. Science 1995; 267:381. 42. Romeo G, Ronchetto P, Luo Y, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprungs’s disease. Nature 1994; 367:377. 43. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994; 367:378. 44. Borst MJ, VanCamp Jm, et al. Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung’s disease. Surgery 1995; 117:386. 45. Howe JR, Norton JA, Wells SA. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery 1993; 114:1070. 46. Bigner ML, Mendelsohn G, Wells SA, et al. Medullary carcinoma of the thyroid in the multiple endocrine neoplasia IIa syndrome. Am J Surg Pathol 1981; 5:459. 47. Sletten K, Westermark P, Natvig JB. Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid. J Exp Med 1976; 143:993. 48. Tisell LE, Dilley WG, Wells SA. Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels. Surgery 1996; 119:34. 49. Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma. Ann Surg 1997; 229:880. 50. Melvin KEW, Miller HH, Tashjian AH. Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N Eng J Med 1971; 285:1115. 51. Hennessy JF, Wells SA, Ontjes DA, Cooper CW. A comparison of pentagastrin injection and calcium infusion as provocative agents for the detection of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 1974; 39:487. 52. Wells SA, Baylin SB, Linehan WM, et al. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978; 188:139. 53. Lips CJM, Landsvater RM, Hoppeneer JWM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2a. N Engl J Med 1994; 331:828. 54. Gagel RF, Tashjian AH, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a: an 18-year experience. N Engl J Med 1988; 318:478. 55. Niccoli-Sire P, Murat A, Baudin E, et al. Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. Eur J Endocrinol 1999; 141(5):468. 56. Rodriquez GJ, Balsalobre MD, Pomares F, et al. Prophylactic thyroidectomy in MEN 2A syndrome: experience in a single center. J Am Coll Surg 2002; 195(2):159. 57. Dralle H, Gimm O, et al. Prophylactic thyroidectomy in 75 children with hereditary medullary thyroid carcinoma. World J Surg 1998; 22:744. 58. Herfarth KK-F, Bartsch D, GM, et al. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2a. Surgery 1996; 120:966. 59. Samaan NA, Schultz PN, Hickey RC. Medullary thyroid carcinoma: prognosis of familial versus nonfamilial disease and the role of radiotherapy. Horm Metab Res 1989(suppl 21): 20–25.

medwedi.ru

1034

Part Seven: The Endocrine System

60. Fife KM, Bower M, Harmer CL. Medullary thyroid cancer: the role of radiotherapy in local control. European J Surg Oncol 1996; 22:588–591. 61. Brierley J, Tsang R, Simpson WJ, et al. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996; 6(4):305–309. 62. Orlandi F, Caraci P, Berruti A, et al. Chemotherapy with dacarbazine and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol 1994; 5:763–765. 63. Schlumberger M, Abdelmoumene N, Delisle MJ, et al. Treatment of advanced medullary thyroid cancer with an alternating combination of 5-FU-streptozocin and 5-FUdacarbazine. Br J Cancer 1995; 71:363–365. 64. Nocera M, Baudin E, Pellegriti G, et al. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5-FU-dacarbazine. Br J Cancer 2000; 83:715–718. 65. Tisell LE, Hansson G, Jansson S, Salander H. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986; 99:60. 66. Moley JF, Dilley WG, DeBenedetti MK. Improved results of cervical reoperation for medullary thyroid carcinoma. Ann Surg 1997; 225:734. 67. Tung WS, Vesely TM, Moley JF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995; 118:1024. 68. Melvin KEW, Tashjian AH, Miller HH. Studies in familial (medullary) thyroid carcinoma. Recent Prog Horm Res 1972; 28:399. 69. Sisson JC, Frager MS, Valk TW, et al. Scintigraphic localization of pheochromocytoma. N Engl J Med 1981; 305:12. 70. Lairmore TC, Ball DW, Baylin SB, Wells SA. Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 1993; 217:595.

71. Cheah WK, Clark OH, Horn JK, et al. Laparoscopic adrenalectomy for pheochromocytoma. World J Surg 2002; 26(8):1048. 72. Matsuda T, Murota T, Oguchi N, et al. Laparoscopic adrenalectomy for pheochromocytoma: a literature review. Biomed Pharmacother 2002; 56(suppl 1):126s. 73. Lee JE, Curley SA, Gagel RF, et al. Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 1996; 120(6):1064. 74. Schuffeneker I, Virally-Monod M, Brohet R, et al. J Clin Endocrinol Metab 1998; 83:487. 75. O’Riordan DS, O’Brien T, Grant CS, et al. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery 1993; 114:1031. 76. Raue F, Kraimps JL, Dralle H, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 1995; 238:369. 77. Gagel RF, Levy ML, et al. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med 1989; 111:802. 78. Hofstra RMW, Sijmons RH, et al. RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia. J Invest Dermatol 1996; 107:215. 79. Cohen MS, Phay JE, Albinson C, et al. Gastrointestinal manifestations of multiple endocrine neoplasia type 2. Ann Surg 2002; 235(5):648. 80. Eng C, Mulligan LM, Smith DP, et al. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol 1995; 43:123. 81. Bryant J, Farmer J, Kessler LJ, et al. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst 2003; 95(16):1196.

PART EIGHT: The Integument and Body Wall

55 The Biology of Wound Healing Dorne R. Yager and Ashley E. Ducale

INTRODUCTION Wound healing is a fundamental and dynamic response to injury. The process of wound healing involves coordinated interactions between a variety of blood- and parenchymally derived cells, soluble factors, and extracellular matrix. Wounds can be caused by any number of physical insults that disrupt the integrity of a tissue. These include surgical incisions, trauma, thermal injury, and radiation injury. Regardless of the cause, most wounds can be expected to heal in a ‘‘timely’’ fashion. A basic understanding of wound healing is fundamental to surgery. This chapter outlines the basic concepts of the biology of wound healing and provides an introduction to the issues facing and options available for wound care management.

PHASES OF HEALING The process of normal healing can be viewed as consisting of a cascade of events with four broadly overlapping phases: hemostasis, inflammation, tissue formation, and tissue remodeling. To understand how each phase contributes to healing, a discussion of these various components is in order.

Hemostasis A direct consequence of injury is local disruption of blood vessels. This triggers three separate responses that work together to stop hemorrhage. Following injury, there is an instantaneous and transient vasoconstriction response by the injured capillaries, thus reducing the flow of blood near the site of injury. A second response involves formation of a platelet plug. Exposure of platelets to fibrillar collagen induces their aggregation at the site of hemorrhage. Serotonin, a vasoconstrictor, adenosine diphosphate, an attractant for platelets, and thromboxane A2, which induces platelet aggregation, degranulation, and vasoconstriction, are all released from stores contained within cytoplasmic granules (1–3). The third response involves coagulation (4). This consists of two different pathways, intrinsic (originating with the release of factor XII by platelets) and extrinsic (originating with the release of factor III from the damaged tissues). Both clotting pathways eventually converge to activate factor X. Activation of prothrombin activator by factor X leads to the sequential conversion of prothrombin to thrombin, and fibrinogen to fibrin. Fibrin initially forms a loose mesh, but then factor XIII causes the formation of covalent cross-links, which convert fibrin to a dense aggregation of fibers. Platelets and red blood cells become caught in this mesh of fiber, thus the formation of a blood clot. The resulting fibrin clot enmeshes the platelet aggregate with two consequences: (i) inhibition of

further blood loss, and (ii) the formation of a provisional matrix that serves as an initial scaffold for repair. This provisional matrix consists primarily of fibrin, fibronectin, and hyaluronan (5). One final consequence of platelet degranulation is the release of a number of bioactive factors. These include growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-b (TGF-b) (6). These growth factors attract and direct the functions of the cells involved in the next phase of healing.

Inflammation Large numbers of neutrophils (polymorphonuclear lymphocytes) begin entering the wound site during the first day following injury. Movement of leukocytes from the circulation into the tissues of the injured site requires three steps. Upon activation by the injury, local endothelial cells express P-selectin and E-selectin, which act to weakly tether circulating leukocytes via their constitutively expressed L-selectin. This loose tethering brings the leukocytes in proximity to chemoattractants and priming factors elaborated by the activated endothelial cells. In response, integrin receptors of the leukocytes are activated and initiate binding to intercellular adhesion molecules and vascular adhesion molecules that are expressed on endothelial cells. Following adhesion, leukocytes then extravasate through the vessel walls and into the damaged tissues (7). Neutrophils have several functions in the repair process. One function is the debridement of the wound by phagocytosis of invading pathogens and devitalized tissue. Neutrophils possess an extensive armamentarium of degradative enzymes that are prepackaged into several types of granules. These include matrix metalloproteinases (MMPs) such as collagenase and gelatinase, and serine proteases such as elastase and cathepsin G (7). Activated neutrophils are also capable of mounting an enormous respiratory burst (8,9). The resulting reactive oxygen intermediates likely act by inactivating invading microbes and perhaps by activating the proteases contained with the neutrophil granules (10). After phagocytosis of devitalized tissue or microbes, neutrophils undergo apoptosis (11). Another prominent leukocyte found in wounds is the macrophage. Macrophages are widely distributed in tissues and are primarily derived from circulating monocytes. Macrophages begin appearing at wound sites 48 to 96 hours following injury and participate in the wound’s debridement, including phagocytosis of apoptotic neutrophils (12,13). Macrophages and to some extent neutrophils, elaborate a number of growth factors that promote healing. These include interleukin-1, tumor necrosis factor-a, fibroblast growth factor (FGF), PDGF, and TGF-b (14,15). These factors have diverse effects. They act to modulate the inflammatory process and help direct the events in the subsequent phase of

medwedi.ru 1035

1036

Part Eight: The Integument and Body Wall

healing. In addition, activated neutrophils and macrophages express inducible nitric oxide synthase (13). Nitric oxide has been implicated in a number of wound-healing events (13).

Fibroplasia (Tissue Formation) Fibroplasia represents the process by which new tissue comprising cells and matrix fills the wound defect. Stimulated by growth factors from the hemostatic and inflammatory phases, mesenchymal cells differentiate into fibroblasts, begin proliferating, and, using the provisional matrix as a scaffold, begin migrating into the wound site. A major function of fibroblasts is to replace the provisional matrix composed primarily of fibrin and fibronectin with one that is composed primarily of fibrillar collagens and proteoglycans. Collagens are the principal structural proteins in skin and all other connective tissues. There are at least 19 types of collagen (16). Types I, II, and III make up approximately 90% of the total collagen found in tissues. By virtue of their unique structures, these collagens form fibrils with enormous intrinsic tensile strength. This is mainly due to interand intramolecular hydrogen bonding. All collagens consist of three subunits coiled into three-stranded helical structures. A repetitive glycine-proline-x motif is found with high frequency and is necessary for the very tight helical structure of the helical portion of the collagen trimer (17). Glycine, the smallest amino acid, is the only one that can fit into the tight center of the helix. Hydrogen bonding between the –NH of glycine with peptide carbonyls of adjacent polypeptides provide stability for the helical structure. After their synthesis, collagen monomers are immediately transported into the lumen of the rough endoplasmic reticulum (Fig. 1). There, they are subjected to a series of posttranslational modifications. Hydroxylation of proline and lysine residues occurs in reactions that require oxygen, ferrous iron, a-ketoglutarate, and ascorbate (18). In turn, hydroxylysines become glycosylated (19). Disulfide bonding between carboxyl termini of the procollagen sequences align the three chains prior to their forming the triple helix. Cleavage of the amino and carboxyl termini of procollagen occurs in the extracellular space as it is secreted. The resulting triple helical molecule, or tropocollagen, begins aggregating into larger structures. Strong,

organized fibrils form by staggered head-to-tail arrangements of the collagen molecules. Lysyl oxidase catalyzes the deamination of lysine that then undergoes intermolecular condensations (20). This cross-linking greatly stabilizes the collagen fibrils. The fibers themselves can form bundles large enough to be viewed by light microscopy (Fig. 2). The collagens vary in the extent of their helical structures and posttranslational modifications. This allows for a great array of structures and thus, functions. Different collagen types, alone or in combination, are characteristic of different types of tissue. For example, skin and bone comprise mainly type I collagen, while cartilage contains mainly type II collagen (17). Distensible structures such as blood vessels are normally a combination of types III for distensibility and type I for strength. The basal lamina is the thin sheet-like structure upon which most epithelial and endothelial cells attach. Therefore, it is extremely important for the structure and function of organs such as skin, renal tubules, and a whole host of other tissues. Type IV collagen forms an irregular two-dimensional backbone on which the basal lamina is formed. In addition to collagen, fibroblasts also deposit a large number of other proteins and carbohydrate-based molecules. These include fibronectin and proteoglycans such as deramatan sulfate, chondroitin sulfate, and the nonsulfated glycosaminoglycan, hyaluronan (21).

Angiogenesis Reestablishment of the blood supply is crucial to provide nutrients and oxygen to the cells involved in repairing the tissue defect and for the continued maintenance of the newly established tissue. Angiogenesis likely initiates immediately after creation of the wound. Exposure of endothelial cells to the extracellular matrix, various cytokines, and possibly hypoxia induces angiogenesis (22–24). Additional cell types also play important roles in angiogenesis. Macrophages release growth factors including acidic and basic FGF (25). Slightly later after wounding, epithelial cells that have been stimulated by hypoxia begin to express vascular endothelial-cell growth factor (26). Together, these growth factors help orchestrate the events involved in angiogenesis. New capillaries sprout from preexisting small blood vessels (22). Beginning as solid sprouts, capillary buds gradually become hollow to form tubes. These tubes continue being extended until they encounter and merge with another capillary, allowing the circulation of blood. Once the wound is sufficiently vascularized, the process of angiogenesis comes to an end. As the vasculature matures, many of the new blood vessels disintegrate via apoptosis (27).

Epithelialization

Figure 1 Phases of wound healing: Regardless of the type of injury or the affected tissue, wound healing usually follows a predictable pattern involving overlapping but identifiable phases. The time frame and relative importance of each of the phases are functions of the wound type and environment.

Epithelium is a vital component of the skin. It controls fluid loss and protects the host from the external milieu such as invasion of foreign substances such as bacteria and ultraviolet light. Because a wound represents a break in the integrity of the epithelium, these functions are compromised and it becomes important to reestablish this barrier. The partial thickness wound is an example of a wound that requires almost exclusive healing by epithelialization. These wounds include superficial burns, split-thickness donor sites, and abrasions. As with all other aspects of repair, epithelialization is regulated in part by growth factors. These include epidermal growth factor, transforming growth factor-a, and keratinocyte growth factor (28,29). These growth

Chapter 55:

The Biology of Wound Healing

1037

Figure 2 Collagen biosynthesis: Collagen monomers are synthesized on the rough endoplasmic reticulum. As the monomer chain grows, hydroxylation of proline and lysine residues takes place (1). In turn, some of the hydroxylysine residues become glycosylated (2). The C-terminal domains associate and direct the formation of the triple helix (3). The resulting procollagen molecule consists of a large domain with a tight triple helical conformation with the N- and C-terminal domains existing in a nonhelical conformation (4). After secretion (5), procollagen peptidases remove the terminal domains generating tropocollagen (6). Tropocollagen molecules self-assemble into fibrils (7), which in turn, further assemble into fibers (8).

factors stimulate the activation of the epidermal cells. Soon after wounding, basal epidermal cells at the wound edge or from within hair follicles remaining within the wound itself undergo dissolution of their desmosomes (cell–cell contacts) and their hemidesmosome links to the basement membrane (30). This allows the epidermal cells to begin migrating on the dermal surface. Receptors on the surface of the migrating epidermal cells, called integrins, allow these cells to interact with a variety of extracellular matrix proteins of the provisional matrix, which include fibronectin, vitronectin, and collagen. The expression of several proteases such as collagenase, gelatinase, and plasmin by the migrating epidermal cells is also important (30,31). Other epidermal cells at the wound edge begin to proliferate and migrate into the wound site. The migrating epidermal cells appear to exhibit ‘‘contact inhibition’’ in that they continue to move until a continuous single layer of cells have resurfaced the wound. In simple incisional wounds, this process is completed within 24 hours. At this point, the epidermal cells begin to differentiate into more basal-like cells. These cells then begin proliferating and reestablish the basilar to apical multilayered epithelium. With time, the basal epidermal cells

recreate their attachments to the dermis via hemidesmosomes. This provides resistance to sheer forces.

Remodeling During this phase, inflammation and fibroplasia come to an end. It is believed that many of the cells involved in the first phases of repair undergo apoptosis, and as a result the scar tissue becomes relatively acellular. Clinically, this is manifested by the scar becoming progressively less pink as the numbers of blood vessels alsodiminish. Net collagen accumulation in the wound reaches a maximum within two to three weeks after wounding. At this time, the tensile strength of the wound is only a small fraction of the bursting strength of uninjured skin. Although there is no further net gain in collagen accumulation, the tensile strength of the wound gradually increases with time (32). This is a reflection of the continuing process of remodeling where the initially synthesized random collagen fibrils are steadily replaced by fibrils that possess greater organization and with more intermolecular cross-links. This process of remodeling requires a carefully maintained equilibrium between degradation of old collagen and synthesis of new collagen (33). In spite of the

medwedi.ru

1038

Part Eight: The Integument and Body Wall

continual and long-term process of remodeling, the tensile strength of scar tissue only achieves approximately 70% of the strength of normal unwounded skin (32). In addition, scar tissue lacks normal dermal appendages such as hair follicles, sweat glands, and sebaceous glands.

OTHER ASPECTS OF REPAIR Proteases Proteases are involved in virtually every process that occurs during repair. For example, thrombin proteolytically converts fibrinogen to fibrin during hemostasis. Thrombin itself is proteolytically converted from prothrombin by factor X. A wide number of proteases participate in wound debridement. These include serine proteases such as neutrophils elastase and cathepsin G and several members of the MMP family. Proteases probably are involved in facilitating the migration of cells from adjacent tissues into the wound site. Proteases also play an essential role in the remodeling of scar tissues. MMPs are particularly important to the process of repair. As a group, these proteases can enzymatically degrade any protein component found in the extracellular matrix (34). This attribute is particularly important to cells (e.g., fibroblasts, endothelial, and epithelial cells) needing to migrate from the adjacent normal tissues into the wound site. The rate-limiting step in the degradation of collagen is its initial cleavage. There are only three enzymes, all members of the MMP family, capable of initiating the lysis of fibrillar collagen. There is good evidence that all three of these collagenases play a part in the repair of one or more tissues. Because of their overall importance in maintaining tissue homeostasis, the MMPs are subject to regulation at several levels. This includes regulation at the transcriptional level, synthesis as inactive proenzymes that require posttranslational activation, and extracellular inhibition by both MMP-specific and nonspecific inhibitors. Disruption of the regulation of proteases can have important and profound effects on the repair process. Because of the continued activity of proteases, the mature wounds of scorbutic individuals have a significantly increased risk of dehiscence (35). An overexuberant inflammatory response may also play a role in the pathophysiology of chronic wounds (36). A significant number of these wounds contain large amounts of neutrophil-derived proteases that likely inhibit the net deposition of new tissues (37–39).

Contraction Open wounds, to varying degrees, can contract as they heal. In other words, the surrounding skin has the appearance of being pulled toward the center of the wound. This provides two related advantages: first, there is a reduction in the amount of granulation tissue and ultimately, scar tissue needed to fill the defect; and secondly, the wound is to some extent resurfaced with normal skin and not scar. The mechanisms involved in contraction are poorly understood. There is growing evidence that fibroblasts may assume a myofibroblast-like phenotype (40,41). This is primarily characterized by the expression of large bundles of a smooth muscle actin (40,41). The appearance of myofibroblasts correlates with the process of contraction. Wounds that occur across flexor joints (e.g., the neck) as well as in hollow organs (e.g., esophagus) can also be subject to scar ‘‘contracture.’’ In essence, contracture will occur anywhere on the surface of the body where there is not enough loose elastic skin to allow

wound closure without contraction (42). Scar contracture can limit the functional range of motion of the involved joint or mechanically block the function of the hollow organ.

WOUND-HEALING PATHOLOGIES Fibrosis The disproportionate accumulation of collagen resulting in excessive or abnormal scar is a hallmark of fibrosis. Several fibrotic diseases such as hepatic fibrosis, retroperitoneal fibrosis, chronic fibrotic lung disease, tendon adhesions, and ankylosed joints are associated with significant morbidity and mortality. Some fibrotic conditions occur on the skin surface and often present to the surgeon for treatment. These include hypertrophic scar and keloid. Although both hypertrophic scars and keloid scars are associated with excessive collagen depositions, they are fundamentally different. Excessive scars that remain within the boundaries of the wound are termed ‘‘hypertrophic scars’’ (43). With time, hypertrophic scars typically regress. In contrast, keloids, from the Greek word kelois (or crab), extend beyond the original boundaries of the wound, rarely regress with time, and frequently reoccur following excision (44). The etiologies of hypertrophic scar and keloid are not known. Hypertrophic scarring is a frequent complication in deep partial-thickness and third-degree burns that are allowed to heal without grafting. Dark-skinned individuals are more at risk for forming a keloid and there may be a genetic component. There are no consistently effective treatments for keloid. Intralesional administration of corticosteroids such as triamcinolone often induces some shrinkage of the keloid (43). There have been reports of regression of lesions by treatment with pressure dressings or silicone sheets (43). However, there is no true efficacy for such therapy. Irradiation therapy has fallen into disfavor. Surgical excision followed by steroid injection or steroid injection alone remains the best therapy for treating some keloids.

Chronic Wounds Chronic wounds can be best described as those wounds that have failed to heal in a timely fashion. Although this definition would seem to also include instances of fibrosis it more often applied to wounds that exhibit ‘‘insufficient’’ healing. The most common chronic wounds are diabetic ulcers, pressure sores, and venous stasis ulcers. As a group, chronic wounds place a significant and growing socioeconomic burden on western societies. These wounds are invariably associated with a number of predisposing conditions that compromise the healing process. However, it has been hypothesized that at least for the majority of chronic wounds (diabetic, stasis, and pressure ulcers), there are three principal common factors—ischemia/reperfusion injury, microbial load, and age (45).

Ischemia/Reperfusion Injury Ischemia and reperfusion injury have been implicated in the pathophysiology of organ transplantation, hemorrhagic shock, cerebral ischemia, and myocardial infarction (46). Restoration of blood flow to ischemic tissues elicits a cascade of events that include free radical–mediated damage and a cascade of inflammatory events. Although it has not been tested, it seems likely that ischemia/reperfusion injury is involved in the formation of stasis, diabetic and pressure

Chapter 55:

ulcers, and can also contribute to the chronicity of these wounds. A significant number of diabetic, stasis, and pressure ulcers display chronic inflammation (39,47). Inflammation that results from ischemia/reperfusion injury may be further exacerbated by the persistence of devitalized tissue, infection, and intermittent or continuous ischemia. The ensuing exuberant leukocytic response creates an environment rich in degradative enzymes and oxidants that do not have the ability to discriminate between intended targets and normal tissue (7,36). This can interfere with the function of growth factors involved in repair, inhibit the proliferation and migration of cells involved in repair, and impede the deposition of new tissue.

Microbiology The skin has many important functions, but perhaps, none are as paramount as its providing a physical barrier against microbial invasion. All dermal wounds contain some level of microbial contamination and this is typically polymicrobial (48). In most cases, these microorganisms are not of pathogenic importance. Colonization or contamination represents the state wherein microorganisms are able to overcome local defense strategies and successfully compete but do not provoke clinical symptoms or a detectable immune response. In contrast, a wound infection represents a situation where local and systemic host responses are unable to eradicate the bacteria contaminating the wound. Although there is wide agreement that infection can impede the ability of a wound to heal, the ability to precisely define infection remains problematic. Whether infection occurs is probably dependent on a number of factors including microbial numbers, microbial type(s), wound location, wound size and depth, and the general health and immune status of the individual. Devitalized tissues, foreign bodies, and hematomas can promote the growth of microbes. Tissue that is poorly perfused can become hypoxic and permits the accumulation of acidic products such as lactate. These conditions may promote the growth of microbes. Microbial virulence is dependent on several factors. The ability to produce toxins can cause further tissue damage. Quantitative and qualitative aspects of the microbial burden may also influence healing. One of the earliest studies attempting to define infection concluded that healing of pressure ulcers was impaired if the bacterial load of fluid exudate exceeded 106 CFU/mL (49). More commonly, it has become generally accepted that wounds with microbial loads greater than 105 CFU/g of tissue will not heal well (48,50,51). Pathogens such as b-hemolytic streptococci, Staphylococcus aureus, Pseudomonas aeruginosa, anaerobes, and enteric coliforms produce potentially destructive virulence factors. In spite of this, with the possible exception of the P-hemolytic streptococci, there is little evidence that supports the idea that a single particular type of bacteria is harmful (48,50,52). Instead, it appears that infection and wound-healing problems resulting from it correlate better with diversity (52). This is perhaps a reflection of possible synergy occurring between different types of bacteria. An ongoing debate has centered on what is the most valuable sampling technique for making a qualitative and quantitative assessment of wound microbiology. It has been proposed that superficial swabs or biopsies provide a reasonably accurate reflection of the microbial flora of a wound (53,54). The rationale for this view is that most if not all microorganisms found in a wound will have originated superficially or from the skin flora. The method is simple

The Biology of Wound Healing

1039

and relatively noninvasive. Juxtaposed to this, is the belief that the deep tissue environment of a wound differs sufficiently from the surface to make swab or superficial biopsies of little value (55). Several studies have made a direct comparison of swab and deep tissue biopsy sampling and not found significant differences between the two methods (48,56–58). In spite of this, the use of deep tissue biopsy sampling for determining microbial load remains an accepted approach.

Age The skin of the elderly is more fragile, and there is a decline in the thickness of the dermis, and rete pegs become smaller and flatter. Healing in the elderly is slower, albeit with less scarring (59). It has been speculated that this may be due in part to a gradual attenuation of the inflammatory/immune response; however, this conflicts with the observation of increased inflammatory cell levels in the aged (60). Levels of MMP-2 and MMP-9 are also increased in acute and chronic wounds of the aged (61). There is also a decreased proliferative potential in fibroblasts and keratinocytes (62).

Other Important Factors A number of other systemic and local factors or conditions can influence healing. These include nutrition, immunological status, pharmacological impairment, and genetics.

Nutrition Surgery, trauma, and sepsis induce a protein catabolic state (63). Wound healing is an energy requiring process, and therefore severely malnourished individuals have difficulty in wound healing (64,65). Insufficient carbohydrate and fat intake result in the catabolism of protein as an alternative energy source. Hypoproteinemia, in turn, limits the supply of amino acids that are available for synthesis of new protein at the wound site (66). Inadequate levels of amino acids such as arginine also inhibit the immune response (67). In spite of the recognition of the importance of nutrition to wound healing, there remains no single measure of nutritional adequacy. Serum albumin (minimum of 3.5 g/dL) is an often used indicator of general protein and nitrogen balance. Several vitamins have important roles in the healing process (64). Ascorbate (vitamin C) is an essential cofactor in the hydroxylation of lysine and proline in collagen synthesis and cross-linking. Scorbutic individuals heal with poor wound strength and have an increased risk of wound dehiscence, because normal baseline collagen synthesis is impaired. Deficiencies in vitamin A, thiamine, zinc, and iron have a negative influence on healing. Vitamins E and C may both act as antioxidants and thus provide some protection from oxidant stress. Alterations in nutrition caused by cancer are also taken into consideration. Cancer typically elevates carbohydrate and protein consumption, and this in turn can impose limits on the nutrients available for repair processes.

Immunologic Status The immunologic status of an individual can be influenced by genetics, pharmaceutically, and by infection with immunosuppressive agents. The leukocytes of individuals with chronic granulomatous disease are unable to mount an effective respiratory burst and thus do not handle invading microbes as efficiently as normal individuals. Some of the

medwedi.ru

1040

Part Eight: The Integument and Body Wall

immunosuppressive effects of glucocorticoid steroids probably are responsible for the detrimental effect on healing by this class of agents. Similarly, immunosuppression of transplant recipients may also influence the wound healing of these individuals (68,69). Patients with human immunodeficiency virus (HIV) infection have been found to have impaired wound healing (70). The wounds of patients with HIV infection when measured biomechanically are weaker than those of normal non-HIV controls (69).

Genetic The wound care provider must be alert to the existence of the possible role of genetics in wound repair. There are several known defects that reduce the numbers of or effectiveness of cells involved in the repair process (e.g., chronic granulomatous disease and leukocyte adhesion deficiency). A number of defects in connective tissue components have been described. These include osteogenesis imperfecta (congenital form of osteopenia resulting from defects in type I collagen); Ehlers-Danlos syndrome (broad group of collagen and collagen processing enzyme defects); epidermolysis bullosa (defects resulting in poor adhesion between the epidermal and dermal layers); and Marfan’s syndrome (defects in fibrillin or collagen). Although relatively rare, and variable in manifestation, individuals with connective tissue defects represent a significant challenge to the ability of wounds to heal effectively.

Oxygen Adequate levels of oxygen at the site of tissue injury are necessary for repair. Tissue hypoxia or anoxia results in cell and tissue death. Without adequate levels of oxygen, neutrophils and monocytes are unable to mount a respiratory burst response (71). Oxygen is also required to support the migration and proliferation of cells involved in tissue formation. Proliferation requires a tissue oxygen tension (pO2) of 30 mmHg. Collagen synthesis is dependent upon oxygen. It has been shown that wounds with pO2 less than 20 mm heal poorly, whereas those with pO2 greater than 40 mm have a better chance of healing in a timely fashion (72,73). The surgeon must be mindful of key factors required to ensure adequate oxygen perfusion of the wound. Pain and hypothermia result in vasoconstriction, which decreases oxygen delivery to the wound bed. Hypovolemia, even in the presence of normal arterial gases can reduce wound oxygen.

Pharmacologic Impairment There are a variety of agents that while not used directly in the treatment of wounds, may have a significant influence on the repair process. Glucocorticoids possess antiinflammatory and immunosuppressive functions and have a detrimental influence on leukocyte functions, fibroblast proliferation, and on the synthesis of collagen (74). Cancer chemotherapy is frequently directed at inhibiting cell proliferation. It seems likely that chemotherapy, especially regimens utilizing multiple agents, could have a negative influence on repair. Surprisingly, there is little evidence suggesting that this is indeed the case. Studies have shown that doxorubicin and 5-fluoruracil can have deleterious effects on wound-healing events (75,76). Chemotherapeutic agents that target tumor angiogenesis may also influence wound healing. This also raises the issue of whether some other commonly used agents that may inhibit angiogenesis as a side effect might also have an impact on wound healing. This could include such agents as Vioxx,

Celebrex, Enbrel, Doxycycline, Captopril, and Furosemide (Lasix) (77–81). Nicotine is a major pharmacologic threat to efficient healing. Nicotine induces vasoconstriction and elevates carboxyhemoglobin levels (82,83). The resulting reduction in oxygen perfusion to the wound has the potential for impairing repair events.

WOUND MANAGEMENT The management of wounds requires consideration of the wound as well as the patient. As seen from the previous sections, a number of local and systemic factors can interact in a variety of ways to influence wound-healing outcome. In exploring treatment options, wound characteristics such as necrosis, infection, edema, and wound environment, and wound etiology must be assessed. It is not enough to treat the wound itself. Consideration must be given to the fact that behind each wound is a patient; a patient who may have attendant physical and emotional needs that go beyond the boundaries of the wound itself. To be consistently successful, the healer must treat the patient first and the wound second. Legally, one must record the circumstances of the event, which caused the injury. Will the injury cause a functional impairment at work? Do the patients and their families understand the events of healing that one must expect even after the simplest of lacerations? When can the patient resume normal activities? Time and circumstances of injury are also important. Wounds open for longer than l0 to 12 hours are more prone to infection as the bacterial flora within the wound becomes protected by wound proteinaceous secretions and will not be easily removed by lavage. Did the injury occur in a contaminated environment? This may increase the bacterial burden to the tissues and make debridement and cleaning extremely important. Wound location is also an important consideration. Wounds in the extremities tend to have a slower rate of healing than those of the face.

Cleaning and Debriding The first steps in the treatment of traumatic wounds are to bring bleeding under control, to cleanse the wound, and to remove foreign material and devitalized tissue. Acceptable agents for irrigation of wounds without gross contamination include physiological saline solutions and Ringer’s lactate solution. Irrigants containing antiseptics may be warranted for wounds that are badly contaminated (84). However, they require judicious use, because these agents do not discriminate between microbes and otherwise healthy tissues of the patient. Debridement involves the elimination of devitalized and contaminated tissues of the wound. Physically removing dead tissue and bacteria from the wound removes an environment that is favorable to microbial growth. There are several methods by which debridement can be accomplished. (i) Mechanical debridement: When changed, moist to dry gauze dressings provide some measure of physically debriding wounds. When performed properly, these dressings are extremely useful in facilitating the debridement of the interstices of deep irregular wounds. It must be taken into consideration that this form of debridement is nonselective, removing both healthy and necrotic tissue, and can be painful. (ii) Autolytic debridement: Use of some barrier-type dressings such as the hydrocolloid alginates promotes the breakdown of necrotic tissue by the body’s own white blood cells. However, such treatment may actually increase

Chapter 55:

the bacterial count within the wound and thus increase the incidence of infection and subsequent sepsis. (iii) Sharp debridement: Sharp dissection is by far a more effective and rapid form of debridement (85). However, there are drawbacks that may limit its use. For example, pain and bleeding may be problematical unless the procedure is performed in the operating room. In the very elderly and infirm, when wound closure is not the long-range objective, extensive debridement of a large pressure ulcer is rarely indicated unless a simpler method proves unsatisfactory. (iv) Enzymatic debridement: A notable advantage of this method is that it does not necessitate the same skill level that is required for surgical debridement. This method is widely used in nursing homes and situations where surgical debridement by sharp dissection cannot be performed. Ridding the wound of necrosis using this type of debridement, however, is usually slower than sharp debridement. Overall, the type, consistency, adherence, and amount of necrosis will ultimately influence the debridement method utilized. Proper aseptic technique in the operating theater can minimize infection from contamination. Prophylactic use of antibiotics during the perioperative period is justified by the premise that the potential benefit outweighs the possible risk of developing and selecting for resistant strains. There is some general agreement as to the use of systemic antibiotics for treating infection involving deeper tissues. Topical antibiotics and antiseptics are frequently used for treating wounds with no or minimal signs of infection. To what extent their use is efficacious is not clear. There is little evidence supporting the usefulness of routine administration of systemic antibiotics to individuals with chronic wounds (86).

Wound Closure After trauma wounds have been cleaned and debrided, they can be typically closed by direct approximation. Closure by direct approximation (primary closure) facilitates the repair process and usually minimizes scar formation. Wound closure can involve the use of sutures, staples, adhesive tape strips, or tissue adhesives (e.g., cyanoacrylate or fibrin glue). There are two classifications of sutures: absorbable or nonabsorbable. A common example of an absorbable suture is that made from polyglycolic acid polymers. This material maintains its integrity for two to three weeks and induces little inflammatory response. Nylon and silk are typical examples of nonabsorbable sutures. However, many have abandoned silk because it has interstices and may be inflammatory if it remains in the host for a prolonged period of time. Because they are less conducive to wicking, monofilament sutures have the advantage of inducing minimal inflammation. On the other hand, multifilamentous sutures are easier to manipulate. Epithelial tracks followed by scarring can develop in skin sutures left in place longer than 7 to 10 days. However, at this time, the wound has attained only a fraction of strength of unwounded skin. This necessitates a decision whether to compromise cosmesis in lieu of continued support of the direct approximation. Therefore, before the placement of sutures on the surface of the skin, one should try to relieve as much tension on the wound as is possible. Placement of absorbable sutures in the dermis will relieve tension. The skin sutures themselves can be removed after approximately five days without fear of the incision site reopening. Another very popular way of closing skin wounds without the fear of leaving suture marks is to close with a running subcuticular suture of monofilament material such as polypropylene (it is easier to remove

The Biology of Wound Healing

1041

than nylon). A running suture can be left in place until one is confident that the incision has gained sufficient tensile strength for removal without wound margin separation.

Delayed Primary Closure Not all wounds can be immediately closed. In the event of overt or suspected microbial infection, wounds can be left open at the time of injury or surgery. The wounds can then be examined over the course of several days. If there is no evidence of infection, or if it has been brought under control, then the edges can be approximated. Alternatively, wounds can be allowed to heal secondarily. This can require a mixture of granulation tissue formation, re-epithelialization, and contraction. Candidate wounds for secondary closure are encountered in instances of heavy contamination, where there has been significant tissue loss (e.g., pressure ulcers), or in locations where the tissues will not tolerate the strain imposed by approximating the wound edges.

Dressings A plethora of options are available to the clinician for dressing wounds. Appropriate selection and use of dressings require that the dressing needs of a wound be matched with the dressing type that is optimal for that wound. Simple incisional wounds that have been primarily closed require only simple, clean dressings that provide protective coverage. Since the 1960s, it has become generally accepted that a moist environment is advantageous to the healing of partial-thickness and open wounds (87,88). In the absence of a scab, epithelial cells can proliferate and migrate more efficiently to resurface the wound. Collagen synthesis, angiogenesis, and contraction also appear to benefit from a moist wound environment (89). Appropriate selection of a dressing product is dependent upon the wound type and conditions (90,91). Partial-thickness wounds such as graft donor sites, abrasions, and first and second degree burns are best treated with semiocclusive dressings. These dressings provide a moist environment that prevents the formation of scab on the wound surface and reduces desiccation. The absence of a scab physically facilitates re-epithelialization and reduces the amount of scar formation. It is also believed that by preventing desiccation, semiocclusive dressings also promote an environment that is more conducive to the migration and proliferation of the cells involved in repair. A potential problem with semiocclusive dressings is their limited absorption capacity. Excessive fluid accumulation, as might occur during the early phase of repair, can lead to maceration of the wound and surrounding tissues. In these instances, the use of more absorbent dressings such as hydrocolloids is indicated. Hydrocolloids are composed of natural (e.g., gelatin and pectins) or synthetic (polyurethane) hydrophilic materials combined with an adhesive and covered by a semipermeable membrane. Hydrocolloids adhere firmly to the skin surrounding a wound without directly adhering to the wound itself. They are highly absorptive yet maintain a moist wound environment. They also promote some autolytic debridement by virtue of their maintaining a moist environment. Known or suspected infection with anaerobes is a counter indication for the use of occlusive dressings and hydrocolloids. Absorptive fillers are useful in exudative wounds that contain dead space not easily reached by other dressing types. Absorptive fillers can be powders, pads, ropes, or pastes made from alginates, starches, or simple gauzes. Some fillers such as

medwedi.ru

1042

Part Eight: The Integument and Body Wall

collagen dressings have the advantage of liquefying as they are being absorbed, making them easier to remove. Hydrogels are dressings composed primarily of water. Their primary function is to hydrate relatively dry wounds. These dressings have a cooling effect when applied to superficial burns. They are also recommended for application to wound surfaces that might need to be kept moist (e.g., exposed bone or tendon). Because these dressing do not absorb moisture, they are not particularly useful on exudative wounds. Cellulose-based gauze dressings are relatively inexpensive and remain the most commonly used type of wound dressing. Gauze is useful in large exudative wounds that require frequent dressing changes. Gauze can also be used to facilitate mechanical debridement. However, gauze has a propensity to dry out and adhere tightly to the wound bed. Several new dressings intended to provide features that go beyond providing physical protection and moisture control have become available. These include several dressings that possess antimicrobial properties (e.g., iodine or silver releasing dressings). Dressings based on the glyosaminoglycan and hyaluronan have recently entered the market. Hyaluronan is a major component of the provisional matrix and probably is involved in the formation of a highly hydrated environment that promotes cell proliferation and migration. Another dressing product based on a composite of denatured bovine collagen and oxidized regenerated cellulose can seemingly reduce levels of proteolytic activity in wounds. This product probably acts as a competitive inhibitor by introducing a large amount of substrate for the proteases that may be present in a wound.

Skin Grafts, Flaps, and Skin Substitutes Skin grafting provides an effective means of treating burns and some chronic wounds. When first placed onto a wellvascularized bed, the graft receives nutrients by passive diffusion from the underlying tissue. With time, revascularization of the graft occurs primarily from ingrowth of capillaries from the underlying tissues. Skin grafts are classified as partial or split-thickness (0.01–0.015 in. in thickness) and full-thickness grafts. Partial-thickness grafts consist of a layer of epidermis and some dermis. The donor site heals primarily by re-epithelialization from the edges and from islands of keratinocytes that proliferate and migrate out from the hair follicles and other dermal appendages. In contrast, full-thickness grafts include all of the epidermis and dermis. For grafting to be successful, the recipient site must be well vascularized and microbial contamination minimized. In addition, the graft must make complete and stable contact with the recipient site (seroma or hematoma formation will compromise a graft’s survival). In general, partial-thickness grafts have better survival rates than fullthickness grafts and the donor sites also heal more readily. However, wounds treated with full-thickness grafts are subject to less contraction. Skin grafts are not a viable option in wounds that are heavily contaminated with bacteria or lack a wellvascularized base. In these cases, flaps are used to close the wound. Skin flaps differ from grafts in that the intrinsic blood supply of the donor tissue remains intact or the blood supply is reestablished surgically at the time of transfer. There are essentially two types of flaps. Random-pattern flaps receive their blood supply from a number of vessels located within the subdermal plexus. Random-pattern flaps are limited in size because of the limited nature of their

blood supply. In contrast, an axial-pattern skin flap receives its blood supply from a major vessel. In some instances where the axial vessel enters the underlying muscle, the muscle and the overlying skin can be elevated as a single musculocutaneous flap. The development of skin substitutes offers a possible alternative to autografting and allografting of skin. Substitutes range in complexity from nonliving allogeneic acellular matrices to cultured, allogeneic, bi-layered human skin equivalents derived from neonatal skin. INTEGRA1 is a collagen matrix covered with a thin sheet of silicone, which can be placed into a fresh wound bed and allowed to vascularize. The silicone is then removed and the vascularized collagen matrix is covered with a very thin split-thickness skin graft. The use of this material has been successful in skilled hands. However, two procedures are required and ‘‘take’’ is variable. Some reports suggest that there is a reduction in hypertrophic scarring from this method. Other skin substitutes currently marketed include Dermagraft and Apligraf1. The use of skin substitutes in chronic wounds has shown a measure of success. However, their cost is high compared to conventional therapies.

Perfusion/Hyperbaric Oxygen Therapy Ischemic wounds heal poorly. A hypoxic environment is not conducive to the proliferation, migration, and function of cells involved in the wound-healing process; whereas, it favors the growth of anaerobic microbes. There is now some evidence that hyperbaric oxygen (HBO) therapy involving the intermittent inhalation of 100% oxygen at pressures greater than 1 atm can improve wound-healing outcome (92,93). Increased oxygen tension may promote leukocyte microbicidal functions, angiogenesis, and fibroblast proliferation. At present, HBO therapy should be restricted to wounds involving acute traumatic ischemia, infection by clostridial organisms, necrotizing soft tissue infections, and selected nonhealing problematic wounds.

Vacuum-Assisted Wound Closure Developed in the past decade, vacuum-assisted closure has experienced a rapid growth in acceptance (94,95). A foam dressing is applied to the wound and the wound sealed with an occlusive dressing. Low-level (125 mmHg) negative pressure is then cyclically applied. This approach is effective in accelerating closure of open acute wounds and in successful application of skin grafts (96). The mechanism(s) by which this device assists healing is not clear. Candidate mechanisms include removal of interstitial pressure, restoration of blood flow and perfusion, removal of cytotoxic factors and proteases, and mechanical induction of wound-healing activity.

Treatment of Chronic Wounds Chronic wounds are broadly defined as open wounds that have failed to heal in a timely (i.e., three months) fashion. As a group, chronic wounds place a significant and increasing socioeconomic burden on Western societies. These wounds are almost invariably associated with predisposing conditions that compromise the healing process. The pathophysiologies of chronic wounds are complex and diverse. Underlying conditions can be neurological, metabolic, vascular, psychiatric, or perhaps most commonly, a combination of these factors. Successful management of chronic wounds is generally dependent upon recognition of and concomitant treatment of the underlying causes for the

Chapter 55:

chronic wound. A large percentage of chronic wounds are associated with chronic inflammation. This may be the result of persistence of devitalized tissue, infection, and intermittent or continuous ischemia. The ensuing exuberant leukocytic response creates an environment rich in degradative enzymes and oxidants that do not have the ability to discriminate between intended targets and normal tissues. This concept has led to some recent interest in developing strategies that modulate the inflammatory component of chronic wounds. Debridement removes devitalized tissue and reduces the microbial burden, and antibiotics (topical or systemic) are used to control infection. Management of the nutritional and pharmacological state of the individual helps set the stage for healing. As addressed below, specific approaches are used to treat chronic wounds resulting from pressure, venous insufficiency, and diabetes.

Leg Ulcers Leg ulcers can occur in individuals displaying lower limb arterial or venous insufficiency. Smoking, hyperlipidemia, hypertension, obesity, and age all predispose individuals to local tissue ischemia in the lower limbs with a greatly increased risk of retarded wound healing. Treatment requires addressing the need for adequate perfusion along with cleaning and debriding of the wound site. More than half of all leg ulcers are directly the result of increased pressure in the venous system. Most venous hypertension is a reflection of the insufficiency of the valves in the deep venous system and the lower perforating veins (97). Valvular incompetence negates the ability of the calf muscle pump to aid in the return of blood to the heart from the lower limbs. The capillaries are subjected to increased tension and become malformed. There is leakage of plasma proteins resulting in a protein-rich edema and the appearance of discontinuous fibrin cuffs. Microthrombi form, occlude the capillaries, and activated leukocytes accumulate. The resulting edema likely contributes to a localized tissue hypoxia. Eventually, this hypoxia in conjunction with the activated leukocytes leads to a breakdown of tissue, resulting in a venous stasis ulcer. Initial treatment involves cleansing and debridement of proteinaceous exudate. Compression therapy aimed at controlling edema and the venous hypertension itself is essential. The first objective in treating ulcers resulting from arterial insufficiency is to improve perfusion. This requires surgical interventions including grafting, percutaneous transluminal angioplasty, thrombolysis, and placement of stents.

Diabetic Ulcers There are approximately 15 million diabetics in the United States. The yearly incidence of foot ulcers in diabetics is between 2% and 3% (98). In poorly controlled diabetes, collagen and other proteins are subject to nonenzymatic glycosylation events. This can result in disrupted function of proteins within the tissues. As a consequence, neuropathy resulting in unrecognized pressure and tissue trauma, in conjunction with arterial insufficiency caused by atherosclerotic occlusion of the tibioperoneal arteries, is the likely cause of diabetic foot ulcers. Angiopathy probably contributes to the poor healing quality often associated with diabetic wounds. There is an impairment in granulocyte chemotaxis and phagocytic function. The absolute numbers of capillaries are lower in diabetics and differ from nondiabetics in morphology.

The Biology of Wound Healing

1043

The risk of infection in diabetic wounds is substantially greater than it is for the wounds of nondiabetics. Effective treatment of diabetic ulcers involves utilizing a combination of approaches. Control of glucose levels is paramount for successful therapy. In the case of foot ulcers, devices that off-load pressure from susceptible areas may be necessary. Aggressive sharp debridement, restoring circulation, and microbial control are also important. Topically applied recombinant PDGF (Becaplermin gel) has been demonstrated to be an aid in the healing of diabetic ulcers (99).

Pressure Ulcers Pressure and shear forces over bony prominences have a key role in the formation of pressure ulcers. Individuals immobilized as the result of general anesthesia, sedation, coma, and spinal injury are at significant risk. Prolonged pressure occludes the microcirculation, producing ischemia. Ischemic damage initially occurs in the fat and deep muscles. Skin is relatively resistant to ischemia; thus small skin ulcers often cover large areas of subcutaneous necrosis. There is leakage of plasma proteins and accumulation of activated leukocytes. As a result, there is release of significant levels of active proteases and reactive oxygen metabolites. The National Pressure Ulcer Advisory Panel has developed a staging system for classifying pressure ulcers. This system is detailed below: Stage I. Nonblanchable erythema of intact skin, the heralding lesion of skin ulceration. Stage II. Partial-thickness skin loss involving epidermis and/or dermis. The ulcer is superficial and presents clinically as an abrasion, blister, or shallow crater. Stage III. Full-thickness skin loss involving damage or necrosis of subcutaneous tissue that may extend down to, but not through, underlying fascia. The ulcer presents clinically as a deep crater with or without undermining of adjacent tissue. Stage IV. Full-thickness skin loss with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures.

Other Chronic Wound Types Radiation Exposure to irradiation damages the DNA of tissues. To minimize damage to normal cells, dosage is fractionated and administered in tangential fields. In spite of this, irradiation can result in rapid death of cells or prevent them from proliferating normally. Due to their exposure to radiation, fibroblasts that migrate into a site damaged by radiation are themselves morphologically abnormal. In addition, these fibroblasts synthesize elevated levels of collagen, which probably have an important role in the characteristic fibrosis of irradiated tissues. Healed irradiated skin has fewer dermal appendages (e.g., hair follicles and sebaceous glands), the walls of blood vessels are thickened, and the vessel lumens have a tendency to become occluded. The epidermis is thin and there are alterations in pigmentation. Therefore, radiated skin is more prone to bacterial invasion and infection. Once irradiated skin has broken down, the best treatment is to bring in new blood supply. This is accomplished by excision of as much radiated tissue as possible and replacement with vascularized tissue either in the form of a pedicle flap or free tissue transfer to restore blood supply to the radiated area. If one must perform elective surgery

medwedi.ru

1044

Part Eight: The Integument and Body Wall

through radiated skin, it is best to do the same to avoid potential catastrophic results.

Marjolin’s Ulcer This condition often presents as a chronic wound, but is indeed a squamous cell carcinoma that has developed in an old scar from a burn wound or trauma (100,101). These lesions are very aggressive with a high rate of metastasis. After a metastatic work-up, treatment consists of total local excision followed by appropriate reconstructive coverage.

The Future of Wound Healing Research in wound healing is one of the most exciting areas for investigative young surgeons to consider as part of their careers. Although there has been great progress over the past two decades, the possibilities remain enormous. The use of growth factors, skin substitutes, novel antimicrobials, and biologically active dressings has only begun in the last decade and there is much room for improvement. There are also the potential benefits from gene therapy. One example would be to modulate the inflammatory phase of repair. There is a wealth of evidence that in the absence of infection, wound healing is accelerated, and has a better outcome when inflammation is inhibited or prevented (102–104). As the process of wound healing is more completely understood, it should become possible to design new strategies for the treating of problem wounds and perhaps even improving the healing of otherwise normal wounds.

SUMMARY Wounds can be caused by a wide variety of insults that disrupt the integrity of a tissue. Factors influencing the healing process include hemostasis, associated inflammation/infection, underlying nutrition and immune status, and the adequacy of blood flow to enable the necessary provision of nutrients and oxygen to the cells involved in repairing the tissue defect. The individual response of a given wound to these various parameters will dictate the efficiency and speed of overall healing and the appearance of the resultant scar. Wounds that can be closed primarily generally result in rapid epithelialization through the effective production of collagen and its cross-linking. Wounds that need to be left open to heal in a more delayed fashion undergo the same process of collagen maturation, but the overall time required for this is usually prolonged when compared to its closed counterpart. Ultimately, though, the resultant scar is amazingly small due to a concomitant wound contraction. The principles of wound management to effect optimal healing are well established so that even the most complex and challenging wound can be expected to heal with a good-toexcellent result. In those wounds that do not respond to standard management strategies, additional approaches for care, such as skin grafts, flaps, and skin substitutes, have often proved helpful.

REFERENCES 1. Esmon CT. Cell mediated events that control blood coagulation and vascular injury. Ann Rev Cell Biol 1993; 9:1. 2. Williams TJ, Peck MJ. Role of prostaglandin-mediated vasodilatation in inflammation. Nature 1977; 270:530. 3. Boucek RJ. Factors affecting wound healing. Otolaryngol Clin North Am 1984; 17:243.

4. Dahlback B. Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases. J Intern Med 2005; 257:209. 5. Clark RA. Fibrin and wound healing. Ann NY Acad Sci 2001; 936:355. 6. Ross R, Glomset J, et al. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 1974; 71:1207. 7. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med 1989; 320:365. 8. Babibr BM. Oxygen-dependent microbial killing by phagocytes (second of two parts). N Engl J Med 1978; 298:721. 9. Babior BM. Oxygen-dependent microbial killing by phagocytes (first of two parts). N Engl J Med 1978; 298:659. 10. Reeves EP, Lu H, et al. Killing activity of neutrophils is mediated through activation of proteases by Kþ flux. Nature 2002; 416:291. 11. Theilgaard-Monch K, Knudsen S, et al. The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing. J Immunol 2004; 172:7684. 12. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975; 78:71. 13. Park JE, Barbul A. Understanding the role of immune regulation in wound healing. Am J Surg 2004; 187:11S. 14. Leibovich SJ, Ross R. A macrophage-dependent factor that stimulates the proliferation of fibroblasts in vitro. Am J Pathol 1976; 84:501. 15. Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol 2001; 69:513. 16. Nimni ME. Collagen: structure, function, and metabolism in normal and fibrotic tissues. Semin Arthritis Rheum 1983; 13:1. 17. Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Ann Rev Biochem 1995; 64:403. 18. Hutton JJ Jr, Trappel AL, et al. Requirements for alphaketoglutarate, ferrous ion and ascorbate by collagen proline hydroxylase. Biochem Biophys Res Commun 1966; 24:179. 19. Blumenkrantz N, Rosenbloom J, et al. Sequential steps in the synthesis of hydroxylysine and the glycosylation of hydroxylysine during the biosynthesis of collagen. Biochim Biophys Acta 1969; 192:81. 20. Siegel RC, Pinnell SR, et al. Cross-linking of collagen and elastin. Properties of lysyl oxidase. Biochemistry 1970; 9:4486. 21. Hassell JR, Kimura JH, et al. Proteoglycan core protein families. Ann Rev Biochem 1986; 55:539. 22. Folkman J, Klagsbrun M. Angiogenic factors. Science 1987; 235:442. 23. Tonnesen MG, Feng X, et al. Angiogenesis in wound healing. J Investig Dermatol Symp Proc 2000; 5:40. 24. Richard DE, Berra E, et al. Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Commun 1999; 266:718. 25. Koch AE, Polverini PJ, et al. Induction of neovascularization by activated human monocytes. J Leukoc Biol 1986; 39:233. 26. Berse B, Brown LF, et al. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 1992; 3:211. 27. O’Reilly MS, Holmgren L, et al. Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol 1994; 59:471. 28. Nanney LB, Sundberg JP, et al. Increased epidermal growth factor receptor in fsn/fsn mice. J Invest Dermatol 1996; 106:1169. 29. Thomas KA. Fibroblast growth factors. FASEB J 1987; 1:434. 30. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999; 341:738. 31. Pilcher BK, Dumin JA, et al. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 1997; 137:1445.

Chapter 55: 32. Forrester JC, Zederfeldt BH, et al. Wolffs law in relation to the healing skin wound. J Trauma 1970; 10:770. 33. Kuzuya M, Iguchi A. Role of matrix metalloproteinases in vascular remodeling. J Atheroscler Thromb 2003; 10:275. 34. Parks WC. Matrix metalloproteinases in repair. Wound Repair Regen 1999; 7:423. 35. Lind J. In: Kincaid A, Donaldson A, eds. Treatise of the scurvy. 1st ed. Edinburgh, Sands, Murray and Cochran, 1753:192–196. 36. Nussler AK, Wittel UA, et al. Leukocytes, the Janus cells in inflammatory disease. Langenbecks Arch Surg 1999; 384:222. 37. Yager DR, Nwomeh BC. The proteolytic environment of chronic wounds. Wound Repair Regen 1999; 7:433. 38. Yager DR, Zhang LY, et al. Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. J Invest Dermatol 1996; 107:743. 39. Yager DR, Chen SM, et al. Ability of chronic wound fluids to degrade peptide growth factors is associated with increased levels of elastase activity and diminished levels of proteinase inhibitors. Wound Repair Regen 1997; 5:23. 40. Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003; 200:500. 41. Hinz B, Gabbiani G, et al. The NH2-terminal peptide of alphasmooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J Cell Biol 2002; 157:657. 42. Ehrlich HP. Scar contracture: cellular and connective tissue aspects in Peyronie’s disease. J Urol 1997; 157:316. 43. Alster TS, Tanzi EL. Hypertrophic scars and keloids: etiology and management. Am J Clin Dermatol 2003; 4:235. 44. Datubo-Brown DD. Keloids: a review of the literature. Br J Plast Surg 1990; 43:70. 45. Mustoe T. Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy. Am J Surg 2004; 187:65S. 46. Anaya-Prado R, Toledo-Pereyra LH, et al. Ischemia/reperfusion injury. J Surg Res 2002; 105:248. 47. Nwomeh BC, Yager DR, et al. Physiology of the chronic wound. Clin Plast Surg 1998; 25:341. 48. Bowler PG, Duerden BI, et al. Wound microbiology and associated approaches to wound management. Clin Microbiol Rev 2001; 14:244. 49. Bendy RH Jr, Nuccio PA, et al. Relationship of quantitative wound bacterial counts to healing of decubiti: effect of topical gentamicin. Antimicrob Agents Chemother 1964; 10:147. 50. Robson MC, Stenberg BD, et al. Wound healing alterations caused by infection. Clin Plast Surg 1990; 17:485. 51. Murphy RC, Robson MC, et al. The effect of microbial contamination on musculocutaneous and random flaps. J Surg Res 1986; 41:75. 52. Trengove NJ, Stacey MC, et al. Qualitative bacteriology and leg ulcer healing. J Wound Care 1996; 5:277. 53. Armstrong DG, Liswood PJ, William J, et al. Stickel Bronze Award. Prevalence of mixed infections in the diabetic pedal wound. A retrospective review of 112 infections. J Am Podiatr Med Assoc 1995; 85:533. 54. Levine NS, Lindberg RB, et al. The quantitative swab culture and smear: a quick, simple method for determining the number of viable aerobic bacteria on open wounds. J Trauma 1976; 16:89. 55. Robson MC. Wound infection. A failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am 1997; 77:637. 56. Bill TJ, Ratliff CR, et al. Quantitative swab culture versus tissue biopsy: a comparison in chronic wounds. Ostomy Wound Manage 2001; 47:34. 57. Bornside GH, Bornside BB. Comparison between moist swab and tissue biopsy methods for quantitation of bacteria in experimental incisional wounds. J Trauma 1979; 19:103. 58. Lookingbill DP, Miller SH, et al. Bacteriology of chronic leg ulcers. Arch Dermatol 1978; 114:1765.

The Biology of Wound Healing

1045

59. Marcus JR, Tyrone JW, et al. Cellular mechanisms for diminished scarring with aging. Plast Reconstr Surg 2000; 105:1591. 60. Cohen BJ, Cutler RG, et al. Accelerated wound repair in old deer mice (Peromyscus manicularus) and white-footed mice (Peromyscus leucopus). J Gerontol 1987; 42:302. 61. Ashcroft GS, Horan MA, et al. Age-related differences in the temporal and spatial regulation of matrix metalloproteinases (MMPs) in normal skin and acute cutaneous wounds of healthy humans. Cell Tissue Res 1997; 290:581. 62. Ashcroft GS, Mills SJ, et al. Ageing and wound healing. Biogerontology 2002; 3:337. 63. Biolo G, Toigo G, et al. Metabolic response to injury and sepsis: changes in protein metabolism. Nutrition 1997; 13:52S. 64. Russell L. The importance of patients’ nutritional status in wound healing. Br J Nurs 2001; 10:S42, S44. 65. Williams JZ, Barbul A. Nutrition and wound healing. Surg Clin North Am 2003; 83:571. 66. Thompson WD, Ravdin IS, et al. Effect of hypoproteinemia on wound disruption. Arch Surg 1938; 36:509. 67. Barbul A, Lazarou SA, et al. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990; 108:331. 68. Davis PA, Corless DJ, et al. Increased risk of wound complications and poor healing following laparotomy in HIV-seropositive and AIDS patients. Dig Surg 1999; 16:60. 69. Davis PA, Wastell C. A comparison of biomechanical properties of excised mature scars from HIV patients and non-HIV controls. Am J Surg 2000; 180:217. 70. Lord RV. Anorectal surgery in patients infected with human immunodeficiency virus: factors associated with delayed wound healing. Ann Surg 1997; 226:92. 71. Sen CK, Khanna S, et al. Oxygen, oxidants, and antioxidants in wound healing: an emerging paradigm. Ann NY Acad Sci 2002; 957:239. 72. LaVan FB, Hunt TK. Oxygen and wound healing. Clin Plast Surg 1990; 17:463. 73. Drucker W, Pearce F, et al. Subcutaneous tissue oxygen pressure: a reliable index of peripheral perfusion in humans after injury. J Trauma 1996; 40:S116. 74. Howes EL, Plotz CM, et al. Retardation of wound healing by cortisone. Surgery 1950; 28:177. 75. Graf W, Ivarsson M, et al. The influence of early postoperative intraperitoneal chemotherapy on human wound healing. J Surg Res 1994; 57:394. 76. Noh R, Karp GL, et al. The effects of doxorubicin and mitoxantrone on wound healing. Cancer Chemother Pharmacol 1991; 29:141. 77. Dicker AP, Williams TL, et al. Targeting angiogenic processes by combination low-dose paclitaxel and radiation therapy. Am J Clin Oncol 2003; 26:e45. 78. Fife RS, Sledge GW Jr, et al. Effects of tetracyclines on angiogenesis in vitro. Cancer Lett 2000; 153:75. 79. Gilbertson-Beadling S, Powers EA, et al. The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism. Cancer Chemother Pharmacol 1995; 36:418. 80. Qiu JG, Factor S, et al. Wound healing: captopril, an angiogenesis inhibitor, and Staphylococcus aureus peptidoglycan. J Surg Res 2000; 92:177. 81. Weis M, Heeschen C, et al. Statins have biphasic effects on angiogenesis. Circulation 2002; 105:739. 82. Mall T, Grossenbacher M, et al. Influence of moderately elevated levels of carboxyhemoglobin on the course of acute ischemic heart disease. Respiration 1985; 48:237. 83. Sepkovic DW, Haley NJ, et al. Cigarette smoking as a risk for cardiovascular disease. III: Biochemical effects with higher nicotine yield cigarettes. Addict Behav 1983; 8:59. 84. European Pressure Ulcer Advisory Panel. Pressure Ulcer Treatment Guidelines, 2005. 85. Steed DL. Foundations of good ulcer care. Am J Surg 1998; 176:20S.

medwedi.ru

1046

Part Eight: The Integument and Body Wall

86. O’Meara SM, Cullum NA, et al. Systematic review of antimicrobial agents used for chronic wounds. Br J Surg 2001; 88:4. 87. Winter GD. Formation of the scab and the rate of epithelisation of superficial wounds in the skin of the young domestic pig. J Wound Care 1995; 4:366. 88. Hinman CD, Maibach HI. Effect of air exposure and occlusion on experimental human skin wounds. Nature 1963; 200:377. 89. Seaman S. Dressing selection in chronic wound management. J Am Podiatr Med Assoc 2002; 92:24. 90. Choucair M, Phillips T. A review of wound healing and dressing materials. Wounds: A Comp Clin Res Pract 1996; 8:165. 91. Kannon GA, Garrett AB. Moist wound healing with occlusive dressings. A clinical review. Dermatol Surg 1995; 21:583. 92. Zamboni WA, Wong HP, et al. Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study. Undersea Hyperb Med 1997; 24:175. 93. Bouachour G, Cronier P, et al. Hyperbaric oxygen therapy in the management of crush injuries: a randomized double-blind placebo-controlled clinical trial. J Trauma 1996; 41:333. 94. Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg 1997; 38:563. 95. Fleischmann W, Strecker W, et al. Vacuum sealing as treatment of soft tissue damage in open fractures. Unfallchirurg 1993; 96:488.

96. Blackburn JH, Boemi L, et al. Negative-pressure dressings as a bolster for skin grafts. Ann Plast Surg 1998; 40:453. 97. Mekkes JR, Loots MA, et al. Causes, investigation and treatment of leg ulceration. Br J Dermatol 2003; 148:388. 98. Frykberg RG. Epidemiology of the diabetic foot: ulcerations and amputations. Adv Wound Care 1999; 12:139. 99. Steed DL, Goslen JB, et al. Randomized prospective doubleblind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo. Diab Care 1992; 15:1598. 100. Fleming MD, Hunt JL, et al. Marjolin’s ulcer: a review and revaluation of a difficult problem. J Burn Care Rehabil 1990; 11:460. 101. Stankard CE, Cruse CW, et al. Chronic pressure ulcer carcinomas. Ann Plast Surg 1993; 30:274. 102. Dovi JV, He LK, et al. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 2003; 73:448. 103. Ashcroft GS, Mills SJ, et al. Role of Smad3 in the hormonal modulation of in vivo wound healing responses. Wound Repair Regen 2003; 11:468. 104. Flanders KC, Major CD, et al. Interference with transforming growth factor-beta/Smad3 signaling results in accelerated healing of wounds in previously irradiated skin. Am J Pathol 2003; 163:2247.

56 Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States Rakhshanda Layeeque and V. Suzanne Klimberg

INTRODUCTION The breast is a modified sweat gland that is unique to the mammalian species. It is therefore also called the mammary gland. The breast is a functional part of the reproductive system, which is subject to a variety of neuroendocrine stimuli dictating specific morphology and physiology at various stages of life. An understanding of the interplay of the morphology and physiology of the breast and the many endocrine and paracrine controls is essential to study the pathophysiology and management of benign and neoplastic disorders. In the present chapter, we cover the morphological, endocrine, paracrine, and genetic aspects of the various stages of development, function, and involution of human breast tissue. Using this information, special attention is directed to its clinical application in the diagnosis and management of both benign and malignant conditions.

PHYSIOLOGY OF DEVELOPMENT The development of the human breast begins in the fifth week of gestation and progresses through 10 stages until birth (1). Further development continues throughout childhood, puberty, adulthood, and pregnancy. Menopause marks the beginning of involution of the breast glandular tissue. All these stages are associated with specific alterations in local and systemic neuroendocrine changes.

Embryology to Childhood During the fifth week of fetal development, the ectodermal primitive milk streak, called the ‘‘galactic band’’ (Stage 1), appears from the axilla to the groin along the milk line on the embryonic trunk (2). Normally the galactic band regresses except in the region of the thorax where it develops to form the ‘‘mammary ridge’’ (Stage 2). At seven to eight weeks, the mammary ridge thickens further marking the Stage 3 called the ‘‘milk hill stage.’’ This is followed by the invagination of the ridge into the thoracic mesenchyme (Stage 4—disc stage) and then rapid growth (Stage 5— globular stage). As the invagination progresses through the 10- to 14-week period, the ridge flattens, marking Stage 6 also known as the ‘‘cone stage.’’ Between 12 and 16 weeks of gestation, the mesenchymal cells differentiate to form the smooth muscle of the nipple-areolar complex. During the same time, the epithelial cells form buds (Stage 7— budding stage), which then branch into 15 to 20 strips of epithelium at the end of 16 weeks, marking the branching stage (Stage 8). These strips become the secretory alveoli (3). The secondary mammary anlage then develops followed

by differentiation of the hair follicle, sebaceous glands, and sweat glands. Only the sweat glands develop fully at this time, along with the growth of special apocrine glands around the nipple, called the Montgomery glands. The developmental stages described thus far are independent of hormonal influences. In the third trimester between the 20th and 32nd week of pregnancy, the placental sex hormones enter the fetal circulation and induce canalization of the epithelial strips (Stage 9—canalization stage). During 32 to 40 weeks, the parenchyma differentiates, with development of lobuloalveolar structures containing ‘‘colostrum’’ (Stage 10—endvesicle stage). At this time, the mammary gland mass rapidly increases and the nipple-areolar complex forms with pigmentation. In the neonate, the stimulated mammary tissue secretes colostral milk. This secretion declines over three to four weeks postpartum owing to the withdrawal of placental hormones, causing involution of breast tissue (4). During childhood, the end vesicles become further canalized and develop into ductal structures, which further grow isometrically with the stroma and the rest of the body until puberty in both sexes (5). The lymphatics grow simultaneously with the ductal system and maintain connection with the subareolar plexus (physiology of drainage and clinical relevance is discussed in the section ‘‘Blood flow and Lymphatic drainage’’). Abnormalities ranging from inappropriate regression of the galactic band to gross maldevelopment of the pectoral region account for various clinical anomalies.

Puberty to Adulthood Puberty in girls begins on an average between 10 and 12 years of age and is under the influence of hormones controlled by the hypothalamic-pituitary-ovarian axis (Fig. 1). The development of the breast, as evaluated by external appearance, parenchymal mass, and differentiation is subject to individual variation (6). At the onset of puberty, the rudimentary gland begins to show signs of growth, both in the glandular tissue and stroma. Glandular growth entails multiple divisions of primary and secondary ducts to form club-shaped terminal end buds. Cleavage of terminal end buds gives rise to new branches and alveolar buds. Approximately 11 alveolar buds form a lobular unit called type 1 or virginal lobule (lob 1). This is the predominant lobule found at this point. Through adulthood, the process of sprouting of new alveolar buds continues under the influence of ovarian hormones and some of the lob 1 further divides and differentiates to form lobule 2 (lob 2). These are smaller and more numerous, approximating 47 in

medwedi.ru 1047

1048

Part Eight: The Integument and Body Wall

Figure 1 Neuroendocrine control of breast development. Abbreviations: GnRH, gonadotropin releasing hormone; TRH, thyrotropin releasing hormone; GHRH, growth hormone releasing hormone; FSH, follicle stimulating hormone; LH, leutinizing hormone; PRL, prolactin; GH, growth hormone.

number, and dominate in late teens, declining after the midtwenties. Continuous proliferation gives rise to mature ductules or alveoli in lobule 3 (lob 3), containing 80 lobules per unit (7). The distribution of lob 1, 2, and 3 in the breast is dictated by parity, age, and menopause (Fig. 2). Nulliparous women have mostly lob 1, while in parous women lob 3 is most common, decreasing in number after the fourth decade (8). Thereafter lob 3 progressively converts back to lob 1. As the number of pregnancies increase, the number of cycles of lobular differentiation increases and lowers the risk of cancer (discussed in the clinical implications of the section on Menopause).

The Endocrine Control of Development

of the breast (Fig. 1). The ovary, the major determining factor of mammary development, functions under the control of hypothalamic activity (9). During infancy, the secretion of gonadotropin-releasing hormone (GnRH) is centrally inhibited and slowly increases, achieving pulsatile release at puberty (10). The frequency and amplitude of GnRH release controls the synthesis and release of pituitary-luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH bind ovarian receptors and trigger the release of androgens during infancy and childhood. During puberty and adulthood the androgen production is mostly replaced by that of estrogen, progesterone, inhibin, and activin (8,9,11). Activin and inhibin are glycoproteins produced by the ovary, which have a feedback control over the pituitary synthesis of FSH and LH, which in turn modulate ovarian steroidal synthesis in conjunction with prolactin (PRL) and growth hormone (GH). This function is also affected by epinephrine from the adrenal medulla (10). GH has positive regulation over ductal development but estrogen and progesterone are essential for normal growth (12,13). Estrogen and progesterone induce proliferation by stimulation of DNA synthesis. Endocrine disturbances of these hormones can therefore be reflected in abnormalities of mammary development. Changes During Menstrual Cycle The histology of mammary stroma and epithelium is normally subject to changes dictated by endocrine variations during the menstrual cycle (Fig. 3) (14). The breast passes through five histologic phases during a normal menstrual cycle, viz: early follicular, follicular, luteal, secretory, and menstrual phase. The early follicular phase occurs from day 3 to day 7 in a 28-day cycle. The low level of estrogen at this point is associated with compact alveoli with poorly defined lumina and single cell type embedded in dense stroma. As the level of estrogen rises during the follicular phase (day 8–14), the epithelium exhibits sprouting with increased cellular mitoses and differentiation into three cell types: luminal, basal myoepithelial, and intermediate cells. Ovulation marks the beginning of the luteal phase, when progesterone synthesis reaches maximum and a second estrogen peak occurs. During this phase, the mammary ducts dilate and alveolar epithelial cells differentiate into

Numerous hormones and factors secreted by the pituitary, adrenals, thyroid, and ovaries influence the development

Figure 2 Changes in lobular structure during various phases of mammary development and involution.

Figure 3 Mammary responses to endocrine changes during menstrual cycle. Mammary epithelial proliferation begins as estrogen level rises and secretory differentiation is caused by rising progesterone level such that maximal breast volume is achieved at the end of secretory phase. A sharp decline in serum concentration of sex steroids causes mammary epithelial regression.

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

secretory cells. The stromal density decreases markedly to allow for ballooning of alveolar cells as the luminal proteins and glycogen accumulate. Increase in endogenous estrogen also has a histamine-like effect on microcirculation (15), resulting in an increased maximal blood flow three to four days before menstruation. This may in part contribute to premenstrual breast fullness and pain. The maximum number of alveoli and maximum lobule volume occur in the secretory phase (16). There is active protein synthesis and apocrine secretion at this time with peak mitotic activity following the progesterone peak and the second estrogen peak (17,18). The menstrual phase marks the rapid decline in circulating sex steroids, causing diminution of secretory activity by the acinar cells. The regression of epithelium never reaches the premenarche baseline because the new cycle begins and interrupts the process; thus the final regression ensues at menopause (7).

Local Factors and Paracrine Control of Development In addition to the systemic mammotrophic hormones, normal mammary development entails complex local cell–cell interactions and paracrine influences (19,20). These effects are mediated by a variety of growth factors including epidermal growth factor (EGF), transforming growth factor beta (TGF-b), fibroblast growth factor (FGF), and the wingless type (Wnt) gene families (21–24). TGF-a, a member of the EGF family, may influence ductal growth as well as alveolar differentiation. It has been localized at the actively growing end of the mammary alveolar buds in mice (21). Similarly, FGF-1 and FGF-2 have a role in promoting ductal development during puberty (22). FGF-1 is expressed in the ductal epithelium, while FGF-2 has been localized in the mammary stroma at the onset of ovarian function. These factors contribute to the mesenchymal and epithelial development and may also have a role in neovascularization of the developing gland. Wnt gene family encodes a myriad of glycoproteins, many of which are expressed in the developing mouse mammary gland, suggesting their role in normal development (25,26). The local growth factors are regulated just like the circulating hormones and act in conjunction with them to control mammary growth and differentiation.

Clinical Implications Various clinical scenarios can result from abnormalities of intrauterine development, maturation, or pubertal growth.

1049

Figure 4 Polythelia. Arrows point to the two accessory nipple-areolar complexes.

declines rapidly within three to four weeks as the endocrine influence is withdrawn and is of no clinical significance.

Anomalous Maturation The breast development progresses slowly through childhood with a sudden growth spurt in puberty, called thelarche. Premature thelarche is defined as development of the breast before the age of eight without other signs of puberty. Usually bilateral, it occurs within the first few years of life and resolves spontaneously within three to five years, with no adverse sequelae (30). While maternal hormones may initially affect infant breast growth, persistent mammary growth is suggested to result from infantile FSH, LH, and estradiol (31,32). Serum androgen levels (33), free estrogen levels (34), and altered FSH levels (35) have been implicated, as because occurs before the pubertal surge of estrogens. Breast development under the age of eight, associated with other signs of puberty, is defined as precocious puberty. Abnormality of the hypothalamic-pituitary-ovarian axis, resulting in end-organ hyperfunction, is the main pathophysiology. This may be caused by hypothalamic or pituitary hyperfunction, called central precocious puberty (36), or ectopic excess production of estrogen (37), called peripheral precocious puberty. Investigation and treatment of the underlying pathology is essential to halt the process. This involves a thorough history and physical examination and assessment of serum gonadotropin and sex steroid levels to identify the endocrine defect and its cause so that targeted therapy can be offered.

Congenital Anomalies The most common abnormality observed in both males and females is an accessory nipple or polythelia (Fig. 4). This results from incomplete regression of the galactic band. Less frequently, accessory breast tissue is also present, called polymastia (Fig. 5), which can function during pregnancy (27). Mutations in the t-box family of transcription factors, normally activated during embryogenesis, can result in hypoplasis (underdevelopment) or amastia (nondevelopment). A wide variety of unilateral or bilateral involvement of these abnormalities may be seen (28), e.g., Poland syndrome, which comprises unilateral hypoplasis of the breast, thorax, and pectoral muscles. A normal observation, which is often thought to be an abnormality, is when the newborn secretes colostral milk, as a result of maternal hormonal influence (29). Secretion

Figure 5 Accessory breast tissue in the anterior axillary fold.

medwedi.ru

1050

Part Eight: The Integument and Body Wall

Abnormalities of Pubertal Development Several normal variants of breast development may occur at puberty, which may be a source of embarrassment but do not carry any significant clinical risk. These include initial unilateral development and asymmetry (Fig. 6) that disappears or becomes less obvious during adulthood (32). Adolescent, juvenile, or virginal hypertrophy is a postpubertal continuation of epithelial and stromal growth, which results in breasts weighing up to three to eight kilograms. The diagnosis should be limited to severe breast enlargement resulting in physical limitations. The condition is usually bilateral but unilateral presentation is also seen, suggesting the role of local factors. There is an association with ancillary breast tissue in the axilla (38). Drugs like pencillamine have been implicated but hypertrophy does not regress after withdrawal (39). Serum endocrine profile is usually normal; however endocrine manipulation with bromocriptine, tamoxifen, danazol, and medroxyprogesterone has been reported (40,41). Male gynecomastia presents around 13 to 14 years of age, when pubertal changes have established a male pattern (42). Gynecomastia presents as a small mound of breast tissue directly under the nipple, which represents proliferation of ductal and stromal tissue without evidence of lobuloaveolar differentiation (4). An initial rise in estrogen levels, altered ratios of peripheral and central androgens to estrogens, increased diurnal periods of estrogen excess, and peripheral aromatization of androgens have been implicated (31). Drugs like marijuana and cimetidine may contribute to gynecomastia (43). Altered endocrine profile resulting from gonadal tumors and altered metabolism from liver dysfunction must be ruled out because they require urgent treatment (44,45). Failure of estrogen production leads to insufficient ductal development. This may result from failure of the ovaries or from lack of stimulation by the hypothalamicpituitary axis. The most common cause of primary ovarian failure is the Turner syndrome of gonadal dysgenesis and requires early institution of cyclical estrogen therapy to minimize sexual infantilism (46). Intrinsic errors in aromatase activity and steroid biosynthesis may also result in failure of development of female sexual characteristics and virilization (46,47). Hypogonadotropism may result from isolated GnRH insufficiency, space-occupying lesions of the brain, or genetic abnormalities. Persistent high IGF levels in tall girls have been implicated in their predisposition toward breast cancer, while high adipose-derived estrogen has been hypothesized to

cause earlier differentiation of ductal epithelium, thereby protecting obese girls against breast cancer (48).

Blood Flow and Lymphatic Drainage The blood supply of the breast is derived from internal mammary and lateral thoracic arteries, augmented by perforators from the third, fourth, and fifth intercostal arteries and minor contributions from the vascular network around the scapula. Generally, the blood flow through the breast is similar to the rest of the systemic circulation; however an endocrine-dependent increase in microcirculation is seen with estrogen peaks of menstrual cycle and pregnancy (15). The lymphatic drainage of the breast follows two main pathways. Most breast tissue drains centripetally into the subareolar plexus and then into the axilla via large lymph trunks to the axilla (49). Embryologically, about 25% of lymphatics arise from the breast lobules, leave the posterior surface of the breast, and pass through the pectoral and intercostal muscles to reach the internal mammary lymph nodes (50). The lymphatic flow through the breast is dictated physiologically by a very fine equilibrium between intra- and extralymphatic pressure (51). This has implications in the metastatic spread of tumor, as well as the clinical utility of sentinel lymph node biopsy techniques.

Clinical Implications Altered mammary blood flow has significant impact on benign conditions and malignant lesions of the breast. The increase in circulation during the luteal phase of the menstrual cycle has been implicated in causing premenstrual breast tenderness (27). Angiogenic factors are not only expressed by breast cancer cells, but the plasma levels of these factors have also been correlated with local and metastatic recurrence potential (52). Blood flow through the tumor is directly related to prognosis, suggesting the role of altered vascular physiology in causing metastasis and death (53). Recently, the mammary hypervascularity in the nulliparous woman has been implicated in enhancing her risk toward the development of breast cancer (54). Lymph node involvement is the single most important prognostic factor in breast cancer. Recently, sentinel lymph node biopsy techniques have been used to exactly stage the lymph nodes in breast cancer. Optimal use of this technique requires precise understanding of the physiology of lymph flow. Slight changes in lymphatic pressures within the breast, caused by the volume or particle size of the material used for sentinel lymph node mapping, can alter equilibrium pressures and compromise identification or cause identification of incorrect nodes (51).

PREGNANCY

Figure 6 Asymmetry of the breast during pubertal development.

Mammary growth and differentiation during pregnancy is directed toward preparation for lactation. During the first three to four weeks of pregnancy, marked ductular sprouting occurs, with some branching and lobular formation (Fig. 2). During the first five to eight weeks of pregnancy, breast enlargement is significant, with dilatation of superficial veins, heaviness, and increasing pigmentation of the nipple-areolar complex. During the second trimester, lobular proliferation and differentiation exceeds ductal sprouting. This results in the formation of the more differentiated lobule 3 (lob 3) and lobule 4 (lob 4) (Fig. 2). Lob 3

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

1051

outnumbers the more primitive lob 1 and lob 2 by the end of first trimester, having up to 10 times more alveoli per lobule compared to lob 1 (8). Lob 3 is the dominant structure in all parous women until menopause. From the second half of pregnancy, the breast enlargement is attributable to progressive dilatation of alveoli differentiating into acini containing colostrum, as well as myoepithelial hypertrophy replacing adipose tissue. Abnormalities of lobuloalveolar differentiation at this stage can cause problems with lactation.

during pregnancy also suggests that it may function in mediating lobuloalveolar development (61). TGF-a is upregulated in ductal epithelium as well as stromal fibroblasts in pregnancy, signifying its paracrine role in directing hormonal morphogenesis. Mutations in other factors including activins, inhibins, and members of TGF-b family result in an inhibition of alveolar development during pregnancy (62). Recently, a decrease in integrin factor alpha 2 was demonstrated in the luminal epithelium of expanding acini during pregnancy (63).

Endocrine Control During Pregnancy

Clinical Implications

The mammary ductal, lobular, and alveolar growth during pregnancy occurs under the influence of placental sex steroids, human placental lactogen (HPL), PRL, and human chorionic gonadotropin (Fig. 7). These effects can be reproduced in experimental animals when high estrogens and progesterone inhibit the release of PRL-inhibiting factor (PIF), causing a rise in PRL release (55). PRL secretion increases throughout pregnancy and stimulates epithelial growth and secretion (56). Ductular sprouting and branching is mainly under the influence of estrogen while lobular differentiation is under the influence of progesterone (27). HPL, biologically related to PRL, is secreted during the second half of pregnancy and reaches a concentration that is 30 times higher compared to PRL by the end of gestation (57). HPL contributes toward PRL effects of lobuloalveolar differentiation and final maturation of the mammary gland (58). During pregnancy, PRL primes the breast for lactation; however the initiation of lactogenesis is inhibited by the presence of progesterone. Although estrogen and progesterone are necessary for PRL receptor expression, paradoxically, progesterone reduces the binding and antagonizes the positive effects of PRL at its receptor (59).

Gravid hypertrophy is the rapid and massive enlargement of the breast during pregnancy. The reason for this hyperresponsiveness to gestational hormones is unknown; however its appearance is a risk factor for recurrence in future pregnancies (41). Most clinical conditions encountered during pregnancy also exist in nonpregnant patients. Conditions peculiar to pregnancy include lobular hyperplasia and galactoceles (64). An important pathophysiological event during pregnancy is enhanced growth of preexisting lesions, along with generalized mammary development (65). Another lesion peculiar to pregnancy is a breast infarct resulting either spontaneously or from overgrowth of hormone-responsive fibroadenoma (66,67). Bloodstained nipple discharge during pregnancy is common (Fig. 8). Long-term follow-up of these women revealed neither cancer nor a benign lesion (68). It has been contemplated that rapid ductal proliferation and hypervascularity may be responsible (69). Having said that, bloodstained discharge should be worked up on the same grounds as in nonpregnant women.

Local Factors and Paracrine Control

PHYSIOLOGY OF LACTATION

The EGF family–related neuregulins are expressed in the stroma of the mammary gland during pregnancy (60). Neuregulins have been shown to stimulate alveolar development and secretory activity, suggesting a potential role in mediating PRL activity. In addition, the changing temporal and spatial expression pattern of TGF-a in the breast

While the first half of pregnancy is marked by significant ductal proliferation and lobuloalveolar proliferation giving rise to lob 3, the second half of gestation involves the final maturation of the gland into the secretory organ of lactation mainly comprising lobule 4 (lob 4) structures (Fig. 2). At the beginning of second trimester, the mammary alveoli, but not the ducts, lose the superficial layer of A cells. This monolayer differentiates into the colostrum-cell layer during the third trimester and accumulates eosinophilic cells, plasma cells, and leukocytes around the alveoli.

Figure 7 Endocrine control of mammary development and differentiation during pregnancy and lactation. Abbreviations: PIF, pituitary inhibitory factor; PRL, prolactin; HPL, human placental lactogen.

Figure 8 Bloodstained discharge from the nipple during pregnancy. The work-up of this patient did not reveal any pathology.

medwedi.ru

1052

Part Eight: The Integument and Body Wall

LACTOGENESIS The synthesis and secretion of milk products is termed ‘‘lactogenesis.’’ Lactogenesis comprises two stages. Stage I is the synthesis of unique milk components. This is accompanied by morphological changes in the alveolar epithelial cell structure, geared toward protein synthesis. Changes include increased DNA and RNA of nuclei, abundant mitochondria and ribosomes, and rough endoplasmic reticulum, along with prominent Golgi apparati. Complex protein, milk fat, and lactose synthetic pathways are activated but with minimal secretion into the alveolar lumen (70,71). Urine lactose concentration, a marker of this synthetic activity, has confirmed that this process begins between 15 and 20 weeks of gestation (72). The alveoli distend with colostrum and along with increased vascularity contribute to the increase in breast volume seen in the later part of gestation. Lob 4 thus formed during pregnancy lasts throughout lactation. Stage II of lactation is the onset of copious milk secretion during the first four days postpartum (73). This involves a seemingly carefully programmed set of changes in milk composition and volume. Initially, the colostrum provides nutritional elements along with passive immunity. Maternal immunity is transferred to the infant via antibodies, primarily of the immunoglobulin A type, as well as leukocytes including effector and memory T-lymphocytes (74). After a few days of colostrum secretion, transitional milk follows, which has less total protein and less immunoglobulin. The ultimate product is mature milk that comprises fat and protein suspended in a lactose solution secreted in paracrine fashion. Mature milk secretion begins 30 to 40 hours postpartum and averages 1 to 2 mL/g of breast tissue per day (72). The rate of lactation remains constant for the first six months of breast-feeding (75). The stromal lymphatics increase during lactation; interepithelial gaps widen to allow for direct uptake of particles and fluids and improve clearance from the breast (76). After weaning, the breast involutes and returns to a state resembling that of prepregnancy. The lobules decrease in size with a decrease in the number of alveoli per lobule. The postlactation involution process involves two phases. The first phase is reversible and is associated with accumulation of milk. It is triggered either by the physical distortion of the luminal epithelial cells or by accumulation of apoptosis-inducing factors in the milk (77). The second phase is marked by active tissue remodeling, including destruction of basement membranes and alveolar structure, with irreversible loss of differentiated lactational function of the mammary gland (78).

Endocrine Control of Lactation PRL is the principal hormone for the synthesis of milk proteins and the maintenance of lactation (5). PRL works via membrane receptors in the mammary epithelial cells. Production of casein, the primary milk protein, ceases in the absence of PRL (58). This hormone is secreted throughout pregnancy and peaks around delivery. However, presence of the PIF and luteal and placental sex steroids, especially progesterone, prohibits PRL from achieving its full lactational effect (Fig. 7). Glucocorticoids work along with PRL to differentiate mammary epithelium and stimulate milk synthesis and secretion. Both glucocorticoids and their receptors are increased in late pregnancy and during lactation. Progesterone binds the glucocorticoid receptor and acts as a glucocorticoid antagonist (71).

After parturition, an immediate withdrawal of placental lactogen and sex steroids occurs. Luteal production of steroid hormones also ceases. At this point, the secretion of PIF decreases from the hypothalamus, causing an increase in the release of PRL from the pituitary. Subsequent physiologic increases in sex steroids, resulting from ovulatory cycles, do not inhibit the effect of PRL. PRL, along with GH, insulin and cortisol, converts the mammary epithelial cells from the presecretory to the secretory state. Other secretogogues identified for PRL include thyrotropin-releasing hormone (TRH) (79), vasoactive intestinal peptide (VIP) (80), and local factors EGF (81) and FGF (82). Oral TRH may improve lactation in partially breastfeeding women (83). Extrapituitary synthesis of PRL occurs in the mammary gland and contributes to the high levels of hormone secreted in the milk. Maturation of the fetal and newborn hypothalamic neuroendocrine system may be modulated by PRL secretion in the amniotic fluid and milk, respectively (84).

Local Factors and Paracrine Control Cell-to-cell interactions play an important regulatory role in lactational differentiation and milk synthesis. It has been demonstrated that each breast has an independent rate of milk synthesis, suggesting a key role of local and paracrine factors in modulating mammary function. As synthesis of milk products is induced, direct regulatory effects of milk proteins (in addition to PRL) such as lactoferrin and lactoglobulin on local growth factor pathways and epithelial proliferation have been observed (85). Milk proteins are encoded for by the specific consensus sequence in their promoters, called the milk box (86). These genes have specifically programmed expression. Defective expression may lead to altered milk composition (87,88). The transcription factor that activates milk protein synthesis has been termed as ‘‘mammary growth factor (Mgf),’’ which belongs to the signal transducers and activators of transcription family (89). The regulation of the expression of casein gene depends on the balance of activation by Mgf and inhibition by other local proteins (90,91). Complete mammary differentiation and milk secretion depend not only on proper endocrine stimulation, but also on proper adhesion to the basement membrane through integrins (92) and to each other through occluding cytoskeletal organized tight junctions (93). Moreover, the rate of milk secretion is independent of PRL concentration. Luminal volume may have a rate-limiting effect by altering the interaction between the basement membrane and the lactocyte, causing PRL receptor inhibition (92). A specific compound has now been identified and termed as ‘‘feedback inhibitor of lactation (FIL).’’ FIL has been shown to inhibit lactocyte differentiation, disrupt Golgi vesicle secretions, and inhibit protein synthesis in lactocytes (94). Involution of the mammary epithelium involves apoptotic cell death. This is a genetically programmed process implemented by genetically directed local factors (95). Disintegration of the tight junctions has been implicated in induction of involution (96). This results from an altered balance between mammary survival factors such as integrins (97) and programmed cell death factors such as proteases (98), which take effect through cell–matrix interaction. The principal enzyme family in the signaling pathway during alveolar epithelial cell death is the aspartate-specific cysteine proteases, called caspases (99). Another important factor in causing programmed cell death is the upregulation of insulin-like growth factor–binding protein

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

1053

5 (IGFBP-5). This protein vividly binds with the IGF and inactivates it, thereby compromising IGF-mediated cell survival (100,101). The balance between these cell-survival and cell-death factors can be affected by stress and disease states, causing abnormalities of lactation and involution.

BREAST-FEEDING Upon commencement of breast-feeding, the removal of milk is aided by active ejection. This involves the milk let-down reflex stimulated by the infant suckling (Fig. 9). Sensory nerve endings of T4, T5, and T6 are stimulated by the tactile sensation at the nipple-areolar complex. Impulses pass through the sensory nerves of the dorsal root to the spinal cord. These impulses are then relayed to the hypothalamus via the dorsal, lateral, and ventral spinothalamic tracts. Two separate efferent signals are initiated: the release of PIF is inhibited, which allows the unimpeded secretion of PRL from the anterior pituitary, and simultaneously oxytocin synthesis and release is activated at the paraventricular nucleus in the posterior pituitary. PRL maintains the synthesis of milk. Oxytocin acts on the myoepithelial cells, which contract and eject milk from the alveoli into the lactiferous ducts and sinuses. Milk ejection is uniquely effected by oxytocin, and mammary ductal pressures up to 25 mmHg may be seen with peak blood levels of oxytocin (27). Oxytocin can also be released in response to anticipation of nursing in the presence of a crying infant (58). An understanding of the mechanisms of lactation helps in the identification and treatment of problems associated with breast-feeding.

Clinical Implications Physiological changes in the endocrine environment during normal lactation have clinical relevance with contraception and cancer prevention. Breast-feeding suppresses fertility by initial complete inhibition of GnRH and LH release, followed by erratic secretion associated with increased inhibin secretion by the ovary and a prolonged period of anovulatory cycles (102). A decrease in risk of cancer, resulting from breast-feeding is in part attributable to enhanced differentiation of lobular structure (discussed under clinical

Figure 10 Breast abscess during lactation; notice edema and erythema of the breast with a collection below the nipple.

implications of section on Menopause); molecular events such as increased production of anticarcinogenic molecules during lactation have also been documented (103). Various clinical scenarios arise as a result of altered endocrine and local physiology during lactation. The onset of lactation can be delayed if the endocrine withdrawal at the end of pregnancy is altered by unscheduled cesarean section or interruption of milk let-down reflex by inadequate suckling stimulus (104). Because progesterone inhibits lactation, high postpartum levels maintained by the retained placenta may inhibit lactogenesis (105). Other causes of compromised lactation include type I diabetes mellitus (106) and maternal stress (107). Rare causes of lactational failure include Sheehan’s syndrome, lymphocytic hypophysitis, and isolated or pituitary-related hypoprolactinemia (29). Galactorrhea is common and is defined as inappropriate secretion of milky fluid in the absence of pregnancy or breast-feeding for more than six months. It is usually bilateral and involves multiple ducts. Amenorrhea is often associated with galactorrhea (108). Endocrine disorders causing hyperprolactinemia or hyperresponsiveness to normal PRL levels also cause galactorrhea (109). Drug-induced hyperprolactinemia can also cause galactorrhea, which usually resolves over time after use of the drug is discontinued (110). Pituitary tumors, hypothalamic lesions (111), adrenal insufficiency (112), Cushing’s syndrome (113), acromegaly (114), renal failure (115) and paraneoplastic syndrome (116) may also cause galactorrhea. Mammary infection is relatively common during lactation. Mastitis is the generalized infection of the breast. Breast abscess may result from a localized collection of purulence, usually occurring in areas of inadequate emptying during nursing (Fig. 10). Staphylococcus aureus and streptococci are the most common organisms causing mammary infections, usually entering from the infant’s throat through the nipple abrasion (117). Lactating adenoma is a rare lesion arising during pregnancy and lactation. It presents as a breast mass and excision is often necessary for a definitive diagnosis of this benign lesion and confident exclusion of cancer (118,119).

PHYSIOLOGY OF INVOLUTION Figure 9 Neuroendocrine reflexes involved in breast-feeding. Abbreviations: PIF, pituitary inhibitory factor; PRL, prolactin.

Postlactational involution is accompanied by dramatic apoptosis; however the alveolar structure is largely maintained and the gland reorganizes for another cycle of

medwedi.ru

1054

Part Eight: The Integument and Body Wall

lactation. Definitive involution takes place as the ovarian function declines at menopause.

Menopause Declining ovarian function through premenopause and menopause leads to regression of epithelial structures and stroma of the mammary gland. Menopause is marked by an increase in lob 1, and a decline in lob 2 and lob 3, such that all women have mostly lob 1 by the end of the fifth decade of life (Fig. 2). Independent of age, nulliparous women have 65% to 80% lob 1, 10% to 35% lob 2, and 0% to 5% lob 3. Lobules in parous women, from postlactational involution to the fourth decade, are 70% to 90% of lob 3. Thereafter, mammary involution starts and after menopause the distribution of lobule structure is the same as in nulliparous women (8). Otherwise, the menopausal regression is the same in both parous and nulliparous women. The climacteric phase from age 45 to 55 has a moderate decrease in glandular epithelium. The postmenopausal phase is characterized by apoptosis of glandular epithelium and replacement of interlobular stroma by fat and intralobular tissue by collagen. Only residual islands of ductal tissue remain scattered throughout the fibrous tissue and fat.

Endocrine Control of Involution Multihormonal withdrawal is responsible for changes of menopause. The estrogen- and progesterone-induced proliferation and differentiation ceases and programmed cell death ensues.

Local Factors and Paracrine Control There is little understanding of local influences dictating involution. Tumor suppressor gene p53 has been shown to have a proapoptotic role in secretory mammary epithelium (95). Other local factors involved in cell death have been studied in the setting of postlactational involution, and have been discussed above.

Clinical Implications One of the most significant clinical entities in the postmenopausal woman is breast cancer. Although cancer may occur in young (1 in 20,000 women at 20 years of age), premenopausal and pregnant women, the incidence rises to one in eight women by the age of 80. The pattern of lobular differentiation dictates the proliferative index of mammary epithelium, thereby influencing its vulnerability toward cancer. The highest proliferative activity is observed in lob 1 of the breasts of young nulliparous women. Progressive differentiation to lob 2 and lob 3 under hormonal control and full differentiation to lob 4 during lactation results in a significant drop in proliferative activity. Postmenopausal women return to lob 1, and in nulliparous women these lob 1 have a higher proliferative index. Thus, all postmenopausal women are more susceptible to carcinogens, nulliparous women being at greater risk.

CLINICAL APPROACH TO BREAST PATHOLOGY Clinical evaluation of breast disease is directed toward confident exclusion of cancer at presentation and assignment of the risk of developing one in future. To achieve this, a schematic approach involving a comprehensive relevant history taking, detailed physical examination, and rational work-up of presenting symptoms is necessary.

History Taking An understanding of physiological and genetic risk factors for breast cancer, discussed previously in this chapter, assist in obtaining a comprehensive history to characterize an individual’s risk of breast cancer. Detailed inquiry should include age, parity, and menstrual and nursing histories. The age at menarche and cyclical alterations in breast pain or masses, which occur with menses, are significantly related to benign or malignant disease. Previous surgical and medical history, particularly of treatments involving alterations in endocrine environment, is very important. These include oophorectomy, hysterectomy, adrenalectomy, and other pelvic surgeries and use of exogenous estrogens, contraceptives, or other steroids. Previous surgeries on the breast and the histopathological diagnosis from any biopsies must be recorded. Malignant or premalignant lesions in the past increase the patient’s risk of breast cancer. Social history should focus on ascertaining the amount of caffeine, nicotine, and alcohol intake. These factors are specifically related to mastalgia. Details of the presenting symptoms such as pain, mass, or nipple discharge should be obtained. The relationship of the presenting symptom to the menstrual cycle is important; hormone-sensitive lesions may be associated with mastodynia with breast fullness and swelling in the immediate premenstrual and postmenstrual periods. Inquiry into growth characteristics of a mass and its association with any possible constitutional symptoms must be made. The spontaneity and nature of nipple discharge and whether or not it is bilateral or multiductal should be ascertained. In addition to the hereditary factors, the determinants of breast cancer risks may be related to the patient’s environment and cultural background that is common to patient’s family. This may give rise to aggregations of cancer clusters in families. Thus, a complete family history must be obtained to determine if an individual is at hereditary or familial risk of breast cancer. If a diagnosis of breast cancer is suspected or already known, constitutional symptoms of anorexia, weight loss, skeletal pain, fever, or chest pain must be recorded because they indicate advanced regional and systemic disease. An insight into a woman’s postmenopausal symptoms helps in selecting appropriate therapy for breast cancer and simultaneous management of its side effects.

Physical Examination Breast examination involves inspection, palpation, and checking for systemic disease. Inspection should be done from the front as well as lateral position to note any asymmetry, changes in skin color, retraction, or ulceration. The examination should be conducted with patient’s arms by her side, held behind her head, and on her hips, with contraction of pectoral muscles to enhance the contour and identify any subtle signs.

Inspection Edema of the skin should be recorded; it may be focal or diffuse and may or may not be associated with erythema. Skin edema results from lymphatic obstruction. Although edema with redness is generally a feature of mastitis or breast abscess, the possibility of inflammatory carcinoma should be borne in mind. Sometimes, the edema produces a skin texture change, with prominent skin pores resembling the skin of an orange, hence the name peau d’orange. Skin dimpling results either from entrapment of Cooper’s ligaments

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

or from direct infiltration of dermis by the tumor, and is therefore an ominous sign. Inspection of the entire breast with full abduction of shoulders and while contracting pectoral muscles is necessary to pick up subtle dimpling caused by deeper lesions, especially in large breasts. Some chronic inflammatory conditions may cause skin tethering but carcinoma must be ruled out if this sign exists. The bilateral symmetry of the nipple-areolar complex should be documented; nipple inversion may result from central tumors infiltrating into the surrounding ducts just before they open to the exterior. Scales and erosion of the nipple may reflect Paget’s disease. The physician must make note of all the surgical scars and their locations. They help in interpreting parenchymal scars on mammograms and planning future incisions if required.

Palpation The breast is a sensitive organ and the physician must be insightful of this fact lest the palpation be a painful experience and the patient lose confidence in the physician. A systematic gentle palpation of all quadrants and nipple-areolar complex should be carried out with the patient fully relaxed in the supine position with arms extended and shoulders externally rotated. The object of palpation is to detect masses that are separate from the rest of the parenchyma. Once a mass is detected, its shape, consistency, edges, tenderness, and mobility are recorded. Well-circumscribed, painful, mobile, and smooth masses are usually benign; while lesions with indistinct borders, restricted mobility, or fixity to the skin or chest wall should be considered malignant. However, the distinction between benign and malignant lesions is often impossible on the basis of physical examination. The examination of the breast is incomplete without palpation of the regional lymph nodes in the axilla and the supraclavicular fossa. Examination of the axillae should be done with a patient in sitting position, with the shoulder girdle completely relaxed. Gentle pressure with fingertips demonstrates the enlarged nodes. The size and location of palpable nodes and whether or not they are matted should be recorded. The sensitivity and specificity of clinical examination of the axillary lymph nodes is 70%. The supraclavicular fossa should be palpated with the neck completely relaxed. Pressure effects of large nodes in the neck should be noted.

1055

WORK-UP OF COMMON CLINICAL SYMPTOMS All patients presenting to the breast clinic should undergo a complete history taking and physical examination emphasizing the specific features outlined above. A thorough history and examination can reasonably narrow the differential diagnoses to a few considerations, and systematic work-up of the pertinent symptoms yields a confident final diagnosis and appropriate treatment. The approach to common clinical scenarios encountered in the office setting is described below.

Mastalgia Mastalgia is the most common presenting symptom of women attending specialized breast clinics or general practice (120). It is generally believed not to be a symptom of breast cancer; however, about 7% of patients with breast cancer have breast pain as one of their presenting complaints (121). Therefore, a complete physical examination and age-appropriate screening must be carried out for all patients presenting with mastalgia. The responsibility of the physician does not end with a confident exclusion of cancer because mastalgia can be a distressing symptom significantly compromising the patient’s quality of life. The severity and association of pain with the menstrual cycle should be ascertained. A daily breast pain chart that employs the visual analogue scale is used at the author’s institution for at least two menstrual cycles to characterize the degree of mastalgia into mild to moderate and severe and temporal relation into cyclical and noncyclical. It is important to distinguish between cyclical, noncyclical, and chest wall pain because their response to therapy is different (122). Various nutritional, endocrine, and molecular events have been implicated in the etiology of mastalgia and therefore, no single therapeutic approach has been identified to ameliorate this vexing problem (123). However, a methodical approach toward evaluation and treatment based on the classification of mastalgia suffices for most patients (Fig. 11). History of associated symptoms such as masses or nipple discharge should be documented. Dietary pattern, smoking, and associated pregnancy should be recorded. A detailed physical examination should be performed to exclude masses and focal tenderness of costochondritis

Systemic Evaluation A thorough systemic examination is carried out to detect metastatic disease. Cachexia may be obvious from the general health status. Alterations of gait or restricted ambulation may result from metastatic bone disease involving spine and pelvis. Respiratory distress can result from lung involvement from cancer or malignant pleural effusion. Mediastinal lymphadenopathy may manifest as superior vena caval obstruction. These are signs of very advanced disease. However, metastatic disease can exist without obvious manifestations. Spine and ribs should be palpated for tender spots. Lungs should be percussed and auscultated; liver should be palpated and span should be measured; surface and edge should be checked for smoothness if they are palpable. Shifting dullness should be checked to rule out ascites. Metastatic disease is unlikely to exist in the absence of axillary lymph node involvement.

Figure 11 Clinical approach to mastalgia. Abbreviation: LHRH, luteinizing hormone–releasing hormone.

medwedi.ru

1056

Part Eight: The Integument and Body Wall

and bursistis, which may be mistaken for mastalgia. Most patients respond to counseling and reassurance that they do not have cancer. Dietary modifications emphasizing on decreasing caffeine intake and smoking are helpful. Oral analgesics like nimesulide may be helpful (124). Severe cyclical mastalgia has been associated with abnormal levels of some essential fatty acids (125) and has been shown to respond to gamma-linolenic acid (Evening Primrose Oil) (126). Hormonal manipulation with androgen analogues and luteinizing hormone–releasing hormone antagonists should be reserved for severe and acute cases because of serious side effects. Refractory cases should be evaluated for other pathology. Some patients respond to antidepressant treatment.

LUMP A breast mass is second only to mastalgia as a presenting symptom to the breast clinic. A lump in the breast is the most anxiety-provoking discovery for the woman. However, not all lumps reported by the patient are confirmed during a surgical evaluation (127). After a thorough history and physical examination, as described above, and age-appropriate imaging evaluation (mammogram over age 40 and ultrasound under age 40), the clinician can reasonably ascertain whether the lump is benign or malignant in nature. However, the false-negative rate of clinical and imaging assessment is too high to settle without a biopsy. Therefore, a core needle biopsy is recommended for all palpable lesions. Further management of the lump is based on the triple assessment, viz. clinical evaluation, imaging criteria (see below) biopsy results (Fig. 12). Lumps smaller than 1 cm in size can safely be subjected to expectant management if the triple test is negative. Larger or suspicious lumps must be excised for confident exclusion of cancer. Once cancer is diagnosed, appropriate oncological staging and treatment should follow.

Nipple Discharge Nipple discharge accounts for 5% of referrals to the breast clinic (128) and around 7% of all breast surgeries (129). The objective of evaluating nipple discharge in the office setting is to identify surgically significant nipple discharge. To be significant, a discharge should be true, spontaneous, persistent, and nonlactational. It is often uniductal, although significant discharge can involve multiple ducts. When duct excision is carried out for significance derived by these

criteria, about one-fourth of cases have a malignant or premalignant lesion as the etiology (129). The characteristics of the discharge also need to be defined: whether it is milky, multicolored and sticky, purulent, clear (watery), serous (yellow), serosanguinous (pink), or sanguinous (bloody). Hemoccult testing may help to discover occult blood in secreted fluid. Around 10% of patients with bloodstained nipple discharge have a malignant lesion. Another important correlation between malignancy and isolated nipple discharge is the patient’s age; in one series of patients undergoing excision for isolated nipple discharge, malignancy was present in 3%, 10%, and 32% in the below 40, 40 to 60, and over 60 age group, respectively (130). History and physical examination should concentrate on identifying the significant discharge and assessing systemic problems that may cause bilateral multiductal discharge. Bilateral spontaneous milky discharge is galactorrhea, which may result from conditions altering the endocrine profile (pituitary adenoma, chronic hepatic failure paraneoplastic syndromes, etc.) or from certain medications. Breast examination should emphasize identifying the presence of an associated breast mass. Of all cases eventually diagnosed as cancer, only 13% do not have a mass (129). Firm pressure around the areola helps identify the dilated duct by discharge from the nipple upon compression. The location of the discharging duct on the nipple should be carefully recorded. Age-appropriate screening with mammography must be performed and suspicious lesions must be addressed; however, the sensitivity and specificity of mammography are 57% and 62%, respectively (131). Other nonoperative modalities have been investigated to avoid surgery for benign conditions. These include nipple aspirate cytology, ductography, retroareolar sonography, ductoscopy, and magnetic resonance imaging, with variable success rates. The sensitivity of cytology ranges between 11% and 75%, while specificity is between 86% and 96% (131,132). The sensitivity and specificity of ductography range between 0% to 70% and 62% to 90%, respectively (131,132). Ductoscopy identifies 81% of malignancies. The most recent technique used to evaluate nipple discharge is magnetic resonance imaging, which has been shown to correlate with the histopathological diagnosis 73% of the time (133). However, the negative predictive value of none of these investigations is 100%. Therefore, although they may be useful adjuncts in evaluation of nipple discharge, they cannot preclude excisional biopsy for significant discharge. Figure 13 depicts a practical approach for working up patients presenting at the clinic with nipple discharge.

Breast Imaging

Figure 12 Clinical work-up of a breast mass.

Two imaging techniques are commonly used to evaluate potential breast pathology: mammography and ultrasonography. Of the two, mammography is more commonly employed. It can be used as a screening technique in women at risk for breast cancer but in whom no physical abnormalities are palpated, or to help establish a diagnosis in women who present with a palpable mass or other breast abnormality. The standard approach is to use film screen mammography, which is performed in a fashion similar to other X rays, with black and white radiographs being produced, which are viewed on a light box. Xeroradiography takes an electrostatic image of the breast and converts it to a blue on white photocopy image for viewing. The standard film screen imaging uses a slightly less radiation dose than xeroradiography and has proved to be just as effective in diagnosing breast

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

1057

Figure 13 Clinical approach to nipple discharge.

cancer. Because of the high-quality radiologic images that are now available with modern film screen mammography, this technique has largely replaced xeromammography. Mammography is very sensitive in detecting breast pathology. Although some concern was previously expressed about radiation exposure when used repeatedly as a screening technique, careful evaluation of this concern has proved that it is not an issue in women of screening age. Thus, current recommendations are that all women 50 years of age or older undergo mammography once yearly regardless of whether the physical examination is negative. Women in high-risk groups (e.g., mother had breast cancer) should be screened at least every other year, starting at age 40, and annually when they reach age 50. Mammographic findings suggestive of malignancy include masses, architectural distortions, asymmetric densities, and microcalifications (Fig. 14). Despite the high sensitivity of mammography in detecting abnormalities, its specificity is considerably less. Only about 25% of lesions that cannot be palpated on physical examination turn out to be cancer. Previously, a suspicious lesion resulted in a woman being subjected to open surgical biopsy utilizing needle location to make a definitive diagnosis. With modern stereotactic techniques, these lesions can now be biopsied percutaneously using specialized computer and X-ray equipment to guide the biopsy needle to a mammagraphically suspicious lesion. Because multiple biopsies of the lesion in question can be obtained using this technology, the presence or absence of malignancy can be ascertained with a high degree of accuracy (greater than 95%), obviating the need for open biopsy. Ultrasonography uses acoustic waves to image the breast. For cancer screening, it is totally ineffective. However, it can be quite useful for distinguishing between cystic and solid lesions. For example, in a woman with a palpable mass on physical examination or a nonpalpable mass on mammographic evaluation, which appears benign, ultrasound evaluation can help confirm its cystic or solid nature. If it proves to be cystic, biopsy to rule out malignancy is usually not needed.

TREATMENT OF BENIGN BREAST PATHOLOGY Benign breast diseases incorporate a wide spectrum of conditions presenting with or without acute symptom. Broadly,

Figure 14 Typical appearance of microcalcifications in breast carcinoma. These calcifications (arrow) are irregular in size and shape and occur in small clusters or in linear configurations.

three main categories of benign problems are clinically encountered, viz. inflammatory conditions, aberrations of normal development, and proliferative lesions. The latter category is further stratified into high or low risk according to the risk they incur toward development of cancer in the future. The following is an account of clinical approach toward the management of these conditions.

Inflammatory Conditions Acute mastitis and breast abscess most commonly affect women between the ages of 15 and 50. The condition can occur in lactational or nonlactational setting. Staphylococci or streptococci are the most common organisms responsible for infection, and gain entry through disruption of the nipple-areolar complex. Diffuse inflammatory response throughout the breast constitutes ‘‘mastitis,’’ whereas a localized collection of pus, most commonly in the subareolar region, represents an ‘‘abscess.’’ Mastitis is treated with appropriate antibiotics, e.g., penicillin derivatives, and with supportive therapy like antipyretics and analgesics. Focal heat compresses may benefit the local pain. Abscess requires urgent surgical drainage. Thorough debridement through a circumareolar incision (or multiple incisions) should be done keeping dependent drainage in mind. All loculi of pus must be broken to ensure hygienic drainage. Open drainage system is sometimes necessary to ensure continuous adequate drainage from the entire cavity. The chronic inflammatory conditions with abscess formation are less common. The differential diagnosis includes chronic infection and malignancy. Tuberculosis is the most common cause of chronic mastitis (134). Tuberculosis may clinically and mammographically resemble

medwedi.ru

1058

Part Eight: The Integument and Body Wall

malignancy. Biopsy of the breast mass is useful to diagnose the condition, because the yield of acid-fast bacilli culture is very low. A combination of antituberculous drugs is essential to treat mammary tuberculosis. Granulomatous lobular mastitis is associated with noncaseating granulomata confined to the breast lobule that some times responds to treatment with steroids (135).

Aberrations of Normal Development Nonproliferative lesions of the breast present with various clinical and imaging abnormalities. These include cysts, apocrine changes, fibrocystic changes, mild hyperplasias, and other epithelium-related calcifications (136). On most occasions, the biopsy is done to exclude malignancy, and no further management is required (137). Occasionally, breast cysts can be symptomatic with a lump, pain, and infection requiring aspiration excision and antibiotic treatments. A cyst presenting with rapid refilling after repeated aspirations must be excised to exclude intracystic cancer (138). Fibrocystic disease refers to a condition in which the breast undergoes a variety of fibrocystic changes characterized by micro or macro cyst formation, fibrous alterations, metaplasia of apocrine glands and ductal or lobular hyperplasia. Clinically, the breasts are often lumpy on palpation and the range symptomatically from intermittent dull achiness to marked pain and tenderness. Severe cystic disease giving rise to tender mastopathy may respond to hormonal manipulation with estrogen modulators or testosterone derivatives (139). However, no hormonal correlation between fibrocystic changes and breast pain has been conclusively identified.

Proliferative Lesions Proliferative lesions of the breast require careful clinical and pathological evaluation to ascertain their association with atypia. This discrimination is important because women with proliferative lesions without atypia have a slightly higher risk of developing cancer (1.5–2 times), while those with atypia have a substantially higher risk (3.5–5 times) toward malignancy compared with the general population (140). Proliferative lesions without atypia include moderate florid hyperplasia of the usual type: intraductal papilloma, sclerosing adenosis, and fibroadenoma. Most of these lesions are incidental microscopic findings. Fibroadenomas and occasionally sclerosing adenosis may present as palpable lumps. Fibroadenomas, especially, may reach sizes of 1 to 2 cm and on palpation appear smooth and rubbery. Once the pathological evaluation of an imaging or palpable abnormality concordantly establishes the diagnosis of one of these lesions, no further treatment is usually necessary. Large fibroadenomas are occasionally removed for cosmesis. On the contrary, lesions with atypia (atypical ductal hyperplasia or atypical lobular hyperplasia) need to be completely excised if the diagnosis is based on core needle biopsy because up to 30% of lesions are histologically upgraded to malignant lesions upon complete excision (141). Other proliferative lesions that require complete excision to exclude associated malignancy include radial scars, lobular carcinoma in situ (a neoplastic lesion that is generally considered to be benign), and papillomatosis. Once the diagnosis of cancer is excluded after complete excision, the risk toward subsequent malignancy must be discussed with the patient, including information regarding risk modification (142) and chemoprevention (143).

TREATMENT OF MALIGNANT BREAST PATHOLOGY Historically, two opposing views concerning the natural history of breast cancer have been put forth (144). Some physicians postulate that it is a systemic disease at inception and surgery has little impact on the risk of death from cancer. Others argue that it is often localized at the time of diagnosis and that timely extirpation of the tumor reduces the risk of death. Randomized controlled trials indicate that screening, adjuvant systemic therapy, and adjuvant radiotherapy can reduce the risk of mortality from breast cancer. The best outcome of treatment for breast cancer can be achieved by careful planning of the workup and therapy at the time when the diagnosis is suspected. The following is an account of the staging system, surgical principles, and the principles of adjuvant therapy that should be employed to plan a rational treatment.

Surgical Principles A century ago, Halsted published his first report on radical mastectomy for breast cancer (145). At that time, this procedure was truly an appropriate solution to the problem. The typical presentation of breast cancer then was what would qualify as locally advanced disease today. Moreover, the systemic treatment available today was nonexistent. A later report showed that this extensive surgery did improve local recurrence rates, making Halsted mastectomy the standard of treatment at that time. The procedure performed by Halstead was known as a radical mastectomy, which involved total removal of the breast with its underlying pectoralis muscles and the associated axillary lymph nodes. Fisher’s work in the l950s concentrated on lymphaticvenous channel communications in the drainage of the breast (146). This led to the belief that cancer may already be a systemic disease by the time a clinical diagnosis is established. This conclusion led to clinical trials on adjuvant treatment. As adjuvant systemic treatment developed, the real value of the extent of surgery for local treatment was again questioned. Individual reports of breast-conserving surgery (BCS) appeared in the 1950s and 1960s (147,148). Subsequently, six randomized prospective controlled trials were undertaken (Table 1) (149–154). The largest of the BCS trials was recently updated with a 20-year follow-up (155). The results continue to show the equivalence of BCS followed by radiotherapy with that of mastectomy. This trial required microscopically negative margins; however many ipsilateral recurrences occurred several years after treatment, which may represent residual tumor foci not detected at the time of original surgery. The real importance of these findings is that BCS is feasible in many patients and all attempts should be made to obtain negative margins. Positive margins do not necessarily mean that mastectomy is indicated and patients can have another procedure to revise the surgical margin if possible without grossly compromising the cosmetic outcome. Some tumors are still more suitable for mastectomy than BCS. There is a cutoff tumor size limit to dictate mastectomy. The breast size and the tumor size should be kept in mind when judging if adequate margins can be obtained while maintaining the cosmetic outcome. Extensive multiple cancers of the breast are best treated with mastectomy. Locally advanced tumors can be subjected to preoperative systemic chemotherapy to achieve BCS (156). Patients who do not respond to preoperative chemotherapy or in whom radiation therapy is contraindicated are suitable candidates

1059

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

Table 1 Clinical Trials of Mastectomy vs. Breast-Conserving Therapy 10 year survival (%) Study NSABP B-06 Milan NCI EORTC IGR Danish

No. of cases 1845 701 237 903 180 1153

Treatment MRM vs. BCS þ DXRT RM vs. BCS TM vs. BCS MRM vs. BCSþDXRT MRM vs. BCSþDXRT MRM vs. BCSþDXRT

Margins

Mastectomy

BCS

Negative 2–3 cm – 1 cm 2 cm Negative

82 (LNþ), 66 (LN) 83 85 73 91 82

92, 75 85 89 79 95 79

Abbreviations: NSABP, National Surgical Adjuvant Breast and Bowel Project; NCI, National Cancer Institute; EORTC, European Organization for Research and Treatment in Cancer; IGR, Institut Gustave-Roussy; MRM, modified radical mastectomy; BCS, breast-conserving surgery; DXRT, radiotherapy; RM, radical mastectomy; TM, total mastectomy.

for mastectomy. In summary, most early breast cancers should be considered for BCS. If margins are extensively involved, especially after surgical revision, mastectomy may have to become the appropriate option. If margins are only focally positive, a second revision may provide adequate local control. If mastectomy is deemed to be the best management option, it is far less radical than in the days of Halstead. It often involves removing the breast and sparing the pectoralis muscles or at worst removing the pectoralis minor muscle but sparing the pectoralis major. The degree of axillary node dissection is also less radical.

Preoperative Biopsy Regardless of whether the patient presents with a palpable lump or an imaging abnormality on mammography or ultrasound, such as microcalcifications or a density, it is always desirable to obtain a preoperative pathological diagnosis to plan the surgical approach. This can be achieved on an out-patient setting with a core biopsy guided by ultrasound (preferable if the lesion is sonographically visible) or stereotaxis (if the lesion is only visible on mammogram) (157). If a preoperative diagnosis is not possible for technical or logistic reason, excision of the lesion is indicated as if it was a carcinoma. The excision is guided by clinical examination (for palpable lesions), ultrasound (for sonographically visible lesions) (158), or radiological needle localization (for lesions visible only on mammogram) (159). In any event, incision should be placed directly over the lesion (discussed under the section ‘‘incision’’) and the specimen should be appropriately oriented (discussed under the section ‘‘specimen orientation’’). Excision should ensure a wide margin of normal tissue around the lesion so that chances of reoperation for margin clearance are minimized in the event that it is a cancer.

Incision The incision should be placed directly over the tumor mass. Circumareolar incisions to preserve cosmetic outcome should not be used unless the tumor lies directly beneath the areola. Although it is a cosmetically desirable incision, any need to tunnel toward the mass exposes healthy tissue to tumor seeding, increases the risk of incomplete removal of a known carcinoma, and makes revision of margins extremely difficult. The use of curvilinear versus radial incisions is debatable. In the National Surgical Breast and Bowel Project (NSABP) workshop report, radial incisions were advised for the lower-half lesions and curvilinear incisions were suggested for the upper-half tumors. We believe that a radial incision is cosmetically superior and provides an

excellent approach toward cancer resection with adequate margins because tumor grows centripetally along the ducts.

Flaps The subcutaneous tissue contains a network of blood vessels that nourish the skin. If this layer is removed by creating flaps that are too thin, a broad flat scar results, collapsing inwards and creating a saucer-like defect. If the tumor is close to the skin, it is preferable to excise a wider ellipse of skin together with underlying tissue down to the tumor rather than create thin flaps. This approach provides an excellent anterior resection margin as well as a cosmetically superior result.

Specimen Orientation Correct orientation of the specimen for the pathologist is the key element in breast surgery for cancer. It is important not only for resection of known malignant lesions for proper margin evaluation, but also for diagnostic excisions lest they turn out to be cancer on final pathology. Every institution should have a standard method of orientation well known to surgeons as well as the pathologists; at least three anatomical directions should be marked for complete orientation. At the author’s institution, the superior aspect of the specimen is always marked with a short silk stitch while the lateral aspect is marked with a long silk stitch; the posterior margin is inked. Such marking allows precise evaluation of reporting on the margins so that any positive margins can be accurately reresected.

Hormone Receptor Analysis In addition to a thorough microscopic analysis of breast cancer, measurement of steroid hormone receptors on a portion of the tumor should also be performed. Current immunochemical techniques are highly accurate and can assess both the proportion of tumor cells staining positively for the receptors, and the intensity of this staining. Although estrogen and progesterone receptors are routinely evaluated, estrogen activity seems to correlate best with outcome. The higher the measured value of ER activity, the better patient outcome. The reason for this is incompletely understood, but women in this group usually have malignancies that are more differentiated, exhibiting both nuclear and histologic grades that are more compatible with long-term survival. A further reason for knowing a patient’s ER activity relates to the potential benefit that could accrue from using tamoxifen as adjuvant therapy. Tamoxifen is an ‘‘antiestrogen’’ drug and has been shown to prolong the disease-free

medwedi.ru

1060

Part Eight: The Integument and Body Wall

interval in postmenopausal ER-positive women with histologically positive nodes, as well as in premenopausal and postmenopausal ER-positive women with negative nodes. Although tamoxifen is associated with an increased risk of developing uterine cancer, this risk overall appears to be quite low. Despite this risk, tamoxifen is clearly less toxic than standard chemotherapy so that it has become the treatment of choice for postmenopausal women with node-positive, ER-positive tumors (see below). Further, in women receiving tamoxifen as adjuvant therapy for breast cancer, a reduction in the incidence of a second-primary breast cancer in the contralateral breast has been noted.

Staging Staging refers to the grouping of patients according to the extent of their disease, so that appropriate treatment recommendations can be made and adequate estimates of prognosis can be provided. In addition, the staging system provides a framework for reporting treatment outcomes and thereby permits the efficacy of new treatments to be assessed. The most widely used staging system for breast cancer is the TNM (tumor, nodes, and metastasis) classification provided by the American Joint Committee on Cancer (AJCC). Changes in the staging system are periodically required to incorporate new diagnostic and therapeutic advances that affect risks of disease recurrence and patient survival. The new criteria for breast cancer TNM staging have been implemented by AJCC since January 2003 (Table 2) (160). The exact tumor size is obtained from the pathological measurement of tumor in the excised specimen. Caution must be exercised to include the tissue resected during core needle biopsy; sometimes the entire lesion is excised during preoperative biopsy and no residual tumor is identified in the lumpectomy specimen, in which case the tumor size should be measured from the biopsy specimen. The most important prognostic factor and staging criteria is the lymph node status (161). Clinical examination of the axilla is notoriously inaccurate for lymph node staging. Approximately 30% of patients with palpable lymph nodes prove to be node negative following axillary dissection, and about 30% of clinically node-negative patients have nodal involvement (162). Axillary lymph node dissection has been the standard method of evaluating the lymph node status in breast cancer patients for many years. However, more than half of the patients treated today for breast cancer have node-negative disease, and the axillary lymph node dissection procedure has significant complications (163). The current standard approach to assess the lymph node status is changing from complete axillary lymph node dissection to sentinel lymph node biopsy (164). The sentinel lymph node is the first lymph node to receive lymphatic drainage from a tumor. This provides more accurate evaluation of one or several target nodes rather than the entire axillary tissue specimen. The technique of performing sentinel lymph node biopsy has been evolving. Blue dye and/or radiocolloid is injected at a target site (varies with institution and preference) and allowed to drain to the sentinel node, which is then identified visibly (blue dye), by gamma probe (radioisotope), or both and then excised. The consensus statement made by experts in this field reports best results with the use of both radioisotope and the blue dye to identify the sentinel nodes (165). At the author’s institution, subareolar injection of both radioisotope and blue dye is performed for sentinel lymph node biopsy (166). Theoretically, sentinel node–negative patients should not require complete axillary dissection. However, the overall long-term

Table 2 AJCC Staging System for Breast Cancer—2003 Primary tumor (T) TX Primary tumor cannot be assessed TO No evidence of primary tumor Tis Carcinoma in situ (ductal or lobular), or Paget’s disease without evidence of tumor T1 Tumor less than 2 cm in greatest dimension T2 Tumor greater than 2 cm but less than 5 cm in greatest dimension T3 Tumor greater than 5 cm in greatest dimension T4a Tumor of any size with extension into chest wall T4b Tumor of any size with extension into skin, or setallite skin nodule or peau d’ orange T4c T4a and b T4d Inflammatory carcinoma Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed NO No lymph node metastasis N1 Metastasis in 1–3 nodes-axillary and/or internal mammary by sentinel node biopsy (not clinically) N1mi Micrometastasis (greater than 0.2 mm, less than 2.0 mm) N2 Metastasis in 4–9 axillary nodes, or clinically þ internal mammary nodes without axillary nodes N3 Metastasis in more than 10 axillary nodes, or inftaclavicular nodes, or clinically þ internal mammary nodes with þ axillary nodes, or ipsilateral supraclavicular nodes Distant metastasis (M) MO No detectable distant disease M1 Distant disease detectable clinically or by imaging including contralateral axillary nodes Stage Stage Stage Stage Stage Satge Srage Satge Stage

groupings 0 I IIa IIb IIIa IIIb IIIc IV

TisNOMO T1N0M0 T0N1M0, T1N1M0, T2N0M0 T2N1M0, T3N0M0 T0N2M0, T1N2M0, T2N2M0, T3N1M0, T3N2M0 T4, N0M0, T4N1M0, T4N2M0 Any T N3 Any T Any N M1

Abbreviation: AJCC, American Joint Committee on Cancer.

effects on survival, local recurrence, and morbidity of omitting axillary clearance have not been fully elucidated. The NSABP-32 trial, which was initiated in October of 1998 has randomized patients with negative sentinel nodes to no further axillary treatment or follow-up axillary dissection (167). The results of this trial will answer the abovementioned questions and delineate whether sentinel node biopsy should become the national standard of care.

Adjuvant Systemic Therapy The conceptual approach toward the treatment of breast cancer has changed from the late 1800s to the present time. The earlier Halstedian concept emphasized that breast cancer slowly grows locally and spreads via lymphatics and subcutaneous facial planes; hence the extensive local en bloc removal of all these tissues should affect cure. Only 12% of patients treated by Halstead survived 10 years and attempts to perform even more radical resections failed to improve the outcome, leading to the belief that it is a systemic disease from the outset. Efforts were then directed toward identifying systemic treatment that could target the nonmanifest

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

systemic disease left behind after local resection of tumor. The type of treatment administered after surgery has always been guided by the experience accumulated from treating patients with metastases. In 1896, Beatson reported on two premenopausal women with metastatic breast cancer, who improved after oophorectomy (168). This approach became a common therapy for women with metastatic breast cancer, and trials involving oophorectomy or radiation-based ovarian ablation were started (169). In the 1950s, chemotherapy was incorporated in the postoperative treatment of breast cancer patients (170). The first randomized clinical trials of adjuvant therapy were performed in the 1970s in North America and Europe. A series of trials showed that adjuvant chemotherapy increased disease-free survival and overall survival rates (171), that polychemotherapy was better than single-agent therapy (172), that adjuvant tamoxifen improved overall survival rates in postmenopausal women (173), and that ovarian ablation prolonged disease-free survival in premenopausal women (174). At present, the role of adjuvant systemic treatment is well established for early-stage breast cancer, but the benefits in disease-free survival and overall survival are of small magnitude. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) conducted a series of overviews focusing on randomized clinical trials to detect these small benefits. The first EBCTCG meta-analysis was based on pooled raw data from 75,000 women who participated in 133 clinical trials conducted worldwide between 1957 and 1985 (175). This review showed that at 10-year follow-up, adjuvant chemotherapy reduced the risk of recurrence by 22% to 37% and the risk of death by 14% to 27%, depending on age. An update of the EBCTCG overview concluded that anthracycline-based chemotherapy regimens are superior to the regimens that do not contain anthracycline (176). Ovarian ablation resulted in improved survival rates among premenopausal women, with a risk reduction similar to that of adjuvant chemotherapy (177). Five years of tamoxifen therapy reduced the risk of recurrence and death in ER-positive women regardless of age (178). It is however important to understand that all these benefits are reported in terms of relative risks and may actually incur very small benefit in patients with low risk of recurrence and death. The single most important predictor of risk of recurrence and death is the status of lymph nodes; in lymph node–negative patients, the tumor size and grade and receptor expression status are important in dictating recurrence and death. All these factors and other comorbid conditions should be kept in mind to compute a given patients risk of recurrence and death so that the absolute benefit of adjuvant treatment can be presented to the patient. Patients with low risk of recurrence and death from tumor or high risk of death from other illnesses may not be good candidates for adjuvant treatment. Web-based computer softwares (e.g., adjuvantonline.com) have been developed to assist in the computation of a given patient’s risk of tumor recurrence and death and the potential benefit from hormonal or chemotherapy. Aromatase inhibitors (agents that block the conversion of androgens to estrogens) are an effective second-line hormonal therapy for patients with breast cancer. They have been used in the treatment of metastatic disease for a long time and are now rapidly moving into the adjuvant setting. Results of a multi-institutional and multinational study of anastrazole versus tamoxifen, alone and in combination (ATAC Trial), have recently been published (179). The combination arm was stopped because of significant side effects. The hazard ratio for recurrence at four years was 0.86 in

1061

favor of anastrazole. Anastrazole was also found to have a superior therapeutic index except for musculoskeletal disorders, which had a relative risk of 1.5 in the anastrazole arm. The other area of significant advancement is the findings of molecular biology on breast cancer pathogenesis, which have reached therapeutic application on several fronts. The most studied molecule is the human EGF 2 (HER-2), which is an overexpressed gene in 25% to 30% of invasive cancers and associated with a worse prognosis (180). Trastuzumab is a humanized monoclonal antibody that binds to HER-2 with great affinity, resulting in growth arrest of HER-2 overexpressing cancer cells. It has been shown to be effective in the metastatic setting (181), but trials studying its role in the adjuvant setting are underway. As the advances in adjuvant treatment are being made, the armamentarium of therapeutic options is likely to increase. The physician must present all the risk and benefits to the patients and involve them in the decision-making process regarding adjuvant treatment. The quality of life for patients undergoing adjuvant treatment is not well defined (182), and prospective studies are clearly needed.

Adjuvant Local Therapy In the last 20 years, BCS for cancer has become more acceptable and is commonly coupled with radiation therapy for local control of disease. After the results of six randomized trials from the United States and Europe (Table 1), radiation therapy to the breast has become an integral part of early breast cancer treatment. These trials reported that the rates of local and regional recurrences, distant metastasis, and overall survival were not significantly different between mastectomy and breast conservation coupled with radiation. Moreover, in an updated meta-analysis of data, Morris et al. found that the pooled odds ratio for overall survival at 10 years favored BCS and radiation therapy over mastectomy (183). Whether radiation therapy is required for every patient after BCS for invasive cancer is still unresolved. In a phase II single-arm trial, the Joint Center of Radiation Therapy selected patients with favorable prognosis to follow-up after breast conservation without radiation (184). The inclusion criteria included tumor size less than 2 cm, histologically negative nodes, no extensive intraductal component, no lymphovascular invasion, and pathologically 1 cm negative margins. The trial was closed prematurely because of a 16% local recurrence at a median follow-up of 56 months. Several randomized trials compared BCS alone versus adjuvant radiation therapy; the rate of local failure in the radiation therapy group was reduced by an average of 85% (Table 1). Despite these findings, the use of partial mastectomy and tamoxifen without breast irradiation might be appropriate in a select group of patients, particularly those older than 70 years of age with small ER positive tumors excised with wide margins. In a retrospective study of 122 patients treated with partial mastectomy and systemic therapy without breast irradiation therapy, Nemoto et al. showed that overall local failure rate was 19% (185). The rate of recurrence correlated with the size of the tumor and age of the patient; lowest failure rate being in women older than 70, having tumors of size less than 1 cm. The goal of adjuvant radiation therapy after mastectomy is the sterilization of subclinical disease in the chest wall. Many studies showed that the rate of local failure is reduced when mastectomy is coupled with adjuvant radiation; however deaths related to cardiopulmonary causes in the radiation arm make adjuvant radiation of chest wall unfeasible for all patients with mastectomy. Fowble et al.

medwedi.ru

1062

Part Eight: The Integument and Body Wall

analyzed 627 patients enrolled in an Eastern Cooperative Oncology Group adjuvant chemotherapy study, in which radiation therapy was not used, to identify patients who would benefit from adjuvant radiation after mastectomy (186). In patients with four to seven positive lymph nodes, the isolated local failure rate was 10% and 31% for tumors less than and greater than 5 cm in size, respectively. Other unfavorable prognostic indicators for local recurrence included negative ER status, pectoral fascia involvement, and tumor necrosis. Two trials [British Columbia (187) and Danish Breast Cancer (188)] have shown a significant increase in disease-free and overall survival after chest wall radiation following mastectomy in patients with lymph node–positive disease and large tumors. Therefore, the indications for postmastectomy radiation therapy to the chest wall include the presence of four or more positive lymph nodes, extracapsular extension, and tumor stage of T3 or more. Techniques of radiation therapy have improved over time and late cardiac deaths are much less common now. Newer advances are being made in the area of partial breast irradiation by concentrating on primary tumor site with an objective to minimize complications and affect local control. These techniques are still in trial phases and should not be used outside of study setting.

SUMMARY The breast is a functional part of the reproductive system and as such is subject to a variety of specific morphologic and physiologic changes at various stages of life, which are under neuroendocrine control. Understanding these variations is essential if appropriate treatment of its multifarious disorders is to be effectively administered, and the natural history of benign and malignant diseases adequately conceptualized. Although most diseases of the breast are benign and can be effectively managed with relatively simple supportive measures and reassurance, the fear of malignancy is the driving force that brings the majority of patients to a physician. Fortunately, our understanding of breast cancer has evolved considerably from the days of Halstead so that its systemic nature is now universally accepted. Thus, the radical, mutilative procedures that were previously performed, based on the assumption that breast cancer was primarily a local disease, have been replaced with breastsparing procedures with equally good outcomes. In fact, as our knowledge of the biology of breast cancer has increased, breast conservation surgery in conjunction with adjuvant treatment when needed has enabled most patients with this disease to enjoy long-term survival. As the genetics underlying breast cancer development becomes better clarified, it is envisioned that even more precise treatment will be possible by specific gene manipulation.

REFERENCES 1. Russo J, Hu YF, Silva ID, et al. Cancer risk related to mammary gland structure and development. Microsc Res Tech 2001; 52:204–223. 2. Hamilton NJ, Boyd JD, Mossman HW. Human Embryology. Cambridge, U.K.: Heffer, 1968:428–432. 3. Hughs ESR. Development of mammary gland. Ann R Coll Surg Eng 1950; 6:99–105. 4. Howard BA, Gusterson BA. Human breast development. J Mammary Gland Biol Neoplasia 2000; 5:119–137.

5. Horseman ND. Prolactin and mammary gland development. J Mammary Gland Biol Neoplasia 1999; 4:79–88. 6. Russo J, Russo IH. Development of the human breast. In: Encyclopedia of Reproduction. New York: Academic, 1998; 3:71–97. 7. Russo J, Russo IH. Development of human mammary gland. In: Neville M, Daniel CW, eds. The Mammary Gland. New York: Plenum Press, 1987:67–79. 8. Russo J, Rivera R, Russo IH. Influence of age and parity on the development of the human breast. Breast Cancer Res Treat 1992; 23:211–218. 9. Russo IH, Russo J. Role of hormones in cancer initiation and progression. J Mammary Gland Biol Neoplasia 1998; 3: 49–61. 10. Yen SSC. Clinical endocrinology of reproduction. In: Baulieu E-E, Kelly PA, eds. Hormones: From Molecules to Disease. New York: Chapman and Hall, 1990:445–459. 11. Tong S, Wallace EM, Burger HG. Inhibins and activins: clinical advances in reproductive medicine. Clin Endocrinol (Oxf) 2003; 58:115–127. 12. Brisken C, Park S, Vass T, et al. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci USA 1998; 95:5076–5081. 13. Zeps N, Bentel JM, Papadimitriou JM, et al. Estrogen receptornegetive epithelial cells in mouse mammary gland development and growth. Differentiation 1998; 62:22–26. 14. Vogel PM, Georgiade NG, Fetter Bf, et al. The correlation of histologic changes in the human breast with the menstrual cycle. Am J Pathol 1981; 104:23–34. 15. Zeppa R. Vascular response of the breast to estrogen. J Clin Endocrinol Metab 1969; 29(5):695–700. 16. Hussain Z, Roberts N, Whitehouse GH, et al. Estimation of breast volume and its variation during the menstrual cycle using MRI and stereology. Br J Radiol 1999; 72:236–245. 17. Longacre TA, Bartow SA. A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol 1986; 10:382–393. 18. Ferguson DJ, Anderson TJ. Morphological evaluation of cell turnover in relation to the menstrual cycle in the ‘‘resting’’ human breast. Br J Cancer 1981; 44:177–181. 19. Cunha GR, Hom YK. Role of mesenchymal-epithelial interactions in mammary gland development. J Mammary Gland Biol Neoplasia 1996; 1:21–35. 20. Robinson GW, Karpf AB, Kratochwil K. Regulation of mammary gland development by tissue interaction. J Mammary Gland Biol Neoplasia 1999; 4:9–19. 21. Snedeker SM, Brown CF, Di Augustine RP. Expression and functional properties of transforming growth factor alpha and epidermal growth factor during mouse mammary gland ductal morphogenesis. Proc Natl Acad Sci USA 1991; 88(1): 276–280. 22. Jackson D, Bresnick J, Dickson C. A role for fibroblast growth factor signaling in the lobulo-alveolar development of the mammary gland. J Mammary Gland Biol Neoplasia 1997; 2(4):385–392. 23. Daniel CW, Robinson S, Silberstein GB. The transforming growth factors beta in development and functional differentiation of the mouse mammary gland. Adv Exp Med Biol 2001; 501:61–70. 24. Smalley MJ, Dale TC. Wnt signaling in mammalian development and cancer. Cancer Metastasis Rev 1999; 18(2):215–230. 25. Tepera SB, McCrea PD, Rosen MJ. A beta-catenin survival signal is required for normal lobular development in the mammary gland. J Cell Sci 2003; 166(pt 6):1337–1349. 26. Buhler TA, Dale TC, Kieback C, et al. Localization and quantification of Wnt-2 gene expression in mouse mammary development. Dev Biol 1993; 155(1):87–96. 27. Osborne M. Breast development and anatomy. In: Harris LM Jr, Morrow M, Osborne CK, eds. Diseases of the Breast.New York: Lippinkott & Wilkins, 2000:1–13. 28. Rohrich RJ, Hartley W, Brown S. Incidence of breast and chest wall asymmetry in breast augmentation: a retrospective

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States

29.

30.

31. 32. 33.

34.

35.

36. 37. 38.

39. 40. 41.

42. 43. 44.

45.

46.

47.

48.

49.

50. 51.

52.

analysis of 100 patients. Plast Reconstr Surg 2003; 111(1): 1513–1523. Rosenbloom A. Breast Physiology: normal and abnormal development and function. In: Bland KCEI, ed. The Breast: Comprehensive Management of Benign and Malignant Diseases. Vol. 1. Philadelphia: W.B. Saunders, 1998:38–50. Mills JL, Stolley PD, Davies J, et al. Premature thelarche. Natural history and etiologic investigation. Am J Dis Child 1981; 135:743–745. Laurence DJ, Monaghan P, Gusterson BA. The development of the normal human breast. Oxf Rev Reprod Biol 1991; 13:149–174. Sloand E. Pediatric and adolescent breast health. Lippincotts Prim Care Pract 1998; 2:170–175. Murakami M, Kawai K, Higuchi K, et al. Correlation between breast development and hormone profiles in puberal girls. Nippon Sanka Fujinka Gakkai Zasshi 1998; 40:561–567. Radfar N, Ansusingha K, Kenny FM. Circulating bound and free estradiol and estrone during normal growth and development and in premature thelarche and isosexual precocity. J Pediatr 1976; 89:719–723. Stanhope R, Abdulwahid NA, Adams J, et al. Studies of gonadotrophin pulsatility and pelvic ultrasound examinations distinguish between isolated premature thelarche and central precocious puberty. Eur J Pediatr 1986; 145:190–194. Styne D. Puberty. In: Greenspan F, Gardner D, eds. Basic and Clincal Endocrinology. New York: McGraw-Hill, 2001:547–574. Bongiovanni AM. An epidemic of premature thelarche in Puerto Rico. J Pediatr 1983; 103:245–246. Frantz A, Wilson JD. Endocrine disorders of the breast. In: Wilson JDFD, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia: WB Saunders, 1998: 877–900. Finer N, Emery P, Hicks BH. Mammary gigantism and D-pencillamine. Clin Endocrinol (Oxf) 1984; 21:219–222. Lafreniere R, Temple W, Ketcham A. Gestational macromastia. Am J Surg 1984; 148:413–418. Baker SB, Burkey BA, Thornton P, et al. Juvenile gigantomastia: presentation of four cases and review of literature. Ann Plast Surg 2001; 46:517–526. Lee PA. The relationship of concentrations of serum hormones to pubertal gynecomastia. J Pediatr 1975; 86:212–215. Thompson DF, Carter JR. Drug-induced gynecomastia. Pharmacotherapy 1993; 13:37–45. Kuhn JM, Mahoudeau JA, Billaud L, et al. Evaluation of diagnostic criteria for Leydig cell tumors in adult men revealed by gynecomastia. Clin Endocrinol (Oxf) 1987; 26:407–416. Kirschner MA, Cohen FB, Jespersen D. Estrogen production and its origin in men with gonadotrophin-producing neoplasms. J Clin Endocrinol Metab 1974; 39:112–118. Grumbach M, Conte F. Disorders of sex differentiation. In: Wilson J, Foster D, eds. Williams Textbook of Endocrinology. Philadelphia: WB Saunders, 1992:853–951. Morishima A, Grumbach MM, Simpson ER, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995; 80:3689–3698. Hilakivi-Clarke L, Forsen T, Eriksson JG, et al. Tallness and overweight during childhood have opposing effects on breast cancer risk. Br J Cancer 2001; 85:1680–1684. Sappey MPC. Injection preparation et conservation des vaisseaux lymphatiques. These pour le dectorat en medicine, no 241. Paris: Rignoux Imprimeur de la Faculte de Medicine, 1834. Turner-Warwick RT. The lymphatics of the breast. Br J Surg 1959; 46:574–582. Tanis PJ, Neiweg OE, Olmos RAV, Kroon BBR. Anatomy and physiology of lymphatic drainage of the breast from the perspective of sentinel node biopsy. J Am Coll Surg 2001; 192(3):399–409. Nishimura R, Nagao K, Miayama H, et al. Higher plasma vascular endothelial growth factor levels correlate with menopause, overexpression of p53, and recurrence of breast cancer. Breast Cancer 2003; 10(2):120–128.

1063

53. Osanai T, Wakita T, Gomi N, et al. Correlation among intratumoral blood flow in breast cancer, clinicopathological findings and Nottingham Prognostic index. Jpn J Clin Oncol 2003; 33(1):14–16. 54. Simpson HW, McArdle CS, George WD, et al. Pregnancy postponement and childlessness leads to chronic hypervascularity of the breasts and cancer risk. Br J Cancer 2002; 87(1): 1246–1252. 55. Chepko G, Smith GH. Three-division competent, structurallydistinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell 1997; 29(2):239–253. 56. Chepko G, Smith GH. Mammary epithelial stem cells: our current understanding. J Mammary Gland Biol Neoplasia 1999; 4(1):35–52. 57. Tyson JE, Hwang P, Guyda H, et al. Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 1972; 113:14–20. 58. Speroff L, Glass RG, Kase NG. The Breast. Clinical Gynecologic Endocrinology and Infertility. Baltimore: Lippincott Williams & Wilkins, 1999:600–641. 59. Kelly PA, Djiane J, Postal-Vinay MC, et al. The prolactin/ growth hormone receptor family. Endocr Rev 1991; 12: 235–251. 60. Yang Y, Spitzer E, Meyer D, et al. Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesisand differentiation of the mammary gland. J Cell Biol 1995; 131:215–226. 61. Liscia DS, Merlo G, Ciardiello F, et al. Transforming growth factor-alpha messenger RNA localization in the developing adult rat and human mammary gland by in situ hybridization. Dev Biol 1990; 140(1):123–131. 62. Robinson GW, Henninhausen L. Inhibins and activins regulate mammary epithelial cell differentiation through mesenchymalepithelial interactions. Development 1997; 124:2701–2708. 63. Suzuki R, Atherton AJ, O’Hare MJ, et al. Proliferation and differentiation in the human breast during pregnancy. Differentiation 2000; 66(2–3):106–115. 64. Scott-Conner CEH. Diagnosing and managing breast disease during pregnancy and lactation. Medscape Womens Health 1997; 2(5):1. 65. Slavin JL, Billson R, Ostor AG. Nodular breast lesions during pregnancy and lactation. Histopathology 1993; 22(5):481–485. 66. Jiminez JF, Rickey RO, Cohen C. Spontaneous breast infarction associated with pregnancy presenting as a palpable mass. J Surg Oncol 1986; 32(3):174–178. 67. Harigopal M, Mudrovich SA, Hoda SA, Rosen PP. Secondary tumors in mammary adenolipomas: a report of 2 unusual cases. Arch Pathol Lab Med 2003; 127(3):el51–e154. 68. Scott-Conner CE, Schorr SJ. The diagnosis and management of breast problems during pregnancy and lactation. Am J Surg 1995; 170(4):401–405. 69. Lafreniere R. Bloody nipple discharge during pregnancy: a rationale for conservative treatment. J Surg Oncol 1990; 43: 228–230. 70. McCarty K, Nath M. Breast. In: SS S, ed. Histology for Pathologists. Philadelphia: Lippincott-Raven, 1997:71–82. 71. Kaplan CR, Schenken R. Endocrinology of the breast. In: Mitchell G, Bassett L, eds. The Female Breast and Its Disorders. Baltimore: Williams & Wilkins, 1990:22–44. 72. Cregan MD, Harttman PE. Computerized breast measurement from conception to weaning: clinical implications. J Hum Lact 1999; 15:89–96. 73. Neville MC, Morton J. Physiology and endocrine changes underlying human lactogenesis II. J Nutr 2001; 131 911 0: 3005s–3008s. 74. Kelleher SL, Lonnerdal B. Immunological activities associated with milk. Adv Nutr Res 2001; 10:39–65. 75. Kent JC, Mitoulas L, Cox DB, et al. Breast volume and milk production during extended lactation in women. Exp Physiol 1999; 84:435–447. 76. Ohtani O, Shao XJ, Saitoh M, et al. Lymphatics of the rat mammary gland during virgin, pregnant, lactating and post-weaning periods. Ital J Anat Embryol 1998; 103:335–342.

medwedi.ru

1064

Part Eight: The Integument and Body Wall

77. Marti A, Feng Z, Altermatt HJ, et al. Milk accumulation triggers apoptosis of mammary epithelial cells. Eur J Cell Biol 1997; 73:158–165. 78. Lund LR, Romer J, Thomasset N, et al. Two distinct phases of apoptosis in mammary gland involution: proteinaseindependent and -dependent pathways. Development 1996; 122:181–193. 79. Yan GZ, Pan WT, Bancroft C. Thyrotropin-releasing hormone action on the prolactin promoter is mediated by the POU protein pit-1. Mol Endocrinol 1991; 5:535–541. 80. Bredow S, Kacsoh B, Obal F Jr, et al. Increase of prolactin mRNA in the rat hypothalamus after intracerebroventricular injection of VIP or PACAP. Brain Res 1994; 660:301–308. 81. Pickett CA, Gutierrez-Hartmann A. Ras mediates Src but not epidermal growth factor-receptor tyrosine kinase signaling pathways in GH4 neuroendocrine cells. Proc Natl Acad Sci USA 1994; 91:8612–8616. 82. Porter TE, Wiles CD, Frawley LS. Stimulation of lactotrope differentiation in vitro by fibroblast growth factor. Endocrinology 1994; 134:164–168. 83. Tyson JE, Perez A, Zanartu J. Human lactational response to oral thyrotropin releasing hormone. J Clin Endocrinol Metabol 1976; 43:760–768. 84. Ben-Jonathan N, Mershon J, Allen D, et al. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocrine Rev 1997; 17:639–669. 85. Bezault J, Bhimani R, Wiprovnick J, Furmanski P. Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Res 1994; 54(9): 2310–2312. 86. Hennighausen L. Signal networks in the mammary gland: lessons from the animal models. In: Dickson RB, Salomon DS, eds. Hormones and Growth Factors in Development and Neoplasia. New York: Wiley-Liss, 1998:239–277. 87. Greenberg MM, Wolfe J, Rosen JM. Casein gene expression: from transfection to transgenics. In: Dickson RB, Lippman ME, eds. Genes, Oncogenes and Hormones. Boston: Kluver, 1991:379–398. 88. McKnight RA, Burdon T, Pursel VG, Shamay A, Wall RJ, Hennighausen L. The whey acidic protein. In: Dickson RB, Lippman ME, eds. Genes, Oncogenes and Hormones. Boston: Kluver, 1991:399–406. 89. Wakao H, Gouilleux F, Groner B. Mammary gland factor (Mgf) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J 1994; 13:2182–2188. 90. Happ B, Groner B. The activated mammary gland specific nuclear factor (Mgf) enhances in vitro transcription of the beta-casein gene promoter. J Steroid Biochem 1993; 47: 21–30. 91. Altiok S, Groner B. b-casein mRNA sequesters a single-strandednucleic acid-binding protein which negatively regulates the b-casein gene promotor. Mol Cell Biol 1994; 14(90):6004–6012. 92. Streuli CH, Edwards GM. Control of normal mammary epithelial phenotype by integrins. J Mammary Gland Biol Neoplasia 1998; 3:151–163. 93. Nguyen DD, Neville MC. Tight junction regulation in the mammary gland. J Mammary Gland Biol Neoplasia 1998; 3(3):233–246. 94. Daly SE, Owens RA, Hartmann PE. The short-term synthesis and infant-regulated removal of milk in lactating women. Exp Physiol 1993; 78:209–220. 95. Jerry DJ, Dickinson ES, Roberts AL, Said TK. Regulation of apoptosis during mammary involution by the p53 tumor suppressor gene. J Dairy Sci 2002; 85(5):1103–1110. 96. Shamay A, Shapiro F, Mabjeesh SJ, Silanikove N. Caseinderived phosphopeptides disrupt tight junction integrity, and precipitously dry up milk secretion in goats. Life Sci 2002; 70(23):2707–2719. 97. Prince JM, Klinowska TC, Marshman E, et al. Cell matrix interactions during development and apoptosis of the mouse mammary gland in vivo. Dev Dyn 2002; 223(4):497–516.

98. Strange R, Metcalfe T, Thackray L, Dang M. Apoptosis in normal and neoplastic mammary gland development. Micros Res Tech 2001; 52(2):171–181. 99. Marti A, Graber H, Lazar H, et al. Caspases: decoders of apoptotic signals during mammary involution. Caspase activation during involution. Adv Exp Med Biol 2000; 480: 195–201. 100. Tonner E, Barber MC, Travers MT, et al. Hormonal control of insulin-like growth factor-binding protein-5 production in the involuting mammary gland of the rat. Endocrinology 1997; 138(12):5101–5107. 101. Tonner E, Allen G, Shkreta L, et al. Insulin-like growth factor binding protein-5 (IGFBP-5) potentially regulates programmed cell death and plasminogen activation in the mammary gland. Adv Exp Med Biol 2000; 4880:45–53. 102. McNeilly AS. Lactational control of reproduction. Reprod Fertil Dev 2001; 13(7–8):583–590. 103. Covington C, Mitchell-Gieleghem A, Lawson D, et al. Presence of carotenoid, an anticarcinogenic marker, in nipple aspirates postlactation. Adv Exp Med Biol 2001; 501: 143–152. 104. Chapman DJ, Perez-Escamilla R. Identification of risk factors for delayed onset of lactation. J Am Diet Assoc 1999; 99: 450–454. 105. Anderson AM. Didruption of lactogenesis by retained placental fragments. J Hum Lact 2001; 17(2):142–144. 106. Arthur PG, Kent JC, Hartmann PE. Metabolites of lactose synthesis in milk from diabetic and nondiabetic women during lactogenesis II. J Pediatr Gastroenterol Nutr 1994; 19: 100–108. 107. Dewey KG. Maternal and fetal stress are associated with impaired lactogenesis in humans. J Nutr 2001; 131(11): 3012s–3015s. 108. Forbes A, Hennemen P, Griswold G, et al. A syndrome, distinct from acrorriegamenorrhea, and low follicle-stimulating hormone excretion. J Clin Endocrinol 1951; 12:1087–1094. 109. Archer DF. Current concepts of prolactin physiology in normal, and abnormal conditions. Fertil Steril 1977; 28:125–134. 110. Frantz AG. Prolactin. N Eng J Med 1978; 298:201–207. 111. Blackwell RE. Diagnosis and management of prolactinimas. Fertil Steril 1985; 43:5–16. 112. Kelver M, Nagamani M. Hyperprolactinemia in primary adrenal cortical insufficiency. Fertil Steril 1985; 44:423–425. 113. Mahesh VB, Pria SD, Greenblatt RB. Abnormal lactation with Cushing’s syndrome-a case report. J Endocrinol 1969; 29: 978–981. 114. Nabarro JD. Acromegaly. Clin Endocrinol (Oxf) 1987; 26: 481–512. 115. Sievertsen GD, Lim VS, Nakawatase C, et al. Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure. J Clin Endocrinol Metab 1980; 50:846–852. 116. Turkington RW. Ectopic production of prolactin. N Eng J Med 1971; 285:1455–1458. 117. Petrek JA. Abnormalities of the breast during pregnancy and lactation. In: Harris LM Jr, Morrow M, Osborne CK, eds. Diseases of the Breast. New York: Lippinkott & Wilkins, 2000: 63–66. 118. Choudhury M, Singal MK. Lactating adenoma-cytomorphologic study with review of literature. Indian J Pathol Microbiol 2001; 44(4):445–448. 119. Baker J. Lactating adenoma: a diagnosis of exclusion. Breast J 2001; 7(5):354–357. 120. Nichols S, Water WE, Wheeler MJ. Management of female breast disease by Southhampton general Practitioner. Br Med J 1980; 281:1450–1453. 121. Preece PE, Baum M, Mansel RE, et al. The importance of mastalgia in operable breast cancer. Br Med J 1982; 248: 1299–1300. 122. Maddox PR, HarrisonBJ, Mansel RE, Hughes LE. Non-cyclical mastalgia: Improved classification and treatment. Br J Surg 1989; 76:901–904.

Chapter 56: Breast: Physiologic Considerations in Normal, Benign, and Neoplastic States 123. Klimberg VS. Etiology and management of breast pain. In: The Breast: Comprehensive Management of Benign and Malignant Diseases. Vol. 1. Philadelphia: WB Saunders, 1998. 124. Gabrielli G, Binazzi P, Scaricabarozzi L, Massi GB. Nime sulide in the treatment of mastalgia. Drugs 1993; SI:137–139. 125. Gateley CA, Maddox PR, Pritchard GA, et al. Plasma fatty acid profiles in benign breast disorders. Br J Surg 1992; 79: 407–409. 126. Mansel RE, Pye JK, Hughs LE. Effects of essential fatty acids on cyclical mastalgia and non-cyclical breast disorder. In: Horrobin DF, ed. Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine. New York: Willey-Liss, 1990:557–649b. 127. Morrow M, Wong S, Venta L. The evaluation of breast masses in women younger than forty years of age. Surgery 1998; 124:634–641. 128. Dixon JM, Mansel RE. Symptoms assessment and guidelines for referral. ABC of breast diseases. Br Med J 1994; 309:722–726. 129. Leis HP Jr. Management of nipple discharge. World J Surg 1989; 13(6):736–742. 130. Seltzer MH, Perloff LJ, Kelly RL, Fitts WT. Significance of age in patients with nipple discharge. Surg Gynecol Obstet 1970; 131:519–522. 131. Simmons R, Adamovich T, Brennan M, et al. Non-surgical evaluation of pathologic nipple discharge. Ann of Surg Oncol 2003; 10(2):113–116. 132. Baitchev G, Gortchev G, Todorova A, et al. Intraductal aspiration cytology and galactography for nipple discharge. Int Surg 2003; 88(2):83–86. 133. Oral SG, Dougherty CS, Reynolds C, et al. MR imaging in patients with nipple discharge: initial experience. Radiology 2000; 216(1):248–254. 134. Haagenson CD. Anatomy of the mammary gland. In: Haagenson CP, ed. Diseases of the Breast. 3rd ed. Philadelphia: WB Saunders, 1986:1–23. 135. Howell JD, Barker F, Gazet JC. Granulomamtous lobular mastitis; report of a further two cases and a comprehensive literature review. Breast 1994; 3:119–123. 136. Hamed H, Fentiman IS. Benign breast disease. Int J Clin Pract 2001; 55(7):464–464. 137. Dupont WD, Page DL. Risk factors for breast cancer in women with benign breast disease. N Eng J Med 1985; 312:146–151. 138. Drukker BH, de Mendonca WC. Fibrocystic change and fibrocystic disease of the breast. Obstet Gynecol Clin North Am 1987; 14(3):685–702. 139. Norlock FE. Benign breast pain in women: a practical approach to evaluation and treatment. J Am Med Womens Assoc 2002; 57(2):95–80. 140. Schnitt SJ, Connolly JL. Pathology of benign breast disorders. In: Harris LM Jr, Morrow M, Osborne CK, eds. Diseases of the Breast. New York: Lippinkott & Wilkins, 2000; 75–93. 141. Liberman L. Percutaneous image-guided core biopsy. Radiol Clin North Am 2002; 40(3):483–500. 142. Salih AK, Fentiman IS. Breast Cancer prevention. Int J Clin Pract 2002; 56(4):267–271. 143. Kinsinger LS, Harris R, Woolf SH, et al. Chemoprevention of breast cancer: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002; 137(1):59–69. 144. Jatoi I. Breast cancer: asystemic or local disease? Am J Clin Oncol 1997; 20:536–539. 145. Halsted WS. The results of radical operations for the cure of carcinoma of the breast. Ann Surg 1907; 56:1–19. 146. Fisher B, Fisher ER. Transmigration of lymph nodes by tumor cells. Science 1966; 152:1397–1398. 147. Peters V. Wedge resection and irradiation, effective treatment in early breast cancer. JAMA 1967; 200:134–139. 148. Crile G. Results of conservative treatment of breast cancer at 10 and 15 years. Ann Surg 1975; 182:26–29. 149. Fisher B, Bauer M, Margolese R, et al. Five year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in treatment of breast cancer. N Eng J Med 1985; 312:665–673.

1065

150. Veronesi U, Sacrozi R, Del Vecchio M, et al. Comparing radical mastectomy with quadrentectomy, axillary dissection and radiotherapy in patients with small cancers of the breast. N Eng J Med 1981; 305:6–11. 151. Jacobson JA, Cowan KH, D’ Angelo T, et al. 10 year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Eng J Med 1995; 332: 907–911. 152. Van Dongen JA, Bartelink H, Fentimen IS, et al. Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 Trial. Monogr Natl Cancer Inst 1992; 11:15–18. 153. Srrazin D, Le M, Arriagada R, et al. Ten year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989; 14: 177–184. 154. Cady B. Another editorial perspective. Ann Surg Oncol 1998; 5:103–104. 155. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Eng J Med 2002; 347:1233–1241. 156. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997; 15:2483–2493. 157. Helbich TH, Matzek W, Fuchsjegar MH. Stereotactic and ultrasound-guided breast biopsy. Eur Radiol 2004; 14(3): 383–393. 158. Gittleman MA. Single-step ultrasound localization of breast lesion and lumpectomy procedure. Am J Surg 2003; 186(4): 386–390. 159. Abrahamson PE, Dunlap LA, Amamoo MA, et al. Factors predicting successful needle-localized breast biopsy. Acad Radiol 2003; 10(6):601–606. 160. Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002; 20:3262–3636. 161. Dent DM. Axillary lymphadenectomy for breast cancer. Arch Surg 1996; 131:1125–1127. 162. Sacks NPM, Baum M. Primary management of carcinoma of the breast. Lancet 1993; 342:1402–1408. 163. Jatoi I. Management of the axilla in primary breast cancer. Surg Clin North Am 1999; 79(5):1061–1073. 164. Edge SB, Niland JC, Bookman MA, et al. Emergence of sentinel node biopsy in breast cancer as standard-of-care in academic comprehensive cancer centers. J Natl Cancer Inst 2003; 95(20):1514–1521. 165. Schwartz GF, Guiliano AE, Veronesi U. Proceeding of the consensus conference of the role of sentinel lymph node biopsy in carcinoma or the breast April 19–22, 2001, Philadelphia, PA, USA. Breast J 2002; 8(3):124–138. 166. Smith LF, Cross MJ, Klimberg VS. Subareolar injection is a better technique for sentinel lymph node biopsy. Am J Surg 2000; 180:434–438. 167. Krag D. Current status of sentinel lymph node surgery for breast cancer. J Natl Cancer 1999; 91:302–303. 168. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 1896; ii:104–107. 169. Taylor GW. Artificial menopause in carcinoma of the breast. N Eng J Med 1934; 211:1138–1142. 170. Nissen-Meyer R, Kjellgren K, Manson B. Preliminary report from the Scandinavian Adjuvant Chemotherapy Study Group. Cancer Chemother Rep 1971; 55:561–566. 171. Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophospharnide, methotrexate, and fluorouracil in nodepositive breast cancer: the results of 20 years of follow-up. N Eng J Med 1995; 332:901–906. 172. Bonadonna G, Valagussa P, Rossi A, et al. Ten-year experience with CMF-based adjuvant chemotherapy in respectable breast cancer. Breast Cancer Res Treat 1985; 5:95–115.

medwedi.ru

1066

Part Eight: The Integument and Body Wall

173. Nolvadex Adjuvant Trial Organization. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer: interim analysis at four years. Lancet 1983; 1:257–261. 174. Fisher B. Status of adjuvant therapy: results of the National Surgical Adjuvant Breast Project studies on oophorectomy, postoperative radiation therapy and chemotherapy. Other comments concerning clinical trials. Cancer 1971; 28:1654–1658. 175. Early Breast Cancer Trialists Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31000 recurrences and 24000 deaths among 75000 women. Lancet 1985; 339:1–15. 176. Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998; 352:930–942. 177. Early Breast Cancer Trialists Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomized trials. Lancet 1996; 348:1189–1196. 178. Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998; 351:1451–1467. 179. Cizick J. The ATAC (’Arimidex’, tamoxifen, alone or in combination) trial in postmenopausal women with early breast cancer-updated efficacy results based on a median followup of 47 months. Breast 2003; 12(suppl 1):S47. 180. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235:177–182. 181. Slamon D, Leyland-Jones B, Shak S, et al. Addition of Herceptin (humanized anti HER-2 antibody) to first-line chemotherapy

182.

183.

184.

185.

186.

187.

188.

for HER-2 overexpressing metastatic breast cancer markedly increases anticancer activity: a randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 1998; 17:377a. Bernhard J, Hurny C, Coates AS, et al. Quality of life assessment in patients receiving adjuvant therapy for breast cancer: The International Breast Cancer Study Group (IBCSG) approach. Ann Oncol 1997; 8:825–835. Morris A, Morris R, Wilson J, et al. Breast-conserving therapy versus mastectomy in early-stage breast cancer: a metaanalysis of 10 year survival. Cancer J Sci Am 1997; 3:6–12. Schnitt S, Hayjman J, Gelman R, et al. A prospective study of conservative surgery alone in the treatment of selected patients with stage I breast cancer. Cancer 1996; 77:1094–1100. Nemoto T, Patel J, Rosner D, et al. Factors affecting recurrence in lumpectomy without irradiation for breast cancer. Cancer 1991; 67:2079–2083. Fowble B, Gray R, Gilchrist K, et al. Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving chemotherapy who may benefit from post-operative radiotherapy. J Clin Oncol 1988; 6:1107–1117. Ragaz J, Jackson S, Le N, et al. Adjuvant radiotherapy and chemotherapy and chemotherapy in node positive premenopausal women with breast cancer. N Eng J Med 1997; 337:956–962. Overgaard M, Hansen P, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Eng J Med 1997; 337: 949–955.

57 Hernias of the Abdominal Wall and Its Contents Philip E. Donahue

INTRODUCTION ‘‘Hernia’’ (a Latin term for ‘‘rupture’’) is a descriptive term for the protrusion of abdominal cavity contents through an opening or defect in the fascial and muscular layers of the abdominal wall. The abdominal wall is the locus of many opposing physical forces, which ordinarily remain in balance according to established mechanical principles; when this balance is disrupted a hernia appears. While physical breakdown or defect of the abdominal wall is present in all hernias, nutritional, environmental, and congenital cofactors can also be implicated in their appearance. Therefore, the term ‘‘rupture’’ is literally correct for a minority of hernias that appear in the abdominal envelope. Most hernias appear unheralded as anatomic sites predisposed to weakening by virtue of position, function, or structure succumb to natural forces. The most common hernias occur in males as a result of the patent processus vaginalis present in the majority of full-term infants, and persisting in some 25% throughout life, with or without symptoms; approximately 5% of groin hernias appear in women, whose inguinal canal contents are less likely to contain a patent canal (of Nuck) (1–3). Other hernias occur at various stress points within the abdominal wall, including the midline, ‘‘rings,’’ foramina, and other natural openings or potential defects. Many hernias will require surgical repair, although there is renewed interest of late in the natural history of unoperated adult hernias that are minimally symptomatic or asymptomatic, because the incidence of hernia strangulation in such patients is quite low. The results of prospective randomized studies comparing nonoperative treatment (‘‘watchful waiting’’) for minimally or asymptomatic groin hernias with elective surgical repair will provide important evidence for clinicians and for administrators of health care organizations (4,5). Until recently, hernia repair was always performed in an intuitive way—suture approximation of tissues at the border of the hernia defect. This ‘‘old-fashioned’’ approach, performed in various ways since the Middle Ages, was reasonably successful and performed worldwide until the latter half of the last century, when three major developments were shown to have benefits in terms of patient acceptance and overall success. The concepts embodied by ‘‘tensionfree’’ repair combined with advances in prosthetic materials have revolutionized the repair of primary and recurrent hernias worldwide (6,7). The abdominal wall, unfortunately, for patients with huge hernias, still contains unsolved problems and challenges for future generations of hernia surgeons. The clinical signs and symptoms of hernia presentation in a given patient are remarkably varied, as are the anatomic findings observed in the operating room. Experience teaches the lesson that the appearance of groin

structures differs markedly in individuals, especially in the presence of stretching, edema, or distortion of the boundary structures. As a result, surgeons find hernia repair challenging, especially when sliding, strangulated, or recurrent hernias are encountered. Although the overwhelming majority of patients have an uneventful convalescence and prompt return to gainful employment after hernia repair, an unfortunate few will be plagued by a complication of the procedure. If infection, hernia recurrence, or persistent groin pain develops after hernia repair, an entire new world of problems arises for the patient and his or her surgeon. Hernia repair is a major surgical event, undervalued by many in the community, including surgeons, which demands technical awareness and precise skill in performance. The evaluation and care of patients postoperatively often challenges the collective wisdom of the most experienced practitioner. Most of these problems are not life threatening, and most can be solved by attention to the basic facts of hernia science; however, taking hernias for granted is a recipe for disaster. This chapter will highlight the important developments that have occurred during the past several decades in our understanding of hernia formation and how this knowledge is used in the modern practice of herniorrhaphy (6,7).

CONCEPTS AND DEFINITIONS An abdominal wall hernia exists when tissues protrude through a defect (congenital or acquired) in the musculofascial supports of the abdominal wall, including the endoabdominal fascia, the innermost layer, which lines the entire abdominal cavity. The transversalis fascia on the anterior abdominal wall and groin is the boundary between the peritoneum and the intra-abdominal contents and the abdominal wall, through which the hernia protrudes; if a sac is not present, the hernia consists of preperitoneal fat protruding through a weakened or defective transversalis fascia (8,9). A standard nomenclature is useful in classifying different types of hernias and evaluating the contents of the hernia. A hernia that can be returned to the abdominal cavity is said to be ‘‘reducible’’ in contrast to an ‘‘irreducible’’ or ‘‘incarcerated’’ hernia, which remains present despite physical manipulation. Incarcerated hernias, regardless of their size, may be present for years without causing problems, but their contents are always at some risk for vascular compromise (‘‘strangulation’’) if edema, hernia contents, or boundary structures interfere with blood supply. When incarcerated hernias are (or become) extremely painful or are accompanied by systemic signs such as vomiting, fever, or prostration, the hernia repair becomes a relative surgical emergency, because ischemic or infarcted tissues may be present.

medwedi.ru 1067

1068

Part Eight: The Integument and Body Wall

The term ‘‘sliding’’ hernia describes a hernia in which an organ, usually a hollow viscus, is part of the hernia sac. Sliding hernias pose particular problems for management, because inadvertent perforation of the cecum or sigmoid colon, the most common sliding components, can easily occur during manipulation and dissection of the hernia sac. When an incarcerated hernia cannot be easily reduced, the hernia sac is opened to facilitate the reduction of hernia contents; needless to say, perforation of the intestine markedly increases the risk of infection and restricts the possible use of prosthetic materials to achieve a ‘‘tension-free’’ repair. Sliding hernias often cannot be diagnosed preoperatively, but can be suspected in very large hernias, because any organ attached to the retroperitoneum can be pulled through the internal ring with the hernia contents. A ‘‘Richter’’ hernia is an incarcerated hernia containing a portion of the circumference of the bowel as opposed to an entire loop or segment of intestine; if the incarcerated portion of bowel becomes strangulated and necrotic, a lifethreatening process unfolds without the signal events of a large groin mass or bowel obstruction which generally accompany incarcerated inguinal hernias. Richter hernias occur most commonly with inguinal hernias, followed by femoral and umbilical hernia sites; a ‘‘Littre’s’’ hernia contains a Meckel’s diverticulum. A ‘‘ventral’’ hernia is any hernia developing in the ventral abdominal wall, including umbilical, epigastric, and incisional hernias, as well as the Spigelian hernia. ‘‘Groin’’ hernias develop in the inguinofemoral region, including direct and indirect inguinal hernias, as well as femoral hernias. An ‘‘internal’’ hernia is one containing a loop of intestine protruding through a congenital or acquired orifice within the abdominal cavity, such as defects in the intestinal mesentery, the boundaries of various structures including the foramen of Winslow and the sciatic foramen. Congenital omphalomesenteric connections or postoperative adhesions, as well as postoperative ‘‘spaces’’ such as ‘‘retroanastomotic’’ hernias following antecolic gastrojejunal anastomosis (Peterson hernia) can result in internal hernia formation. Any of these defects may allow a loop or several loops of intestine to become trapped and occasionally strangulated as a result of twisting and peristaltic activity, and may not become symptomatic for years after the initial operation. Parenthetically, the Peterson hernia, thought to have disappeared largely as a result of the decreased incidence of ulcer operations, now has a modern counterpart in the aftermath of Roux-en-y gastric bypass performed laparoscopically (10). A new constellation of unusual hernias has been described, often recognized by postoperative radiographic studies, which provide previously unparalleled insights regarding the presence of internal hernias (11–13). Internal hernias are generally not diagnosed before surgery, but should be considered in the differential diagnosis of painful abdominal crisis, or small bowel obstruction in the virgin abdomen. Internal hernias comprise about 1% of all hernias, and are recognized in up to 1% of autopsies (11).

PATHOPHYSIOLOGY OF HERNIA DEVELOPMENT Hernias may develop in any of the structures supporting or surrounding the abdominal cavity. They may be encountered where a previous fetal communication existed between the abdominal cavity and some distant site, when an embryologic canal fails to obliterate, when maldevelopment of a supporting structure occurs, when dilation of a normally

situated hiatus results, and when the mesenchymal supporting structures constituting a portion of the body wall become attenuated for some reason. Common sites for abdominal wall hernias include the groin, the umbilicus, the linea alba, various parts of the diaphragm, the lumbar region, along adjacent foramina in the pelvis where blood vessels and nerves exit, and within previously performed surgical incisions. All of these sites are natural foci for stretching, weakening, or rupture as a result of natural, pathologic, or traumatic causes.

Patent Processus Vaginalis and Omphalomesenteric Duct The role of congenital factors in the development of hernia is reflected by the incidence of hernia in neonates and infants. Umbilical hernias occur where the umbilical ring has failed to obliterate the embryologic opening of the allantoic duct, which is ordinarily prevented by growth of the contiguous fascia of the linea alba. Similarly, indirect inguinal hernias (also called oblique hernias) arise due to the presence of an unobliterated processus vaginalis, the peritoneal connection between the abdominal cavity and the scrotum. A corresponding weakness and potential space exist in the canal of Nuck in the female, which accompanies the fibers of the round ligament through the inguinal canal. The peak incidence of indirect inguinal hernia occurs during infancy, when over 50% of males have a patent vaginal process. Congenital factors also play a role in the development of direct inguinal hernias, which occur between the superior pubic ramus and the arching border of the transversus abdominis muscle, medial to the deep inferior epigastric vessels. Patients with a high-arching lower border of the transversus abdominis aponeurosis (conjoined tendon) are at an increased risk for the development of this type of hernia (2,3). The appearance of hernia, however, depends upon other factors, as shown by autopsy findings of a patent processus vaginalis in 20% of individuals without any clinical evidence of a hernia before death (14–16). Similarly, the incidence of contralateral patency of the processus vaginalis in patients who have undergone repair of an inguinal hernia indicates that patency of this structure does not necessarily lead to inguinal herniation. Further, patency of the canal/ diverticulum of Nuck in women occurs without clinical appearance of hernia, as shown by incidental herniography after hysterosalpingography (17,18). The high incidence of patency of the processus vaginalis is one reason why bilateral exploration of the groin has been recommended in children found to have clinical evidence of unilateral groin hernia. Laparoscopic tools have shown that 30% to 50% of children have a patent processus vaginalis when examined by direct vision, a much higher rate than shown by air insufflation of the peritoneal cavity (19–21). Because meta-analysis has shown only 7.0% of hernia development during five-year follow-up, parents and surgeons have been led to reconsider the routine exploration of the contralateral side, which is sometimes recommended; watchful waiting, an option that has come to the fore in the adult hernia arena, is an option that avoids the low but unavoidable risk of damage to the vas deferens or spermatic artery, with subsequent testicular atrophy (22,23).

Altered Collagen Metabolism Important causes of hernia development that cannot be easily defined are related to the ‘‘wear and tear’’ of living itself, including such stresses as repetitive local trauma,

Chapter 57:

degenerative changes associated with increased or constant intra-abdominal pressure, and altered collagen synthesis; all of these are possible etiologic factors in patients developing hernias in middle and older age (24,25). Renewed interest in the biochemical and structural aspects of herniology has followed the description of some of the molecular and cellular elements of the protective fascia and collagenous tissues that normally prevent the formation of hernia. Collagen, the major constituent of the various aponeuroses and fascial structures of the body wall, has been studied intensively. Interestingly, collagen, like all other tissues in the body, is in a state of dynamic equilibrium in which there appears to be a constant synthesis of this substance,is matched by a parallel and constant rate of degradation. When Peacock and Madden (26) studied the transversalis fascia medial to the contralateral internal inguinal ring in patients with unilateral hernia, they compared rates of collagen synthesis and collagenolysis in both inguinal regions and found that the rates of both the processes were increased markedly. These findings of an earlier era were thought to support the concept that an abnormality of local collagen metabolism might be a factor in the eventual appearance of a hernia, and have yet to be expanded in a modern setting. Further support for the view that abnormal collagen underlies hernia formation is provided by studies of hydroxyproline (the major amino acid constituent of collagen) content in the rectus muscle aponeurosis of patients with and without groin hernia. Fibroblasts cultured from the anterior rectus sheath of these patients proliferated poorly, incorporating labeled precursors at a much lower rate than control specimens (24). Additional studies have focused on the procollagen content of the dermal matrix in patients with primary and recurrent hernias of the groin and abdominal wall and have shown a decreased amount of procollagen III mRNA in cultured fibroblasts. This abnormality in the transcriptional regulation of collagen in hernia patients may indeed affect the appearance of frank hernias, as may other abnormalities such as a difference in the relative proportion of collagen and elastic fibers in the transversalis fascia of patients with direct inguinal hernias.

Malnutrition The specific effects of malnutrition on the evolution of hernias of the groin or other parts of the abdominal wall are as yet undefined. If the collagenous structures that guard the abdominal wall are vital living structures that constantly experience remolding and resynthesis, there is a balance between synthesis and destruction of these supporting structures that could conceivably be altered by one’s nutritional status. Other systemic factors such as uremia have definite effects on nutrition, and are interwoven with other mechanical factors in patients who develop hernias (27–29). In the surgical clinic of any large public hospital, many individuals with adult-onset hernias and malnutrition are encountered suggesting a correlation between these conditions; in the absence of experimental data, however, the routine use of supplemental vitamins or other adjunctive nutritional elements is not indicated. Sailors in the 18th century learned that the absence of citrus fruits on long voyages led to systemic signs, including bleeding gums, periosteal pain, and weakness; an additional element of this ‘‘scurvy’’ was the onset of hernias or ruptures of healed scars. Later, a specific effect of vitamin C on collagen maturation was described, allowing a reasonable explanation of the observed effects in these patients. A similar condition occurring naturally is lathyrism, a disease resulting from ingestion

Hernias of the Abdominal Wall

1069

of the flowering sweet pea. The active agent in the pea, beta-amino-proprionitrile, prevents the maturation of collagen and is capable of causing the appearance of groin hernias in young rats and mice (25,26,30–32). Interestingly, groin hernias developed in animals less than a month old, which were given sweet pea seeds in their diet in contrast to older rats, which did not develop hernias when fed with a similar diet. These examples of how nutrition may influence the formation of hernias are of particular importance, illustrating the effect of environmental factors on the natural balance between collagen synthesis and breakdown, which is sometimes accompanied by the appearance of hernia (33). Defects in collagen maturation and synthesis are present in patients with excessive numbers of hernias or recurrent herniations (vide supra), and may be related in some way to critical vitamin or mineral deficiencies, altered immunity or resistance to infection, or underlying systemic disease. Further, altered levels of circulating enzymes in patients with emphysema add another dimension to the possible role of biologic factors in hernia formation. In a provocative article by Cannon and Read (34), serum elastolytic and antiproteolytic activity in smokers and nonsmokers was measured. Earlier work had confirmed the systemic effects of chronic smoking on elastin and collagen, the essential components of all anatomic support structures, utilizing a positive correlation between skin wrinkles in smokers or those exposed to secondary smoke as the basis for their conclusion. In this study, it was found that smokers had the potentially undesirable combination of increases in proteolytic activity combined with reductions in alpha1antitrypsin, a major naturally occurring circulating antiprotease, possibly adversely affecting the synthesis: degradation equilibrium of groin collagen toward collagen degradation and hernia formation.

Mechanical Stress The reaction of the abdominal wall to extreme tension or hydrostatic challenge provides some insight into hernia formation, because there is a linear and sequential relationship between the presence of stress (e.g., cirrhosis with ascites and chronic peritoneal dialysis exert hydrostatic forces pushing toward the exterior, whereas morbid obesity produces additional forces that exert continuous pull on the abdominal wall) (28,29). The fact that hernias appear with regularity provides ample testimony about the stress, although it is impossible to determine which site will become a hernia prospectively. The stress of repetitive exercise in athletes may be a cause of hernia as shown by the results of herniography to define the cause of obscure groin pains in young athletes; the hernia discovered included abnormalities in the obturator canal and incipient hernia defects at the inguinal ring that could not be diagnosed by other means (35). These individuals had severe pain that prevented their usual physical activity; yet they had an unremarkable initial examination (14,17). The utility of herniography in experienced centers provides a noninvasive method for documentation of hernia, which is extremely useful at times, and which could be performed widely. However, the technique is resource intensive (and expensive) and requires highly motivated examiners and patients, but is not applicable to all patients (36). Ultrasonography (US) is a noninvasive method for the examination of the inguinal canal, which has yielded impressive sensitivity and specificity data regarding the presence or absence of hernia in the hands of some (37,38).

medwedi.ru

1070

Part Eight: The Integument and Body Wall

Because of variable accuracy and other confounding issues, US has not supplanted clinical judgment in the selection of patients for inguinal hernia repair. Laparoscopic examination is indeed more sensitive in demonstrating the presence of all varieties of inguinal hernia, but the success of identifying hernias is also tempered by the small but real possibility of injury to the spermatic artery or vas deferens, if an asymptomatic hernia is repaired as a result of an incidental discovery. While the percentage chance of injury is impressively small according to published reports, the potential effects on an individual patient and his family are vast, prompting many surgeons to recommend repair of only those hernias that are symptomatic. The utility of the ultrasound examination is proven mainly in the postoperative period, when problems such as seroma, recurrence, or prosthesis displacement can be identified (39). Recent data suggest that up to 90% of patent processes will close spontaneously, and add support to the notion that a ‘‘watchful waiting’’ approach is appropriate for asymptomatic patients, that is now being proposed in the prospective evaluation of adults (4,5). Other issues such as the cost–benefit analysis of routine ultrasonographic studies remain unresolved, but it is hard if not impossible to demonstrate the value added by an unnecessary test. In the absence of compelling data, experienced surgeons can be comfortable in relying upon the physical exam as the gold standard in determining which patients require operative treatment of hernia; suspected hernias which cannot be demonstrated can be managed by watchful waiting and reexamination. A persistent complaint of severe groin pain or intermittent bulge is usually a reliable indicator for surgical exploration of potential hernia sites. Happily for the moment, the use of adjunctive tests for the diagnosis of groin and other hernias is not required for the simple fact that they do not provide reliable evidence in many cases.

Iatrogenic Factors Several iatrogenic factors may result in the subsequent development of a hernia. A conventional open-appendectomy may damage innervation of the muscular constrictors of the internal ring shutter mechanism, allowing later herniation of abdominal contents through a patent processus vaginalis. In one report, laparoscopic views of the internal inguinal ring shortly after acute appendicitis and subsequent appendectomy demonstrated poor-to-absent contraction of the internal ring during coughing or straining. The possibility of a temporary neuropraxia related to surgical trauma could have been responsible, but there is a threefold greater incidence of right inguinal hernia in men who had undergone appendectomy (40). During surgical exposure of the common femoral artery and the distal external iliac artery for various types of vascular procedures (e.g., aortofemoral bypass), the inguinal ligament and the musculoaponeurotic borders of the inguinal ring must be divided. If closure of the abdominal wall is made with attention to reconstruction of the specific layers of the abdominal wall, including the internal ring, these hernias can be avoided. When the important layers are missing or deficient, the use of mesh reinforcement in the preperitoneal position is definitely indicated at present. Some individuals with severe groin pain after vascular access operations have no discrete hernia sac, but instead possess a lax internal ring that allows preperitoneal fat to bulge (herniate) through it; these individuals are comparable to adults with a symptomatic lipoma of the cord, who

often have pain indistinguishable from frank groin hernia, and who do extremely well with removal of the lipoma and reconstruction of the floor of the inguinal canal (41). Increased hydrostatic intra-abdominal pressure associated with chronic ambulatory peritoneal dialysis (CAPD) frequently results in hernia development (28,29). An incidence rate of 20% to 50% depends upon the length of follow-up, with most of the hernias occurring in the groin and umbilicus. Hernias may also occur at the exit site of the dialysis catheter, or at other weak points in the abdominal lining. Because the groin is the most frequent site, there is no doubt that congenital factors have set the stage for the appearance of the hernia in this area; because renal failure per se has a deleterious effect on collagen metabolism, a multifactorial causality due to increased abdominal pressure, poor wound healing, and defective or suboptimal collagen synthesis exists (29,35). Hernia may also appear at trocar sites or at points of egress of various tubes and drainage devices; advances in trocar technology, which avoid cutting the fascia (bladeless or dilating devices), have reduced but not eliminated the possibility of late hernia, and not surprisingly hernias have been reported after closure of port sites.

TYPES OF ABDOMINAL WALL HERNIAS Groin Hernias Hernias may develop in any structure supporting the intraabdominal contents. Most of these involve the anterior abdominal wall, and the vast majority occur in the inguinofemoral region. Of hernias occurring in the groin, the indirect inguinal variety is most frequently encountered (50–60%), with direct inguinal hernias representing 25% to 35% and femoral hernias comprising approximately 5% to 10%. Because of the frequency of groin hernias, an understanding of their anatomy, clinical presentation, and surgical management is important for any student of surgery (9).

Indirect Inguinal Hernia Indirect hernias are protrusions of weakened transversalis fascia, fat, or abdominal contents through a defect in the internal ring. The internal ring, at one end of the inguinal canal, is the transit point for gonadal tissue in males, or for the round ligament in females, and lies lateral to the deep epigastric artery and vein (Fig. 1A). Indirect hernia occurs 20 times more commonly in males compared to females, representing retention or incomplete obliteration of the embryologic processus vaginalis, which accompanies the testicle in its descent into the scrotum; in females, the indirect hernia is related to a persistent canal of Nuck, which is adherent to the round ligament. Normally the processus vaginalis obliterates postnatally except for the tunica vaginalis portion that covers the testicle; a patent processus vaginalis is either a ‘‘communicating hydrocele’’ or an indirect inguinal hernia is present. Whether the hernia is evident at birth or in the months thereafter depends upon other factors. A hernial sac that tracks into the scrotum is a complete indirect inguinal hernia. The peak incidence of indirect inguinal hernia recurrence is at birth or shortly thereafter, with a second peak occurring in the teen years and in early adulthood (22,23).

Direct Inguinal Hernia Direct hernias arise medial to the deep epigastric artery and somewhat inferior to the internal inguinal ring due to a frank defect or diffuse weakening of the transversalis fascia, in a

Chapter 57:

Hernias of the Abdominal Wall

1071

Figure 1 (A) Right indirect inguinal hernia. Hernial sac begins at the internal inguinal ring lateral to the inferior deep epigastric artery and exits from the inguinal canal at the external ring to descend into the scrotum. The sac lies anteromedial to the cord structures. (B) Right direct inguinal hernia. Hernial sac arises in Hesselbach’s triangle medial to the inferior deep epigastric artery and just above the pubic tubercle. It does not descend into the scrotum. (C) Right femoral hernia. Hernial sac arises below the inguinal ligament and medial to the femoral vein. Source: From Ref. 42.

triangular space known as Hesselbach’s triangle (Fig. 1B). Hesselbach’s triangle is bounded laterally by the inferior epigastric artery, medially by the lateral border of the rectus sheath, and inferiorly by the inguinal ligament. Direct hernias occur later in life than congenital groin hernias, often after the age of 35. They are usually due to a weakened transversalis fascia as opposed to an opening in the transversalis, which occurs in a minority of cases. In contrast to an indirect inguinal hernia in which the neck of the hernia may be narrow and incarceration always a potential problem, the neck with direct hernias is wide, and incarceration is infrequent. Direct hernias are more common in males.

Sliding Hernia A sliding hernia is one in which a viscus comprises part of the hernia sac, and is the term applied to slippage of part of an abdominal organ through a hernia orifice, and is common in huge groin hernias. On the right side, the appendix and cecum are commonly seen, while on the left side, the sigmoid colon is a common participant in this type of hernia. In females with inguinal hernia, the fallopian tube and ovary are commonly involved.

Femoral Hernia A femoral hernia develops as a peritoneal outpouching through an enlarged femoral ring (Fig. 1C). This space is the most medial compartment of the femoral canal, and is bounded below by the inguinal ligament, above by the pubic bone, and medially by the lacunar ligament. The sac of a femoral hernia is always medial to the femoral vein and may progress to the level of the foramen ovale. Because the neck of a femoral hernia is narrow, incarceration and strangulation is always a risk. Femoral hernias occur more often in females for unknown reasons, possibly due to stretching of the pelvic supports during pregnancy.

Clinical Presentation The usual complaint that brings a patient to the physician’s attention when a groin hernia is present is a bulge or a problem with pain, either of which may be persistent or intermittent. The pain is due to compression or irritation of contiguous structures by the hernia. The characteristics of the pain are variable; while usually localized to the groin, it may be sharp, aggravated by a change in position or straining. The pain is often relieved by cessation of the physical activity that precipitated it. When hernia contents are incarcerated, persistent pain may reflect the onset of strangulation in the trapped contents; the presence of systemic signs or symptoms such as elevated temperature, tachycardia, vomiting, and abdominal distention must be recognized as urgent signals by clinicians, if catastrophic consequences due to intestinal necrosis are to be avoided. Symptoms of chronically incarcerated segments of intestine are highly variable, ranging from none to those of bowel obstruction. Diagnosis of Hernia Groin hernias are sometimes extremely difficult to diagnose and at other times quite apparent. The standard maneuver to diagnose a groin hernia is based on digital palpation of the floor of the inguinal canal. The patient should initially stand while visual inspection of the groin is conducted. The physician examines the external genitalia to check for any localized swellings along the spermatic cord on either side, or for abnormalities in the testicle or scrotal contents. In a female, there may be palpable swelling noted on the symptomatic side. In any case, ipsilateral swelling in a groin in which pain is apparent requires definite explanation, and the inference that a hernia is present becomes quite tenable. However, inflammation of the vas deferens and seminal vesiculitis must always be considered in the differential diagnosis.

medwedi.ru

1072

Part Eight: The Integument and Body Wall

When examining the floor of the inguinal canal in the male, there are three prerequisites for a complete examination: first, invagination of the scrotal skin along the axis of the canal allowing digital palpation of the external inguinal ring. The external ring is a landmark for examination; its size or consistency has nothing to do with the hernia itself. Secondly, digital palpation of the floor of the canal and the overlying spermatic cord are performed to ascertain any apparent weakness. A weakness or mass in the region of the external ring is usually indicative of a direct hernia. Finally, examination of the face of Hesselbach’s triangle itself is performed. After the preliminary palpation to determine whether exquisite tenderness is present, the examining finger is withdrawn 5 to 10 mm, and the patient is asked to ‘‘push down’’ or ‘‘strain’’ for 5 to 10 seconds to increase intra-abdominal pressure. Next, the patient is asked to give a gentle cough. A positive response is a palpable ‘‘tap’’ against the fingertip (suggestive of an indirect hernia) or along the medial side of the finger (indicative of a direct hernia), caused as the distended hernia sac transmits the cough-induced increase in pressure. Alternatively, a ‘‘gurgle’’ of peritoneal fluid may be appreciated passing beneath the examining finger. What Next? When there is no palpable hernia defect, no history of groin lump or mass, and no ultrasound findings or positive peritoneography indicative of hernia. If no previous operation has been performed, the author advises the patient that there may be a hernia present, but that a groin strain or stretch might also be present; analgesics, tincture of time, and warm soaks (tub baths) are recommended during a six- to eight-week observation period. If the pain is unchanged or worse after that time, surgical exploration of the groin can be justified even when the examiner has no absolute evidence that a hernia exists; this would not be the case if noninvasive testing could detect all hernias. Patients must have realistic expectations however, and understand that the operation might not resolve the pain issue; the overall incidence of chronic groin pain or discomfort is high enough, approximately 1.0%, that some experienced surgeons have recommended routine division of the ilioinguinal nerve during hernia repair (43). As with any condition with a low frequency, individual surgeons have limited experience with this problem; further, because there is no clear cause for the problem, responses to treatment are highly individualized. The differential diagnosis of postoperative pain includes ilioinguinal nerve entrapment or neuroma, nonspecific pain syndrome, or inflammation of the pubis or cord contents. In the presence of a typical pain syndrome but negative physical examination in the early postoperative period, one or several injections (local anesthesia combined with triamcinolone acetate) may resolve the issue; if pain persists despite exclusion of other causes, surgical re-exploration of the groin is performed early if there is radiation of pain to the leg or medial thigh, attempting to remedy nerve entrapment or encroachment. Because the scarified groin is hostile to reexploration as a rule, the patient must know that some numbness in the groin or proximal leg might result; this type of patient is extremely challenging, and requires all of the interpersonal and scientific skills of the surgeon and pain-management team. Some individuals will have persistent postoperative discomfort despite everyone’s best efforts. In a world in which litigious patients sometimes have no tolerance for postoperative discomfort,

the informed surgeon should make certain that the risk of chronic pain is well understood and documented to the patient. If the patient is an adolescent, the discussion regarding risk of testicular atrophy should also be documented. Duplex ultrasound is invaluable at times in demonstrating that spermatic artery function is normal in a postoperative patient, and can relieve much of the mental anguish of patient and surgeon alike. In contrast to most inguinal hernias that can be diagnosed with a minimum of difficulty, the femoral hernia is often a diagnostic challenge. It may appear as a subtle mass lesion in the inguinal crease, somewhat medial to the femoral artery, and may be quite small (approximately 1.0 cm diameter); in obese individuals, the hernia may be clinically occult. In such situations, the general condition of the patient will have to serve as a guide for the specific management plan undertaken. Patients who experience an unexplained acute onset of local pain in the femoral region, or develop pain or tenderness in a groin mass may have an incarcerated hernia and should have prompt surgical exploration. Inattention to sentinel signs places the patient at extreme risk for strangulation of hernia contents with subsequent complications.

Surgical Management Until recently, hernias in the groin were considered, with rare exceptions (e.g., terminal malignant disease), as indications for surgical repair to prevent complications such as incarceration and strangulation. This concept has been challenged by modern surgeons and by health system analysts in the context of ‘‘watchful waiting’’ as discussed earlier (4,5). The prospective trials that will be reported in the next few years will shed light on an important (and expensive from a resource-utilization perspective) topic; the importance of these studies to the community at large is immense, and the surgeons who devised these trials deserve our thanks and recognition. The anatomy of the groin hernia is defined in terms of the various ‘‘fasciae, aponeuroses, and ligaments’’ present; a fascia is a condensation of connective tissue into a definable, homogenous layer that varies from a thin layer to an easily observed stout structure (9). An aponeurosis is a tendinous insertion of a major muscle composed of strong, individual, collagenous fiber bundles. A ligament is any definable tissue ‘‘banding’’ two or more structures, whether bony or visceral, and may refer to structures of either areolar or aponeurotic consistency. The transversus abdominis aponeurosis is the dense connective tissue at the boundary of that specific muscle; the transversalis fascia, in contradistinction, is a separate connective tissue entity that lines the entire abdominal cavity, and is the first anatomic boundary that visceral structures stretch or pass through as they herniate through a defect in the abdominal wall. Transversalis fascia has little anatomic strength, and cannot form an anatomic basis for hernia repairs; instead, all herniated structures are restored to their anatomic position behind the transversalis fascia prior to suture repair of the hernia by approximation of neighboring tendinous aponeuroses and ligaments that can hold sutures properly (9). Formerly, the repair of all common groin hernias was designed to permanently eliminate anatomic defects by means of sutures placed into adjacent solid structures; recently this concept has been supplanted by the recognition that the appearance of a hernia is a declaration that tissues cannot withstand the tension or force exerted at the specific hernia site. At

Chapter 57:

present, therefore, ‘‘tension-free’’ approaches, which eliminate or minimize the tension by a variety of mechanisms have been widely adopted, with resulting improvement in long-term success of hernia repairs (7,44,45). Groin Hernia Anatomy The aponeurosis of the external oblique muscle inserts at the pubic tubercle and has a flattened medial portion, which curves beneath the floor of the inguinal canal, and is termed the ‘‘inguinal ligament’’. The inguinal ligament abuts fascia of the transversus abdominis muscle as a contiguous but separate structure. The lacunar ligament is a triangular portion of the inguinal ligament, which extends from the posterior border of the inguinal ligament downwards to the pectineal fascia (1 cm below the pectin); it is separate and superficial to the ileopubic tract. These anatomic details are illustrated in Figure 2. Before the tension-free concept was widely recognized, the rationale for hernia repair was reconstruction of the separate layers of the abdominal wall, ‘‘preserving’’ (at least from a theoretical perspective) the ‘‘shutter’’ mechanism effected by the muscles of the abdominal wall. Analogously as a camera shutter mechanism, the oblique muscles comprising the internal ring move simultaneously in different planes, constricting the internal ring in so doing. As a result, the superior and inferior crus of the internal inguinal ring compress the internal ring and spermatic cord, narrowing the aperture of Hesselbach’s triangle. The end result is continuous protection for the two most vulnerable areas of the groin: posterior wall of the inguinal canal, where direct hernias appear, and the entrance to the canal itself, through which ‘‘oblique’’ herniation occurs. Anterior Repair—Groin Hernia Inguinal Hernias. The goal of repair in the modern era is the creation of a tension-free union between the arching transversalis abdominus aponeurosis (and adherent fascia) above and the ileopubic tract below; the best way to achieve

Hernias of the Abdominal Wall

1073

tension-free status is interposition of a piece of mesh between the boundaries of the weakened floor of the inguinal canal. Whether this approach (the Lichtenstein repair) is supplemented with a ‘‘plug,’’ is a matter of personal preference and choice; either approach has the benefit of a lower recurrence rate (0.5–1.0% vs. 5–8%) compared to conventional repair. For both direct and indirect inguinal hernias, the repair is carried out through a transverse skin incision positioned above (approximately 2 cm) and parallel to the inguinal ligament, to prevent injury to the iliohypogastric and ilioinguinal nerves (Fig. 3). For hernias lateral to the inferior epigastric vessels (i.e., indirect inguinal hernias), the communication that exists between the peritoneal cavity and the hernial sac is obliterated, with or without excision of the sac. Very large or vascularized sacs can be left in situ with the expectation that they will gradually disappear; aggressive dissection of these sacs is mentioned only to be condemned, because of the risk of damage to the fragile blood supply of the vas deferens (Fig. 4). In infants and children, high ligation of the sac is usually all that is required; in older children and adults, some reconstruction of the musculoaponeurotic structures is generally performed (Marcy repair) to tighten the internal inguinal ring around the cord structures. Occasionally, an indirect inguinal hernia will be encountered, which has been present for many years and has enlarged to such an extent that a good portion of the supporting structures medial to the internal ring has been destroyed. In this situation, a definitive tension-free repair will be required, following the principles described below, for the repair of a direct inguinal hernia. The cremaster muscle fibers surrounding the spermatic cord can usually be spared, thus avoiding circumferential dissection of the internal inguinal ring. Through careful dissection, the attenuated floor of the inguinal canal is exposed or excised; the original Bassini repair included excision of the attenuated floor, and provided direct exposure of the edge

Figure 2 Left pelvis: Origins of the three flat muscles are shown. The oblique and transversus muscles arise from the iliacus fascia and iliopectineal arch (not shown). Inset shows the insertions of the muscle layers of the groin into the pubis. Right pelvis: Internal oblique is not shown, but would arch above the spermatic cord to insert into the rectus sheath. Source: From Ref. 46.

medwedi.ru

1074

Part Eight: The Integument and Body Wall

defect; (Figs. 7 and 8) while the utility of relaxing incisions is widely accepted, the wide use of mesh repairs has made relaxing incisions less important (43). When repairing direct hernias, the surgeon should consider the simultaneous presence of an indirect hernia, which will exist in many of the patients; the spermatic cord should be inspected to demonstrate the junction of the obliterated vaginal process with the peritoneum at the internal ring.

Figure 3 Skin incision is made approximately 2 cm above the inguinal ligament in a gentle curve following Langer’s lines. Source: From Ref. 47.

of the attenuated fascia. The repair must obliterate or bridge the defect by suture or prosthetic patch as the first goal and prevent recurrence as the second goal. Suture repairs help achieve the first goal well by the transversus/transversalis complex above the ileopubic tract below (Fig. 5) with interrupted nonabsorbable suture material; tension-free repairs, as we now recognize, are far superior in preventing recurrence of hernias. In the past, surgeons utilized various ‘‘relaxing incisions’’ to achieve a relatively tension-free approach; however, when all tension is removed by a bridge or patch of synthetic material as in the Lichtenstein approach (a literally ‘‘tension-free’’ repair), the result is superior to any purely mechanical approach described (Fig. 6). Formerly, surgeons debated the merits of several maneuvers to reduce the stresses created by hernia repair, including the Tanner ‘‘slide’’ procedure, one of the approaches for reducing tension by means of a relaxing incision (43). Incision along the internal oblique portion of the anterior rectus sheath allows the lateral portion of this sheath and its attached transversus arch to ‘‘slide’’ inferolaterally, so as to close a large inguinal hernial

Figure 4 Spermatic artery.

Synthetic Mesh, Plugs, and Patches At present, it is apparent that routine mesh insertion lowers recurrence rates substantially; in groin hemiorrhaphy, mesh insertion results in an expected recurrence rate of 0.5% to 2.0% versus 7% to 12% when mesh is not employed. The choice of mesh is a matter of judgment, and the flat mesh prosthesis of Lichtenstein, and the various ‘‘plugs’’ and patch devices are commonly employed (7,44). Surgeons, formerly preoccupied with creative uses of endogenous ligaments and tissues to repair hernia defects, now apply the mesh prostheses with confidence that the problem will be solved. The routine use of mesh in adults is the most important advance in hernia repair in the last 50 years. In children or young adults primary repair consisting of sac excision—with or without the Marcy ‘‘plastic repair or the internal ring,’’ is still practiced widely (50). Femoral Hernias. Although femoral hernias are less commonly encountered than inguinal hernias, surgical repair is the treatment of choice. The principles underlying inguinal hernia repair also apply to femoral hernias. Usually the same type of skin incision is used; the sac, once identified, is reduced of its hernial contents, divided, and ligated at its neck; and the entrance into the femoral canal giving rise to this entity is obliterated. This can be accomplished by attaching the transversus/transversalis complex to Cooper’s ligament to close off the empty space in the femoral canal. Posterior Repair The posterior approach to the transversalis/transversus layers of the abdominal wall (Fig. 9) has been advocated by several surgeons over the past 60 years, but predominantly by Nyhus et al. (52). This technique, when properly applied, is extremely useful in the repair of three major types of hernia: (i) the recurrent inguinal hernia, (ii) the primary femoral hernia, and (iii) incarcerated hernias of all types. Surgeons unfamiliar with the posterior appearance of groin structures may have difficulty in defining the proper tissue planes, but the widespread interest in laparoscopic hernia repairs has served to educate the surgical community regarding the preperitoneal repair. Many surgeons have abandoned the laparoscopic approach, because the overall risks and benefits are unproven and the cost is high; proponents of the repair are extremely enthusiastic about its benefits, but cannot demonstrate any superiority of the repair when compared head-to-head with open surgical techniques. When performed as an open procedure, the skin incision is placed transversely, 2.0 cm above and parallel to the inguinal ligament. After the incision to the level of the rectus sheath is deepened, the anterior fascia layer of this sheath is incised, and the rectus muscle retracted toward the midline. The exposed transversalis fascia is then incised to gain access to the preperitoneal space; this space always has a variable amount of fat present, and the appearance of fatty tissue is the signal that the proper plane has been entered. The incision through the abdominal musculature is widened toward the anterior iliac spine, to pass about 2.0 cm above

Chapter 57:

Hernias of the Abdominal Wall

1075

Figure 5 (A) Steps in the repair of a right indirect inguinal hernia. The external oblique aponeurosis has been opened. The cord is freed from the inguinal floor. The freed ilioinguinal nerve is seen overlying the retracted lower leaflet of the external oblique aponeurosis. The cremaster muscle is being dissected free of the cord. (B) Peritoneal sac must be dissected free of the cord and the abdominal wall at the internal abdominal ring. (C) Technical detail of high ligation of the sac is important in an orderly repair. The peritoneum must be freed of omentum, and adherent viscera must be detached. Appendices epiploicae or omentum must not be caught in the closure. (D) Components of the transversus abdominis lamina must be accurately identified and closed at the internal ring. Triangulation of the transversalis fascia (shown here) is a useful detail to help achieve accurate closure at the internal ring. (E) Transversus abdominis arch is sutured to the iliopubic tract and inguinal ligament. (F) External oblique aponeurosis is closed over the spermatic cord. Slight imbrication of this structure gives an excellent closure. Scarpa’s fascia is then closed with interrupted sutures of 3–0 plain catgut, and the skin edges approximated with sutures or sterile strips. Source: From Ref. 47.

the internal inguinal ring. When this has been accomplished, the posterior inguinal wall is bared of fatty and areolar tissue from the line of incision to the superior pubic ramus. If the deep epigastric vessels obscure proper exposure, they can be ligated and divided as needed. After the posterior inguinal wall has been exposed, the herniated structures are identified and reduced. If there

is an incarcerated hernia, it is prudent (and easy) to inspect all portions of incarcerated bowel for signs of ischemia or infarction. If there is any doubt concerning these possibilities, the surgeon can easily observe the tissues in question until he/she is satisfied about the need for surgical resection. After the walls of the hernial defect have been identified, the repair is fashioned to approximate the margins of

medwedi.ru

1076

Part Eight: The Integument and Body Wall

Figure 6 Lichtensein Repair. Source: From Ref. 48.

the defect with interrupted sutures of permanent material or bridge the hernia defect with a suitably large prosthetic patch. As with the anterior approach to hernia repair, the internal ring and spermatic cord must also be examined to ensure that an additional oblique hernia is not present; the vas deferens is pushed to the lateral margin of the operative field, and overlapped widely by the preperitoneal mesh. This practice of ‘‘lateralization’’ as opposed to the construction of a ‘‘keyhole’’ aperture in the mesh may have less tendency to constrict the vas deferens in the postoperative period. The posterior approach is strongly recommended for the repair of a recurrent hernia, because it provides an

Figure 7 External oblique aponeurosis (superficial lamina rectus sheath) has been dissected medially and superiorly to the line of fusion with rectus sheath. Placement of a relaxing incision in the deep lamina of rectus sheath (transversus abdominis and internal oblique aponeurosis) is shown by dotted line. Source: From Ref. 49.

Figure 8 Completed direct hernia repair demonstrates that the relaxing incision allows the transversus abdominis to slide inferiorly. As the relaxing incision opens, the rectus muscle is exposed, but the overlying intact superficial lamina (external oblique aponeurosis) of the rectus sheath supports the muscle externally while the intact fascia posteriorly shields the potential hernial defect. Source: From Ref. 49.

Figure 9 The preperitoneal exposure of the posterior inguinal wall displays the important structures that form the boundaries of groin hernias. Repair of hernial defect(s) is readily accomplished by suture, after preliminary reduction of the hernia. If an indirect hernial sac extends into the scrotum, it is not necessary that the entire distal sac be removed. Note that application of mesh is quite easy, because the posterior wall is completely exposed. Source: From Ref. 51.

Chapter 57:

opportunity to perform the operation in virgin tissue, which is clearly a distinct advantage over any anterior approach. As with all recurrent hernias, a synthetic mesh buttress should be sutured to the posterior wall (Fig. 10), the only caveat regarding mesh in the preperitoneal space is the avoidance of sutures near the femoral nerve or the lateral femoral cutaneous nerve. Laparoscopic Repair—Abdominal Wall and Groin Hernia Laparoscopic Approaches to Groin Hernia Repair. Laparoscopic hernia repair, which evolved rapidly following the first demonstration of the feasibility of this approach in the early 1980s, is now being widely performed in many hospitals. The earlier success of posterior approaches to hernia repair, incorporating the concepts of tension-free repair as propounded by Lichtenstein (7), Stoppa, Condon and Nyhus, and Read (44), sets the stage for the rapid development and popularity of this approach. At this time it is clear that early recurrence rates after laparoscopic hernia repair are at least comparable, but possibly worse than those observed following open herniorrhaphy. The recent Type I evidence favoring open repair over laparoscopic hemiorrhaphy is of immense interest in this regard (53). Several innovative approaches have been attempted in laboratory and clinical settings: plugs, double-patches, intraperitoneal onlay of mesh (IPOM), preperitoneal patch, self-expanding patches, etc. All of these are variations on the theme of the current best approaches regarding hernia repair elucidated above; in 2005, the important components of these repairs are that they are tension-free, and reinforced with synthetic mesh (Figs. 11–13). IPOM appeared satisfactory in both laboratory and clinical settings when first introduced; presently it continues to be reported with enthusiasm in sporadic reports, but possible concerns about mesh in the peritoneal cavity still persist. The attraction of the totally extraperitoneal (preperitoneal) approach to groin hernia repair is real, but there is still the problem of gaining access without entering the peritoneal cavity and the risk of injury to structures in the vicinity. It is hard to predict whether this approach will become a favored one with surgeons at large, because of technical difficulties.

Figure 10 Large arrow illustrates the approach to the preperitoneal space, above the inguinal canal. Small arrow shows the preliminary repair of the hernia defect before insertion of the ‘‘regional’’ prosthetic reinforcement that extends from the primary incision to the pubic ramus and from the midline to lateral of the internal ring.

Hernias of the Abdominal Wall

1077

Laparoscopy, per se, puts the patient at some risk for injury to small intestine, either immediately during the operation, or as a late complication due to the contiguous synthetic mesh materials employed in the hernia repair. If the prolene or marlex mesh is used, there is concern about adhesions or irritation of adjoining organs, similarly as that observed following insertion of these artificial agents in abdominal wall repairs. Additional injuries have been rarely noted in other structures, including hollow organs (vas deferens, urinary bladder, and colon), nerves (ilioinguinal, genitofemoral, lateral femoral cutaneous, and femoral), and vessels (iliac artery and vein and femoral artery and vein). While operative injuries are higher after laparoscopic procedures than following open operations, the advantage of being able to return to work earlier is appreciated by many patients, and many patients (who have had both approaches) favor the use of minimally invasive means. The earlier return to full activity with minimal pain is compelling for some but not all patients; whether the increased cost of performing hernial repair by this means can thus be justified or will continue to be supported by providers is still uncertain (53,54). Which minimally invasive approach to hernial repair will become the most desired cannot be predicted at this time. It is clear that this approach has unique risks, and that some of the problems with laparoscopic procedures are unknown; long term follow-up and analysis of these problems will clarify the issue for a worldwide group of interested surgeons and patients. Complications There are many possible problems that may develop following inguinofemoral herniorrhaphy as summarized in Table 1. These should be recognized and discussed with the patient in a direct and supportive way, because the patient’s initial reaction will often be one of suspicion and fear that something bad may happen. Several complications related to the hernia repair itself need to be considered. Swollen Testicle. The swollen testis is a major concern for patients undergoing groin hernia repair, may be due to venous engorgement or lymphatic congestion secondary to the repair itself, compromise to the arterial blood flow as a result of intraoperative trauma, a subfascial hematoma, or a missed hernia (such as an indirect inguinal hernia when a direct hernia was being repaired). In these troubling cases, the management is usually guided by evaluating the overall clinical picture over a period of time. It will usually resolve over a period of 4 to 12 weeks, and the patient will only need the mature guidance of the surgeon during this interval to allay any fears that he may have. In those situations in which the blood supply to the testicle has been compromised, late atrophy of the testis will be noted; this complication is not rare, yet the true incidence is hard to determine because of limited follow-up studies in most reported series of patients undergoing groin herniorrhaphy. Occasionally, an acute infarction of the testicle will develop postoperatively, which will require immediate surgical intervention and eventual orchiectomy; there is never an indication for immediate excision, however, and the availability of duplex ultrasound is of immense value in determining viability (i.e., adequate arterial blood flow) of the affected testis. Ultrasound can also distinguish between ‘‘normal’’ and abnormal masses in the groin after herniorrhaphy (55). Pain. Occasionally, a patient will develop a persistent pain following groin herniorrhaphy. Most of the pain is of the

medwedi.ru

1078

Part Eight: The Integument and Body Wall

Figure 11 Laparoscopic view illustrates the major advantages of this approach: the vas deferens, testicular vessels, and surrounding structures are seen with clarity and definition, which is not possible by other means.

rapidly subsiding variety, and the pain is usually manageable for three to five days postoperatively. The tension-free repairs are remarkably free of pain in most patients by the second day, although many complain of residual discomfort for several weeks. By the third or fourth week, there is only a residual tenderness to deep palpation, and by three to four months, there are no symptoms referable to the operation. The presence of a ‘‘healing’’ ridge of tissue along the line of incision may be a concern to patients and their families, but reassurance that this is a commonly encountered phenomenon is usually all that is required. The importance of non-narcotic analgesics, heating pads, and avoidance of unnecessary stress is very important during the first week after operation. Some patients, conditioned to self-denial and personal effort, may believe they can and should ignore and ‘‘work through’’ the pain, but this is unrealistic and unnecessarily taxing to their family and medical supervisors. Occasional patients have persistent complaints that can be quite troublesome and that can prove difficult to assess and treat successfully. The physical examination is very useful because it gives precise information about the possible sources of pain. For example, if the testicle is swollen or inflamed or if the epididymis is quite tender, a genitourinary infection might be suspected. Alternatively, the floor of the inguinal canal may be painless, whereas the pubic tubercle area is exquisitely tender. Is this an indication of periostitis of the pubic bone? Is this due to a suture that was placed to effect adequate repair? Usually, the surgeon is not sure, but in such cases, no specific intervention

aside from local care, anti-inflammatory medications, and local treatments is needed. After at least three to four months have passed, the acute perioperative reaction has usually subsided and most subjective complaints will have disappeared. When persistent pain is found along the floor of the inguinal canal (but not at the internal ring), the possibility of a trapped nerve or neuroma must be considered; the problem for the surgeon is that the degree of pain is hard to assess immediately postoperatively. If a patient has excruciating pain immediately after operation, reoperation should be considered; if there is a radiation in the dermatome of the ilioinguinal nerve, the case for reoperation becomes even stronger. If the pain is less intense, but is persisting beyond two to three weeks, and centered along the floor of the inguinal canal, an injection of 2 to 3 mL of 1% xylocaine can be made at the point of tenderness to determine whether the groin discomfort disappears. If so, a ‘‘trigger’’ point has been identified, and the site can be injected with a mixture of cortisone (triamcinolone acetate 40 mg/mL with 1.0% xylocaine) and local anesthesia. Most patients will respond to this type of treatment with a clear decrease in symptoms and not require more than two injections. If unsuccessful, the patient has shown him/herself to be part of a special group of patients with chronic, moderately severe groin pain, for which there is often not a definite cure. Surgical excision of the superficial scar tissue and nerve tissue is indicated at some point, but most patients prefer to have initial treatment through a pain clinic approach.

Figure 12 (A) View from the peritoneum reveals a right indirect inguinal hernia. After exposure of the collagenous supports, which will serve as an anchor for the prosthetic mesh, it is easy to plan a safe and effective repair of the defect. The tension-free approach will be used, with fixation only to the pubic ramus and the superior aspect of the transversus arch. (B) Landmarks that must be clearly identified include Cooper’s ligament, the spermatic vessels and vas deferens, and the iliopubic tract.

Chapter 57:

Hernias of the Abdominal Wall

1079

minimize the risk of these complications, but cannot prevent all postoperative problems.

Figure 13 The essential concept governing mesh placement is that the mesh should be large enough to cover all potential hernia sites. The anchoring of the mesh is probably less important than previously thought, because the mesh will be held firmly by inflammatory adhesions postoperatively. When sutures or staples are used, none are placed inferior to the iliopubic tract and the lateral aspect of the internal ring is avoided. Staples placed in the iliopubic tract lateral to the internal ring may jeopardize branches of the femoral nerve.

Nerve Injury After Laparoscopic Repair. Laparoscopic hernia repairs provide unique risks for nerve injury due to the proximity of important nerves to the mesh, sutures, or staples utilized in repair. The femoral nerve, lateral femoral cutaneous nerve, genital branch of genitofemoral nerve, and ilioinguinal nerves have all been reported as injured during these operations. Caution in staple and mesh placement will Table 1 Local or Regional Complications After Repair of Groin Hernias Acute Wound infection/hematoma Ilioinguinal/iliohypogastric nerve injury Preperitoneal hemorrhage Femoral vein/artery laceration or trauma Thrombosis femoral vein/pulmonary embolus Transection of vas deferens Ligation of spermatic artery Perforation of viscus (sliding hernia) Nonclosure of internal ring Loss of domain of erstwhile incarcerated structures Scrotal ecchymosis/hematoma Swollen testis Missed hernia Urinary retention Chronic Recurrent hernia Hernia in a contiguous area Late wound/suture sepsis (>5 to 10 years later) Neuroma Testicular atrophy Hydrocele Pseudoaneurysm of femoral artery Groin pain Loss of cremasteric reflex Periostitis of pubis Sexual dysfunction

Hernia Recurrence. The most important complication directly relating to the repair itself is that of hernia recurrence. Because of the mobility of our society and the consequent difficulty of following patients over the long term, the actual incidence of recurrence is probably not known. Most series would suggest that this incidence is somewhere between 2% and 10%. In a 22-year analysis of inguinal and femoral hernias repaired by McVay and Chapp (8), a 3.2% recurrence rate in over 1200 cases was noted. Almost 40% of the recurrences occurred after five years following the initial operation, illustrating the constraints of short evaluation periods. The best results ever reported in terms of recurrence rates are those from specialty groups such as the Shouldice Clinic and the Lichtenstein Hernia Institute (7). The Shouldice repair is performed through an anterior incision and includes maneuvers to ensure adequate exposure of the internal inguinal ring followed by an overlapping repair of the floor of the inguinal canal. The principles of this repair are narrowing of the internal ring and a multilayer reinforcement of the transversalis fascial layer. This repair is made without relaxing incisions and maximizes tension in the hernia site. Despite the lack of prosthetic mesh insertion, several authors have reported less than a 1% recurrence rate with this technique, regardless of whether primary or recurrent hernias were being treated. The tension-free approaches of Lichtenstein and others have achieved similar results, and have been used by surgeons throughout the land as previously discussed.

Umbilical Hernia Umbilical hernias occur where the umbilical ring has failed to obliterate the opening of the allantoic duct. The majority of these hernias are congenital in origin and are particularly common in Afro-American infants. Most of these hernias close spontaneously by the ages of four to six and almost never become incarcerated or strangulated, and therefore, infant congenital umbilical hernias rarely require surgical closure. Exceptions to this stance include hernias that are symptomatic, those in which the umbilical ring is excessively large so that external trauma poses a threat, and those that have demonstrated no significant closure by six years of age. Umbilical hernias may also develop in adults. When they occur in this population, a number of predisposing factors appear to give rise to their development, including abdominal distention secondary to massive ascites from underlying disease such as Laennec’s cirrhosis; induced ascites as occurs in patients undergoing CAPD, in patients who are pregnant, and in those who are obese; and in certain situations where there may be abnormal or defective collagen synthesis secondary to nutritional deficiencies or advancing age (10). Because many of these hernias have a small neck, the risk of incarceration and strangulation remains a continuing threat. Thus, most of these hernias should be surgically repaired, which can be easily accomplished through an infraumbilical or supraumbilical skin incision in which the sac is removed and the fascial edges surrounding the hernial defect are directly approximated with nonabsorbable sutures.

Hernias of the Linea Alba In addition to the umbilical hernia, a number of other hernial defects traverse the linea alba. These hernias usually

medwedi.ru

1080

Part Eight: The Integument and Body Wall

occur between the xiphoid process and the umbilicus, in which case they are termed as ‘‘epigastric’’ hernias; occasionally they may appear below the umbilicus. Hernias of the linea alba are usually small, often multiple, and typically contain preperitoneal fat. Their presentation clinically is often deceptive and may be apparent only as pinpoint convexities overlying the erect patient’s linea alba. If the physical examination is negative, but the patient’s complaint is persistent pain in this region anatomically, surgical exploration may be required to provide a definite diagnosis. The most cogent explanation for their development is the anatomy of the linea alba, a complex network of the three musculoaponeurotic components of the rectus sheath, which varies considerably in its inherent strength. There are at least three recognizable patterns of decussation of these fibers in the midline, all of which may be aggravated by marked distention of the abdominal wall. In addition, there are discreet areas midway between the xiphoid process and umbilicus that are subjected to repetitive stresses by phrenic aponeurotic bands that insert in the midline fascia; perhaps these latter structures eventually weaken the midline fascia and therefore help explain the location of most hernias in this area. Like umbilical hernias, repair of hernias involving the linea alba consist of excision and closure of the hernial sac and direct approximation of the edges of the defect in the fascia, with nonabsorbable sutures.

Spigelian Hernia The spigelian hernia develops through a defect in the spigelian fascia (named after the Flemish anatomist Spieghel who described it in the 1600s). The locus of intersection of the semilunar and semicircular lines, the spigelian point, just lateral to where the lower one-third of the rectus fascia (Fig. 14). The development of a hernia in this area is often subtle; as an interparietal hernia, which does not penetrate the external oblique layer, it frequently presents a diagnostic challenge. Persistent pain and tenderness, and occasionally a palpable mass along the rectus muscle may be found. Most of the difficulty in the diagnosis results from the fact that these hernias are usually intramural, so that they may track from their site of origin in almost any direction, being covered by the external oblique muscle. Consequently, they are not obvious as hernial defects traversing the abdominal wall. US has been demonstrated to be of value in the diagnosis of spigelian hernia and for the evaluation of patients with unexplained abdominal wall pain; however, US has been supplanted by computerized axial tomography because it achieves the twofold goal of examination of the abdominal wall and intra-abdominal contents. Since incarceration and strangulation may occur with spigelian hernias, they should be surgically repaired when diagnosed. Such repair is accomplished through a transverse incision over the site of origin, with division of the external oblique fascia for proper exposure of the hernial defect. Because the defect involves the aponeurosis of the transverse abdominus and internal oblique muscles, conventional repair involves approximation of these two fascial layers and subsequent closure of the divided external oblique fascia. Laparoscopic repair of these defects is also highly successful, and has the added advantage of not weakening the abdominal wall in the process.

Laparoscopic Ventral Hernia Repair The tension-free approach has achieved moderate success in the repair of large ventral hernias, although the technical challenges of successful repair require the skill of an

Figure 14 The rectus muscle aponeurosis extends from the fourth, fifth, and sixth ribs. The hernias along the lateral border of the rectus muscle do not penetrate the external oblique layer.

advanced laparoscopic surgeon. In general, the hernias of the abdominal wall can be treated successfully if there is sufficient overlap of mesh onto the abdominal wall, and if sufficient fixating sutures are placed through and through the abdominal wall. The newly available mesh materials, which include a smooth surface (to face the intestines) and a rough edge (to face the fascia and become incorporated), have been popular and have achieved the goals of successful hernia repair and minimal complications. The presence of a seroma is an ongoing concern, but with patience and periodic aspiration, these collections eventually disappear. If infection occurs, the mesh must be removed, but this occurs in less than 2% of cases.

Lumbar Hernia Hernias arising in the lumbar region through the posterior abdominal wall are called lumbar or dorsal hernias. One of two sites is generally involved. The superior lumbar triangle, also called Grynfeltt’s triangle, is the most common site of origin; the inferior lumbar triangle (also called Petit’s triangle) is less frequently involved. The common clinical presentation is usually a mass in the flank that may or may not be associated with pain. On palpation, this mass is generally reducible, and incarceration and strangulation are usually not problems. Most lumbar hernias represent incisional hernias occurring in old nephrectomy incisions, but they may on occasion occur spontaneously. Surgical repair with approximation of the fascial edges of the hernia defect is the treatment of choice.

Chapter 57:

Pelvic Hernias A variety of rare hernias may occur through the various foramina in the pelvic floor through which nerves and blood vessels pass into the buttocks or out of the pelvis. Various intra-abdominal structures may make up the hernial contents, small bowel being particularly frequent. The two common types of pelvic hernias include those that pass through the greater sciatic foramen and the obturator foramen. The diagnosis of these types of hernia is often first made at the time of surgery, when a portion of intestine becomes incarcerated, necessitating abdominal exploration. Occasionally an obturator hernia will be diagnosed as a swelling in the upper and medial aspect of the thigh associated with pain radiating to the medial aspect of the knee in the distribution of the obturator nerve (i.e., Howship-Romberg sign). In a patient in whom a sciatic or obturator hernia is suspected, herniography provides confirmation. Both types of hernias are usually repaired through an abdominal approach in which the hernial sac and its contents are reduced (with resection of necrotic bowel if indicated) and primary closure of the fascial defect is performed. Another type of pelvic hernia may occur when there is a defect in the levator sling in the floor of the pelvis. A protrusion through this defect is called a perineal hernia and usually appears as a bulge just lateral to the midline perineal raphe. These hernias are usually secondary to a previous surgical procedure such as an abdominoperineal resection or a prostatectomy. Repair involves fascial closure of the perineal defect, usually through a combined abdominal and perineal approach. Perineal hernias are often asymptomatic, but depending on their location they may be associated with pain on sitting or a variety of urinary complaints, predominantly dysuria.

Incisional Hernia An incisional hernia is one that develops through a surgical incision in the abdominal wall. These hernias most commonly involve incisions of the anterior abdominal wall, although they may be responsible for other types of hernias such as those occurring in the lumbar region (from a previous nephrectomy incision) and in the perineal region (from a previous abdominoperineal resection). The hernia may appear clinically shortly following the placement of the initial incision or develop many years thereafter. When arising in the anterior abdominal wall, incisional hernias are more commonly encountered in vertical than in transverse incisions. A variety of etiologic factors are involved in the development of incisional hernias that can generally be grouped under the two broad headings of poor postoperative wound healing or postoperative wound infection. Any factor related to poor surgical technique can result in inadequate wound healing. Whether sutures are placed too close to the edges or are tied too tightly so as to necrose the involved tissues, poor wound healing may result. Other contributing factors relating to surgical technique include knots becoming untied, use of the wrong type of suture material for a particular incision, suture damage due to shearing stresses, wound hematomas from poor hemostasis, and the placement of drains through the incision itself, all of which may adversely affect healing. Further, if the incision has not been closed properly and the patient develops a problem with increased intra-abdominal pressure (secondary to such factors as hiccupping, abdominal distention, and postoperative coughing), undue strain may be placed on the suture line that ultimately may give way. Finally, wound infections increase the risk of subsequent incision hernia, particularly if the infection

Hernias of the Abdominal Wall

1081

extends to the level of the fascia. Thus any factor contributing to the development of a wound infection also influences the likelihood of recurrent incision hernia. The treatment of incisional hernias is similar to that of other hernias. At present, the major question is whether mesh reinforcement should be used in all patients. When a mesh is used, the underlay or sublay technique is the most desirable, with the latter term (sublay) being used to indicate the positioning of the mesh within the rectus sheath, behind the muscle, and in front of the posterior component of the sheath (56–58). If a mesh must be used to bridge intraabdominal defects, the use of smooth mesh surfaces such as Goretex or Composix is recommended. In all cases, it is now apparent that the mesh requires fixation with sutures that traverse the abdominal wall, and these should be placed at intervals of approximately 5.0 cm whether the repair is performed open or closed (59). Similarly, the mesh should overlap healthy fascia for a suitable distance (3–6 cm) to allow the buttressing effect to be most effective. There is no level 1 evidence available to distinguish the difference between 3.0 and 6.0 cm, and there are other issues such as the presence of boundary structures that are not friendly to suture placement, such as pericardium, costochondral junction, os pubis, etc., which can compromise gratuitous descriptions of ‘‘necessary’’ margins (60–62). In some cases, the goal of avoiding direct contact of mesh with intestines is impossible, but there is reasonable evidence that the mesh materials can be safely implanted without excessive risk of intestinal fistula as a complication (61,62).

Parastomal Hernias A variant of the incisional hernia is that which occurs through the same fascial opening created for a colostomy or ileostomy. This type of hernia is termed as a ‘‘parastomal hernia’’ and usually occurs when the stomal opening is placed lateral to the rectus muscle. Often this type of hernia can be managed by tightening the fascial defect around the stoma with interrupted sutures. When this is not possible, the colostomy or ileostomy should be taken down and moved to a new site, preferably through the rectus muscle. The remaining fascial defect from the previously placed ostomy is then closed from within the peritoneal cavity. There is a laparoscopic alternative here as well, with the advantage of totally isolating the stoma from the operative field, allowing the use of mesh to buttress the repair without incurring the automatic contamination of the operative site.

Diaphragmatic Hernias A number of hernias may occur within the diaphragm that separates the thoracic from the abdominal cavity. These hernias may be congenital, in which case they arise through defects or apertures resulting from developmental abnormalities, or they may be acquired through enlargement of preexistent apertures or disruption of points of weakness. A congenital diaphragmatic hernia represents an arrest in the development of some portion of the diaphragm (Fig. 15). Posterolateral defects in the pleuroperitoneal membrane (the foramen of Bochdalek) occur on the left side in 70% to 85% of the cases and allow abdominal viscera to readily migrate into the left thorax; while most present as surgical emergencies of the newborn period, with substantial mortality rate due to accompanying respiratory distress, occasional cases present in adult life. The clinical presentation of this type of hernia and the physiologic principles underlying its management are discussed in detail in

medwedi.ru

1082

Part Eight: The Integument and Body Wall

Figure 16 Paraesophageal hernia. Source: From Ref. 63. Figure 15 Sites of congenital diaphragmatic herniation. Source: From Ref. 63.

Chapter 14. Another type of congenital hernia is that which results from failure of fusion anteriorly of the sternal and costal portions of the diaphragm. The resulting midline defect creates a hiatus, known as Morgagni’s foramen, through which a hernia may occur. When normal fusion results, only the internal mammary vessels pass through this area and continue into the abdomen as the superior epigastric vessels. When the defect remains, however, various portions of bowel (usually small bowel) or omentum may herniate through this abnormal hiatus. In contrast to the Bochdalek hernia, which clinically presents at birth, most hernias protruding through Morgagni’s foramen do not become symptomatic until middle age or later. Often their presence is first shown by a mechanical bowel obstruction with intestinal strangulation and mediastinitis. These hernias should be repaired as soon as they are diagnosed, usually by a transabdominal approach. Of the acquired types of hernias that may affect the diaphragm, the most common is the sliding hiatus hernia, which may or may not be associated with esophagitis. This type of hernia is discussed in detail in Chapter 14. Less commonly encountered clinically is the parahiatal hernia, also called the paraesophageal hernia (Fig. 16). Because the esophagogastric junction is not disturbed in this condition, esophagitis is not a problem, although heartburn is not unusual as a presenting complaint due to poor esophageal emptying. Usually the presenting symptoms are vague epigastric and lower chest pain that may be aggravated on recumbency. With this type of hernia, all or part of the stomach may herniate into the thorax adjacent and to the left of the gastroesophageal junction. Radiologically, this type of hernia may give the appearance of an upside-down stomach on barium contrast study. Paraesophageal hernias are often associated with the complications of ulceration and bleeding and not uncommonly become incarcerated and at times even strangulated. For many years, the most prudent method of management was thought to be immediate repair of the hernia; however, because many patients survive for years without these complications, the necessity of routine

closure in asymptomatic patients has been questioned (64). When symptoms occur, however, the repair should be performed promptly. Often in our clinic, patients who are operated upon discover the importance of their symptoms only when they experience the joy of being normal again in the postoperative period; as a result, I usually find that patients have chronic discomfort or digestive difficulties which can be reasonably expected to disappear by operative treatment; interestingly, the best results are reported by surgeons who routinely employ mesh prostheses in reconstruction of the esophageal hiatus (65). This interesting phenomenon is one that explains our bias toward operating on large hernias once discovered; occasionally, however, if there is a truly asymptomatic patient, we simply describe the possible risks and ask the patient and family to stay in touch periodically. One additional type of acquired hernia of importance is that produced by rents in the diaphragm, which may result from penetrating or blunt trauma. Because of the protective effects of the liver on the right side, these traumatic hernias almost always occur on the left side and can result in considerable respiratory embarrassment from herniation of abdominal viscera into the left chest, if they are of sufficient size. Surgical repair of the diaphragmatic tear with reduction of the herniated viscera into the abdomen is the treatment of choice.

SUMMARY Hernias of the abdominal wall are commonly encountered in the practice of surgery and may arise in any structure surrounding or supporting the contents of the abdominal cavity. These hernias are particularly common anteriorly, with the vast majority arising in the groin. Other sites of relatively frequent occurrence include the umbilicus and previous incisions. The clinical presentation of a hernia usually consists of an obvious bulge at the site of the hernial defect, and is often associated with pain. Less commonly, an unexplained intestinal obstruction may be the presenting finding, in which a segment of bowel has become trapped in the hernial defect. Because hernias generally do not resolve spontaneously (an exception being the congenital umbilical hernia), surgical repair has until recently been the treatment of choice

Chapter 57:

once the diagnosis has been established; this concept has been the subject of rethinking, and the role of observation has achieved new currency in modern parlance. Hernial repairs consist of careful identification of the hernial boundary, reduction of the hernial sac contents, and in many but not all cases, excision of the sac itself. The hernial defect is then repaired by approximating its edges with sutures in one of several ways—with interrupted or continuous, permanent, or absorbable sutures. When the hernial defect is so large that primary closure without tension is impossible, a tension-free repair is performed; the choice of repair is left to the experience and judgment of the surgeon. Anatomic approaches such as ‘‘component separation’’ are sometimes used, but most often, a prosthetic material of some type is utilized. Further, the routine use of a mesh in groin hernias is now well established, and has led to a much-improved outcome for patients with groin hernias. Whether the mesh has a comparable role in umbilical and incisional hernias is not as clear, despite the wide use of mesh in these sites. The key to any successful hernia repair is an understanding of the underlying anatomy and its restoration to normalcy. With this principle in mind, most hernias can be repaired without difficulty and a goodto-excellent result can be expected.

REFERENCES 1. Hughson W. The persistent or preformed sac in relation to oblique inguinal hernia. Surg Gynecol Obstet 1925; 41:610–618. 2. Keith A. On the origin and nature of hernia. Br J Surg 1924; 11:455–460. 3. Anson BJ, Morgan EH, McVay CB. Surgical anatomy of the inguinal region based upon a study of 500 body-halves. Surg Gynecol Obstet 1960; 111:707–724. 4. Fitzgibbons RJ, Jonasson O, Gibbs J, et al. A clinical trial to determine if watchful waiting is an acceptable alternative to routine herniorrhaphy in patients with minimal or no hernia symptoms. J Am Coll Surg 2003; 196:737–742. 5. Read RC. Milestones in the History of Hernia Surgery – Prosthetic repair. Hernia 2004; 8(1):8–14. Epub Hernia 2003: Oct 28. 6. Toki A, Watanabe Y, Sasaki K, Tani M, Ogura K, Wang ZQ. Adopt a wait-and-see attitude for patent processus vaginalis in neonates. J Pediatr Surg 2003; 38:1371–1373. 7. Amid PK. Lichtenstein tension-free hernioplasty: its inception, evolution, and principles. Hernia 2004; 8(1):1–7. Epub 2003, Sep 20. 8. McVay CB, Chapp JD. Inguinal and femoral hernioplasty-the evaluation of a basic concept. Ann Surg 1958; 148:499–510. 9. Condon RE. The anatomy of the inguinal region and its relationship to groin hernia. In: Nyhus LM, Condon RE, eds. Hernia. 4th. Philadelphia: JB Lippincott Co., 1995:16–72. 10. Higa KD, Ho T, Boone KB. Internal hernias after laparoscopic Roux-en-Y gastric bypass: incidence, treatment and prevention. Obes Surg 2003; 13(3):350–354. 11. Armstrong O, Letessier E, Genier P, Laserre P, Le Neel JC. Internal hernia. Report of nine cases. Hernia 1997; 1:143–145. 12. Nikfarjam M, Christophi C. Internal hernia traversing the lesser sac. Ann Coll Surg Hong Kong 2003; 7:99. 13. Nishida S, Pinna AG, Nery JR, et al. Internal hernia of the small bowel around infrarenal arterial conduits following transplantation. Clin Transplant 2002; 16:334–338. 14. Gullmo A, Broome A, Smedberg S. Herniography. Surg Clin N Am 1984; 64:229. 15. van Wessem KJ, Simons MP, Plaisier PW, Lange JF. The etiology of indirect inguinal hernias: congenital and/or acquired? Hernia 2003; 7(2):76–79. Epub 2003 Mar 18. 16. Gullmo A. Herniography: the diagnosis of hernia in the groin and incompetence of the pouch of Douglas and pelvic floor. Acta Radiol Suppl (Stockh) 1980; 361:1–76.

Hernias of the Abdominal Wall

1083

17. Gullmo A. Herniography: the diagnosis of hernia in the groin and incompetence of the pouch of Douglas and pelvic floor. Acta Radiol Suppl 1980; 361:1–76. 18. Gullmo A. Herniography. World J Surg 1989; 13:560–568. 19. DuBois JJ, Jenkins JR, Egan JC. Transinguinal laparoscopic examination of the contralateral groin in pediatric herniorrhaphy. Surg Laparosc Endosc 1997; 7:384–387. 20. Rescorla FJ, West KW, Engum SA, Scherer LR III, Grosfeld JL. The ‘other side’ of pediatric hernias: the role of laparoscopy. Am Surg 1997; 63:690–693. 21. Wulkan ML, Wiener ES, VanBalen N, Vescio P. Laparoscopy through the open ipsilateral sac to evaluate the presence of contralateral hernia. J Pediatr Surg 1996; 31:1174–1176. 22. Miltenburg DM, Nuchtem JG, Jaksic T, Kozinetiz C, Brandt ML. Laparoscopic evaluation of the pediatric inguinal hernia-a meta-analysis. J Pediatr Surg 1998; 33(6):874–879. 23. Miltenburg DM, Nuchter JG, Jaksic T, Kozinetz CA, Brandt ML. Meta-analysis of the risk of metachronous hernia in infants and children. Am J Surg 1997; 174:741–744. 24. Read RC. Attenuation of rectus sheath in inguinal herniation. Am J Surg 1970; 120:610–614. 25. Peacock EE Jr. Biology of hernia. In: Nyhus LM, Condon RE, eds. Hernia. 2nd ed. Philadelphia: JB Lippincott Co., 1978. 26. Peacock EE Jr, Madden JW. Studies on the biology and treatment of recurrent inguinal hernia. II. Morphological changes. Ann Surg 1974; 179:567–571. 27. Colin JF, Elliot P, Ellis H. The effect of uraemia upon wound healing: an experimental study. Br J Surg 1979; 66:793–797. 28. Karahan OI, Taskapan H, Tokgoz B, Coskiun A, Utas C, Gulec M. Continuous ambulatory peritoneal dialysis. Acta Radiol 2002; 43:170–174. 29. Engeset J, Youngson GG. Ambulatory peritoneal dialysis and hernia complications. Surg Clin N Am 1984; 64:385–392. 30. Zheng H, Si Z, Kasperk R, et al. Recurrent inguinal hernia: disease of the collagen matrix? World J Surg 2002; 26:401–408. Epub 2002 Jan 02. 31. Si Z, Bhardwaj R, Rosch R, et al. Impaired balance of type I and type III procollagen mRNA in cultured fibroblasts of patients with incisional hernia. Surgery 2002; 131:324–331. 32. Rodrigues AJ Jr, Rodrigues CJ, da Cunha AC, Jin Y. Quantitative analysis of collagen and elastic fibers in the transversalis fascia in direct and indirect inguinal hernias. Rev Hosp Clin Fac Med Sao Paulo 2002; 57:265–270. Epub 2003 Feb 17. 33. Hiebert CA. Gastroesophageal reflux and ascorbic acid deficiency. Ann Thorac Surg 1977; 24:108–112. 34. Cannon DJ, Read RC. Metastatic emphysema, a mechanism for acquiring inguinal herniation. Ann Surg 1981; 194: 270–278. 35. Kesek P, Ekberg O, Westlin N. Herniographic findings in athletes with unclear groin pain. Acta Radiol 2002; 43: 603–608. 36. Heise CP, Sproat IA, Starling JR. Peritoneography (Herniography) for detecting occult inguinal hernia in patients with inguinodynia. Ann Surg 2002; 235:140–144. 37. Dattola P, Alberti A, Dattola A, Giannetto G, Basile G, Basile M. Inguino-crural hernias: preoperative diagnosis and postoperative follow-up by high-resolution ultrasonography. A personal experience. Ann Ital Chir 2002; 73:65–68. 38. Lilly MC, Arregui ME. Ultrasound of the inguinal floor for evaluation of hernias. Surg Endosc 2002; 16:659–662. Epub 2001 Dec 17. 39. Hata S, Takahashi Y, Nakamura T, Suzuki R, Kitada M, Shimano T. Preoperative sonographic evaluation is a useful method of detecting contralateral patent processus vaginalis in pediatric patients with unilateral inguinal hernia. J Pediatr Surg 2004; 39(9):1396–1399. 40. Arnbjornsson E. Development of right inguinal hernia after appendectomy. Am J Surg 1982; 143:367–369. 41. Lilly MC, Arregui ME. Lipomas of the cord and round ligament. Ann Surg 2002; 235:586–590. 42. Soper RT. Abdominal hernia. In: Liechty RD, Soper RT, eds. Synopsis of Surgery. 5th. St. Louis: Mosby, 1985.

medwedi.ru

1084

Part Eight: The Integument and Body Wall

43. Dittrick GW, Ridl K, Kuhn JA, McCarty TM. Routine ilioinguinal nerve excision in inguinal hernia repairs. Am J Surg 2004; 188(6):736–740. 44. Rutkow IM. The PerFix plug repair for groin hernias. Surg Clin N Am 2003; 83(5):1079–1098. 45. Read RC. The contributions of Usher and others to the elimination of tension from groin herniorrhaphy Hernia. 2005 (Epub ahead of print). 46. Condon RE. Anatomy of the inguinal region and its relation to groin hernia. In: Nyhus LM, Condon RE, eds. Hernia. 2nd ed. Philadelphia: JB Lippincott, 1978. 47. Ponka JL. Hernias of the Abdominal Wall. Philadelphia: WB Saunders, 1980. 48. Coll JR. Surg Edin 2001; 46:349–353. http: www.edu.rcsed.ac.uk. 49. Condon RE. Anterior iliopubic tract repair. In: Nyhus LM, Cordon RE, eds. Hernia. 2nd ed. Philadelphia: JB Lippincott, 1978. 50. Scott NW, McCormack K, Graham P, Go PM, Ross SJ, Grant AM. Open mesh versus non-mesh for repair of femoral and inguinal hernia. Cochrane Database Syst Rev 2002(4):CD002197. 51. Nyhus LM. The preperitoneal approach and iliopubic tract repair of inguinal hernia. In: Nyhus LM, Condon RE, eds. Hernia. 2d ed. Philadelphia: JB Lippincott, 1978. 52. Nyhus LM, Pollak R, Bombeck CT, Donahue PE. The preperitoneal approach and prosthetic buttress repair for recurrent hernia: the evolution of a technique. Ann Surg 1988; 208:733–37. 53. Neumayer L, Giobbie-Hurder A, Jonasson O, et al. Open mesh versus laparoscopic mesh repair of inguinal hernia. N Engl J Med 2004; 350(18):1819–1827. Epub 2004 Apr 25. 54. Rutkow IM. Demographic and socioeconomic aspects of hernia repair in the United States in 2003. Surg Clin N Am 2003; 83(5):1045–1051. 55. Amid PK. Radiologic images of meshoma: a new phenomenon causing chronic pain after prosthetic repair of abdominal wall hernias. Arch Surg 2004; 139(12):1297–1298.

56. de Vries Reilingh TS, van Geldere D, Langenhorst B, et al. Repair of large midline incisional hernias with polypropylene mesh: comparison of three operative techniques. Hernia 2004; 8(1):56–59. Epub 2003 Oct 28. 57. Bauer JJ, Harris MT, Gorfine SR, Kreel I. Rives-Stoppa procedure for repair of large incisional hernias: experience with 57 patients. Hernia 2002; 6(3):120–123. Epub 2002 Jul 13. 58. Schumpelick V, Klinge U, Junge K, Stumpf M. Incisional abdominal hernia: the open mesh repair. Langenbecks Arch Surg 2004; 389(1):1–5. Epub 2003 Mar 06. 59. Eid GM, Prince JM, Mattar SG, Hamad G, Ikrammudin S, Schauer PR. Medium-term follow-up confirms the safety and durability of laparoscopic ventral hernia repair with PTFE. Surgery 2003; 134(4):599–603; discussion 603–604. 60. Vrijland WW, Jeekel J, Steyerberg EW, Den Hoed PT, Bonjer HJ. Intraperitoneal polypropylene mesh repair of incisional hernia is not associated with enterocutaneous fistuia. Br J Surg 2000; 87(3):348–352 (see comment by Amid P. Br J Surg 2000; 87(10):1436–1437). 61. Ujiki MB, Weinberger J, Varghese TK, Murayama KM, Joehl RJ. One hundred consecutive laparoscopic ventral hernia repairs. Am J Surg 2004; 188(5):593–597. 62. Carbonell AM, Kercher KW, Matthews BD, Sing RF, Cobb WS, Heniford BT. The laparoscopic repair of suprapubic ventral hernias. Surg Endosc 2004 (Epub ahead of print). 63. Grimes OF, Way LW. Esophagus and diaphragm. In: Way LW, ed. Current Surgical Diagnosis and Treatment. 7th ed. Los Altos, CA: Lange Medical Publications, 1985. 64. Stylopoulos N, Gazelle GS, Rattner DW. Paraesophageal hernias: operation or observation? Ann Surg 2002; 236:492–501. 65. Frantzides CT, Madan AK, Carlson MA, Stavropoulos GP. A prospective, randomized trial of laparoscopic polytetrafluoroethylene (PTFE) patch repair vs simple cruropiasty for large hiatal hernia. Arch Surg 2002; 137(6):649–652.

58 Pathophysiology of Thermal Injury Ronald M. Barton, Evan R. Kokoska, David J. Wainwright, and Donald H. Parks

INTRODUCTION

Recipient Tissue

Thermal injury elicits major pathophysiologic alterations beyond the obvious cutaneous manifestation. Although the burn wound itself can present unique challenges in terms of therapeutic management and is responsible for the high incidence of infection that occurs in thermally injured patients, a number of metabolic aberrations and associated dysfunction of various organs are also commonly encountered, which directly contribute to morbidity and mortality. The magnitude of these latter derangements has led to the proposal that the burn patient is the universal trauma model with the greatest dysregulation of homeostasis of any injury (1,2). Major progress has been achieved in recent years in understanding many of the pathophysiologic mechanisms that occur in burn injury, and has facilitated patient management and improved survival. Such progress has been attributed to the development of specialized burn centers, increased investigative efforts in burn research, and the development of the team concept in patient management (3).

THE BURN WOUND Biophysics of Thermal Injury When skin is heated, damage occurs from the transfer of thermal energy. The magnitude of this tissue destruction is a function of both the quantity of heat transferred and the speed at which it dissipates. These factors are determined by the physical properties of the burning agent, the recipient tissue that is burned, and the incipient environment.

Certain physical properties of the heated object are also important in determining the extent of damage. These parameters reflect how much energy must be expended to raise the temperature of the object and how efficiently and quickly the heat is transferred. Skin, because of its high water content, has a high specific heat and a low thermal conductivity. Thus slow overheating of the tissues and delayed dispersion of the energy result. This is illustrated by measuring the temperature 1 mm below the skin surface after a 10-second scald burn (Fig. 2). There is an initial rapid, but not immediate, rise in temperature as the heat is applied. Even more dramatic is the length of time required for the temperature to return to baseline values. In this way, heat damage may continue after the offending agent is removed. Heat energy is lost primarily by conduction to the surrounding tissues, with removal of the circulating blood making only a small contribution (7).

Environment Heat dissipation occurs not only through adjacent tissue but also into the surrounding environment. Heat loss is therefore maximized in a cooler environment. For example, the rapid application of cold water to burned skin has been shown to decrease the severity of the injury by rapidly reducing the elevated tissue temperature (8). There is also evidence that cooling the burn wound minimizes edema (9,10) by decreasing the amount of histamine released (11)

Burning Agent The temperature and duration of exposure to the burning agent are the most important determinants of the degree of injury. For a specific level of injury, there is an inverse relationship between these two parameters (4,5) (Fig. 1). As the temperature is reduced, a progressively longer exposure time is required to inflict the same injury. At a theoretic ‘‘threshold temperature,’’ the heat source would have to be applied for an infinite time. Temperatures below this ‘‘threshold’’ do not result in tissue damage, regardless of the duration of application. The exposure interval is related not only to the actual removal of the offending agent but also to the rate at which the heat source loses its energy to the environment. For example, at lower temperatures at which duration is important, a different degree of injury results when a metallic object and liquid are exposed to the same temperature. The liquid loses its heat more slowly.

Figure 1 Relationship between temperature and the duration of contact for first-degree (A), second-degree (B), and third-degree (C) injuries. Source: From Ref. 4.

medwedi.ru 1085

1086

Part Eight: The Integument and Body Wall

damage. Elevated concentrations of several chemical mediators (i.e., prostaglandins) have also been reported in the blister fluid. In a partial-thickness injury or second-degree burn, the epidermal appendages are preserved and are responsible for resurfacing the wound. The epithelium in the surviving sweat glands and hair follicles multiplies and begins to migrate across the wound, coverage being complete within 7 to 14 days. This injury is typically painful because of direct nerve-ending damage coupled with the release of irritant chemical mediators into the wound. An even greater thermal insult leads to additional thermal necrosis. The cellular components are irreversibly damaged, and the connective tissue is sufficiently disrupted that it is unable to fulfill its function of support and protection. If this extends to a depth below the level of the epidermal appendages, a full-thickness injury or third-degree burn has occurred. Reepithelialization is only possible from the wound edge, a process that would take a considerable length of time for even small defects. A dry, leathery appearance is seen clinically, because the tissues have lost their ability to retain water. This wound is painless because the nerve endings have been destroyed.

Pathophysiology of the Burn Wound Major Mediators Figure 2 Temperature curve measured by a thermocouple 1 mm below the skin surface during a 10-second scald. The skin’s low thermal conductivity results in a slow dispersion of the energy, leading to an additional tissue injury subsequent to the removal of the offending agent. Source: From Ref. 6.

through the stabilization of the mast cell membrane (12). Preservation of the dermal microcirculation has likewise been demonstrated by immediate cooling of the thermally injured tissues (9,10), presumably through a reduction in thromboxane production (13).

Histopathology of the Burn Wound The severity of a burn injury is determined by the anatomic surface area involved and the pathologic depth. A firstdegree burn is characterized by a painful erythematous and edematous skin. Histologically, vasodilation is present in the dermal microvasculature, and there is an increase in the interstitial fluid volume secondary to increased permeability. If the insult is more severe, necrosis of the epidermis occurs, and blistering of the skin is found clinically. A hyperemic response is again observed in the vessels within the dermis, accompanied by extravasation of fluid. In this instance, the fluid accumulates not only within the connective tissue of the dermis, but also at the dermal–epidermal junction leading to vesicle formation. The composition of the blister fluid has been extensively examined by a number of investigators (14–17). Compounds with a relatively low molecular weight (i.e., electrolytes, urea, glucose, and antibiotics) diffuse freely into the tissues and are found in the same concentrations in the serum, interstitial fluid, and blister fluid. On the other hand, low-molecular-weight proteins that are generally found only in small concentrations in tissue fluid have been shown to attain up to 80% of their plasma concentration within the vesicles. Significant quantities of intracellular enzymes and purine/pyrimidine compounds are also found, reflecting the extent of cellular

Prior to discussing the specific derangements involved with burn injuries, a brief review of the major mediators produced, both local and systemic, is warranted (Table 1). As a general principle, under normal conditions these mediators, at low levels, are required to maintain proper blood flow and host immunity. However, either prolonged low levels or sustained elevations following injuries such as burns can be detrimental, both within the local site and at distant organ sites. Cytokines are low-molecular-weight glycoproteins that act as intercellular messengers in an autocrine, paracrine, or endocrine fashion. They are synthesized de novo in response to potential threats to the organism (antigens, lipopolysaccharides, etc.), must bind receptors, as they are unable to penetrate cell membranes (18), and are not governed by a major negative feedback loop (19). Cytokines are difficult to detect, because they are bioactive at extremely low concentrations, and their levels do not always correlate with the degree of injury (19). Some effects of cytokines are clearly beneficial, but they may become counterproductive during derangements in the body’s homeostatic responses. Imbalances may lead to immunosuppression, and excessive activity has correlated with injurious effects (20). Eicosanoids are produced through the metabolism of arachidonic acid, an unsaturated fatty acid essential in nutrition. Prostaglandins and thromboxanes are generated through the action of cyclooxygenase, whereas 5-lipooxygenase converts arachidonic acid to leukotrienes. A variety of prostaglandin end products have been identified in the burn wound, and many appear to have divergent effects (21). For example, prostaglandin E2 (PGE2) and prostacyclin (PGI2) are vasodilators and inhibit platelet aggregation, whereas thromboxane A2 (TXA2) is a potent vasoconstrictor and promotes platelet aggregation. A steady-state relationship exists between these oppositely functioning prostanoids (e.g., PGE2 and PGI2 vs. TXA2) in uninjured tissues. However, a traumatic stimulus may disrupt this balance and favor increased production of a particular group of eicosanoids. Several different isoforms of cyclooxygenase have been recognized: a

Chapter 58: Pathophysiology of Thermal Injury

1087

Table 1 Local and Systemic Mediators of Burn Injuries Mediators

Major sources

Cytokines IL-1

Monocytes, macrophages

IL-2

T-lymphocytes

IL-6 TNF (cachectin)

Macrophages, PMNs, fibroblasts Macrophages, endothelial cells

Eicosanoids PGE2, PGI2 TXA2, TXB2

Endothelial cells, macrophages, PMNs Platelets, macrophages

LTB4, LTC4, LTD4

Mast cells, macrophages, PMNs

Nitric oxide

Endothelial cells, macrophages

Oxygen free radicals

PMNs

Complement C3a, C5a C3b C5b C6 to C9 Acute phase proteins Hepatocytes

Major actions Immunologic Activate B- and T-cells, natural killer cells, PMNs, and macrophages Cell-mediated immunity, enhanced cytotoxic T-cell function B-cell proliferation, immunoglobulin production PMN release, margination, and activation

Metabolic Fever, APP production, catabolism, wound healing, and anemia (19,20) Hypermetabolism (19) Hepatic APP production (19) Catabolism, APP production, and fever (19)

Vasodilation, increased vascular permeability, and immunosuppression (PGE2) (19,20,27–29) Vasoconstriction, platelet aggregation, and local tissue ischemia (30–32) Increased vascular permeability, potent PMN chemoattractant (LTB4), and small airway constriction (LTC4, LTD4) (20,34) Low levels: vasodilation High levels: Cytotoxic, vascular decompensation (22,35,36) Lipid peroxidation (increased cell membrane permeability and fluidity) (19,20) Anaphylaxis Opsoninization Increased vascular permeability and smooth muscle contraction Cytotoxic (20) Inactivate proteases, scavenge oxygen free radicals, and modulate wound healing (37)

Abbreviations: APP, acute phase protein; IL, interleukin; LT, leukotriene; PG, prostaglandin; PMN, polymorphonuclear leukocyte; TX, thromboxane; TNF, tumor necrosis factor.

constitutively expressed (Cox-1) and inducible (Cox-2) form. However, the role of these two differentially expressed enzymes following burn injury remains to be completely characterized. Burns are also associated with enhanced nitric oxide formation. Similar to cyclooxygenase, nitric oxide is generated from two isoforms of nitric oxide synthase: a constitutive and inducible form. Under basal conditions, low levels of nitric oxide provide a continuous state of active vasodilation and inhibit platelet and polymorphonuclear leukocyte (PMN) adhesion to the endothelium (22). After major injury, however, inducible nitric oxide synthase activity is significantly upregulated by stimuli such as elevated temperature (23) and tumor necrosis fator (TNF) or interleukin-1 (IL-1) released from activated macrophages (22). Excessive nitric oxide is associated with circulatory failure and vascular decompensation. PMNs and macrophages are primarily responsible for phagocytosis of necrotic tissue. In the phagosome of the neutrophil, superoxide anion radicals and hydrogen peroxide are produced in large quantities to oxidize the ingested debris. These free radical species are normally rendered harmless by the action of superoxide dismutases and catalases that convert them to harmless products including oxygen and water. However, following burn injury, oxygenderived free radicals are generated secondary to both ischemia/reperfusion via activation of xanthine oxidase (19) and histamine released from stimulated mast cells (24), and it has been postulated that a sufficient quantity of these substances may escape into the interstitial fluid, where the necessary enzymes for their reduction are present in only small amounts (25). These radicals not only increase

capillary permeability directly but also may induce peroxidation of tissues and can also result in enhanced prostaglandin release by their action on the phospholipid bilayer of the cell membrane (26). Complement acts to attract PMNs and degranulate mast cells and further increases oxygen free radical synthesis in addition to the other actions (20) depicted in Table 1.

Progressive Ischemia An important conceptual model of the burn wound is that proposed by Jackson (38). He described three zones of graded thermal trauma (Fig. 3). Centrally, the ‘‘zone of coagulation’’ is an area of irreversible tissue destruction. Temperatures in this region are extreme and lead to immediate cell death, the depth of necrosis being directly dependent on the quantity of heat transferred. On the periphery, a ‘‘zone of hyperemia’’ exists, where vasodilation and permeability changes are present. Here the tissues are viable and generally heal uneventfully. The ‘‘zone of stasis’’ lies between these two areas. In this zone, the flow through a microvasculature is sluggish or has ceased, leading to progressive ischemia and cell death (39). Jackson (38) conceived that these changes were a direct effect of the heat energy on the tissues, and that eventual tissue necrosis within the zone of stasis was inevitable within 24 to 48 hours. However, other investigators believe that the tissues in this region have not been permanently damaged and thus possess the potential for a full recovery (40). Any deterioration is the result of a combination of physical factors and local inflammatory processes leading to persistent stasis and ischemia with conversion to a ‘‘zone of coagulation’’.

medwedi.ru

1088

Part Eight: The Integument and Body Wall

Figure 3 Jackson’s three zones of graded thermal injury. Source: From Ref. 6.

Systemic Factors The progressive nature of the dermal ischemia occurs secondary to the influence of both systemic and local factors as outlined in Table 2. Depletion of the intravascular volume from fluid leaking into the injured tissues diminishes the filling pressure of the left ventricle and in turn the perfusion pressure within the microcirculation. However, even prior to measurable decreases in plasma volume, there is an alteration in ventricular compliance and a decrease in myocardial contractility (41). This direct myocardial toxicity is thought to be related to the release of a ‘‘myocardial depressant factor,’’ although no such factor has been identified chemically (42,43). Other proposed mediators contributing to early myocardial depression resulting in the ‘‘ebb’’ phase following burn injury include TNF (44), interleukins, antidiuretic hormone (ADH), oxygen free radicals (45–47), and nitric oxide (22). Constricting eschar in circumferential burns of the extremities can also lead to reduced perfusion pressures in distally burned tissues (48). Local Factors Local factors can be categorized into intraluminal, extraluminal, and those associated with changes in the vessel wall itself. Within the lumen of blood vessels, cellular debris may accumulate, leading to a reduction in the functional Table 2 Factors Contributing to Progressive Ischemia Systemic factors Diminished circulating volume Myocardial depression Constricting eschar Local factors Intraluminal White blood cell margination Platelet microthrombi/microemboli Erythrocyte agglutination Vessel wall changes Endothelial cell shape Vasoconstriction Direct Through chemical mediators Extraluminal Interstitial edema

diameter for flow. White blood cells respond to the thermal injury with increased margination along the vessel wall. As fluid leaks out of the intravascular space, hemoconcentration occurs, which may encourage erythrocyte aggregation and agglutination, further diminishing local blood flow. Platelet microthrombi and microemboli have also been observed to block the microvasculature within the injured area (49). Release of tissue thromboplastin from the injured tissues and the platelet-aggregating properties of thromboxane are both believed to contribute to the generation of these products of coagulation. Despite these observations, the use of anticoagulants has been unsuccessful in reducing the extent of tissue damage (50). Outside the vessel wall, the interstitial tissue pressure slowly increases, because the lymphatics are unable to contend with the enhanced and continual fluid extravasation. This leads to the compression of the microvasculature within this region and a subsequent reduction in flow. The vessel wall itself contributes to the reduction of nutrient flow by structural changes in the endothelial cells and vasoconstriction. As a response to direct damage or ischemia, the endothelial cells are less able to regulate their internal electrolyte balance. Water therefore enters the cells, and the cells’ normally hexagonal shape assumes a more spherical form (51). In this way the thickness of the vessel wall increases and impinges on the diameter of the lumen. The vasoconstriction is likely the result of a multitude of factors. Increased sympathetic tone and TXA2 release appear to be the most important causes. Because the changes in the caliber of the lumen secondary to vessel wall alterations are often transient (49), the other pathophysiologic changes detailed above probably play a more important role in reducing blood flow. For the cells within the zone of stasis to survive, nutrient flow within the microvasculature must be maintained. By preserving these tissues, one may prevent a partialthickness injury from becoming a full-thickness injury and therefore requiring grafting. Clinically, this is achieved by maintaining the vascular volume and, in turn, the perfusion pressure through adequate resuscitation with intravenous fluids at the time of initial treatment. Similarly, wound care is important to prevent dehydration and infection that can contribute to increasing the depth of injury. There is evidence that, by preserving an intact blister or covering the denuded partial-thickness injury with a skin substitute, dehydration of the exposed dermis is minimized, and maximal tissue preservation is achieved (40,52). More recent attempts at pharmacologic manipulation of the offending chemical mediators have been made to preserve and/or reestablish the flow in this vascular bed. Several studies have demonstrated that TXA2 is the responsible agent for many of the progressive ischemic changes seen in the dermal microcirculation, and that selectively inhibiting its production can prevent necrosis and attenuate hemodynamic disturbances (27,53,54).

Cellular Alterations In areas of irreparable damage, cell membranes are disrupted with the escape of intracellular contents. The connective tissue proteins undergo denaturation, and the water content is lost, leaving a solid amorphous substance. This fusion of the dermal and epidermal heat-damaged tissue is referred to as coagulation necrosis. As a reaction to the presence of this damaged and necrotic tissue, a marked inflammatory response characterizes the early phase of the burn

Chapter 58: Pathophysiology of Thermal Injury

wound. In locations where destruction is less extensive, cellular ultrastructure remains intact; however, function is often compromised. Resting membrane potentials are found to be above normal (greater than –90 mV) in this region, and cellular swelling is observed histologically (55). This is likely the result of decreased adenosine triphosphate (ATP) production from tissue ischemia (56,57). The function of the ATP-dependent sodium pump is impaired, permitting a shift of sodium and water into the cell, further compounding the loss of intravascular volume. A specific example of this is the altered function of the endothelial cells, the shape of which has been changed in response to a local thermal insult (51), as discussed earlier in this chapter. A toxin derived from the cell membranes of burned skin has also been described (58). This burn toxin, called lipid protein complex (LPC), is a complex of lipids and proteins fused together by the effect of thermal injury. LPC has been associated with erythrocyte hemolysis (59,60), immunosuppression (61), and generalized membrane and mitochondrial damage (62). The injurious effects of LPC are thought to be unrelated to lipid peroxidation (63) or bacteria (64), and can be neutralized with antiserum (58). However, the best treatment appears to be the removal of the burn wound.

Fluid Shifts in the Wound The inflammatory response typical of heat-damaged tissues is characterized by tremendous edema formation. Although various physical and chemically mediated factors are responsible, the fluid efflux depends on the restoration of adequate blood flow to the injured area. Perfusion is maintained by a combination of fluid resuscitation and local vasodilation, the latter following an initial period of transient sympathetic vasoconstriction. The magnitude and the time course of the tissue edema are subject to the timing and volume of fluid resuscitation (65). The cause of the increased fluid extravasation is multifactorial, with a tremendous amount of synergism between the responsible mechanisms. These can be broadly grouped into two major categories: (i) those that affect the permeability or ‘‘leakiness’’ of the vessel wall and (ii) those whose effect is mediated through alteration of the Starling forces (Table 3).

1089

(66), the latter secondary to these cells and assuming a more spherical shape (51). These findings are first observed in the venules and later in the capillary bed. Because more channels are open along the vessel wall than exist normally, the outflow of fluid naturally increases. Humoral Correlates The release of vasoactive substances is perhaps the most important cause of the increased permeability seen in the early burn wound. The effect of these agents is primarily on endothelial cells of the microvasculature where they cause both an increase in the number and an increase in size of the channels. This allows a number of macromolecules to enter the interstitial compartment, and thus increases the amount of fluid escaping from the vessel lumen. Proteins ˚ have been shown to escape into the interstitial of up to 150 A compartment, resulting in a decreased intravascular oncotic pressure (67,68). Studies have demonstrated that the integrity of the microvasculature to macromolecular leak is restored by 8 to 12 hours following thermal injury. Hence, at 12 hours postinjury, some clinicians initiate colloid infusions in their resuscitation regimens (69). A variety of mediators have been implicated in the generation of these permeability changes, but the most important appear to be the prostaglandins, leukotrienes (27–29), and oxygen free radicals (20). Kinins (70) and serotonin (71) released from platelets have been shown to play only a minor role. A stimulus for the mediator response is the connective tissue protein that has been modified by thermal injury. Its effect on activating the complement and clotting mechanisms leads to the generation of the various mediator compounds. Specifically, the C3 and C5 components of complement are responsible for mast cell histamine release and PMN recruitment, whereas the C9 component initiates prostaglandin release from platelets (26). The permeability changes seen within the burn wound take on a biphasic pattern (72) (Fig. 4). The initial increase is primarily caused by the action of histamine (73) and the direct thermal

Physical Factors The ease by which fluid, solutes, and macromolecules can exit the vessel lumen is influenced directly by architectural changes in the vessel wall and indirectly by a variety of chemical mediators. Vasodilation opens the endothelial gaps, promoting the efflux of fluid. The damaged endothelial cells exhibit an increase in both the number of intracellular vacuoles and the number of open intercellular junctions Table 3 Causes of Edema Formation Vessel wall changes Vasodilation Heat-induced damage Vasoactive substances Altered Starling forces Increased capillary hydrostatic pressure Vasoconstriction Partial blockage (platelets, white blood cells, red blood cells) Decreased intraluminal colloid osmotic pressure Increased interstitial colloid osmotic pressure Lymphatic obstruction

Figure 4 Biphasic pattern of capillary permeability. Source: From Ref. 6.

medwedi.ru

1090

Part Eight: The Integument and Body Wall

damage to the microvasculature. The specific cause of the second, more prolonged phase is less clear, but is likely the result of prostaglandin and leukotriene release and oxygen free radical generation. The use of specific histamine H2 receptor blockers (e.g., cimetidine) in reducing the early phase of edema formation has been successful in animals (74,75); however, their clinical use seems to be ineffective in this regard (76) and is occasionally associated with undesirable side effects (77). These findings are consistent with the fact that histamine is not responsible for the longer, more pronounced phase of increased permeability; therefore its inhibition is unlikely to have an appreciable effect. Topical ibuprofen, as cyclooxygenase inhibitor, has been reported to decrease burn edema (78). If molecular oxygen is reintroduced to previously underperfused tissue, oxygen-derived free radicals such as hydrogen peroxide and superoxide will be produced, which can result in further tissue damage. However, persistent tissue hypoxia will result in cell death. Therefore the burn patient becomes a victim of the ‘‘oxygen paradox’’ (79). Accordingly, other work directed toward decreasing permeability changes following burns has involved either blocking or scavenging oxygen free radicals. Permeability changes have been attenuated with xanthine oxidase inhibitors (44,80–82), but these trials have not been effective when inhibition is attempted after the burn (83). More promising is the use of vitamin C (a free radical scavenger) during fluid resuscitation, which, when initiated two hours after injury, in an animal model, has been associated with decreased burn wound edema and fluid requirements (84). Starling Forces In normal tissues, the balance of the Starling forces results in a slight efflux of fluid from the intravascular to the extravascular compartment (Fig. 5). A steady state is maintained by

resorption of this fluid through lymphatic channels. The lymphatic route is also the only avenue by which proteins can be returned to the vascular space to maintain the oncotic pressure gradient between the interstitial and intravascular compartments. In the burn wound these forces are altered so that this extravasation of fluid is greatly enhanced. Within the capillary lumen, hydrostatic forces are increased above normal. The opening of the precapillary sphincters allows the arterial pressure to be transmitted directly to this vascular bed. In addition, intraluminal pressures rise proximal to a partial obstruction to flow caused by platelet microthrombi/microemboli, white blood cell margination, and red blood cell debris. In contrast, capillary intravascular osmotic pressure is decreased by the loss of colloid molecules into the interstitial space (especially albumin), whereas the extravascular osmotic activity rises, which tends to pull fluid out of the vessels (14). Heat-denatured collagen is thought to be responsible for this effect. This denatured protein tends to hold the fluid within the interstitial space, thereby delaying resorption. Initially, the lymphatics increase their flow to compensate for this additional interstitial volume; however, the maximal effect of this flow is achieved within one hour following thermal injury. Not infrequently, blockage or destruction of the lymphatic channels delays resorption of the increased interstitial volume, further compounding this problem. Although tissue pressures rise as the quantity of edema fluid increases (85), this alteration is not sufficient to counteract the forces responsible for flow out of the vessels. Nonburn Wound Edema In large burns (i.e., over 40% body surface area), edema is observed in both burned and nonburned tissues. Increased capillary permeability of distant vascular beds may be caused by the systemic effect of chemical mediators released from the damaged tissue (29,68,86). Excessive white blood cell

Figure 5 Starling forces.

Chapter 58: Pathophysiology of Thermal Injury

margination in the nonburned microcirculation has also been considered as a possible cause (87). Demling et al. (24,88) have proposed that intravascular hypoproteinemia may be responsible for this effect. They suggested that the plasma oncotic pressure is lowered not only by protein loss through the burn wound, but also by dilution from the crystalloid solutions used in burn resuscitation. By administering colloid during the resuscitative period, they noted that the edema observed in nonburned tissues was significantly diminished.

Systemic Inflammatory Response Syndrome Following burn injury, the generalized release of systemic mediators can eventually lead to multiple systems organ failure and death. As mentioned earlier, although some of the effects of cytokines are clearly beneficial, imbalances and excessive activity are universally detrimental, as the body’s homeostatic responses become counterproductive. One hypothesis that summarizes the development of the systemic inflammatory response syndrome (SIRS) involves the ‘‘two hit’’ theory. The initial insult (burn injury or gut ischemia) primes the inflammatory factories (cellular elements such as PMNs and macrophages). Subsequent challenge, either by endotoxemia (from gut or wound) or persistent gut ischemia, acts as the ‘‘second hit’’ that initiates a prolonged, exaggerated release of inflammatory mediators resulting in hemodynamic instability and tissue injury (19). A simplified diagram is depicted in Figure 6. A growing body of evidence currently suggests that infection is not necessary for the development of SIRS. Fewer than half of septic-appearing patients who subsequently die have untreated infections (3,53,90,91), and the overall relationship between endotoxemia and survival is poor (58). It is becoming increasingly clear that devitalized tissue (denatured protein and bacterial products) and gut ischemia are important stimuli for the inflammatory response (3,90). Changes in intestinal permeability and the promotion of bacterial translocation are evident shortly after a burn injury (90,92). The mucosal injury is mediated in large part by oxygen free radicals derived from increased xanthine oxidase activity (90) as a result of decreased mesenteric blood flow and ischemia/reperfusion and does not appear to be related to bacteria, as germ-free rats

1091

demonstrate similar responses (90). Even in the absence of translocating organisms or endotoxin into the portal circulation, gut mucosal damage is injurious through the activation of the gut-associated lymphoid tissue (GALT) (18). The GALT, in addition to the burn wound, serves as a primary site for PMN priming and cytokine release (90). Gut ischemia also results in the release of eicosanoids (93) and complement (94). Efforts directed toward preventing SIRS by mediator antagonism have been largely disappointing in part because of the enormous costs and the difficulty detecting circulating levels of the various cytokines. Several studies have been stopped, and the results remain unpublished as a result of safety concerns (18). Trials with TNF and IL-1 antagonism have demonstrated no survival benefit (95,96). Currently, there is no ‘‘magic bullet’’ cure for SIRS, and future work involves combination therapy (18). Attempts toward decreasing bacterial translocation, including selective gut decontamination, have demonstrated decreases in infectious complications but no affect on survival (97). Others have reported a decrease in bacterial translocation through preservation of intestinal perfusion with vasodilators (nitroprusside) and TXA2 inhibitors (98,99). However, the best means of preserving mucosal integrity and minimizing GALT activation likely involves early delivery of enteral nutrients (90).

METABOLIC ALTERATIONS After the ‘‘ebb’’ phase that immediately follows a major burn and involves circulatory depression, local tissue and gut ischemia, and wound edema, patients develop a ‘‘flow’’ phase, which includes an elevated resting consumption of oxygen, coupled with increased nitrogen losses, autocannibalism (100), insulin resistance, hyperglycemia, and futile substrate cycling (101). Management of burn patients during the ‘‘flow’’ phase can be just as challenging as during the acute resuscitation.

Hypermetabolic Response The insult of a major burn results in a greater elevation of the metabolic rate than is observed in all other forms of trauma (Fig. 7). The hypermetabolic response to thermal injury,

Figure 6 Mediator interactions following burn injury. Abbreviations: GALT, gut-associated lymphoid tissue; IL, interleukin; LPS, lipopolysaccharide; PG, prostaglandin; PMN, polymorphonuclear leukocyte; SIRS, systemic inflammatory response syndrome, TNF, tumor necrosis factor. Source: From Ref. 89.

medwedi.ru

1092

Part Eight: The Integument and Body Wall

wound. During this time, a protein catabolic state is produced that is characterized by increased urinary nitrogen loss, which is associated with protein degradation proportional to the severity of the burn. The hypermetabolic state generates a net caloric deficit. Although much of that deficit can be met through the use of fat deposits, the oxidation of fat requires simultaneous oxidation of carbohydrates. Once glycogen stores are exhausted, protein catabolism becomes the obligatory source of the carbohydrate (116). In the process of gluconeogenesis, muscle protein is expended to liberate alanine and glutamine (116,117). Without exogenous nutritional support, skeletal muscle becomes a prime target organ of the catabolic process (106).

Postinjury Catabolism

Figure 7 Relative metabolic rates for various forms of trauma. Source: From Ref. 102.

which generally begins within 48 hours after injury, appears to be associated with an intrinsic elevation in body core temperature as a result of a direct resetting of the hypothalamic temperature-regulating mechanism. The resetting of the central core temperature to 38.5 C occurs between the 5th and 15th day postinjury. This remains elevated for up to two months (103). The zone of neutrality, or ambient temperature at which energy expenditure is minimal, is increased in burn patients from 27–29 C to 30–32 C (104). Evidence supporting this contention relates to the observations that unburned skin remains vasoconstricted even when ambient temperatures are increased and evaporative losses are minimized (105,106). On the other hand, although the hypermetabolic state does not depend on changes in ambient room temperature, it does appear to be sensitive to such alterations, because heat production and the energy cost of healing a large surface area can be reduced by keeping patients in a warm environment (107,108). Factors mediating postburn hypermetabolism include inflammatory agents (IL-1, IL-6, TNF, eicosanoids, and oxygen free radicals) (109) and counter-regulatory hormones (catecholamines, cortisol, and glucagon) (110,111). The central nervous system appears to be important for this response, as it is decreased in patients with neurologic impairment (112– 114). Of additional interest, Hart et al. reported, in pediatric patients who underwent delayed excision, that aggressive feeding was required for the full expression of burn-induced hypermetabolism. However early treatment did improve the net balance of leg skeletal muscle protein (115). The magnitude of the hypermetabolic response reflects the extent of the thermal injury. It increases over the first week following injury and decreases in response to wound healing and the diminishing size of the burn

The postinjury period is characterized by prolonged protein catabolism (particularly in muscle), negative nitrogen balance, hyperglycemia, lipolysis, hepatic fat deposition, and weight loss, all of which vary according to the extent of thermal injury. Derangements in the counter-regulatory hormones contribute to this ‘‘autocannibalism’’ (Fig. 8). Although it remains in a nonsteady state for weeks, the catabolic state ultimately reaches a plateau and does not change in response to caloric replacement (119,120). For a 50% total body surface area burn, the magnitude of catabolism may be twice that which normally occurs following an injury. Weight loss develops because of a breakdown of lean body mass. The loss of 300 to 600 g of body weight per day can be equated to a daily loss of 75 to 150 g of protein (121). Although treatment with calories and nitrogenous source does not affect breakdown of muscle protein, it can increase in synthesis. This apparent metabolic paradox can be appreciated by briefly reviewing the cycle through which carbohydrates are produced and used. Gluconeogenesis uses amino acids, principally alanine and glutamine. The source of these two gluconeogenic amino acids is skeletal muscle. Although the source appears to be obligatory, exogenous amino acids can either decrease muscle efflux or contribute to increased muscle synthesis (122). The increase in conversion of alanine to glucose is accompanied by a reduction in the incorporation of exogenous alanine into protein and an increase in the release and synthesis of alanine by muscle (30). At the same time, a reduction in circulating branched-chain amino acids suggests that the administration of exogenous amino acids, especially those of the branched-chain variety, may stimulate de novo synthesis of alanine and glutamine by skeletal muscle (123). The process of gluconeogenesis from skeletal muscle substrates requires energy. In this process, skeletal muscle uses fatty acid substrates (124). Meanwhile, glucose from the liver’s new stores is only partially used in the periphery, being converted to a three-carbon precursor, which in turn must return to the liver for reconversion into new glucose. The process of reconversion, referred to as the Cori cycle, also requires fatty acid substrates (125). Although increased lipolysis and lipid mobilization occur in the burn patient, exogenous administration of fatty acids appears to be of little nutritional value and may be related to variation in the body’s ability to clear lipids when in a state of stress (126), Following thermal injury, it has been noted that a diet consisting of 5% to 15% of the nonprotein calories as fat is optimal, and that a diet consisting of more is deleterious (127). In humans, the inhibition of triglyceride lipase by insulin may lead to a futile cycle of triglyceride metabolism (128). Immediately after a burn, for example, there is increased lipoprotein lipase activity and clearance of triglycerides,

Chapter 58: Pathophysiology of Thermal Injury

1093

Figure 8 Hormonal interactions following burn injury. Abbreviations: ACTH, adrenocorticotropic hormone. Source: From Ref. 118.

as insulin levels fall and glucagon and glucose levels rise. In response to plasma triglycerides, lipase activity increases. However, the resulting free fatty acids cannot be used without carbohydrates and eventually must be reesterified to triglycerides. For a more detailed discussion of these considerations, see Chapter 1.

Therapeutic Implications The dramatically increased metabolic expenditure following thermal injury must be compensated by increased nutritional support to avoid the plethora of potential complications associated with nutritional deficiency. Energy requirements in terms of caloric needs can be calculated according to the formula below proposed by Curreri et al. (124). 25 kcal/kg of body weight þ 40 kcal/percent of body surface burned Carbohydrate is the major source of calories and contributes to nitrogen sparing. The major carbohydrate form is glucose, and it must be administered with nitrogencontaining nutrients to improve nitrogen balance and allow more calories to be used for the restoration of nitrogen balance. Approximately 20% of caloric requirements should be protein or amino acid equivalents; improved survivals have been demonstrated with a 100:1 calorie-to-nitrogen ratio diet (129), and patients may require up to 2 to 2.5 g protein/kg/day. Essential fatty acids must also be provided, and 2% to 4% of daily caloric requirements should consist of linoleic acid (102). In addition to preventing a state of fatty acid deficiency, fat also provides extra calories and may provide a protein-sparing effect (130). Overfeeding, however, may be just as detrimental as underfeeding. Burn catabolism cannot be overcome by massive overfeeding. Infusion rates of 6000 kcal/day did not improve nitrogen balance, but instead led to hepatic steatosis (131) and increased carbon dioxide production (115,132). Disproportionate lipids may lead to hyperlipidemia, hypoxia, impaired immune function, and increase mortality (133).

In patients with large burns, enteral tube feeding is almost always necessary to achieve nutritional goods. Most patients, when left to their own dietary habits, do not consume adequate nutrients orally. Generally a high-calorie, high-protein diet should be administered in addition to the calculated tube requirement. Early enteral feeding has been determined to be safe (134) and has been shown to improve survival by preserving the intestinal mucosal barrier (130) and attenuating elevations of glucagon, cortisol, and catecholamines (128,135). Further, vitamin and mineral requirements must be provided in all nutritional programs. Glutamine and arginine supplementation has been associated with improved immune function, intestinal growth, and wound healing. Oxandrolone, an anabolic analog of testosterone has been found to improve the net balance of protein by improving muscle protein synthesis and lean mass in burned children. This may be related to changes in gene expression (136). Indiscriminate use of total parenteral nutrition in the face of a functioning gut is not justified as it is fraught with immune defense impairment (137) and increased infectious complications (138,139). Daily weight gain is the most effective single index for assessing the adequacy of nutritional support and must be continually monitored. Nitrogen balance studies generally are inaccurate when large open wounds exist, and indexes of immunologic status and visceral protein pool have not been shown to accurately predict specific nutritional deficiencies (102). Indirect calorimetry (metabolic cart) estimates energy expenditure and therefore nutritional requirements by analyzing inspired and expired gases and calculating the oxygen consumption and carbon dioxide production. However, this technique is expensive, difficult in nonintubated patients, and associated with the error of extrapolating a 20-minute study to 24 hours (130).

ORGAN SYSTEM ALTERATIONS Cardiovascular Responses The initial ‘‘ebb’’ phase following burn injury is likely caused by a combination of hypovolemia and myocardial depression

medwedi.ru

1094

Part Eight: The Integument and Body Wall

(140) and consists of a fall in cardiac output of 50% of normal or greater. This response occurs within minutes of injury, and there is a loss of myocardial contractility and altered ventricular compliance even prior to measurable decreases in plasma volume or after adequate fluid resuscitation (41,141,142). Suggested mediators of this cardiac dysfunction include a myocardial depressant factor (43), TNF (43), interleukins, ADH, oxygen free radicals (45–47), and nitric oxide (22). Myocardial depressant factor, although still not fully identified chemically, is produced by the pancreas during circulatory shock (143) and has negative effects on the cardiovascular, splanchnic, and reticuloendothelial systems (144). Most of these responses tend to normalize as plasma volume is restored through resuscitative efforts, although the cardiac output generally returns to normal and may actually exceed normal values before complete restoration of plasma volume is achieved. This resultant hyperdynamic circulatory response (or ‘‘flow’’ pattern) appears to complement the hypermetabolic response previously discussed, and both appear to reflect an effort of the body to heal the injured wound. During this phase, excessive catecholamine secretion may lead to cardiomyopathy, focal necrosis, and myocarditis (145,146). Studies using selective b-adrenergic blockade demonstrated a decrease in myocardial oxygen requirements while preventing the resulting changes in lipid kinetics (147). Further, Herndon et al. have shown in burned children that giving propranolol in sufficient dosage to decrease the heart rate by 20%, decreased the hypermetabolism and reversed the protein catabolism (148). Although postburn hypermetabolism cannot be completely reversed, the use of continuous low-dose insulin infusion, propranolol, and oxandrolone is cost effective and has low toxicity (149).

Renal Responses The burn patient is initially in a state of antidiuresis. In the presence of a hyperdynamic circulatory response, oliguria occurs as a result of increased and inappropriate ADH secretion. It has also been shown that glomerular vessels become constricted, prolonging transit time through the kidney and decreasing urinary output. Metabolism within the kidney appears to increase, as evidenced by a consistent uptake of glucose, whereas renal plasma flow remains essentially unaltered (150,151). Despite the glomerular vascular changes, renal complications are relatively uncommon in thermally injured patients because of the improved knowledge of resuscitation since 1980. The initial renal lesion following burn injury appears to be biphasic proteinuria. The initial phase includes a mild, transient albuminuria followed in four to seven days by a proteinuria with a relatively low albumin composition (152). Any relationship between the proteinuria and the subsequent development of renal failure remains unclear. When renal failure does ensue, it proceeds characteristically with polyuria in the face of a rising serum creatinine. Oliguric renal failure is quite rare. When it occurs, it develops early and appears to be related to inadequate resuscitation. In contrast, the more common polyuric renal failure generally arises in the second or third week following the burn injury and does not seem to be caused by hypovolemia. The findings of low urinary sodium and high urinary potassium indicate intact distal tubular function. These observations indicate that burn-related dysfunction in the glomerulus and proximal tubule presents the distal nephron with a solute load, producing a ‘‘downstream’’

diuresis (153). The cause of this form of renal failure remains unknown, and it is unique to the burn patient.

Endocrine Responses A complex endocrine response is elicited by thermal injury that probably is related to peripheral nervous system stimulation of the hypophysial-hypothalamic axis of the brain that then in turn intricately interacts with metabolic, immune, and other body systems (154). Pain, through the release of neuropeptides by sensory C fibers, may be a major stimulatory event for the hormonal response (20). Sustained, elevated levels of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland have been reported throughout the acute phase of thermal injury and only decrease to normal as the burn wound heals (155). If one uses measurements of plasma cortisol as an index of ACTH secretion, however, no consistent patterns have been noted in burn patients (156). The activity of the thyroid gland is decreased following injury, and thyroid-stimulating hormone is decreased relative to the availability of thyroid hormones (157). Thyroxine (T4) and triiodothyronine (T3) blood levels are generally low in burn injury, although a less pronounced decrease in T4 and a transitory increase in reverse T3 have been identified (156,158). However, there are no data to support thyroid supplementation. The ‘‘flow’’ phase is likely not thyroid dependent as thyroprivic experimental models also demonstrate a catabolic/hypermetabolic burn response (159–161). Growth hormone secretion is inconsistent in burn patients, but often is elevated following thermal injury. Recent work has been directed toward hormonal modulation in an attempt to improve wound healing. Exogenous growth hormone administration improves the healing time of donor sites in children and accelerates healing after extensive burns, (162,163) but may exacerbate hyperglycemia and insulin resistance (164). Studies by Rose and Herndon have reported that recombinant growth hormone, when administered to burned children in a dose of 2 mg/kg/day, improves skin graft donor site healing and shortens hospital stay by up to 33%. Its anabolic action is related to improving protein synthesis by increasing insulin-like growth factor I (IGF-I) levels (165). Other work with IGF-I supplementation in burn patients showed preservation of lean body mass and gut function without altering glucose metabolism (166). Follicle-stimulating hormone and luteinizing hormone secretion are depressed in burn patients, whereas prolactin secretion may be suppressed in children but elevated in adults (167). The significance of these observations remains unknown. ADH measurements reveal high levels in both blood and urine of adults and children during the first week after burn injury. ADH release is normally modulated by osmoreceptors of the supraventricular and supraoptic nuclei in the hypothalamus, volume receptors in the right atrium, and the carotid bodies. However, oversecretion is apparently independent of plasma and urine osmolality and volume but related closely to the severity of the thermal injury (168). Glucocorticoids, mineralocorticoids, and 17-ketosteroids are the major hormonal groups secreted by the adrenal cortex. Cortisol is high in burn patients with loss of the normal circadian rhythm, particularly in the first week following thermal injury. This elevation is believed to be essentially unrelated to ACTH hypersecretion but does relate closely to the size of the burn (60). Aldosterone is secreted in markedly increased amounts and produces sodium retention and

Chapter 58: Pathophysiology of Thermal Injury

increased potassium loss, which persists for many weeks in adults with major burns (168). The 17-ketosteroids are also elevated in burn patients as measured in the urine, but the significance of this finding is unknown. Epinephrine and norepinephrine synthesis, under hypothalamic control, are dramatically increased in thermal injury, as detected in serum and urine of burn patients, and are major mediators of the hypermetabolic response (169). Immunoreactive insulin is elevated following thermal injury, and this elevation persists until healing of the burn wound. Insulin hypersecretion is usually accompanied by elevated glucose in the blood, implying a relative insulin resistance (170). Plasma glucagon levels are also elevated and appear to play a key role in the hypermetabolic response (171). It is thought that glucagon released from alpha cells of the pancreas is more influential in producing postburn hyperglycemia than the so-called insulin resistance (172). A synergy exists between cortisol, glucagon, and catecholamines that contributes to the increases in glycolysis, gluconeogenesis, proteolysis, and lipolysis observed during the postburn hypermetabolism/catabolism (Fig. 8).

RESISTANCE TO INFECTION The causes of death have changed with the progression of burn management. In the 1940s to 1950s most patients died of burn shock. With more vigorous fluid resuscitation protocols, wound sepsis became the major killer in the 1960s to the 1970s. However, the development of burn centers, topical and systemic antibiotics, nutritional support, and earlier burn wound excision has considerably decreased the mortality caused by wound sepsis. Currently, pulmonary infection remains the most common cause of death in hospitalized burn patients. Resistance is impaired in these patients through disruption of the skin’s mechanical barrier and defects in the body’s immune system. Fauci (173) has conveniently classified the body’s defense capabilities into the categories of nonspecific immune system and specific immune system. Although many defects in the capacity to resist infection have been defined in thermally injured patients, direct relationships between burning and immunologic alterations are complex and unclear and have eluded successful therapeutic intervention. However, it is clear that postburn patients demonstrate generalized immunosuppression. Allografts in burn victims survive longer than expected (174). Both in vivo and in vitro measurements of immune function are abnormal; these include decreased delayed type of hypersensitivity responses (175), cytolytic responses (176), and mixed lymphocytic responses (177).

Disruption of the Mechanical Barrier Loss of the morphologic and physiologic integrity of the skin as a result of thermal injury allows access of microorganisms to deeper tissues and the systemic circulation. Not only is devitalized tissue a nutritious medium for the growth of bacteria, but thermally injured skin may also be a source of circulating substances or toxins that can contribute to multifaceted, systemic alterations, including impairment in the synthesis of secretory immunoglobulins, bone marrow depression, and myocardial depression (14,31,168,178). As discussed earlier, decreased meseneric blood flow also contributes to these systemic effects following burn injury through bacterial/endotoxin translocation into the portal circulation and/or priming of the cellular elements within the GALT.

1095

Impairment of the Nonspecific Immune System Phagocytic cell activity and accumulation are enhanced in response to tissue injury through an inflammatory reaction characterized by increased vascular permeability. This appears to be mediated by vasoactive amines, prostaglandins, C-reactive proteins, and other components of inflammation (179). In addition, the release of chemotactic substances from injured tissues or through the influence of gram-negative organisms enhances the attraction of phagocytes to invading microorganisms. Should bacteria not be contained at the site of invasion, the fixed macrophages, particularly in the regional lymph nodes, may prove effective in killing invading bacteria. Opsonins are antibodies that enhance the phagocytic process by rendering the microorganisms more susceptible to phagocytosis. Complement and fibronectin are characterized opsonins. Complement is a system of serum proteins that participates in inflammation and phagocytosis and in neutralizing viruses, enhancing leukocyte chemotaxis, and killing bacteria. Fibronectin is a glycoprotein existing in a soluble circulating form in the plasma and a relatively insoluble form in connective tissue. Fibronectin enhances macrophage phagocytosis and may prevent organ failure through inhibition of fibrin aggregation among other functions. Other undefined regional defense mechanisms also participate in protecting the host from hostile microorganisms. The presence of major thermal injury adversely affects this nonspecific inflammatory system. Both circulating and fixed phagocytic cells, with or without the help of opsonizing factors, are functionally impaired following a major burn. Not only is phagocytic activity decreased in burn injury, but bacteriocidal activity is also decreased, and chemotaxis is impaired through decreased complement activation (180,181).

Impairment of the Specific Immune System The specific immune system includes both humoral and cellular components and their respective products. The production of specific antibody requires a complex interaction of many cell types. Once an antigen is recognized, it is processed by macrophages and presented to thymicdependent lymphocytes (T-cells). T-cells proliferate and in turn activate bursal-dependent lymphocytes (B-cells) that ultimately produce a specific antibody to the antigen. Stimulated T-lymphocytes have other important functions such as antigen memory storage, direct cytotoxic effects, and production of mediators of immune reactivity regulating both the specific and nonspecific immune responses. Antibody formation is also influenced by a specific subset of T-cells known as T-helper cells and a second subset known as suppressor T-cells. Suppressor T-cells generally modulate responses, preventing uncontrolled immune reactions by inhibiting T-cell stimulation of antibody production. In patients with burns of more than 20% of their total body surface area, essentially all immune functions are affected. Overall, there is a decrease in total lymphyoctye populations, an impairment in the functional capacity of T-cells, and an activation of suppressor T-cells (182). This depresses T-cell—generated responses, including production of cytotoxic cells, B-cell activation, and recruitment of uncommitted lymphoid cells. Immunoglobulin (Ig) synthesis is also decreased, particularly IgG production, in contrast to IgM and IgA, which are little altered. Some investigators suggest that there exists an intracellular T-cell defect (182). Burn injury also interferes with

medwedi.ru

1096

Part Eight: The Integument and Body Wall

the signalling pathways responsible for T-cell activation and effector response generation (89). This has been associated with the release of hormones (glucocorticoids and catecholamines) (183) and the systemic release of PGE2 by activated macrophages. Although the precise mechanisms are unknown, PGE2 decreases IL-2 production and, hence, T-cell activation (184–186). Trials investigating IL-2 and indomethacin (a cyclooxygenase inhibitor) administration in burned mice have demonstrated an improved survival (187). Others have used polymixin B, which neutralized the effects of lipopolysaccharides and may decrease macrophage activation. Although they observed a reversal of the unfavorable T4/T8 ratio and a decrease in endotoxin concentration, there was no change in survival or outcome (188,189).

PULMONARY CONSEQUENCES OF THERMAL INJURY Pulmonary alterations as a result of thermal injury occur in response to direct pulmonary injury caused by the inhalation of the products of combustion and indirectly as a response to cutaneous burns alone.

Inhalation of the Products of Combustion Inhalation injury accounts for the vast majority of deaths in fires, and is responsible for the high mortality in patients who survive and are admitted to hospitals. The following classification has proven useful in categorizing the various disorders related to inhalation injury and is based on mechanisms of disease (190): 1. 2.

Carbon monoxide poisoning Smoke toxicity a. Direct injury caused by i. Hot gases ii. Super-heated particulate matter iii. Conversion of gases to acid and alkali b. Smoke poisoning caused by thermodegradation of i. Natural substances ii. Synthetic substances

Carbon Monoxide Poisoning Carbon monoxide is a clear, colorless, odorless gas produced by the incomplete combustion of organic fuels. Carbon monoxide has an affinity for hemoglobin that is approximately 250 times that of oxygen and shifts the oxyhemoglobin dissociation curve to the left. Thus the oxygen that remains bound to hemoglobin is not readily available to cells, resulting in a decreased tissue oxygen tension that is considerably lower than that seen with simple hypoxia alone (Fig. 9). The toxic effect of carbon monoxide may be the result of this hypoxia alone or its binding to hemecontaining proteins at the cellular level (191). Carbon monoxide impairs the cytochrome chain through competition with oxygen for cytochrome a3 and has been observed to have a direct toxic effect on mammalian lung tissue (192). Carbon monoxide also binds to cardiac and skeletal muscle, producing carboxymyoglobin that dissociates slower than carboxyhemoglobin. This circumstance may become apparent during initial treatment as a rebound type of response. Pure carbon monoxide poisoning produces no grossly detectable lung pathologic alteration, although, histologically, alveolar type II cellular organelles are physically altered (193).

Figure 9 Oxygen–hemoglobin dissociation curve. Note the shift to the left in the presence of carbon monoxide, indicating that oxygen is more tightly bound to the hemoglobin molecule. Abbreviation: PO2, partial pressure of oxygen.

The clinical symptoms of carbon monoxide poisoning range from dyspnea and headache at levels in excess of 10% to 20% to coma and death, when inspired air contains levels of 60%. Cherry red skin discoloration is usually not apparent because of facial burning, but a high index of suspicion based on the history of burning in an enclosed space, orofacial burns, and nasal hair singeing suggests the diagnosis. A laboratory carboxyhemoglobin determination confirms the diagnosis, and treatment consists of rapid evacuation from the toxic source and the administration of 100% oxygen, preferably by endotracheal tube, in symptomatic poisoning. The half-life of carboxyhemoglobin in room air is approximately 210 minutes, but during 100% oxygen administration it can be reduced to 40 to 60 minutes. Hyperbaric oxygen has been proposed as a treatment modality in severe poisoning on the basis of a rapid decrease in the half-life of carboxyhemoglobin and clinical evidence of improved neurologic recovery (194). However, the logistics of caring for patients with significant burns within the confines of oxygen chambers is difficult.

Smoke Toxicity Direct Injury Direct heat injury as a result of inhalation of hot gases is extremely rare below the vocal cords because of the efficiency of heat dissipatory reflexes (195). However, parenchymal injury to the epithelium in distal air passages may be observed by the inhalation of a superheated system that has 4000 times the heat capacity of air. Super-heated particulate matter and soot that is not filtered out in the proximal airways may also produce local thermal burns in the alveoli (196). Corrosive acids and alkalis resulting from the reaction of sulfur and nitrogen oxides adherent to soot particles with lung surface water also produce direct, local parenchymal injury (190). Smoke Poisoning The incomplete combustion of both natural and synthetic products in smoke produces noxious gases that are inhaled and elicit both local and systemic effects. The magnitude of injury is dependent on the type of noxious gas inhaled, its concentration and solubility, and the duration of exposure. Water-soluble chemicals such as ammonia, sulfur dioxide, chlorine, and hydrogen chloride tend to dissolve in the

Chapter 58: Pathophysiology of Thermal Injury

upper respiratory tract, whereas lipid-soluble gases such as the aldehydes, phosgene, and nitric oxide tend to reach more distal lung radicals (197). Cyanide, a product of the combustion of synthetic materials such as polyurethane, produces its effects through systemic absorption and direct cellular poisoning. The effect of inhaled toxic products includes direct epithelial destruction, mucosal edema, ciliary paralysis, and surfactant deficiency, the latter resulting from injury to type II alveolar epithelial cells (198,199). Cast formation occurs causing obstruction, which leads to atelectasis, air trapping, and an increased risk for barotrauma. Pulmonary alveolar macrophages secrete chemotoxins producing leukocyte sequestration, which in turn release proteolytic enzymes and oxygen free radicals that potentiate pulmonary injury from the microvascular side (193). Concurrently, there is an increase in exudation of protein-rich plasma that encourages bacterial overgrowth. Subsequent pathologic alterations depend on the severity and character of the inhalation and include a fulminant adult respiratory distress syndrome, pulmonary edema, bronchial pneumonia, and sepsis, all of which contribute to the high mortality rate observed in patients with inhalation injury. The diagnosis of smoke inhalation is based primarily on history, blood gas analysis, carboxyhemoglobin, and cyanide determinations, as well as on special procedures, including bronchoscopy, xenon clearance, and pulmonary function tests. Physical examination and chest X-ray films, although essential, may be misleading, particularly under acute conditions when a paucity of physical signs tend to be the rule in severe inhalation injury. Careful monitoring of patients suspected of sustaining smoke poisoning is essential. In less severe injuries, treatment consists of the use of humidified air, vigorous pulmonary toilet, and the judicious use of bronchodilators. The early use of aerosolized heparin and acetylcysteine has been useful in preventing mucous plugs and improves pulmonary function (200). Because heparin is ineffective in lysing mucous plugs that have already formed, aerosol administration of tissue plasminogen activator (TPA), which lyses fibrin clots, was studied by Enkhbaatar et al. The study showed, in sheep subjected to cotton smoke, that the administration of 2 mg of TPA improved the pulmonary abnormalities and could be clinically useful (201). Immediate intubation is warranted if signs of laryngeal edema are present (hoarseness or stridor). Rigid bronchoscopy may be required for pulmonary cast removal. Pressure-control ventilation (permissive hypercapnea) may be attempted when pulmonary failure progresses despite conventional volume ventilation. High-frequency jet ventilation may be beneficial by decreasing barotrauma and improving airway clearance through the maintenance of patent distal airways. High frequency oscillatory ventilation (HFOV) has been utilized in the neonatal intensive care unit for infants with respiratory distress syndrome for many years and has recently been used in adult burn patients with ARDS in an attempt to avoid ‘‘ventilator-induced lung injury’’ (202). Cartotto et al. reported a retrospective study of 25 patients with a 28% incidence of inhalation injury, who had severe oxygenation failure from ARDS following 4.8 days of conventional mechanical ventilation (CMV). After switching from CMV to HFOV, there were significant improvements in the PaO2/FiO2 ratio within one hour and in the oxygenation index within 24 hours. HFOV was used for an average of six days and was continued during 26 operations in 14

1097

patients (203). Nitric oxide inhalation has also shown some advantages. Invasive monitoring to include pulmonary wedge pressure and thermodilution cardiac output parameters is often essential, particularly when positive end-expiratory pressure is used. Corticosteroids and prophylactic antibiotics are ineffective (204).

Indirect Pulmonary Injury Pulmonary edema following pure cutaneous burning without inhalation injury relates to alterations in the pulmonary microvasculature. Hemodynamic alterations related to resuscitation, increased capillary permeability, and alterations in blood flow characteristics as a result of cutaneous thermal injury may contribute to indirect lung damage. Patients with major thermal injury and noninhalation pulmonary dysfunction have been shown to have consistently high concentrations of fragment D resulting from fibrinogen degradation. This phenomenon is associated with systemic complement depletion and platelet aggregation with release of platelet products that may cause increased translocation of water and protein from the pulmonary microcirculation contributing to the development of an ARDS picture (205). In addition, activated complement may stimulate leukocyte aggregation, resulting in trapping of these aggregates in the pulmonary microcirculation. These leukocytes may then produce toxic oxygen metabolites that may also contribute to the development of ARDS. Later, pulmonary alterations generally relate to the onset of sepsis and may also manifest themselves as ARDS or bronchial pneumonia. Trials involving the administration of aerosolized free radical scavengers (dimethyl sulfoxide and N-acetylcysteine) have decreased lung fluid accumulation (206). However, current therapies are primarily directed toward supportive intervention, and mortality from the pulmonary manifestations of burns remains high.

PHYSIOLOGIC CONSIDERATIONS IN MANAGING THE BURN PATIENT Fluid Resuscitation The pathophysiologic alterations caused by the fluid losses in acutely burned patients require volume replacement to preserve vital functions and to prevent hypovolemic shock. Fluid losses as a result of increased capillary permeability in injured and noninjured tissues are greatest in the first 24 hours following burning and diminish thereafter. Accompanying intravascular deficits also must be corrected but generally are less responsive to resuscitative efforts until the volume losses from ‘‘capillary leaking’’ are adequately controlled; 20% to 30% of infused crystalloid remains within the vascular system (207). The optimal approach to fluid resuscitation remains controversial in terms of both the volume of fluid to be administered and its composition. A wide variety of fluid replacement formulas have been proposed (208–212), each with its advocates, differing primarily from one another with respect to salt and colloid content. Virtually all formulas are based on patient weight and the extent of skin surface burned. Only burns reaching a depth of second degree or greater are considered in these calculations. The fluid formulas provide guidelines for the resuscitation of burn patients and are altered according to the response to treatment. The two most widely used formulas are the modified Brooke formula (2 mL/kg/% burn) and the Parkland Formula [(also called the Baxter formula) 4 mL/kg/% burn] (213).

medwedi.ru

1098

Part Eight: The Integument and Body Wall

The effectiveness of administered fluid in early burn resuscitation with regard to its colloidal or noncolloidal content remains unresolved. Advocates of colloid-containing fluids recognize their potential use in maintaining plasma oncotic pressure and intravascular volume. Those opposed to such solutions emphasize the increased capillary permeability in the first 24 hours after thermal injury that results in leakage of plasma protein, particularly albumin, into the interstitium. It is argued that adding exogenous protein (i.e., colloid) to the extravascular protein pool raises this interstitial oncotic pressure further, and thereby prevents restoration of an adequate circulating blood volume. Furthermore, controlled trials have demonstrated that colloid use has no effect on clinical outcome (214,215). There is general agreement, however, that the administration of colloid-containing fluids during the second 24 hours following the burn, and thereafter, is associated with intravascular colloid retention and thus decreased fluid requirements. In contrast to the colloid controversy, sodium ion administration appears to be essential to successful resuscitation. Balanced salt solutions are quite popular and effective, although the use of hypertonic saline solutions has been recommended (211). Hypertonic saline (sodium concentration ¼ 250 mmol/L) reduces volume requirements, may be useful in patients with limited cardiovascular reserve but requires careful monitoring (216), and is associated with increased renal failure and death (217). When employed, hypertonic saline is dependent on careful dosing interval and infusion rates (218). Burn resuscitation involves walking a physiologic tightrope: under-resuscitation risks low perfusion of the burn wound as well as the hepatic and splanchnic circulation, while over-resuscitation may lead to pulmonary edema, prolongation of mechanical ventilation, the need for escharotomies, and release of abdominal compartment syndrome. Holm et al. (219) used transpulmonary thermodilution (TTD) for hemodynamic monitoring to compare goal-directed therapy guided by invasive monitoring with standard care (Parkland/Baxter formula). Fluid infusion during the first 24 hours following burn was significantly different between the two groups. The Parkland patients received a mean of 16,232 mL Ringer’s lactate, which was very close to the estimated volume for the first 24 hours (15,988 mL). The TTD patients received a mean of 27,064 mL of Ringer’s lactate with an estimated mean Parkland volume in this group being 17,306 mL. The results showed no significant difference in preload or cardiac output parameters. Their findings also included that ‘‘the additional crystalloid fluid that was infused in the treatment group was lost from the intravascular space, and had no noticeable effect on the plasma volume.’’ The authors suggest that the manipulation of the capillary permeability is an area that ought to be investigated. Pruitt, in an editorial states that ‘‘adequate resuscitation has been succeeded by ‘fluid creep,’ (220) producing excessive resuscitation in the apparent belief that if some fluid is good, lots of fluid will be even better’’ (221). In order to accurately resuscitate the burn patient, there must be a careful estimate of the percent total body surface area that has sustained a second- or third-degree burn. The ‘‘rule of nines’’ (Figs. 10 and 11) divides the adult body surface into single or multiples of 9% (e.g., arm ¼ 9%, anterior trunk ¼ 18%, leg ¼ 18%, and head ¼ 9%). However, it must be modified for children in whom the head is proportionally a greater percentage and the legs are relatively smaller. The Lund and Browder chart is a more accurate

Figure 10 ‘‘Rule of nines’’ for adults. Rapid estimation of extent of burn injury can be accomplished by using the ‘‘rule of nines’’ as an approximation of body surface areas involved. Source: From Ref. 212.

way to estimate TBSA burned (222). The ‘‘surface area graphic evaluation’’ diagram is a computer-based method in which the computer mouse is used to trace the area burned on a template. The program will compute the TBSA burned, based upon the individual patient’s body weight and height, and the resuscitation volume required according to the Parkland formula. It is available on the Internet at http://www.sagediagram.com and there is a version for personal data assistants. Patients with second- and third-degree burns involving greater than 15% of their body surface area should receive parenteral fluids, and the effectiveness of resuscitation should be monitored precisely.

Figure 11 Modified ‘‘rule of nines’’ for ages 1 and 5 years. Adult proportions assumed at age 15. Source: From Ref. 212.

Chapter 58: Pathophysiology of Thermal Injury

An Approach to Resuscitation The replacement program that we use has proven to be convenient and successful over many years of application and is described here. In this program, fluid losses and daily maintenance requirements are related to the total body surface area and the surface area burned (in m2) as calculated from a standard height–weight nomogram. This approach has proven to be highly accurate and allows standardization of fluid therapy in managing both adults and children. During the first 24 hours following burning, fluid requirements are calculated as follows: 2000 mL=m2 of body surface=24 hr ðmaintenance requirementsÞ þ 5000 mL=m2 of body surface burned=24 hr ðfluid lossesÞ One half the calculated volume is infused in the first eight hours following burning, and the remainder in the subsequent 16 hours. Patients should also be given either H2 blockers or proton pump inhibitors to prevent the development of Curling’s ulcers. For such resuscitation, a single, standard solution for intravenous therapy is used with adaptation to the patient’s needs as necessary. This solution consists of: Lactated Ringer’s solution in 5% dextrose and water þ 12:5 g of salt-poor albumin per liter We have found such a solution to be ideal. This isotonic protein-containing fluid ensures the provision of lactate to combat any systemic acidosis and an adequate carbohydrate load to ensure protein sparing. Because of the hyperkalemia associated with tissue injury and increased aldosterone, addition of potassium to this solution during the first 48 hours after burning is inappropriate and may be detrimental. During the second 24 hours following burning, fluid requirements generally decrease and are calculated on the basis of the following formula: 1500 mL=m2 of body surface area=24 hr ðmaintenance requirementsÞ þ 4000 mL=m2 of body surface area burned=24 hr ðfluid lossesÞ Such requirements are administered in equal hourly aliquots during this 24-hour period. Oral alimentation is instituted as soon as possible in the form of elemental diets initially, and the intravenous fluid needs are decreased proportionately. In most cases, oral fluid administration completely replaces intravenous therapy at the end of 48 hours following burning, allowing the removal of the intravenous catheter. Daily fluid requirements after the initial 48 hours of fluid resuscitation generally remain the same as those for the second 24 hours; but as the burn wounds are covered and healing commences, requirements are generally diminished, and fluid therapy is revised accordingly. Initial oral alimentation is usually administered through a nasogastric feeding tube that is retained for several days thereafter to ensure adequate oral nutrition. Until the convalescent phase is well underway, H2 blockers or proton pump inhibitors should be continued to protect the stomach from the development of a Curling’s ulcer. Patients should be started on

1099

regular meals as soon as such alimentation can be adequately tolerated.

Monitoring Fluid Resuscitation The effectiveness of the resuscitation program must be constantly monitored and altered if deviations from the expected course are noted. Among the most useful physical signs to determine the adequacy of resuscitation are the general state of alertness of the patient and the stability of pulse and blood pressure, including peripheral perfusion characteristics. The urine output (by means of an indwelling urinary catheter) is the most readily obtained measure of effectiveness of resuscitation, and a urine volume of 30 to 50 mL/hr in the adult and 20 to 40 mL/m2 of total body surface area per hour in children are expected. A significantly higher urine output may indicate overhydration or other complications (e.g., polyuric renal failure and excessive glucose loading), because in the acutely burned patient an antidiuretic state caused by multiple factors, including ADH secretion, is present. Baseline laboratory studies should be obtained at the time of admission and repeated at 12 to 24 hours or more frequently as needed. Among the values to be obtained initially are a complete blood cell count; serum levels of sodium, potassium, chloride, and bicarbonate; a blood urea nitrogen and creatinine, urine protein, and serum protein electrophoresis; and arterial blood gases. An initial hemoconcentration is expected, regardless of the resuscitation program instituted; and therefore an elevated hematocrit and slight elevation of other parameters may be identified. Metabolic acidosis is particularly significant in children and may indicate inadequacy of resuscitation. A chest X-ray examination, electrocardiogram, and complete urinalysis are usually performed on admission and repeated only as indicated during the subsequent course. Invasive monitoring with Swan-Ganz catheters or central venous lines is not routinely performed except in elderly patients, patients with cardiovascular compromise, or patients with inhalation injury requiring mechanical ventilation. Inotropic agents may be required if cardiac output remains poor, despite adequate volume resuscitation. However, this is generally considered to be a poor prognostic sign. The timely administration of carefully monitored parenteral fluids to the acutely and extensively burned patient facilitating the body’s own compensatory physiologic alterations prevents early complications, minimizes physiologic disturbances, and provides a basis on which future care of the acutely burned patient depends.

Management of the Burn Wound After fluid resuscitation has been successfully ensured, attention is next directed to the burn wound itself. The wound is cleansed with a suitable antiseptic solution such as povidone-iodine (Betadine) and debrided of foreign matter, necrotic tissue, and any blebs or vesicles that may be present. Because hypothermia may be a problem during this debridement period, overhead radiant energy sources are usually used to minimize the loss of body heat. Because the burn wound is essentially an extensive area of coagulation necrosis with accompanying ischemia from the underlying thrombosis of the local microcirculation, this avascular dead tissue is an excellent bacterial culture medium that can rapidly become a source of bacterial growth and the development of sepsis from hematologic dissemination of microorganisms. For this reason, topical

medwedi.ru

1100

Part Eight: The Integument and Body Wall

antimicrobial agents are applied directly to the wound during the early period after the burn. In the historical development of burn management during the past several decades, a variety of agents have been developed for this purpose, each with its particular advantages and disadvantages. Presently four such agents are in use at burn centers across the United States as summarized in Table 4. Each of these agents, in varying degrees, satisfies the characteristics of an ideal topical agent, which include (i) antibacterial activity that is both broad spectrum in nature and nontoxic locally or on absorption, (ii) resistance to the development of strains of bacteria that would not be covered, (iii) adequate permeation and the maintenance of continuing activity in the burn eschar, (iv) absence of pain on application, and (v) absence of adverse effects on the behavior of the wound, including its healing properties. Silver, in various forms, has been used as an effective antiseptic dating back to 1000 BC (224–227). Silver nitrate solution has been used for decades, but is not without clinical problems and it tends to stain all that it touches. Other compounds of silver such as silver sulphadiazine, silver sulphadiazine chlorhexidine, silver sulphadiazine with cerium nitrate as well as products like Acticoat (Westaim Biomedical, Inc.) and Silverlon (Argentum Medical, L.L.C.) release silver into the wound in a controlled fashion. In an investigational setting, silver is toxic to fibroblasts, but when used clinically its toxic effects are modified in concentrations, which are bactericidal. Of the agents currently available, 1% silver sulfadiazine is the most popular among burn specialists and is our choice. This drug is essentially nontoxic, is easy to apply and soothing to the patient, and has a broad spectrum of antimicrobial activity and minimal problems with the development of resistant strains. Its only major disadvantage is its limited penetration through the eschar and its relative ineffectiveness when deep eschar colonization with microorganisms has already occurred. When the latter circumstance exists, a gentamicin cream is usually substituted if the cultured organisms are sensitive. Mafenide (11.1%) also diffuses well through devascularized tissues but is unfortunately associated with metabolic acidosis because of carbonic anhydrase inhibition. Silver sulfadiazine is applied in a thin layer (usually 1 mm thick) two or three times daily, using a sterile glove or tongue depressor. Although some specialists leave the treated burn wound open to the air, we generally apply a thin layer of fine mesh gauze impregnated with the cream over the treated burn area and further retain it with a net-like dressing (212). This approach allows patients to move about freely and

guarantees contact of the cream with the burn wound at all times. At the present time, all first-degree and superficial second-degree burns are managed in this fashion, enabling spontaneous reepithelization to occur. For deep second-degree burns and all third-degree burns, ‘‘early’’ surgical excision is now considered the procedure of choice and is associated with a decreased mortality (228–230). Barret argued for early (within the first 24 hours of injury) excision of the burn wound and coverage with autograft or homograft. The early excision group was compared with patients who were initially treated at another institution and transferred to their hospital and underwent excision and grafting at day 6 post injury. The early excision group had lower bacterial counts and greater skin graft take (231). Although the authors make a valid point that the longer the burn eschar remains in place, the greater the bacterial colonization and lower the graft take, they did not answer the question whether excision during the first 24 hours is superior to excision at 48 to 72 hours in patients initially treated in the same institution. A laboratory study by Chen et al. in rats showed that the early excision group (at 30 minutes after the injury followed with immediate allogenic skin graft) did not show significant changes in the nitric oxide and endothelin-1 levels in plasma (232). For deep partial-thickness burn wounds, a technique called tangential excision is used. This technique involves the excision of the necrotic surface of a burn by removing shavings of eschar until a pattern of pinpoint deep dermal bleeding is reached and then immediately autografting the excised surface. The rationale underlying this approach is that the removal of the zone of coagulation protects the viable elements in the zone of stasis and thereby exposes a surface that readily accepts an autograft. One of the limiting factors in the amount of body surface area burn that can be excised during a single operative procedure is the amount of blood loss. Historically, 20% of the TBSA could be excised at one time. With the advent of the subeschar infiltration of epinephrine containing solution, the 20% limit may be increased. Multiple studies have demonstrated the safety and efficacy of this technique, some reporting almost a 70% reduction in blood loss per unit area excised without causing cardiac arrhythmias or anesthetic problems (233) Of additional interest, fibrin sealant derived from human plasma has been found to accelerate hemostasis on spilt-thickness donor sites in a multicenter prospective, open label, Phase III, randomized, comparative clinical trial. There were no adverse events reported with the use of fibrin sealant (234).

Table 4 Topical Antimicrobial Agents Characteristics Type of preparation Method of wound care Allergic reactions Pain on application Amount absorbed Associated complications

Fungal overgrowth Bacterial resistance Cost Source: From Ref. 223.

Silver nitrate (0.5%) Aqueous solution Closed None None None Significant losses of sodium and potassium into wet dressings, methemoglobinemia – Bacteriostatic Inexpensive

Mafenide Cream Open or closed 10% Severe 5% Acidosis, hyperventilation caused by renal carbonic anhydase inhibition Often Rare Moderate

Silver sulfadiazine

Organic iodine

Cream Open or closed 10% None 1% None

Foam Open or closed 5% Moderate Variable None

Often Rare Moderate

Often Occasional Moderate

Chapter 58: Pathophysiology of Thermal Injury

For full-thickness burns, excision is carried down to the level of the fascia, and an autograft is then placed on the exposed base. These aggressive surgical approaches to burn management have demonstrated several advantages to the more traditional methods of debridement using various proteolytic enzymes, the most popular of which has been sutilains (Travase). Such advantages have included improved function of extremities (particularly hands), a better cosmetic result, a definite decrease in the incidence of hypertrophic scarring after the burn, and a considerable reduction in hospitalization time. In the event that a patient may have extensive body burns limiting the amount of nonburn areas that can be used for the acquisition of skin grafts, temporary coverage of the surgically debrided burn may be obtained with various biologic dressings, including amnion or porcine xenografts. Another innovative approach has been the use of artificial skin. Several types of synthetic skin have been evaluated investigationally. Of these, the bilaminate membrane appears to be the most useful (235). This substance (called Integra1 Dermal Regeneration Template; Ethicon-Endo-Surgery, Inc., Cincinnati, OH, U.S.A.) consists of reconstituted collagen with a silicon synthetic epidermis. Application of Integra1 to the debrided burn surface results in vascularization of the collagen layer with the production of an underlying neodermis. When donor sites become available, the silicon synthetic epidermis is stripped from the underlying collagen, and an autograft is placed on the neodermis. In order to study the safety and effectiveness of Integra1, a multi-institutional study was undertaken involving 216 burn injury patients who were treated at 13 burn care facilities in the United States. The mean take rate of Integra1 was 76.2%, while the incidence of invasive infection was 3.1% and that of superficial infection 13.2% (236). Cultured epidermal cells from a 2 cm2 skin harvest have also been investigated as another option for skin coverage in the hope that these cells might produce growth factors that would enhance the healing process. The use of cultured epithelial autografts (CEA) for life-threatening burns has been in the clinical armamentarium since 1981 (237). Skin biopsies from the unburned skin are grown in tissue culture into thin sheets. The autografts are ready for placement on the burn wound within two to three weeks. While obviating the need for donor sites, CEAs have potential downsides; they are fragile and must be handled very carefully under aseptic conditions. The initial take is often 80% to 90%, with a decrease in subsequent coverage due to the susceptibility to form bullae from shear forces, even months after application. The successfully engrafted CEA will provide a mechanical barrier, but often is fragile and more susceptible to trauma than ordinary meshed split-thickness skin grafts (238). Further, this therapy is very expensive, with estimates of the cost of sheets of CEA ranging from $1000 to $13,000/% body surface area covered (239,240). A unique problem that occasionally develops with deep second-degree or third-degree circumferential burns, especially when involving the extremities or trunk, is the resulting tourniquet effect. This occurs because the elastic membrane of the dermis is destroyed with these types of burns and no longer allows the skin to stretch, which is necessary to accommodate the underlying edema formation. In the chest, such circumferential eschar formation may prevent normal respiration. If not corrected, the rapid development of respiratory acidosis may ensue. When this problem exists, incision through the eschar should be

1101

carried out and deepened into the subcutaneous fat to effect adequate release of the constricted tissue. This can be accomplished by making vertical anterior axillary line incisions that are curved medially to the level of the suprasternal notch. In addition, transverse incisions at the level the diaphragm effect further release of the constricted tissue. In the extremities, eschar constriction often results in decreased venous outflow from the affected part and in time jeopardizes the arterial inflow. Ischemia then results which may be manifest by decreased capillary refill of the nail beds, severe pain within the involved muscle compartment of the extremity, or the development of motor and/or sensory deficits. Often, elevation of the affected extremity may allay the need for escharotomy, but continuous monitoring of the peripheral pulse, usually with a ultrasound detector, must be assured. If this cannot be guaranteed, lateral longitudinal incisions through the burn eschar should be made to the level of the subcutaneous fat to release the pressure in the constricted muscle compartments. Both extremity escharotomies and those involving the chest can generally be performed without the assistance of anesthesia, because the burn wound is usually insensitive to painful stimuli.

SUMMARY The disruption of the physiologic equilibrium of the human organism by thermal injury varies with the extent and depth of the burn. The burn wound is characterized by a central irreversible zone of coagulation necrosis surrounded by reversible altered tissues that may be irreversibly compromised by progressive ischemia as a result of systemic factors such as hypoperfusion and local factors such as prostaglandin derivatives. Major fluid shifts caused by permeability alterations occur as a result of physical changes in the microcirculatory ultrastructure and local release of vasoactive substances. Such alterations disrupt normal Starling forces and potentiate fluid losses. Additional fluid extravasation in unburned tissues contributes to the hypovolemic state and may relate to increased capillary permeability and plasma oncotic pressure alterations. Thermal injury induces a state of marked hypermetabolism mediated by catecholamines and requires an intense nutritional replacement program to overcome the potentially deleterious consequences of malnutrition. The initial fall in cardiac output observed in burns (‘‘ebb’’ phase) is followed by an intense hyperdynamic circulatory response (‘‘flow’’ phase). A state of antidiuresis is induced, and the hormonal milieu of the body is dramatically altered in concert with the metabolic and immune alterations. Resistance to infection is severely compromised in thermally injured patients through alterations in both nonspecific and specific immune systems. Thermally altered tissue allows access of microorganisms and provides a medium for bacterial growth. Phagocytic activity is decreased along with bacteriocidal activity within the phagocytes. T-cell populations are decreased in peripheral blood, and suppressor T-cell activity is increased, whereas T-helper cell activity and other beneficial responses are depressed. Smoke inhalation is responsible for the majority of deaths in fires. Carbon monoxide poisoning is the most common mechanism of injury; if treated quickly enough with oxygen, a successful outcome can be realized. Smoke toxicity as a result of direct injury to the airways or smoke poisoning caused by inhalation of thermodegradation of

medwedi.ru

1102

Part Eight: The Integument and Body Wall

natural and synthetic substances is less well understood. Therapy has been primarily directed toward supportive care. Until the pathophysiology of this pulmonary injury is better understood, the prognosis for these patients will remain poor. Understanding the pathophysiologic events that occur in response to a burn has significantly improved care of the burned patient over the past several decades not only by decreasing morbidity but also by enhancing survival. Particularly germane in this regard has been the recognition of the need for aggressive fluid resuscitation in the first 24 hours following burning and the importance of controlling bacterial colonization of the burn wound with its potentially deleterious effects should infection and sepsis supervene.

REFERENCES 1. Montgomery BJ. Consensus for treatment of the sickest patients you’ll ever see. JAMA 1979; 241:345. 2. Pruitt BA Jr. The Scudder oration on trauma. Bull Am Coll Surg 1985; 70:2. 3. Demling RH. Burns. N Engl J Med 1985; 313:1389. 4. Lawrence JC, Bull JP. Thermal conditions which cause skin burns. J Inst Mech Eng 1976; 5:61. 5. Moritz AR, Henriques FC. Studies of thermal injury. II. The relative importance of time and surface temperature in the causation of cutaneous burns. Am J Pathol 1947; 23:695. 6. Moncrief JA. The body’s response to heat. In: Artz CP, et al., eds. Burns: A Team Approach. Philadelphia: WB Saunders, 1979. 7. Lepenye G, Novak J, Nemeth L. The biophysics of thermal injury. Acta Chir Plast 1978; 20:77. 8. Wilson CE, et al. Cold water treatment of burns. J Trauma 1963; 3:477. 9. deCamara DL, Raine T, Robson MC. Ultrastructural aspects of cooled thermal injury. J Trauma 1981; 21:911. 10. Raine TJ, et al. Cooling the burn wound to maintain microcirculation. J Trauma 1981; 21:394. 11. Boykin JV, Crute SL. Mechanisms of burn shock protection after severe scald injury by cold-water treatment. J Trauma 1982; 22:859. 12. deCamara DL, Heggers JP, Robson MC. Response of mast cell granules to thermal injury. Surg Forum 1981; 32:560. 13. Heggers JP, et al. Cooling and the prostaglandin effect in the thermal injury. J Burn Care Rehabil 1982; 3:350. 14. Arturson G, Mellander S. Acute changes in capillary filtration and diffusion in experimental burn injury. Acta Physiol Scand 1964; 62:457. 15. Heggers JP, et al. Evaluation of burn blister fluid. Plast Reconstr Surg 1980; 65:798. 16. Nanto V, Viljanto J. Observations on the chemical composition of the blister fluid of burned patients. Acta Chir Scand 1962; 124:19. 17. Shakespeare PG, Levick PL, Vaitheespara RB. Proteins in blister fluid. Burns 1978; 4:254. 18. Foex BA. The cytokine response to critical illness. J Accid Emerg Med 1996; 13:154. 19. Youn Y, LaLonde C, Demling R. The role of mediators in the response to thermal injury. World J Surg 1992; 16:30. 20. Gibran NS, Heimbach DM. Mediators in thermal injury. Semin Nephrol 1993; 13:344. 21. Trang LE. Prostaglandins and inflammation. Semin Arthritis Rheum 1980; 9:153. 22. Szabo C, Thiemermann C. Invited opinion: role of nitric oxide in hemorrhagic, traumatic, and anaphylactic shock and thermal injury. Shock 1994; 2:145. 23. Bernard C, et al. Elevated temperature accelerates the induction of nitric oxide synthesis in rat macrophages. Eur J Pharmacol 1994; 270:115.

24. Demling RH, Kramer GC, Harm B. Role of thermal injury– induced hypoproteinemia on edema formation in burned and, nonburned tissue. Surgery 1984; 95:136. 25. Arturson G. Pathophysiology of the burn wound. Ann Chir Gynecol 1980; 69:178. 26. Sasaki J, Cottam G, Baxter C. Lipid peroxidation following thermal injury. J Burn Care Rehabil 1987; 4:251. 27. Robson MC, et al. Increasing dermal perfusion after burning by decreasing thromboxane production. J Trauma 1980; 20:722. 28. Anggard E, Jonsson CE. Efflux of prostaglandins in lymph from scaled issue. Acta Physiol Scand 1971; 81:440. 29. Harms BA, et al. Prostaglandin release and altered microvascular integrity after burn injury. J Surg Res 1981; 31:274. 30. Aulick LH, Wilmore DW. Leg amino acid turnover in burn patients. Fed Proc 1978; 37:536. 31. Asko-Seljavaara S, Sundell B, Rytomaa T. The effect of early excison on bone-marrow cell growth in burned mice. Burns 1976; 2–3:140. 32. Arturson G. Anti-inflammatory drugs and burn edema formation. In: May R, Dogo G, eds. Care of the Burn Wound. Basel: Karger, 1981. 33. Herndon DN, Abston S, Stein MD. Increased thromboxane B2 levels in the plasma of burned and septic burned patients. Surg Gynecol Obstet 1984; 159:210. 34. Lewis R, Austen F, Soberman R. Leukotrienes and other products of the 5-lipoxygenase pathway. N Engl J Med 1990; 323:645. 35. Lepoivre M, et al. Alterations of ribonucleotide reductase activity following induction of the nitrite-generating pathway in adenocarcinoma cells. J Biol Chem 1990; 265:141. 36. Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 1991; 3:65. 37. Biffil WL, et al. lnterleukin-6 in the injured patient: marker of injury or mediator of inflammation. Ann Surg 1996; 224:647. 38. Jackson DM. The diagnosis of the depth of burning. Br J Surg 1953; 40:588. 39. Branemark PI, et al. Microvascular pathophysiology of burned tissue. Ann N Y Acad Sci 1968; 150:474. 40. Zawacki BE. Reversal of capillary stasis and prevention of necrosis in burns. Ann Surg 1974; 180:98. 41. Horton JW, White J, Baxter CR. The role of oxygen-derived free radicals in burn-induced myocardial contractile depression. J Burn Care Rehabil 1988; 9:589. 42. Dobson EL, Warner GF. Factors concerned in the early stages of thermal shock. Circ Res 1957; 5:69. 43. Raffa J, Trunkey DD. Myocardial depression in acute thermal injury. J Trauma 1978; 18:90. 44. Endo S, et al. Plasma tumour necrosis factor-alpha (TNF) levels in patients with burns. Burns 1993; 19:124. 45. Gong KS, Wang CH, Zhu HN. Effect of peripheral injection of arginine vasopressin and its receptor antagonist on burn shock in the rat. Neuropeptides 1990; 17:17. 46. Liu XS, et al. Clinical significance of the change of blood monocytic interleukin-1 production in vitro in severely burned patients. Burns 1994; 20:302. 47. Till GO, et al. Oxygen radical dependent lung damage following thermal injury of rat skin. J Trauma 1983; 23:269. 48. Clayton JM, et al. Sequential circulatory changes in the circumferentially burned limb. Ann Surg 1977; 185:391. 49. Boykin JV, Eriksson E, Pittman RN. Microcirculation of a scald burn: an ‘‘in vivo’’ experimental study of the hairless mouse ear. Burns 1981; 7:335. 50. Robson MC, et al. The effect of heparin on dermal ischemia after burning. Burns 1979; 5:620. 51. Nozaki M, et al. Permeability of blood vessels after thermal injury. Burns 1980; 6:213. 52. Miller TA, White WL. Healing of second degree burns. Comparison of effects of early application of homografts and coverage with tape. Plast Reconstr Surg 1972; 49:552. 53. DelBeccaro EJ, et al. The use of specific thromboxane inhibitors to preserve the dermal microcirculation after burning. Surgery 1980; 87:137.

Chapter 58: Pathophysiology of Thermal Injury 54. Huang YS, Li A, Yang ZC. Roles of thromboxane and its inhibitor anisodamine in burn shock. Burns 1990; 4:249. 55. Baxter CR. Fluid volume and electrolyte changes in the early post-burn period. Clin Plast Surg 1974; 1:693. 56. Carney SA, Hall M, Ricketts CR. The adenosine triphosphate content and lactic acid production of guinea pig skin after mild heat damage. Br J Dermatol 1976; 94:291. 57. Hershey FB, et al. Effect of ATP on glucose metabolism of thermally injured skin in vitro. J Trauma 1971; 11:931. 58. Allgower M, Schoenenberger GA, Sparkes BG. Burning the largest immune organ. Burns 1995; 21:S7. 59. Loebl EC, et al. The mechanism of erythrocyte destruction in the early post burn period. Ann Surg 1973; 178:681. 60. Loebl EC, et al. Erythrocyte survival following thermal injury. J Surg Res 1974; 16:96. 61. Dobke MK, et al. Oxidative activity of polymorphonuclear leukocytes after thermal injury. Eur Surg Res 1982; 14:107. 62. Schoenenberger GA, et al. Experimental evidence for a significant impairment of host defense for gram-negative organisms by a specific cutaneous toxin produced by severe burn injuries. Surg Gynecol Obstet 1975; 141:555. 63. Sparkes BG, et al. Plasma levels of cutaneous burn toxin and lipid peroxides in thermal injury. Burns 1990; 16:118. 64. Schoenenberger GA, et al. Isolation and characterization of a cutaneous lipoprotein with lethal effects produced by thermal energy in mouse skin. Biochem Biophys Res Commun 1971; 42:975. 65. Demling RH, et al. The study of burn wound edema using dichromatic absorptionmetry. J Trauma 1978; 18:124. 66. Cotran RS, Majno G. The delayed and prolonged vascular leakage in inflammation. I. Topography of the leaking vessels after thermal injury. Am J Pathol 1964; 45:261. 67. Arturson G. Microvascular permeability to macromolecules in thermal injury. Acta Physiol Scand 1979; 463(suppl):111. 68. Arturson G, Jonsson CE. Transcapillary transport after thermal injury. Scand J Plast Reconstr Surg 1979; 13:29. 69. Carvajal HF. A physiologic approach to fluid therapy in severely burned children. Surg Gynecol Obstet 1980; 150:379. 70. Arturson G. The plasma kinins in thermal injury. Scand J Clin Lab Invest 1969; 24(suppl):153. 71. Baxter CR, et al. Excretion of serotinin metabolites following thermal injury. Surg Forum 1963; 14:61. 72. Hayashi H, et al. Endogenous permeability factors and their inhibitors affecting vascular permeability in cutaneous Arthurs reactions and thermal injury. Br J Exp Pathol 1964; 45:419. 73. Horakova Z, Beaven MA. Time course of histamine release and edema formation in the rat paw after thermal injury. Eur J Pharmacol 1974; 27:305. 74. Brimblecombe RW, et al. Histamine H2 receptor antagonists and thermal injury in rats. Burns 1976; 3:8. 75. Yoshioka T, et al. Cimetidine inhibits burn edema formation. Am J Surg 1978; 136:681. 76. Burge PD, Gilbert SJ. Effect of a histamine H2 receptor antagonist on the swelling of the burned hand. Burns 1979; 6:30. 77. Watson WC, Kutty PK, Colcleugh RG. Does cimetidine causiileus in the burned patient? Lancet 1977; 2:720. 78. Demling R, LaLonde C. Topical ibuprofen decreases early post burn edema. Surgery 1987; 102:857. 79. Horton JW. Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. Toxicology 2003; 189:75. 80. Demling RH, LaLonde C. Early post burn lipid peroxidation: effect of ibuprofen and allopurinol. Surgery 1990; 107:85. 81. Friedl H, et al. Mediator induced activation of xanthine oxidase in endothelial cells. FASEB J 1989; 3:2512. 82. Oldham K, et al. Activation of complement by hydroxyl radical thermal injury. Surgery 1988; 104:272. 83. Saez JC, et al. Superoxide radical involvement in the pathogenesis of burn shock. Circ Shock 1984; 12:229. 84. Tanaka H, et al. Hemodynamic effects of delayed initiation of antioxidant therapy (beginning two hours after burn) in extensive third-degree burns. J Burn Care Rehabil 1995; 16:610.

1103

85. Kingsley NW, Stein JM, Levenson SM. Measuring tissue pressure to assess the severity of burn induced ischemia. Plast Reconst Surg 1979; 63:404. 86. Cottam GL, Mitchell MD, Baxter CR. Measurement of 13,14dihydro-keto-prostaglandin F and 11-deoxy-13,14-dihydroketo-11,16-cyclo prostaglandin E2 in human plasma following therma, injury. J Burn Care Rehabil 1984; 5:324. 87. Ferguson M, Eriksson E, Robson MC. Effect of methylprednisolone on oedema formation after a major burn. Burns 1979; 5:293. 88. Demling RH, et al. Effect of nonprotein colloid on postburn: edema formation in soft tissues and lung. Surgery 1984; 95:593. 89. Sayeed MM. Alterations in cell signalling and related effector functions in T lymphocytes in burn/trauma/septic injuries. Shock 1996; 5:157. 90. Deitch EA, Rutan R, Waymack JP. Trauma, shock, and gut translocation. New Horiz 1996; 4:289. 91. Goris RJ, Boekhorst T, Nuytinck J. Multiple organ failure: generalized autodestructive inflammation. Arch Surg 1985; 120:1109. 92. Morris SE, Navaratman N, Herndon DN. A comparison of effects of thermal injury and smoke inhalation on bacterial translocation. J Trauma 1990; 30:639. 93. Myers S, et al. Elevated PGI and PGE in the rat ileum following mild hypotension. J Trauma 1988; 28:1202. 94. Hill J, et al. Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemiareperfusion in the rat. J Immunol 1992; 149:1723. 95. Fisher CJ, et al. Influence of an anti-tumour necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Crit Care Med 1993; 21:318. 96. Fisher CJ, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. JAMA 1994; 271:1836. 97. Van Saene HKF, Stoutenbeek CC, Stoller JK. Selective decontamination of the digestive tract in the intensive care unit: current status and future prospects. Crit Care Med 1992; 20:691. 98. Herndon DN, Ziegler ST. Bacterial translocation after thermal injury. Crit Care Med 1993; 21:S50. 99. Tokyay R, et al. Effects of thromboxane synthetase inhibition on postburn mesenteric vascular resistance and the rate of bacterial translocation in a chronic porcine model. Surg Gynecol Obstet 1992; 174:125. 100. Arturson G. The pathophysiology of severe thermal injury. J Burn Care Rehabil 1985; 6:129. 101. Wolfe RR, et al. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N Engl J Med 1987; 317:403. 102. Goodwin CW. Metabolism and nutrition. Crit Care Med 1985; 1:97. 103. Rose JK, Herndon DN. Advances in the treatment of burn patients. Burns 1997; 23(suppl 1):S19. 104. Wilmore DW, et al. Effect of ambient temperature on heat production and heat loss in burn patients. J Appl Physiol 1975; 38:593. 105. Caldwell FT. Energy metabolism following thermal burns. Arch Surg 1976; 111:181. 106. Wilmore DW, et al. Alterations in hypothalamic function following thermal injury. J Trauma 1975; 15:697. 107. Pruitt BA Jr. The burn patient. II. Later care and complications of thermal injury. Curr Probl Surg 1979; 16:1. 108. Wilmore DW, Aulick LH. Metabolic changes in burned patients. Surg Clin N Am 1978; 58:1173. 109. Deitch EA. The management of burns: current concepts. N Engl J Med 1990; 323:1249. 110. Bessey PQ, et al. Combined hormonal infusion stimulates the metabolic response to injury. Ann Surg 1984; 200:264. 111. Wilmore DW, et al. Catecholamines: Mediator of the hypermetabolic response to thermal injury. Ann Surg 1974; 180:653. 112. Hume DM, Egdahl RH. The importance of the brain in the endocrine response to injury. Ann Surg 1959; 150:697.

medwedi.ru

1104

Part Eight: The Integument and Body Wall

113. Woolf PD, et al. The adrenocortical response to brain injury: correlation with the severity of neurological dysfunction, effects of intoxication and patient outcome. Alcoholism 1990; 14:917. 114. Ziegler MG, Morrisey EC, Marshal LF. Catecholamine and thyroid hormones in traumatic injury. Crit Care Med 1990; 18:253. 115. Hart DW, Wolf SE, et al. Effects of early excision and aggressive enteral feeding on hypermetabolism, catabolism, and sepsis after serve burn. J Trauma 2003; 54(4):755. 116. Long CL. A response to trauma and infection: metabolic changes and immunologic consequences. J Burn Care Rehabil 1985; 6:188. 117. Moati F, et al. Biochemical and pharmacological properties of a cardiotoxic factor isolated from the blood serum of burned patients. J Pathol 1979; 127:147. 118. Muller MJ, Herndon DN. Hormonal interactions in burned patients. Semin Nephrol 1993; 13:391. 119. Bartlett RH, et al. Nutritional therapy based on positive caloric balance in burn patients. Arch Surg 1977; 112:974. 120. Wolfe RR, et al. Response of proteins and urea kinetics in burn patients to different levels of protein intake. Ann Surg 1983; 197:163. 121. Newsom TW, Mason AD Jr, Pruitt BA Jr. Weight loss following thermal injury. Ann Surg 1973; 178:215. 122. Freund H, et al. The role of the branched-chain amino acids in decreasing muscle catabolism in vivo. Surgery 1978; 83:611. 123. Blackburn GL, et al. Branched chain amino acid administration and metabolism during starvation, injury, and infection. Surgery 1979; 86:307. 124. Curreri PW, et al. Dietary requirements of patients with major burns. J Am Diet Assoc 1974; 65:415. 125. Wilmore DW. Carbohydrate metabolism in trauma. J Clin Endocrinol Metab 1976; 5:731. 126. Long JM III, et al. Effect of carbohydrate and fat intake on nitrogen excretion during total intravenous feeding. Ann Surg 1977; 185:417. 127. Mochizuki H, et al. Optimal lipid content for enteral diets following thermal injury. J Parenter Enteral Nutr 1984; 8:638. 128. Mochizuki H, et al. Mechanism of prevention of postburn hypermetabolism and catabolism by early enteral feeding. Ann Surg 1984; 200:297. 129. Alexander JW, McMillan B, Stinnett J. Beneficial effects of aggressive protein feeding in severely burned children. Ann Surg 1980; 192:505. 130. Deitch EA. Nutritional support of the burn patient. Crit Care Clin 1995; 11:735. 131. Lowry SF, Brennan MF. Abnormal liver function during parenteral nutrition: relation to infusion excess. J Surg Res 1979; 16:300. 132. Askanazi J, Rosenbaum SH, Hyman AI, Silverberg PA, MilicEmili J, Kinney JM. Respiratory changes induced by the large glucose loads of total parenteral nutrition. JAMA 1980; 243:1444. 133. Nghia MV, et al. Effects of postoperative carbohydrate overfeeding. Am Surg 1987; 53:632. 134. McDonald WS, Sharpe CW Jr, Deitch EA. Immediate enteral feeding in burn patients is safe and effective. Ann Surg 1991; 213:177. 135. Mochizuki H, et al. Reduction of postburn hypermetabolism by early enteral feedings. Curr Surg 1985; 42:121. 136. Wolf SE, Thomas SJ, Dasu MR, et al. Improved net protein balance, lean mass, and gene expression changes with oxandrolone treatment in the severely burned. Ann Surg 2003; 237(6):801; discussion 810–811. 137. Mainous MR, Block EF, Deitch EA. Nutritional support of the gut: how and why. New Horiz 1994; 2:193. 138. Detsky AS, et al. Perioperative parenteral nutrition: a metaanalysis. Ann Intern Med 1987; 107:195. 139. McGeer AD, Detsky AS, O’Rourke K. Parenteral nutrition in cancer patients undergoing chemotherapy: a meta-analysis. Nutrition 1990; 6:233.

140. Carleton SC, Tomassoni AJ, Alexander JK. The cardiovascular effects of environmental traumas. Cardiol Clin 1995; 13:257. 141. Baxter CR. Intracellular electrolyte exchange in early postburn period. Am Burn Assoc 1967; 12:40. 142. Horton JW, Baxter CR, White DJ. The effects of aging on the cardiac contractile response to unresuscitated thermal injury. J Burn Care Rehabil 1988; 9:40. 143. Lefer AM. Interaction between myocardial depressant factor and vasoactive mediators with ischemia and shock. Am J Physiol 1987; 252:R193. 144. Squandrito F, et al. Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury. Agents Actions 1993; 39:143. 145. Joshi W. Effects of burns on the heart. JAMA 1970; 211:2130. 146. Linares HA. A report of 115 consecutive autopsies in burned children, 1966–1980. Burns 1982; 8:263. 147. Maggi SP, et al. Beta-1 blockade decreases cardiac work without affecting protein breakdown or lipolysis in severely burned patients. Surg Forum 1993; 75:1081. 148. Herndon DN, Hart DW, Wolf SE, et al. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001; 345(17):1223. 149. Pereira C, Murphy K, Jeschke M, Herndon DN. Post burn muscle wasting and the effects of treatments. Int J Biochem Cell Biol 2005; 37(16):1948–1961. 150. Aulick LH, et al. Visceral blood flow following thermal injury. Ann Surg 1981; 193:112. 151. Wilmore DW, et al. Effect of injury and infection on visceral metabolism and circulation. Ann Surg 1980; 192:491. 152. Shakespeare PG, et al. Proteinuria after burn injury. Ann Clin Biochem 1981; 18:353. 153. Planas M, et al. Characterization of acute renal failure in the burned patient. Arch Intern Med 1982; 142:2087. 154. Dolovek R. The endocrine response after burns: Its possible correlations with the immunology of burns. J Burn Care Rehabil 1985; 6:281. 155. Popp MB, et al. Anterior pituitary functioning thermally injured male children and young adults. Surg Gynecol Obstet 1977; 145:517. 156. Vaughn GM, Mason AD Jr, Shirani KZ. Hormonal changes following burns: An overview with consideration of the pineal gland. J Burn Care Rehabil 1985; 6:275. 157. Vaughan GM, Pruitt BA Jr. Thyroid function in critical illness and burn injury. Semin Nephrol 1993; 13:359. 158. Becker RA, Wilmore DW, Goodwin CW. Free T4, free T3 and reverse T3 in critically ill, thermally injured patients. J Trauma 1980; 20:713. 159. Caldwell FT, et al. Metabolic response to thermal trauma of normal and thyroprivic rats at three environmental temperatures. Ann Surg 1959; 150:976. 160. Herndon DN. Mediators of metabolism. J Trauma 1981; 21:701. 161. Sellers EA, You SS, You RW. The influence of adrenal cortex and thyroid on the loss of nitrogen in urine after experimental burns. Endocrinology 1950; 47:148. 162. Gilpin DA, et al. Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994; 220:19. 163. Herndon DN, et al. Effects of recombinant human growth hormone on donor site healing in severely burned children. Ann Surg 1990; 212:424. 164. Daughaday WH. The anterior pituitary. In: Wilson JD, Foster DW, eds. William’s Textbook of Endocrinology. Philadelphia: WB Saunders, 1985. 165. Rose JK, Herndon DN. Advances in the treatment of burn patients. Burns 1997; 23(suppl 1):S19. 166. Cioffi WG, et al. Insulin-like growth factor-1 lowers protein oxidation in patients with thermal injury. Ann Surg 1994; 220:310.

Chapter 58: Pathophysiology of Thermal Injury 167. Moltei LB, et al. Prolactin, corticotropin, and gonadotropin concentrations following thermal injury in adults. J Trauma 1984; 24:1. 168. Davies JWL. Physiological Responses to Burning Injury. New York: Academic Press, 1982. 169. Wilmore DW. Nutrition and metabolism following thermal injury. Clin Plast Surg 1974; 1:603. 170. Wolfe RR. Glucose metabolism in burn injury: a review. J Burn Care Rehabil 1985; 6:408. 171. Vaughn GA, et al. Nonthyroidal control of metabolism after burn injury: possible role of glucagon. Metabol Clin Exper 1985; 34:637. 172. Bingham HG, et al. Burn diabetes: a review. J Burn Care Rehabil 1982; 33:179. 173. Fauci A. Host Defense Mechanisms Against Infection: Current Concepts/Scope Publication. Kalamazoo, MI: Upjohn, 1978. 174. Branch CD, Wilkins CF, Ross FP. The coagulum contact method of skin grafting in the treatment of burns and wounds. Surgery 1945; 19:460. 175. Pietsch LB, Meakins JL, Gotto D. Delayed hypersensitivity response: the effect of surgery. J Surg Res 1977; 22:228. 176. Markely K, Smallman ET. Effect of burn trauma in mice on the generation of cytotoxic lymphocytes. Proc Soc Exp Biol Med 1979; 160:468. 177. Ninneman JL. Suppression of lymphocyte response following thermal injury. In: Ninneman JL, ed. The Immune Consequences of Thermal Injury. Baltimore: Williams & Wilkins, 1981. 178. Schoenenberger GA. Burn toxins isolated from mouse and human skin: their characterization and immunotherapy effects. Monogr Allergy 1975; 9:72. 179. Daniels JC, et al. Serum protein profiles in thermal burns. II. Protease inhibitors, complement factors, and C-reactive protein. J Trauma 1972; 14:153. 180. Munster AM, Winchurch RA. Infection and immunology. Crit Care Clin 1985; 1:119. 181. Warden GD, Mason AD, Pruitt BA Jr. Evaluation of leukocyte chemotaxis in vitro in thermally injured patients. J Clin Invest 1974; 54:1001. 182. Munster AM. Alteration of the immune system in burns and implications for therapy. Eur J Pediatr Surg 1994; 4:231. 183. Berczi I. Neuroendocrine defense in endotoxin shock (a review). Acta Microbiol Hung 1993; 40:265. 184. Chouaib S, et al. Analysis of prostaglandin E2 effect on T lymphocyte activation: abrogation of prostaglandin E2 inhibitory effect by the tumor promotor 12.0 tetradecanoyl phorbol-13 acetate. J Clin Invest 1987; 80:333. 185. Chouaib S, et al. The mechanisms of inhibition of human IL2 production: PGE2 induction of suppressor T lymphocytes. J Immunol l984; 132:1851. 186. Goodwin JS, Bankhurst AD, Messner RP. Suppression of human T cell mitogenesis by prostaglandin: existence of a prostaglandin-producing suppressor cell. J Exp Med 1977; 146:1719. 187. Horgan PG, et al. Effect of low dose recombinant interleukin 2 plus indomethachin on mortality after sepsis in a murine burn model. Br J Surg 1990; 77:401. 188. Munster AM, et al. Reversal of postburn immunosuppression with low-dose polymixin B. J Trauma 1986; 26:995. 189. Munster AM, et al. Translocation: true pathology or phenomenology. Ann Surg 1993; 218:321. 190. Trunkey DD. Inhalation injury. Surg Clin N Am 1978; 58:1133. 191. Dolan MC. Carbon monoxide poisoning. CMAT 1985; 133:392. 192. Rhodes ML. The effect of carbon monoxide on mitochondrial enzymes in pulmonary tissue. Am Rev Respir Dis 1971; 103:906. 193. Herndon DN, Thompson PB, Traber DL. Pulmonary injury in burned patients. Crit Care Clin 1985; 1:79. 194. Myers RAM, et al. Value of hyperbaric oxygen in suspected carbon monoxide poisoning. JAMA 1981; 246:2478. 195. Moritz AR, Henriques FC Jr, McLean R. The effects of inhaled heat on lungs: an experimental investigation. Am J Pathol 1945; 21:311.

1105

196. Cox ME, et al. The Dellwood fire. Br Med J 1955; 1:942. 197. Crapo RO. Smoke inhalation injuries. JAMA 1981; 264:1694. 198. Beal DD, Lambeth JR, Conner GH. Follow-up studies on patients treated with steroids following pulmonary thermal and acrid smoke injury. Laryngoscope 1967; 78:396. 199. Pruitt BA Jr, Erickson MD, Morris A. Progressive pulmonary insufficiency and other pulmonary complications of thermal injury. J Trauma 1975; 15:369. 200. Cone JB. What’s new in general surgery: burns and metabolism. J Am Coll Surg 2005; 200(4):607. 201. Enkhbaatar P, Murakami K, Cox R. Aerosolized tissue plasminogen inhibitor improves pulmonary function in sheep with burn and smoke inhalation. Shock 2004; 22(1):70. 202. Dreyfuss D, Saumon G. Ventilator induced lung injury: lessons from experimental studies. Am J Respir Crit Med 1998; 157:294. 203. Cartotto S, Ellis M, Gomez A, et al. High frequency oscillatory ventilation in burn patients with the acute respiratory distress syndrome. Burns 2004; s30(5):453R. 204. Monafo WW. Initial management of burns. N Engl J Med 1996; 335:1581. 205. Curreri PW. Supportive therapy in burn care. J Trauma 1981; 21(suppl):724. 206. Nguyen TT, et al. Current treatments of severely burned patients. Ann Surg 1996; 223:14. 207. Sokawa J, et al. The relationship between experimental fluid therapy and wound edema in scald wounds. Ann Surg 1981; 193:237. 208. Baxter CR, Shires GT. Physiologic response to crystalloid resuscitation of severe burns. Ann N Y Acad Sci 1968; 150:874. 209. Cope O, Moore FD. The redistribution of body water in the fluid therapy of the burned patient [footnote]. Ann Surg 1947; 126:1013. 210. Evans EI, et al. Fluid and electrolyte requirements in severe burns. Ann Surg 1952; 135:804. 211. Monafo WW. The treatment of burn shock by the intravenous and oral administrations of hypertonic lacated saline solution. J Trauma 1970; 10:575. 212. Parks DH, Carvajal HF, Larson DL. Management of burns. Surg Clin N Am 1977; 57:875. 213. Cioffi WG. What’s new in burns and metabolism. J Am Coll Surgeons 2001; 192(2):241. 214. Goodwin CW, et al. Randomized trial of efficacy of crystalloid and colloid resuscitation on hemodynamic response and lung water following thermal injury. Ann Surg 1983; 197:520. 215. Hall KV, Sorensen B. The treatment of burn shock: results of a 5-year randomized, controlled clinical trial of Dextran 70 vs. Ringers lactate solution. Burns 1978; 5:107. 216. Gunn ML, et al. Prospective, randomized trial of hypertonic sodium lactate versus lactated Ringer’s solution for burn wound resuscitation. J Trauma 1989; 29:1261. 217. Huang PP, et al. Hypertonic sodium resuscitation is associated with renal failure and death. Ann Surg 1995; 221:543. 218. Pruitt BA. Does hypertonic burn resuscitation make a difference. Crit Care Med 2000; 28:277. 219. Holm M, Mayr J, Tegeler F. A clinical randomized study on the effects of invasive monitoring on burn shock resuscitation. Burns 2004; 30(8):798. 220. Engrav LH, Colescott PL, Kemalyan N, et al. A biopsy of the use of the Baxter formula to resuscitate burns or do we do it like Charlie did it? J Burn Care Rehabil 2000; 21:91. 221. Pruitt BA. Protection from excessive resuscitation: ‘‘Pushing the Pendulum Back’’ [Editorial]. J Trauma 2000; 49(3):567. 222. Lund CC, Browder WL. Healing of second-degree burns: comparison of effects of early application of homografts and coverage with tape. Plast Reconstr Surg 1972; 49:552. 223. Curreri PW. Burns. In: Polk HC, Stone HH, Gardner B, eds. Basic Surgery. Norwalk, CT: Appleton-Century-Crofts, 1987. 224. Russell AD, Hugo WB. Antimicrobial activity and action of silver. Prog Med Chem 1994; 31:351. 225. Klasen HJ. Historical review of the use of silver in the treatment of burns. Part I. Early uses. Burns 2000; 26:117.

medwedi.ru

1106

Part Eight: The Integument and Body Wall

226. Klasen HJ. A historical review of the use of silver in the treatment of burns. Part II. Renewed interest for silver. Burns 2000; 26:131. 227. Poon VK, Burd A. In vitro cytotoxicity of silver: implication for clinical wound care. Burns 2004; 30:140. 228. Burke JF, Bandoc CC, Quinby WC. Primary burn excision and immediate grafting: a method for shortening illness. J Trauma 1974; 14:389. 229. Desai MH, et al. Early burn wound excision significantly reduces blood loss. Ann Surg 1990; 211:753. 230. Herndon DN, et al. A comparison of conservative versus early excison: therapies in severely burned patients. Ann Surg 1989; 209:546. 231. Barret JP, Herndon DN. Effects of burn wound excision on bacterial colonization and invasion. Plast Reconstr Surg 2003; 111(2):744. 232. Chen X, Soejima K, Nozaki, et al. Effect of early wound excision on changes in plasma nitric oxide and endothelin-1 level after burn injury: an experimental study in rats. Burns 2004; 30(8):793. 233. Robertson RD, Bond P, Wallace B, et al. The tumescent technique to significantly reduce blood loss during burn surgery. Burns 2001; 27:835.

234. Nervi C, Gamelli RL, Greenhalgh DG, et al. A multicenter clinical trial to evaluate the topical hemostatic efficacy of fibrin sealant in burn patients. J Burn Care Rehabil 2001; 22(2):99. 235. Burke JF, et al. Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg 1981; 194:413. 236. Heimbach DM, Warden GD, Luterman A, et al. Multicenter postapproval clinical trial of Integra dermal regeneration template for burn treatment. J Burn Care Rehabil 2003; 24(1):42. 237. Atiyeh BS, Gunn SW, Hayek SN. State of the art in burn treatment. World J Surg 2005; 29:131. 238. Boyce S. Principles and practices for treatment of cutaneous wounds with cultured skin substitutes. Am J Surgery 2002; 183(4):445. 239. Rue LW, Cioffi WG, McManus WF et al. Wound closure and outcome in extensively burned patients treated with cultured autologous keratinocytes. J Trauma 1993; 34:662. 240. Munster AM, Weiner SH, Spence RJ. Cultured epidermis for coverage of burn wound: a single center experience. Am Surg 1990; 211:676.

PART NINE: Special Physiologic Considerations

59 Physiologic Problems in the Pediatric Surgical Patient Daniel J. Ostlie, Shawn D. St. Peter, Sheilendra S. Mehta, and George K. Gittes

INTRODUCTION The care of the pediatric surgical patient can be a daunting task, both technically and clinically. To paraphrase, as many others have, ‘‘children are not little adults.’’ Specifically, congenital anomalies, differences in nutritional requirements, thermoregulation and energy expenditure, and continued maturation of specific organ systems result in a continuum of constant changes in these patients. Additionally, the management of neonatal patients is immensely complex and, in most aspects, altogether different. Successful management requires a complete understanding of the normal physiologic and anatomic differences in relation to the pathophysiology, and leaves little room for error. Driven by these physiologic differences and the breadth of disease processes seen in this population, pediatric surgery has, over the last century, matured into a surgical subspecialty. The purpose of this chapter is to familiarize the general surgeon with the physiologic, thermoregulatory, biochemical, and nutritional changes that occur at birth and in the newborn period, through later stages of development. Understanding these principles will aid in the initial management of these patients. A brief diagnostic and management overview of several of the most common congenital and acquired neonatal and pediatric surgical diseases will also be discussed.

PHYSIOLOGIC CONSIDERATIONS Pediatric surgery encompasses the care of neonates, infants, children, and adolescents. The physiologic characteristics of these subpopulations vary, with the most significant differences existing in neonatal and infant patients. To better categorize neonates and infants, an understanding of the gestational age and birth weight is critical. Preterm infants are defined as those having a gestational age of less than 38 weeks, with an age-appropriate birth weight. Term infants have gestational ages between 38 and 42 weeks, and infants with more than 42 weeks gestation are considered post-term. The relationship between birth weight and gestational age describes the different subgroups of neonates and infants. Small for gestational age (SGA) infants weigh less than the 10th percentile expected for their gestational age and, conversely, large for gestational age infants weigh more than the 98th percentile for their gestational age. SGA babies usually result from intrauterine stress, regardless of cause. They have little reserve fat, higher metabolic rates, and reduced hepatic glycogen stores. Understandably, they are subsequently predisposed to hypothermia and hypoglycemia. Low birth weight and very low birth weight (VLBW) infants are premature and weigh less than expected. Stress related to surgical disease and

other perinatal events combined with the physiologic immaturity of the VLBW and micropremature (< 800 g) neonatal patients make these neonates particularly susceptible to minor changes that may have dramatic effects, requiring urgent identification and management to prevent catastrophic outcomes.

GLUCOSE, FLUID, AND ELECTROLYTE MANAGEMENT Fetal serum calcium, magnesium, and glucose levels are tightly controlled via placental filtration and absorption. Management of pediatric surgical patients requires an understanding of the changes in the levels of electrolytes and glucose, and the loss of body water, all of which occur after birth.

Hypoglycemia/Hyperglycemia The primary source of glucose in the immediate newborn period is hepatic glycogen stores. Typically, a healthy term infant will maintain a normal glucose level (> 40 mg/dL) for two to three hours prior to requiring exogenous glucose. There is little gluconeogenesis to provide additional glucose; therefore, the infant must receive nutrition via enteral or parenteral routes at this time. SGA, VLBW, and premature infants are particularly susceptible to neonatal hypoglycemia (< 40 mg/dL), and should be monitored carefully during the first 48 hours of life. Infants that require surgical intervention and are unable to utilize enteral feeds should receive 10% dextrose solutions and have ongoing glucose monitoring. Occasionally, an infant will have persistent or more significant hypoglycemia. In these instances, dextrose solutions of up to 50% may be used via central access only. Typically, hypoglycemia does not persist beyond two to three days. However, the addition of surgical or medically related stress can perpetuate the process. In this instance, frequent serum and urine monitoring with appropriate adjustment of the dextrose concentrations is required for optimal management. In the absence of total parenteral nutrition (TPN), severe prematurity, or sepsis, hyperglycemia is a rare event in the newborn period. However, when present, it can have significant deleterious effects. Electrolyte and fluid management becomes difficult due to water and electrolyte losses secondary to glucosuria, and intraventricular hemorrhage and retinopathy of prematurity are seen more frequently in infants with hyperglycemia (1). Management is based on reducing the dextrose concentration and, rarely, utilizing insulin to reduce the blood sugar.

Calcium Newborn, and particularly preterm, infants are susceptible to hypocalcemia during the first 24 to 48 hours of life. Late

medwedi.ru 1107

1108

Part Nine: Special Physiologic Considerations

in gestation, the fetus is exposed to high calcium levels due to the rapid transport of calcium across the placenta during the third trimester, for development and growth of the unborn infant. This high serum calcium concentration results in suppression of parathormone and relative hypoparathyroidism, predisposing to postnatal hypocalcemia. Parathormone levels reach normal by around 48 hours after birth, which explains why serum calcium concentrations usually begin to rise to normal at this time. Predisposition to hypocalcemia, which is defined as an ionized calcium level of less than 1 mg/dL, is seen in several subpopulations. Preterm infants, surgical patients, and infants of complicated pregnancies are at increased risk for developing hypoglycemia. Newborns requiring exchange transfusion or large transfusions of citrated blood are also at increased risk, along with those that receive bicarbonate. Because of similar clinical pictures, it is sometimes difficult to differentiate hypocalcemia from hypoglycemia. Symptomatic hypocalcemia presents with jitteriness, myocardial depression, seizures, and cyanosis. A distinctive hallmark of hypocalcemia, as opposed to hypoglycemia, is increased muscle tone. Treatment is based on calcium supplementation during the period of relative hypoparathyroidism. Ten percent calcium gluconate, dosed at 1 to 2 mL/kg over 10 minutes, is effective in most cases. When asymptomatic hypocalcemia occurs, the infants should be managed with supplemental calcium gluconate added to the maintenance fluids. The usual dose is 5 to 10 mL/kg/ day of the 10% solution.

Magnesium As with calcium, magnesium is actively transported across the placenta, and their metabolism is interrelated because of their similar molecular weight and electronic charge characteristics. Infants at risk for hypomagnesemia mirror those at risk for hypocalcemia. Symptoms of hypocalcemia that do not respond to treatment, particularly seizures, should immediately raise the concern of hypomagnesemia, and prompt a measurement of serum magnesium level. Effective treatment is 25 to 50 mg/kg of magnesium sulfate, repeated every six hours until normal serum magnesium levels are achieved.

Fluid and Electrolytes The relationship between total body water (TBW), intracellular body water (IBW), extracellular fluid (ECF), and percentage of body weight is classically depicted in Friis–Hansen’s graphic representation from gestation to 12 years of age (Fig. 1). At birth, the TBW of the newborn is 78%, and drops to 73–75% by day 5 of life. This decline continues during the ensuing 18 months, at which time the TBW reaches adult levels (60%). As seen in Figure 1, the decline of ECF levels follow the decline seen in TBW levels, while levels of IBW increase appropriately beginning at about five months gestation and reaching stable ratios at about 12 to 18 months. Infants born premature have higher percentages of TBW and ECF (Fig 1). This places the premature infant in a physiologic state that requires TBW offloading while simultaneously needing to transition fluid from the ECF to the IBW. The premature infant is adept at accomplishing this task, and is usually able to unload excess water by one week of age, even in the presence of significant fluid variations (2). Renal function is dependent on glomerular filtration rate (GFR) and the concentrating capacity of the nephron. In newborns, the GFR is significantly less than that seen in adolescents or adults, and the ability of the newborn nephron to

Figure 1 Friis–Hansen’s graphic representation of the relationship between total body, extracellular, and intracellular water to percentage of body weight from early gestation to adulthood. Abbreviations: TBW, total body water; IBW, intracellular body water; ECF, extracellular body water.

concentrate urine is about 50% of the adult (3). At term, the GFR is 21 mL/min/1.73 m2. The GFR triples to approximately 60 mL/min/1.73 m2 over the next two weeks and reaches normal adult rates (80 mL/min/1.73 m2), by two years of age. Due to a diminished response of the newborn tubule to antidiuretic hormone, the typical newborn is only able to maximally concentrate urine to 600 mOsm, about 50% of a normal adults’ concentrating capacity. Conversely, their ability to rid themselves of excess free water is superior to adults in that they can excrete urine of 30 to 50 mOsm/kg when needed. The maintenance of sodium and potassium is accomplished primarily in the distal tubule. While potassium excretion is rarely problematic, sodium excretion is significantly limited in term infants. The limitation is thought to be related to a defect in the distal tubule to limit resorption, because infants readily conserve sodium when needed. Consequently, term infants can easily become hypernatremic, especially when they receive exogenous sodium. For this reason, newborns are generally maintained on a onefourth normal saline (NS) intravenous (IV) unless other factors necessitate a different concentration. However, preterm infants are considered ‘‘salt wasters’’ due to their inappropriate sodium excretion, regardless of sodium intake. As such, normal daily sodium replacement is dependent on the gestational age and physiologic condition of the infant. Preterm and ill infants may require up to 5 mEq/ kg/day, while the healthy term infant will only need 2 mEq/kg/day of sodium. Actual replacement should be based upon laboratory measurements of serum and/or urine sodium as needed. Accurate assessment and management of fluid status in pediatric surgical patients is dependent on the amount of insensible fluid losses and the fluid requirements based on the physiologic and surgical stressors endured by the infant. Insensible losses comprise transepithelial water loss and respiratory losses, and total on average 12 mL/kg/day. If the infant is receiving humidified air, whether via endotracheal route or hood/cannula, their respiratory losses are essentially zero. However, if the patient is breathing

Chapter 59:

room air, the clinician can approximate respiratory losses to be 4 to 5 mL/kg/day. More importantly, the vast majority of insensible losses occur across the cutaneous epithelium, termed ‘‘transepithelial water loss.’’ The volume lost via the transepithelial route is inversely proportional to the gestational age of the infant. Premature infants have been noted to lose as much as 130 mL/kg/day; however, for term infants, the volume lost through the skin is only approximately 7 mL/kg/day. As with ventilation, losses through the transepithelial route can be virtually eliminated by placing the infant under an impervious hood with 100% humidity. In circumstances of severe prematurity, this technique is invaluable for the management of fluid therapy. With regard to optimal fluid requirements for infants, the volume needed is, again, entirely dependent on the physiologic state of the newborn. For fluid requirement considerations, surgical diseases in infants can be divided into three groups: moderate, severe, and sepsis/peritonitis. Infants with moderate surgical conditions (e.g., atresias, Hirschprung’s disease, imperforate anus, and colostomy) generally require approximately 80 mL/kg/day. Those with severe conditions (volvulus, abdominal wall defect, and exstrophy) require approximately 50% more volume (120 mL/kg/day), and those with severe sepsis or necrotizing enterocolitis (NEC) with perforation will require still more volume (140 mL/kg/day), due to the third space losses associated with the ongoing responses to illness. Optimal fluid management is often difficult to assess in these patients. Frequently, serial body weight is used as a guide to fluid management. One should caution against using body weight as the cornerstone of fluid assessment, however, because third space losses are inevitable and can mimic fluid overload, whereas, in reality, more fluid is required for tissue and organ perfusion. Measurement of urine output in combination with serial body weights is a much better guide for optimal fluid status and organ/tissue perfusion. Generally, a minimum of 2 mL/kg/hr urine output is required to ensure perfusion and solute excretion in most pediatric surgical patients. Urine concentration is also a helpful tool in this patient population. A goal for urine osmolality should be 250 to 290 mOsm/L, with a specific gravity of 1.010 to 1.103.

THERMOREGULATION Temperature regulation in pediatric surgical patients has implications beyond just the metabolic demands placed on the infant to maintain a level of normothermia. Hypothermia predisposes to coagulation abnormalities, inappropriate response to pharmacologic therapy, and cardiac instability. Newborn infants are predisposed to hypothermia primarily because of their large surface area in relation to body weight. The ability of the newborn to maintain a normal core body temperature is predicated on the utilization of brown fat catabolism, the supply of which is limited. Although infants can produce heat by shivering, it is ineffective and places the newborn under extreme metabolic demands, which cannot be sustained. Therefore, it is of paramount importance that the surgeon caring for these patients be aware of these limitations and prepared to provide thermoregulation when needed. Radiant heat loss (infant warmer than its surroundings) over their large surface area is the most important and significant heat loss mechanism, especially in VLBW and other preterm infants. This heat loss is drastically diminished via the use of automatic servo-controlled incubators

Physiologic Problems in the Pediatric Surgical Patient

1109

that adjust the ambient temperature to a range based on standard thermal nomograms for weight and gestational age. Radiant warmers are often utilized as the infant matures; however, the surgeon should remain cognizant of heat losses associated with convection (air currents over surface areas) and higher insensible water losses associated with these warmers. Heat regulation during transport to the operating suite and during surgical procedures can be difficult to manage. Surgical procedures are often required for correction of abnormal physiologic or anatomic conditions in these patients. Cold stress can be severe during these circumstances, and normothermia should be maintained via appropriate room temperatures, warming blankets, warmed irrigation fluids, and radiant warmers during the operation, if needed.

PULMONARY AND CARDIAC TRANSITIONAL PHYSIOLOGY The changes that occur within the circulatory and respiratory organ systems of the fetus during transition to extrauterine life are critical to normal physiologic function as a newborn. The fetal circulation is adapted to deliver oxygenated blood from the placenta to the systemic organs and tissues, avoiding the pulmonary circulation, because during this stage of development, no oxygenation occurs within the pulmonary capillary bed. Oxygenated blood from the placenta passes through the liver into the inferior vena cava, via the ductus venosus, and enters the right atrium where it mixes with deoxygenated blood from the superior vena cava. The pulmonary circulation is avoided via the foramen ovale and ductus arteriousus, which allow blood to be redirected from the right to the left atrium and from the pulmonary artery to the aorta, respectively (Fig. 2). During the fetal phase, this phenomenon is aided by elevated pulmonary artery pressures. During the transitional phase of newborn physiology, there is a dramatic and rapid decline in pulmonary artery pressure that results from expansion of the neonatal alveoli associated with the initiation of breathing by the infant. This drop in pulmonary artery pressure leads to lower the rightsided heart pressures and subsequent closure of the foramen ovale, eliminating the right-to-left shunt that had existed during the fetal phase, and thus directing blood through the pulmonary vascular bed. The ductus arteriosus spontaneously closes in normal newborns during the first 48 to 72 hours post delivery. The closure of the ductus arteriosus is the result of rapid increases in pO2, as well as the absence of prostaglandin E2 and I2. With regard to pulmonary physiology, the critical components include adequate alveolar expansion and efficient gas exchange. Alveolar expansion occurs with the initial inspiratory efforts of the newborn, which can be as high as 70 mmHg. However, expansion is ineffective if the alveoli are unable to remain open due to increased surface tension, the result of insufficient surfactant. Surfactant is a phospholipid produced by Type II pneumocytes, beginning at about 26 week’s gestation and continuing through delivery. Surfactant allows for lower effective alveolar distending pressures by decreasing surface tension, thereby requiring lower ventilatory pressure to inflate the alveoli and simultaneously decreasing the propensity for alveolar collapse between breaths. Inadequate surfactant results in the need for higher negative inspiratory force, and predisposes to neonatal respiratory support and hyaline membrane disease.

medwedi.ru

1110

Part Nine: Special Physiologic Considerations

Figure 2 Schematic depiction of fetal blood flow. Blood returns to the fetus from the placenta and is shunted through the liver to the suprahepatic inferior vena cava via the ductus venosus. Blood flow bypasses the pulmonary circulation via its redirection through the right atrium directly to the left atrium through the foramen ovale, and from the pulmonary artery to the descending aorta via the patent ductus arteriosus. Closure of these shunts occurs during fetal transitional physiology.

NUTRITIONAL SUPPORT The nutritional demands of the newborn are unique, and the addition of surgical stress requires special attention to the patient to ensure that appropriate energy sources are provided for normal growth and development while simultaneously ensuring recovery from the required operation. A full-term newborn should gain 25 to 30 g/day, or double his weight during the first four months of life (4). The growth patterns for a preterm infant are completely different than those for the term infant. Normally, the preterm infant would receive their nutritional needs via the placenta during the third trimester, the phase of rapid growth and significant caloric requirements, leading to adequate nutrient accumulation for postnatal life. Unfortunately, when an infant is born prematurely, they have not had the advantage of complete growth and development, and simultaneously lack the nutrient reserve normally expected of a term infant. Compared to the normal 10% body weight loss seen in term infants, the preterm infant can be expected to lose approximately 15% of their body weight during the first one to two weeks. After the initial weight loss, the preterm infant greater than 27 weeks gestation needs to gain about 35 g/day (5). The scope of this chapter is not sufficient to allow for a complete description of the nutritional requirements and/or

subtle changes that are necessary for surgical recovery. However, basic guidelines can be provided. Generally, a 1 kg infant has only a four-day reserve, while a full-term infant can survive about one month without nutritional support (6). The daily caloric requirements for pediatric surgical patients are dependent on their level of development and the surgical stress imposed upon them. The hypermetabolic state seen after illness and surgery must be compensated for in relation to the normal nutritional requirements for growth and development. Increased oxygen delivery is needed in these patients, and the cost of this delivery is an increased demand for energy to meet the oxygen demands. Consequently, demands for protein and carbohydrate energy are increased. However, excessive caloric resuscitation can lead to immunosuppression, and it is therefore critical to have a global understanding of the nutritional needs of these infants (7). The full-term infant will require approximately 100 to 120 kcal/kg/day, with 2 to 3.5 g/kg/day of protein, for normal growth. A preterm infant needs more calorie (140–150 kcal/kg/day) and protein synthesis (3–4.5 g/kg/day) for ongoing growth and development. Providing nutrition via the enteral route is superior to that via the parenteral route. Frequently, especially in surgical patients, enteral feeding is not possible; however, even small amounts of enteral feeds are advantageous. Preservation of intestinal integrity is facilitated by enteral feeds, and that integrity assists in preserving the intestinal epithelial barrier, by helping to maintain absorptive processes and inhibiting the entry of potentially toxic luminal contents (8). Enteral feeds can eliminate the need for central venous access and the subsequent complications associated with insertion and management of central venous catheters. Additionally, septic complications develop more often in infants receiving parenteral nutrition than in those receiving enteral feeds (9,10). Optimal carbohydrate delivery is based upon maintaining normal serum glucose levels and preventing the complete utilization of glycogen stores. The primary site of glycogen storage in infants is the liver. Following a meal, circulating levels of glucose gradually fall over the ensuing four hours. After this time, the neonate must begin to utilize hepatic stores to prevent hypoglycemia. These stores can be sufficient for up to 12 hours in the full term infant, but may only last a few hours in the premature patient. Therefore, supplemental carbohydrates must be provided to the surgical patient that is unable to initiate enteral feeds shortly after operation. Also, sufficient carbohydrate delivery provides a protein-sparing substrate, as in its absence somatic protein breakdown occurs in an effort to produce more glucose. Generally, prevention of hypoglycemia due to inadequate reserve and synthetic capacity requires 6 to 8 mg/kg/min continuous infusion of a dextrose solution. This concentration can be increased when central access is available; however, one must remember the detrimental effects of hyperglycemia in relation to fluid loss as a result of exceeding the renal tubular glucose resorption capacity leading to an osmotic diuresis, especially in light of potential stressinduced insulin-resistance. The normal diet of newborns provides adequate quantities of fat to provide calories and essential fatty acids. In the presence of an ileus or other reasons preventing enteral nutrition, the nutritional needs supplied via fats must be provided through TPN. In general, fats should comprise 30% to 50% of all nonnitrogenous calories. Linoleic acid is essential in all newborns and children for the development of cell membranes and the central nervous system as well as the production of prostaglandins and thrombaxanes. Two to

Chapter 59:

four percent of all dietary energy should come from this essential amino acid. The daily fat requirements are usually provided through either 10% or 20% formulations. Twenty percent formulations appear superior in that they contain twice the triglyceride content of 10% lipids with similar phospholipid content, which have been shown to be associated with cholesterol and low-density lipoprotein accumulation (11).

SPECIFIC PEDIATRIC SURGICAL CONDITIONS Infantile Hypertrophic Pyloric Stenosis One of the most common surgical diagnoses encountered by the pediatric surgeon is idiopathic pyloric stenosis (IPS). It is the most common cause of gastric outlet obstruction in infants. Although it was first described in 1717, it was not accepted as a true clinical entity until Hirschprung reported two cases in 1888 (12). Prior to the development of an effective operation (Ramstedt in 1912) to relieve the obstruction created by the hypertrophied pylorus, the mortality rate for infants affected by IPS approached 100% (13). The etiology of IPS remains unknown. Current research focuses on biochemical and neurodevelopmental anomalies. Diminished or absent levels of nitric oxide, which is critical for intestinal relaxation, may be a contributing factor. Levels of nitric oxide synthase have been found to be abnormal in a subset of patients with IPS, however this abnormality is not always present, and no clearly causative abnormality has been identified (14,15). Regardless of mechanism, it is likely that IPS is predominantly an acquired disease, because studies have shown that the pylorus in infants that develop IPS are normal at birth (16,17). The traditional presentation of IPS is the development of nonbilious vomiting between 2 and 10 weeks of life, with a peak at about four weeks. The vomiting may initially be confused with gastroesophageal reflux (GER) or feeding/ formula intolerance, and it is not uncommon for the infant to have changed formulas several times prior to diagnosis. Eventually, the vomiting will become projectile in nature, which prompts the diagnosis of IPS. Historically, the diagnosis has been confirmed via physical exam, with the classic exam finding of a mobile firm mass in the right upper quadrant described as an ‘‘olive.’’ More recently, the diagnosis is usually made with ultrasound. Ultrasonic criteria for IPS are a pylorus channel length of greater than 16 mm with a pylorus muscle thickness of 4 mm or pyloric diameter of 14 mm (18). One should be cautioned regarding ultrasonic diagnosis of IPS in that it is entirely user-dependent, and experience is critical in ensuring the correct diagnosis. Critically important in infants with IPS is their preoperative management. Frequently these patients are significantly malnourished and dehydrated, and fluid resuscitation with electrolyte correction is of utmost importance prior to proceeding with the operation. Electrolyte abnormalities include elevated bicarbonate levels, hypochloremia, and hypokalemia resulting from contraction alkalosis. Benson defined three levels of severity of metabolic derangement based on serum carbon dioxide content (slight: < 25, moderate: 26–35, and severe: > 35 mEq/L) (19). Fluid resuscitation should begin with a 10 to 20 mL/ kg bolus of NS which can be repeated, if needed, depending on clinical and physical exam response (skin turgor, mucous membranes, and anterior fontanelle). Maintenance fluid therapy should consist of 0.45 NS at 1.5 times the normal calculated maintenance requirements until normal volume status and electrolyte composition is achieved. Potassium

Physiologic Problems in the Pediatric Surgical Patient

1111

replacement should be withheld until volume status is appropriate, usually defined as urine output of more than 1 mL/kg/hr. Serum electrolytes should be monitored every six hours to guide fluid and electrolyte replacement, with operative correction delayed until electrolyte and dehydration abnormalities have been corrected. The surgical management of IPS is predicated on the division of the pylorus muscle, which results in relief of the gastric obstruction. This pyloromyotomy can be performed in an open or laparoscopic fashion, and the results of both techniques are excellent. The pyloromyotomy is initiated just proximal to the duodenopyloric junction and carried well onto the antrum. The key to success in the performance of a complete myotomy is ‘‘breaking’’ the concentric musculature that is causing the obstruction. The transition to normal depth of circular muscle is usually apparent on the antral aspect; however, one must approach the duodenal aspect with caution, as the duodenal mucosa may evaginate into the pyloric muscle, predisposing to mucosal perforation during the pyloromyotomy. Acceptable perforation rates are approximately 1% to 4%, and if the complication does occur, the pyloromyotomy should be closed, and a second pyloromyotomy should be performed on the opposite aspect of the pylorus. An alternative approach here is to perform primary closure of the mucosal perforation with omental patch. Both approaches to mucosal perforation repair have reported similar results (20,21). There is significant institutional variation with regard to postoperative management. Our practice is to withhold feedings until the infant has recovered from their anesthetic. Oral feedings are usually begun at about two hours postoperatively. Gradual concentration advancement is used, utilizing the two-hour volume requirements. Pedialyte is initiated at twice the hourly volume requirements every two hours for two consecutive feedings. If the infant tolerates the pedialyte feeds, the concentration is advanced to half strength formula or breast milk at the same volume and feeding schedule. Again, if the feedings are tolerated for two consecutive feeds, the concentration is advanced to full strength and subsequently to ad lib volumes if two consecutive full-strength feeds are tolerated. Most children are discharged by 24 to 36 hours postoperatively.

Abdominal Wall Defects Prior to Robert Gross’ initial description of a staged closure for large abdominal wall defects in 1948 (22), survival of infants born with these congenital anomalies was rare, and literature reports of survivors primarily included small defects in otherwise healthy newborns. Developmental anomalies of the abdominal wall in newborns are classified as either omphalocele or gastroschisis defects, which can be differentiated quickly based on clinical findings (Table 1).

Gastroschisis Gastroschisis (Greek for ‘‘belly cleft’’) defects usually are found to the right of a normally located umbilical cord. The fascial defect is normally small (2–4 cm), which limits organ herniation to primarily intestine. The small defect also predisposes the herniated intestine to vascular compromise. There is no peritoneal sac to protect the herniated organs, so they are in direct contact with amniotic fluid, which leads to the development of an intense inflammatory process. For this reason, the intestine is edematous with an associated serositis and a thickened, foreshortened mesentery (Fig. 3). The extent of intestinal herniation varies and may

medwedi.ru

1112

Part Nine: Special Physiologic Considerations

Table 1 Clinical Characteristics of Gastroschisis and Omphalocele Clinical finding

Gastroschisis

Omphalocele

Location Fascial defect size Peritoneal sac Cord attachment Associated anomalies Intestinal atresia Bowel characteristics Bowel ischemia Herniated organs

To the right of umbilicus Small (usually < 5 cm) None To the left Rare Common Thick, edematous ‘‘peel’’ Occasionally Intestine, liver (rarely)

Intestinal malrotation

Present

Through the umbilicus Variable (up to 10 cm) Present (can rupture) Onto the sac Common Rare Normal Rare Intestine, liver (commonly) Present

include the small and large intestine as well as the stomach, and rarely the liver. Associated anomalies are uncommon in infants with gastroschisis. However, intestinal atresias are seen in approximately 10% of patients, and infants with gastroschisis are more often premature or SGA (23). Controversy exists regarding the etiology of gastroschisis. Most investigators agree that the defect is definitely a separate entity, rather than a ruptured omphalocele. The lack of associated anomalies (commonly seen in omphalocele) supports this concept. Generally, it is believed that the defect is the result of a vascular accident or a rupture of the amniotic membrane at the base of a hernia of the umbilical cord (24,25). Care of the newborn with gastroschisis must begin immediately after birth. These infants should all be cared for at an institution specializing in neonatal and pediatric care, and all require admission to the neonatal intensive care unit (NICU). Fluid and heat losses are substantial due to exposed intestine. Immediately after delivery, the herniated intestine should be placed into an impervious bag to limit these losses. Gastric decompression should be instituted to prevent intestinal dilation secondary to swallowed air. IV access is obtained and fluid replacement/resuscitation is begun. A 20 mL/kg of 5% dextrose in lactated ringers is given over the first hour, followed by 1.5 times maintenance volumes per hour, with fluid boluses as needed. These infants may require two to three times the normal maintenance

Figure 3 This photograph shows an infant with gastroschisis and the classic intestinal ‘‘peel’’ and edematous bowel with shortened mesentery. Also, the umbilical cord inserts superior and medial to the fascial defect.

fluid needs for their age, due to losses associated with the exposed intestine. Fluid management should be based on urine output and acid–base normalization. Occasionally, colloid replacement is utilized to improve retention of intravascular volume, due to the losses from the exposed surface of the intestine. Temperature regulation should be achieved with a radiant, warmer if necessary. Broadspectrum antibiotics should be used in all gastroschisis patients to decrease the risk of infection after peritoneal exposure to vaginal and environmental organisms. Operation should be performed as soon as the infant has been stabilized. Repair should focus on protecting the eviscerated intestine via a staged or primary closure. Primary closure is obtained in approximately 75% of patients. The technique for primary closure involves the reduction of the viscera and closure of the fascial defect, which may need to be enlarged slightly. The fascia is approximated in a single layer using permanent interrupted sutures. The subcutaneous tissues are approximated, followed by the skin, which is closed in a subcuticular fashion. The umbilicus should be reconstructed at the appropriate location using a purse string technique, with tacking of the skin to the fascia using the same suture (Fig. 4). Due to the lack of the intestine being present in the abdomen during development, there is often significant loss of abdominal domain. In these cases, primary closure may be impossible, or may lead to prohibitive intraabdominal pressures placing the abdominal viscera at ischemic risk. Staged closure utilizing a silo is best undertaken in these patients. The intestine is placed in the silo, which may be hand sewn or prefabricated, and the silo is hung from the radiant warmer to place the intestine in a dependent position (Fig. 5). Care should be taken to place the intestine into the silo without rotation of the mesentery, which would lead to vascular compromise. The silo is compressed sequentially over the ensuing three to seven days, with complete closure performed after the abdominal domain has been recovered. Prosthetic closures should be avoided, as they have been shown to have increased risk for sepsis (26). Prior to the development of central TPN, the survival of gastroschisis patients was dismal due to the prolonged

Figure 4 The skin closure after reduction and closure of a gastroschisis is shown. Occasionally, it is necessary to open the skin superiorly and inferiorly to allow for reduction of the herniated organs. The umbilicus is then reconstructed to allow for a more normal location and appearance.

Chapter 59:

Physiologic Problems in the Pediatric Surgical Patient

1113

Figure 5 The placement of a silo for gradual reduction of the herniated viscera is shown. (A) The silo has been hand sewn and secured to the fascia of the abdominal wall. (B) A prefabricated silo is secured to the fascia with the intestine visualized inside. In both cases, the silo is hung to allow for dependent pressure of the viscera. External pressure results in reduction over the ensuing three to seven days, at which time delayed primary closure can be accomplished.

adynamic ileus that developed from the chemical peritonitis and surgical closure. Inability to initiate enteral feeds for as much as 30 days or longer in some patients places these infants in a position of TPN dependence. TPN use is number one determinant for the significant improvement in survival over the last 30 years in infants with gastroschisis. Therefore, infants with gastroschisis should receive central venous access (Hickman catheter or peripherally inserted central catheter line), and initiate TPN after stabilization of their metabolic and surgical stressors. Although intestinal motility returns in all these infants, intestinal transit time is prolonged for up to six months following closure. Additionally, malabsorption is commonly seen and may prompt prolonged TPN use as an adjunct to enteral feeds, to ensure adequate caloric intake until normalization of the motility and absorptive process occurs (27). With advancement in neonatal care, TPN, and closure techniques, the current expected survival for infants born with gastroschisis approaches 95%. Most morbidity and/or mortality are related to sepsis, complications related to prolonged TPN, bowel obstruction, or closure complications (23).

researchers, in 1963 (29). He postulated that omphaloceles were the result of failure of body wall morphogenesis, specifically abnormal fusion of the cephalic, lateral, and caudal folds of the developing abdominal wall. Failure of these folds to close results in a central ‘‘classic’’ omphalocele, an epigastric omphalocele, or an omphalocele inferior to the umbilicus, respectively. An epigastric omphalocele is usually part of the pentology of Cantrell syndrome, which includes a cleft sternum, an anterior diaphragmatic defect, and absence of pericardium and intracardiac defects. Hypogastric defects are seen with exstrophy, cloacal, and imperforate anus defects. Regardless of location, the defect is covered with a peritoneal sac, and its development may be initiated by failure of the intestine to return to the abdomen after the period of growth it undergoes in the extracelomic position. Another, less accepted, theory to explain the omphalocele development is that of abnormal migration of body wall myotomes. The management of infants born with omphalocele is similar to that of newborns with gastroschisis with regard to the abdominal wall defect. However, in more than 50%

Omphalocele An omphalocele is a central defect of the umbilical cord. The cord itself arises from the peritoneal sac that surrounds the herniated organs of the omphalocele. The fascial defect can range from small umbilical cord hernias to large ‘‘giant’’ omphaloceles that may be more than 10 cm (Fig. 6). Herniated organs will include the large and small bowel, stomach, and frequently liver. As a result of the large defect and herniation of most of the abdominal viscera, the abdominal cavity is frequently small and underdeveloped in infants with omphalocele, especially giant omphaloceles. The management of these infants is technically and clinically challenging. In approximately 15% of cases, the sac of the omphalocele may rupture (28). If the rupture occurs early during the fetal development, the visceral contents will be exposed to the amniotic fluid and, as in gastroschisis, will be edematous with serositis and shortened mesentery. In this instance, the defect can be differentiated from a gastroschisis by the position of the cord and the remnant of the omphalocele sac. The embryologic consequences that result in the development of an omphalocele are not understood. Duhamel first described his theory, which is still believed by most

Figure 6 Two infants with omphalocele defects are shown. (A) A moderate-sized omphalocele with liver and intestine contained within the sac. Note the umbilical cord originating from the omphalocele sac. (B) A giant omphalocele that has been treated with an escharating agent to allow for epithelialization. The omphalocele was later closed in multiple operations, with sequential closure of the large ventral hernia defect.

medwedi.ru

1114

Part Nine: Special Physiologic Considerations

of cases, there will be an associated anomaly, and these anomalies will require individual attention. The most common associated anomalies are congenital heart defects followed by chromosomal trisomies (13–15,18,21), and Beckwith–Weidemann syndrome (macroglossia, hypoglycemia, and gigantism) (30). Genitourinary, musculoskeletal, neurologic, and gastrointestinal anomalies have also been reported in association with omphalocele. Similar to infants suffering from gastroschisis, these infants should be cared for in a facility equipped to manage the complex congenital anomalies that are frequently encountered. Although not as severe, water and heat loss are the initial physiologic concerns in these infants. By placing the omphalocele, or lower body if necessary, in a sterile impervious bag, these losses can be minimized. Initial fluid resuscitation is similar to that for gastroschisis. Broad-spectrum antibiotics and gastric decompression should be instituted immediately after birth. Once the resuscitation is accomplished, operation is delayed to allow the evaluation for other anomalies. Renal and spinal ultrasounds are obtained, along with a chest radiograph and an echocardiogram to evaluate for any congenital heart defects. Subspecialty consultation is requested for any abnormal findings, and chromosomal analysis with genetic consultation is obtained in most patients. Surgical closure of the defect is pursued after the evaluation is complete. When possible, primary closure is performed. The sac should be left intact if possible, to maintain a sterile intraperitoneal environment. The fascia of the abdominal wall is meticulously dissected from the sac, and subsequently closed using interrupted permanent sutures. Manual stretching of the abdominal wall is sometimes necessary to allow for reduction of the herniated viscera. Care should be taken with reduction of the liver, as in these infants the hepatic capsule is exceedingly thin and prone to rupture or tearing, which can lead to life-threatening hemorrhage. If the omphalocele cannot be closed primarily, the management is similar to that of gastroschisis. A silo is placed followed by sequential compression of the omphalocele in the NICU over the ensuing five to seven days to allow for rerecruitment of the abdominal domain. Definitive closure is subsequently performed when possible. Rarely, in cases of giant omphalocele, the fascia cannot be approximated due to the severe underdevelopment of the abdominal cavity, despite sequential compressions. In these instances, several nonoperative strategies have been used. Most commonly, epithelialization of the omphalocele sac is promoted with the use of an escharating agent such as silver nitrate or silver sulfadiazine, or with the placement of splitthickness skin grafts (Fig. 6). The resultant ventral hernia is closed at a later date, and, oftentimes, will require multiple operations over an extended period. Immediately following closure, the infant remains intubated and often paralyzed for 24 to 48 hours. A prolonged ileus should not be expected, as the intestine has not suffered the insult seen in gastroschisis. Enteral feeds can usually be started within seven days, and malabsorption or delayed transit is not common. Survival for infants with omphalocele is not as high as for gastroschisis, primarily due to morbidity and/ or mortality related to the associated anomalies.

Necrotizing Enterocolitis NEC is the most common gastrointestinal emergency in newborns affecting approximately 5% of neonates admitted to the NICU (31,32). It is a predominantly a disease of prematurity with less then 10% of cases occurring in term infants (32,33).

Pathogenesis NEC is multifactorial in origin. The most frequently implicated clinical variables contributing to the development of NEC include enteral feeds, ischemia, enteric microorganisms, and attenuated host defense systems (i.e., prematurity). Experimental studies in an animal model have shown that a combination of asphyxia, formula feeds, and bacteria results in a very high rate of NEC (34). In this model, asphyxia was clearly the most significant instigating factor with formula feeding less important. Enteral bacterial colonization was not a significant determinant. However, the relative impact of each of these variables has not been clinically defined for NEC in humans. Since the early descriptions of NEC, enteral feeding had been considered an important etiologic factor in the development of NEC, because 90% of cases occurred after the initiation of feeds (35,36). Initiation of feeds produces a spectrum of physiologic changes within the gastrointestinal tract including the introduction of organisms and increased oxygen demand of the gut (37,38). The type of flora and range of byproducts they produce, as well as the interactions of these variables with the gut mucosa will be affected by the type of substrate used for feeding. Breast milk significantly reduces the risk of NEC (39,40). Maternal milk contains a variety of immunomodulators, including degradative enzymes for some of the most important inflammatory communication molecules behind the propagation of disease in NEC (41,42). When maternal breast milk is not available, the use of human donor milk has also been shown to be associated with a significantly reduced relative risk of NEC (43). However, a superior rate and mode of milk feeding has not been clearly established (44). The role of ischemia in NEC development appears to be important, but not clearly defined. Necrotic lesions seen in NEC bowel specimens appear to be the result of ischemia; however, episodes of systemic hypoxia are not always present in neonates developing NEC, which implicates mechanisms of local ischemia or vasoconstriction. Mechanisms of local ischemia also remain to be delineated. Angiotensin-mediated pathways have been proposed as a theoretical participant in local vasoconstriction, and it is known that intestinal vasculature is rich in angiotensin receptors (45,46). In experimental models of shock, ischemic colitis secondary to mesenteric vasoconstriction has been shown to be irresponsive to adrenergic blockade but abolished by inhibition of angiotensin converting enzyme (47). Microorganisms are also felt to contribute to NEC. Bacterial endotoxin has been shown in experimental models to act through and/or with the release of inflammatory mediators to cause intestinal necrosis and a clinical syndrome similar to NEC (48,49). However, it is unlikely that microbes are causative, because there is little consistency in the bacterial strains cultured from the stool and blood of NEC patients. These cultures range widely including gram-positive, gram-negative bacteria, anaerobes, and even viruses with very few reported epidemic strains (50–53). Moreover, cultures from NEC patients are usually representative of the fecal flora within the NICU, and analysis of these trends has revealed no significant correlation between the disease and either age of the infant or intestinal site of disease (53,54). Therefore, bacteria in the gut of NEC infants become opportunistic participants in the disease process taking advantage of the premature gut injured by ischemia in the presence of substrate.

Chapter 59:

Gut immaturity, enteric substrate, ischemia, and microorganisms contribute to initiation of NEC. After initiation, elaboration of inflammatory mediators results in the activation of responses from polymorphonuclear neutrophils (PMNs). Activated PMNs release proteolytic enzymes, free radicals, and conduct local phagocytosis all causing direct tissue injury. In addition, they further propagate the release of inflammatory mediators, which increase vascular permeability, activate complement and leukocytes, and stimulate leukocyte migration leading to subsequent tissue injury (55–57). The activation of inflammatory mediators contributes to systemic effects similar to those seen with systemic inflammatory response syndrome. Inflammatory pathways promoting the pathologic findings of NEC continue to evolve, but two communication molecules in particular, tissue necrosis factor-alpha (TNF-a) and platelet-activating factor (PAF) have been shown in multiple animal studies to result in ischemic bowel necrosis similar to NEC (58–60). The release of TNF-a facilitates local injury and promotes distant organ dysfunction (61,62). PAF further increases TNF-a expression, and activates gene transcription through the nuclear factor-kB (NF-kB). NF-kB, is a ubiquitous transcription factor which accounts for the gene expression of cytokines, chemokines, growth factors, immunoreceptors and cell adhesion molecules (35,36,63–66). Specifically in the intestine, NF-kB activation causes an increase in mucosal permeability, endotoxemia and tissue necrosis (45). Clinically, the most significant risk factor of a newborn being stricken with NEC is the severity of prematurity (67–74). Its incidence is inversely related to gestational age, and the age-specific attack rate declines sharply after 35 weeks gestational age (69). Similarly, the incidence and severity of NEC are higher in neonates with smaller birth weight, and VLBW infants who develop NEC are more likely to require surgery (72,73,75–79). Congenital heart disease, particularly hypoplastic left heart syndrome and truncus arteriousus, with episodes of poor systemic perfusion of shock has also been shown to be significantly associated with NEC (80). Umbilical artery catheterization had previously been suggested as an etiologic agent of NEC (81); however, accumulating evidence does not support this notion (82). Polycythemia, exchange transfusions, maternal cocaine use, and enteral theophylline have all been implicated as risk factors, but confirmatory data has been conflicting (83–88). However, antenatal theophylline administered to high-risk mothers does appear to subsequently increase the risk of NEC in premature infants (89). It has been shown that newborns with general physiologic compromise, prolonged hypotension, persistent respiratory distress, septicemia, and hypothermia have been shown to significantly increase the incidence of NEC and have a higher risk of developing NEC (74,90–93).

Presentation Early systemic signs of NEC include mild temperature instability, apnea, bradycardia, and lethargy. Acidosis and thrombocytopenia appear as the disease worsens, followed ultimately by neutropenia, disseminated intravascular coagulation, sepsis syndrome, and cardiovascular collapse (Fig. 7). Ileus is the initial clinical finding, and usually presents as feeding intolerance, increased residual gastric volume, mild abdominal distension, and bilious emesis.

Physiologic Problems in the Pediatric Surgical Patient

1115

Gastrointestinal mucosal deterioration leads to the presence of blood in the stool, starting with guiaic-positive stools that can progress to frank bleeding and bright-red blood per rectum. Physical exam findings include abdominal distension proceeding to local peritoneal signs and generalized peritonitis as the NEC worsens. Other advanced physical signs include discoloration of the anterior abdominal wall with cellulitis of the skin and a palpable abdominal mass, most often in the right lower quadrant. Physical findings of NEC are usually necessary to draw attention to the possible diagnosis, because the earliest signs such as mild temperature instability, apnea, bradycardia, and lethargy are nonspecific. Early in the clinical course, abdominal films may be normal or show mild ileus. Progression of disease leads to the development of pneumatosis intestinalis. Late radiographic signs include portal venous air, ascites, and pneumoperitoneum. In the setting of NEC, pneumatosis and portal venous air are pathopneumonic; however, the absence of these signs offers little comfort that NEC is not present or progressing. The specificity of both pneumatosis and portal venous air for the presence of NEC is extremely high at about 100%, while the sensitivity of these signs remains quite poor, about 44% for pneumatosis and 19% for portal venous air (94).

Treatment Once the diagnosis of NEC is considered, enteral feedings should be stopped, and parenteral nutrition is initiated. Conservative management includes nasogastric tube placement, broad-spectrum antibiotics, precise fluid management, and aggressive monitoring, with frequent clinical and radiographic assessment. The necessity for invasive intervention is usually evident within 24 hours. If this level of illness is not reached, conservative management as described above should be continued. Although no data exists regarding length of antibiotic usage, usually 10 to 14 days is employed, during which enteral feedings are held. The decision for intervention is less dogmatic, but pneumoperitoneum is considered an absolute indication for invasive treatments. Portal venous gas and persistent metabolic acidosis are poor prognostic indicators and usually lead to surgical exploration. Additionally, fixedloops of bowel on plain films, a palpable abdominal mass, abdominal wall erythema, positive peritoneal fluid cultures, or progressive illness are relative indications. Operative management is first based upon the extent of diseased bowel found at laparotomy. In focal disease with isolated perforation, limited resection with proximal enterostomy is the historical standard, but primary anastomosis has been advocated by some authors as an alternative (95–98). Advocates of primary anastomosis making note of the high morbidity of enterostomy in neonates report that length of hospital stay, time to full feeds, and length of ventilator requirements are all shorter in patients treated with primary anastomosis (97,98). However, routine use of primary anastomosis has produced inferior survival rates compared to proximal enterostomy (98); therefore, the gold standard remains resection of the diseased segment followed by proximal enterostomy. The presence of diffuse regions of necrosis presents a more posing circumstance. Extensive intestinal involvement with NEC not only increases mortality, but also places survivors at higher risk of the long-term sequelae such as more frequent bowel movements, fecal incontinence, short bowel

medwedi.ru

1116

Part Nine: Special Physiologic Considerations

STAGE 1

STAGE 2

STAGE 3

Neutropenia, DIC, sepsis syndrome, cardiovascular collapse

Temperature instability, apnea, heart rate, lethargy

Metabolic acidosis, thrombocytopenia

PHYSICAL SIGNS

Feeding intolerance, increased residuals, mild abdominal distension and bilious emesis

Blood stools, abdominal tenderness, distention, and discoloration, palpable mass

Diffuse peritonitis, severe abdominal tenderness, distension and discoloration, palpable right, lower quadrant mass

RADIOGRAPHIC FINDINGS

Mild intestinal dilation

Pneumatosis intestinalis moderate/severe ileus, fixed loops of bowel

Pneumoperitoneum, portal venous gas

PHYSIOLOGIC SYMPTOMS

syndrome, dependence on parenteral nutrition, and progressive liver failure (78,99–101). It has, therefore, become surgical priority to minimize the amount of bowel removed when extensive involvement is encountered at laparotomy. One method of accomplishing this goal entails resection of only clearly nonviable bowel with proximal stoma formation and a second-look operation within 36 hours (102). Others have proposed no resection at the time of initial exploration when extensive disease is encountered, but simply proximal enterostomy, allowing for demarcation of all nonviable bowel (103,104). Another approach described to avoid the possible loss of length associated with stomal closure has been termed the ‘‘clip and drop-back’’ technique, which involves resection of only obvious nonviable segments, placing surgical clips on the ends of remaining bowel and closing the abdomen, leaving closed blind ends of intestine with no anastomosis or proximal stoma (105). In the face of severe NEC with a clinically unstable neonate, primary peritoneal drainage has been advocated to facilitate stablization and delay or avert the need for laparotomy (106–109). Peritoneal drainage is accomplished at the bedside with local anesthesia by percutaneous placement of one or two drains into the peritoneal cavity, usually through the right lower quadrant. As most patients will require laparotomy after drainage, some authors view peritoneal drainage as part of resuscitation of the critical NEC patient (110–112). Mortality rates in patients treated with primary peritoneal drainage or initial laparotomy drainage are comparable, and meta-analysis of the studies available to date fail to demonstrate which initial approach is superior (113,114). Primary peritoneal drainage should be considered a useful adjunct in resuscitating critically ill NEC infants, particularly very small premature infants, however, will likely not serve as an alternative to laparotomy, which is usually necessary after clinical stabilization (107,111,115).

Intestinal Atresias Duodenal Atresia Duodenal atresia is reported to occur in approximately 1 in 2500 live births. Developmental insults during the 8th to 10th week of gestation can lead to duodenal obstruction in the form of atresia, web, or stenosis. Duodenal atresia is the most common form of duodenal obstruction, followed by stenosis and webs. The diagnosis of duodenal atresia can be made prenatally. Ultrasonic findings of polyhydramnios (secondary to

Figure 7 Bell’s modified criteria are composed of physical exam findings, clinical symptoms, and radiographic changes. Although these findings exist in a continuum from minimal to severe, the combination of all three predicts the stage and progression of disease.

high intestinal obstruction) and a dilated stomach and duodenum are highly suggestive of duodenal obstruction. Postnatally, the infant usually develops bilious vomiting, several hours after birth. Due to the proximal location of the obstruction, distention may not be present. Bilious, or persistent nonbilious, vomiting should prompt an abdominal film, which will show the classic double bubble sign, which represents the dilated stomach and duodenum. Most commonly, the abdominal film will show a gasless abdomen beyond the double bubble, suggesting atresia. However, the presence of gas distally should raise the suspicion of a duodenal stenosis or web, and contrast UGI should be obtained to rule out malrotation as a cause of bilious vomiting. The management of duodenal atresia, stenosis, or web is surgical. Operation should be undertaken once the fluid and electrolyte abnormalities have been corrected, and an echocardiogram has been obtained to evaluate for congenital heart defects. Gastric decompression should be instituted during this time. The operation is begun with a right upper transverse incision. The abdomen is opened and explored. Attention should be paid to the position of the portal vein, as a preduodenal portal vein can be found, and lead to dire consequences if inadvertently entered. The duodenum is mobilized, and the distal collapsed segment adequately exposed for anastomosis to the dilated proximal portion. A diamond-shaped anastomosis is the preferred technique for duodenoduodenostomy, which is the optimal procedure for duodenal atresia, regardless of cause (annular pancreas, duodenal atresia, stenosis, or web). A transverse duodenotomy is made in the dilated proximal segment, followed by a vertical duodenotomy in the distal segment. A single or two-layer anastomosis is performed depending on surgeon’s preference. Postoperatively, gastric decompression is continued until the return of bowel function. Central venous catheterization is obtained, and TPN is begun and continued until adequate enteral feeds are established. Patient survival should exceed 90%, with most morbidity and/or mortality associated with a congenital heart defect.

Jejunoileal Atresias Jejunoileal atresias are congenital defects resulting in segmental absence of intestinal lumen. They are generally categorized into four types. Type I is a simple mucosal obstruction or web with mural continuity. These are thought to result from embryologic failure of recanalization during

Chapter 59:

the cord stage. Recent data suggests that a defect in smooth muscle actin production within the circular layer of muscularis propria is present in the proximal gut of patients with Type I lesions (116). Type II lesions consist of an atretic cord bridging the two ends of connected bowel. Type IIIa atresias involve complete separation of the bowel ends with a wedge shaped defect in the mesentery, while Type IIIb lesions, referred to as an ‘‘apple-peel’’ or ‘‘Christmas tree’’ deformity, are the same atretric configuration with the distal small bowel spiraled concentrically around an ascending branch of the ileocolic artery. Type IV lesions involve multiple Type III atresias. Types II–IV are felt to be secondary to mesenteric vascular events occurring during fetal development in utero. Although mostly speculation, a range of causes for transient vascular occlusion during intestinal development has been proposed including intussusception, volvulus, internal herniation, embolus, herniation through abdominal wall defects, or complications of meconium ileus. Unlike the true atresia of the duodenum and esophagus, there is a relatively low rate of associated anomalies (< 10%) in infants with intestinal atresia. However, the presence of intestinal atresia does place the infant at a substantially increased risk of having a cystic fibrosis (CF) defect (117). It is therefore reasonable to consider testing all patients with intestinal atresia for the CF mutation. Consistent with the hypothesized causes of a vascular event, patients with gastroschisis have about 10% incidence intestinal atresia (118). The location of atresia is equally distributed between the ligament of Treitz and ileocecal junction, with colon atresia rarely seen. The disease is sporadic, and no clinical risk factors for the development of intestinal atresia have been defined. However, recent evidence raises the question of an increased incidence of intestinal atresia with the maternal use of pseudoephedrine alone, or in combination with acetaminophen (119). Overall mortality of infants with intestinal atresias is approximately 10%; however, it is considerably higher for jejunal than for ileal atresia (120–123). The mortality rates continue to decline with time, experience, and improved neonatal care (89). For those patients who gain independence from parenteral nutrition, the long-term prognosis in terms of development and survival is excellent (124,125). Infants with intestinal atresia present with clinical signs of obstruction including bilious emesis and abdominal distension. Antenatal diagnosis is made in only about one-third of the cases, and most are proximal lesions with polyhydramnios (116,126). At physical examination, the degree of abdominal distension may predict the level of atresia, with worsening distension the more distal the atresia. Likewise, the level can be suggested by the radiographic findings on plain films. The presence of more than two airfilled lumens suggests obstruction beyond the duodenum, with more ‘‘bubbles’’ predicting a more distal lesion. No air is typically seen in the colon or rectum. An upper gastrointestinal series is usually superfluous and adds an unnecessary risk of aspiration. Surgical treatment must first address establishing intestinal continuity. Anastomosis is usually challenging because of an enormous size discrepancy between the dilated proximal bowel and the atrophic, unused distal segment. The classic method for circumventing the size discrepancy is resection of the grossly dilated segment followed by an end-to-end anastomosis (127,128). However, if extensive resection is required or there is a sparse total length of small bowel present, resection of the dilated

Physiologic Problems in the Pediatric Surgical Patient

1117

segment may place the child at risk for short bowel syndrome. Alternatively, simple end-to-end anastomosis without resection may cause a functional obstruction within the dilated segment, because the grossly overdistracted sarcomeres within the musclaris propria are unlikely to regain normal peristaltic function (129). As an alternative, deflating proximal enterostomy has been successfully applied to decompress the dilated segment prior to staged anastomosis (130,131). While the staged procedure preserves bowel length, it substantially increases hospital stay, prolongs parenteral nutrition requirement, and increases the rate of postoperative complications (124,131). Therefore, plication with tapering enteroplasty of the dilated segment to mechanically reduce the size of the lumen is the currently suggested technique utilized to preserve length while alleviating the functional obstruction (132,133). Surgical plication of the dilated segment has been shown to result in faster return of peristalsis in the affected region, especially in the immediate postoperative period (134–136). When multiple atresias are present, maintaining maximal bowel length may be particularly difficult. Several authors have reported utilizing intraluminal stenting of intervening nonatretic segments of bowel without anastomosis. This resulted in spontaneous sutureless anastomoses, allowing the child to tolerate oral feeds (137–139). Unique approaches to minimal access techniques have been reported for both duodenal and jejunoileal atresias. An umbilical approach utilizing a ring retractor to stretch the umbilical ring and gain exposure to repair isolated jejunoileal atresias has been reported, and may shorten postoperative recovery and improve cosmesis (140). Laparoscopic repair of duodenal atresia is being performed by some authors, and it is likely that this approach will find utility in the treatment of intestinal atresias (141,142). Currently, a lack of comparative trials to delineate a superior operative approach to the patient with intestinal atresia allows for and/or requires careful consideration of the technical options, given the findings at laparatomy. The principles of primary importance are maximizing bowel length and assuring functional integrity of the remaining bowel while if at all possible, minimizing postoperative recovery time.

Hirschsprung’s Disease Hirschsprung’s disease (HD), properly termed ‘‘congenital aganglionosis,’’ is manifest by an absence of the enteric ganglia along a variable length of the gastrointestinal tract. Neuron cell bodies derived from the neural crest follow distal progression within the developing gut. In humans, neural-crest–derived cells first appear in the mesenchyme of the developing esophagus at about four weeks gestation. Their migration is in a craniocaudal direction, and they reach the transverse colon by eight weeks and the rectum by 12 weeks gestation (143). The migration of these cells is dependent upon the presence of matrix proteins like fibronectin and hyaluronic acid while other molecules such as laminin and collagen Type IV assure navigation upon the proper matrix. Failure of craniocaudal descent of neural crest-derived ganglia may be minimal, thus limiting disease only to the anal canal, but the severity of disease is defined by the proximal level of aganglionosis. Bowel motility creates a predictable pattern of propulsion via coordinated contraction stimulating reflex relaxation of adjacent segments. An intact enteric nervous system, with both sympathetic and parasympathetic components is the framework of communication upon which these serpentine

medwedi.ru

1118

Part Nine: Special Physiologic Considerations

muscular functions are possible. The absent ganglia in HD would normally provide the postsynaptic connection for parasympathetic nerve fibers from the spinal cord (S2-4) within the submucosal (Meissner’s) and intermyenteric (Auerbach’s) plexi. The functional physiologic defect is abnormal reflex relaxation within the region of aganglionosis producing tonic contraction. The contracted segment is a barrier to normal peristaltic propulsions, thus creating a partial or complete obstruction at the level of aganglionosis. The common presentation in the newborn is failure to pass meconium within the first 24 hours of life. However, this presentation is not uniform as only about 50% of cases are diagnosed in the neonate. HD may manifest simply as constipation or show more significant signs of obstruction with feeding intolerance, abdominal distension, and/or emesis. Plain films are usually nonspecific with multiple gas-filled loops of bowel, but may be more suggestive with substantial proximal rectal or distal colonic dilation. Barium enema is often valuable at identifying the level of demarcation between contracted distal bowel and proximal dilatation. Infrequently, this transition zone may not be present in the first few weeks of life. The combination of rectosigmoid transition zone, retention of barium, and stool mixed with barium appear to offer superior accuracy in the diagnosis of HD than any of these features alone, and comparison films 24 to 48 hours after the enema help to differentiate HD from meconium plug syndrome (144). If the diagnosis is suspected from history and physical and basic radiographic work-up, rectal biopsy is the definitive test. Suction rectal biopsy can be performed safely at the bedside without anesthesia in neonates and infants. The suction biopsy tip is placed 2 to 3 cm above the dentate line, and biopsies in multiple quadrants are obtained to provide a specimen of mucosa and submucosa. Adequate tissue for diagnosis is obtained by suction rectal in about 90% of cases (145). Histologic criteria for diagnosing HD include absence of ganglion cells and hypertrophied myenteric axons in the submucosa with routine hematoxylin and eosin staining. The quantity of acetylcholine esterase can be assessed by specific staining to increase diagnostic accuracy, and is routinely employed in equivocal cases (146). The importance of a pathologist experienced in ruling out HD from a suction rectal specimen has been emphasized by several authors, as has the value of communication between such a pathologist and the pediatric surgeon. Failure to reach a diagnostic conclusion mandates a full-thickness rectal biopsy. Operative treatment is predicated on the principle of overcoming the functional obstruction without a permanent colostomy. Traditionally, a temporary ‘‘leveling’’ colostomy determining the precise level of aganglionosis is performed upon diagnosis. Six to twelve months later, continuity is reestablished with a low, end-to-end colorectal (Swenson), a retrorectal, side-to-side colorectal anastomosis (Duhamel), or an endorectal pull-through coloanal anastomosis (Soave). Over the past 20 years, there has been a progressive movement toward a single-stage primary endorectal pull-through in the neonate without temporary diversion (147–161). Primary surgical treatment was initially approached by combined abdominal and perineal approach with comparable success when compared to the traditional two-stage approach (147–152). Subsequently, the abdominal component of the operation was performed laparoscopically (153–155), and, most recently, a transanal, one-stage endorectal pull-through has been described (156–160). Total colonic aganglionosis represents a severe form of HD, wherein distal migration of enteric cells from neural

crest origin terminates above the level of the colon. This occurs in less then 10% of HD patients, and is naturally associated with much higher morbidity and mortality (162–166). The disease prognosis correlates inversely with the proximal level of disease, with the most severe disease extending to the esophagus, a lesion not compatible with survival (165–169). Physicians involved in the care of HD patients should be cognizant of Hirschsprung’s-associated enterocolitis (HAEC), which occurs in about 25% of the HD population (166,170). Patients more often develop HAEC prior to definitive surgery, although it may recur or strike de novo after the operation (170,171), and risk is correlated with the distance of aganglionosis (168,172). Patients presenting with HAEC usually present with abdominal distension, explosive diarrhea, vomiting, fever, lethargy, rectal bleeding, and shock in decreasing order (172). Abdominal films may be nonspecific, and although pneumatosis intestinalis and perforation can occur, HAEC usually follows a more indolent course than NEC (170–173). The disease may recur, and while severity does not increase with the number of attacks, the mortality does (170). Mortality in these circumstances is related to the development of sepsis, underscoring the importance of early recognition and treatment.

Meconium Ileus Meconium ileus is a term for small bowel obstruction caused by viscous enteric content. The great majority of patients presenting with meconium ileus have CF as the primary diagnosis. The genetic defect in CF disables production of a cell membrane ion channel termed the ’’CF transmembrane conductance regulator,’’ which is a chloride channel. Defective chloride permeability impairs movement of electrolytes across cell membranes, grossly attenuating the water content of secretions, making for abnormally viscous secretions. Negative functional effects are seen in the lungs, pancreas, liver, and gut. Within the gut, the defect results in thick, viscid, high-protein, low-carbohydrate meconium, which may accumulate in the terminal ileum creating an obstruction. Meconium ileus is rare without CF, and may be related to delayed development of the gut motility pacemakers, the interstitial cells of Cajal (174). Initial presentation of meconium ileus is failure to pass meconium follow by typical signs of obstruction with abdominal distension and bilious vomiting. Plain films demonstrate multiple loops of dilated small bowel. In the clinical scenario of an obstructed newborn with multiple dilated loops of bowel on plain films, meconium ileus needs to be differentiated from an atresia. The offending inspissated meconium may encase small bubbles of air producing the radiographic presence of a ground glass or soap bubble appearance in the right lower quadrant, which can help diagnose meconium ileus. Ultrasound can identify echogenic material within the bowel to separate meconium ileus from an atresia (175). Barium enema reveals an unused microcolon as seen in ileal atresia, and with reflux of contrast into the terminal meconium, concretions will be identified and will confirm the diagnosis of meconium ileus. Clinically, meconium ileus is broadly categorized as either complicated or uncomplicated. Complicated meconium ileus is compounded by the presence of volvulus, atresia, perforation, and/or giant cystic meconium peritonitis. In these cases, operative exploration is necessary to manage the complications as well as the meconium ileus. Hypertonic contrast enema is the treatment of choice in simple, uncomplicated cases. Intraluminal hypertonic

Chapter 59:

solution draws water from the mucosa via osmosis to facilitate breaking up of the viscid material, and the progress can be visualized under fluoroscopy. The consequent fluid shifts should be anticipated, and an infusion of crystalloid (20 mL/kg) should be given during the procedure to prevent intravascular volume depletion. Comparative studies of the available hypertonic contrast agents have found Gastrografin to be most effective in relieving the meconium obstruction (176). After instillation of the Gastrografin, the infant will pass portions of the diluted meconium for up to 48 hours. Plain films can be repeated for 12 to 24 hours to assess progress. Successful relief of obstruction can be followed with oral N-acetylcysteine in an effort to prevent recurrence. When feedings are initiated, supplemental pancreatic enzymes should be included for CF-positive patients. If the meconium obstruction is resistant to dilution, or there is a complicated disease, an operation is indicated. The principle of nonoperative management, breaking up the meconium to relieve obstruction, is maintained at operation. The most common surgical approach involves an enterostomy, proximal to the obstruction for the introduction of a catheter, followed by an aggressive flushing of the ileum with a hypertonic solution through the catheter (177–181). In resistant cases, the tube can be left behind as a tube enterostomy to allow for repeat irrigation if needed. If the meconium is refractory to these measures, a resection may be necessary. In this case, maintaining bowel length is the first priority. Enterostomy can be used to allow washing the bowel for a period of time to assure resolution. Operations described for this purpose include double-barreled enterostomy (Mikulicz), distal chimney enterostomy (Bishop–Koop procedure), proximal chimney enterostomy (reverse Bishop–Koop), and side-by-side enterostomy; however, these techniques are not frequently necessary.

Esophageal Atresia and Tracheoesophageal Fistula Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is seen in about 1 in 3000 births, with males and females affected equally. Although initially described in 1697 by Thomas Gibson, the exact embryogenesis is still not fully understood (182). Traditionally, the more accepted theories suggest an abnormal development of the laryngotracheoesophageal groove with persistent communication between the esophagus and the trachea. More recently, with

Physiologic Problems in the Pediatric Surgical Patient

1119

the development of the adriamycin-induced murine model of EA/TEF, along with embryonic microdissection techniques, a new mechanism of embryogenesis has been suggested (183). From these studies, it has been suggested that the fistula tract begins as a trifurcation of the tracheal anlage, which subsequently fistulizes to the stomach, indicating that the fistula tract is actually of respiratory origin with pseudostratified columnar epithelium present in the early embryonic period. As the fetus with EA/TEF matures, this fistula tract undergoes metaplasia to squamous epithelium. This respiratory origin may explain the presence of respiratory epithelium seen in the fistula tract of neonates with EA/TEF and is also consistent with the poor motility of the distal esophagus seen in many of the patients who have undergone surgical correction of the defect (184,185). Further study of the patterning genes of foregut formation have suggested defects in several signaling pathways such as fibroblast growth factor (FGF) and sonic hedgehog (Shh) signaling, which appear to be important in the temporal and spatial pattern ofexpression of normal esophageal and tracheal formation (186–188). There are five variants of EA/TEF (Fig. 8). Often included in this classification is esophageal stenosis which is very uncommon. The most common variant is EA with distal TEF (85% of cases). Other types include EA without a TEF (8%), EA with a proximal TEF (2%), EA with both a proximal and a distal TEF (3%), and a TEF without EA (the so-called ‘‘H’’ or ‘‘N’’-type fistula). There also appears to be an association of EA/TEF with chromosomal abnormalities including trisomy 18 and 21. In addition, EA/TEF may occur as part of the VACTERL (vertebral, anal, cardiac, tracheoesophageal, renal, and limb) association in about 10% of the patients. Accordingly, investigation to identify the presence of other anomalies must be completed prior to definitive surgical therapy, particularly because the mortality rate is usually determined by the presence of some of these other anomalies. The diagnosis of EA may be suggested on prenatal ultrasound by the presence of polyhydramnios and reduced intraluminal fluid of the fetal gut, with a small or indistinct fetal stomach. However, the predictive value of prenatal ultrasound is low. The use of fetal magnetic resonance imaging in patients with suspicious ultrasonographic findings may help confirm the diagnosis, and has been shown to be relatively safe (189). In contrast, antenatal diagnosis of EA is usually quite straightforward. Infants present with

Figure 8 The six variants of esophageal atresia (EA), tracheoesophageal fistula (TEF) are depicted. (A) Pure EA without TEF, (B) Proximal TEF with distal EA. (C) Proximal EA with distal TEF (the most common variant), (D) Proximal and distal TEF, (E) H or N type TEF, and (F) Esophageal stenosis.

medwedi.ru

1120

Part Nine: Special Physiologic Considerations

excessive salivation requiring frequent suctioning. Tachypnea and cough may develop as a result of aspiration from overflow of the proximal pouch or from reflux through the TEF. Early feeding will produce almost immediate regurgitation, and cyanosis may develop as a result. When the diagnosis is suspected, a 10 to 12 French orogastric tube may be inserted into the proximal pouch. The inability to pass the catheter into the stomach confirms the diagnosis. The diagnosis may be less obvious with an N-type fistula, where there is no EA. These infants will present with symptoms of aspiration typically following feeding. Often the diagnosis is not made until years later, while in the interim, the patient suffers from a persistent cough associated with recurrent pneumonia. An upright radiograph should be performed as part of the initial work-up. Typically, it will demonstrate the presence of the catheter in the proximal pouch, defining the level of the EA. In addition, air may be seen in the stomach and small intestines indicating the presence of a fistula. Likewise, absence of air in the stomach indicates a pure EA. The diagnosis of TEF may be less obvious with an N-type fistula where there is no esophageal atresia. These latter infants will present with symptoms of aspiration typically following feeding. Often the diagnosis is not made until years later, while in the interim the patient suffers from a persistent cough associated with recurrent preumonia. Once the diagnosis of EA/TEF in an infant is confirmed, the catheter in the proximal pouch should be placed on continuous suction to prevent distention and subsequent aspiration. The baby should also be placed in semi-Fowler’s position. The infant should then undergo a full evaluation for the presence of other anomalies. This begins with a thorough physical examination. Careful evaluation of the anus (for patency) and extremities (for limb defects) should be done. The vertebral column and heart contour must be evaluated on plain radiographs. An echocardiogram is important in all patients to identify congenital heart defects and laterality of the aortic arch, which is critically important in surgical planning. Renal ultrasonography is also obtained to evaluate for renal anomalies. On occasion, rigid bronchoscopy may be performed to identify the location or presence of a fistula (especially in an N-type fistula). While looking for other anomalies, the infant’s medical condition should also be evaluated in preparation for surgical management. Fluid and electrolyte normalization should be accomplished, and antibiotics initiated. The presence of severe congenital heart defects, or significant pulmonary disease may delay plans for immediate operative repair. Rather, in these unstable patients, an emergent gastrostomy may be performed, with the definitive repair delayed until the patient’s clinical condition improves. For full-term or near full-term infants with mild anomalies and without evidence of significant pulmonary disease, operative therapy may be undertaken shortly after birth. The operative repair is traditionally performed via an extra-pleural or trans-pleural thoracotomy incision (third or fourth intercostals space) made on the side opposite the aortic arch. In general, the extra-pleural approach is preferred because there is no risk of empyema formation, if an anastomotic leak occurs in the postoperative period. A drain in the extra-pleural space will allow evacuation of any leakage with little clinical consequence in most cases. Upon exploration, the azygous vein is identified within the mediastinum and divided. This allows access to the esophagus and the trachea. The proximal esophageal pouch usually has excellent intramural blood supply originating

from the thyrocervical trunk. For this reason, the proximal pouch can be mobilized extensively without compromise to its integrity. However, the dissection should be carried out rather carefully to identify any proximal pouch fistulas. In contrast to the proximal esophageal segment, the blood supply to the distal esophagus is more segmental with branches originating from the aorta. This limits extensive mobilization of the lower esophageal segment. Tension and excessive mobilization of the distal segment may lead to poor healing resulting in an anastomotic leak, or stricture formation. The fistula is identified and divided close to the trachea taking care not to compromise the tracheal lumen. The trachea is closed with 5–0 or 6–0 interrupted silk suture. A primary end-to-end anastomosis of the esophagus is performed in a full-thickness fashion using interrupted silk sutures. A Silastic stent may be placed across the anastomosis extending from the stomach to the oral cavity, where it is secured as it exits the nares. A small drain is left in the retropleural space prior to closure of the thoracotomy incision. A thorascopic approach to the repair of EA/TEF has been described and appears to be feasible. The main issue appears to be the technical difficulties related to the intracorporeal suturing required to complete the esophageal anastomosis. Although the rate of esophageal narrowing at the anastomosis does appear to be somewhat higher than in the historical controls, the actual long-term outcome of this procedure will become clear as more thorascopic cases are performed (190). In infants with isolated EA, the distal segment of the esophagus is usually short, leaving a long gap between the proximal and distal segments of the esophagus. This long gap makes primary repair impossible. The infant is usually taken for a gastrostomy and bronchoscopy under the same anesthesia. The bronchoscopy may reveal an occluded proximal or distal fistula, in which case a primary repair may be indicated. The infants that demonstrate true isolated EA are treated with a gastrostomy by which they are able to receive enteral feeds. The proximal pouch is then allowed to elongate with a sump tube in place with the definitive repair delayed for several months as adequate length is gained in the proximal esophageal segment. If the patient still fails to gain length in the esophagus, complete cervical esophageal mobilization via a collar incision followed by circular myotomies in the proximal segment may allow adequate lengthening for primary anastamosis. On rare occasion, if the patient still lacks the length in the esophagus for a primary anastomosis, an interposition colon or gastric tube may be required. Neither colon nor stomach function as well as the native esophagus, and are used in the rare case where all other efforts at esophageal lengthening are unsuccessful. In patients with the N-type TEF, the repair involves a simple division of the fistula, which is generally performed through a cervical incision. The use of bronchoscopy to place a catheter into the fistula can aid in identifying the fistula tract from the outside during the operative exploration. Careful dissection is important to avoid a recurrent laryngeal nerve injury. Postoperatively, patients are maintained nil per os (NPO), with a contrast study performed around day 7. If no leak is seen, oral feeds may be started. Once the child demonstrates adequate weight gain while tolerating full feeds, he or she can be discharged with regular follow-up. During long-term follow-up, particular attention should be made to the development of symptoms of dysphagia, GER, anastomotic stenosis, and recurrence of the TEF

Chapter 59:

(191,192). Abnormal peristalsis in the distal esophagus is almost always present. GER is also quite common, and severe reflux may lead to a Barrett’s esophagus or chronic aspiration. In these instances, aggressive medical management must be initiated as soon as the diagnosis is apparent. For cases refractory to medical therapy, a fundoplication may be helpful. Stricture formation is not uncommon and may require periodic dilatation. Long-term follow-up also reveals delayed gastric emptying, which further exacerbates GER symptoms (192). Overall, most children do well with a survival rate reported in the 90% range. The majority of the mortality is related to the severity of congenital heart defects and chromosomal abnormalities. Late deaths usually result from tracheomalacia, aspiration, and reactive airway disease (193).

Congenital Diaphragmatic Hernia Congenital diaphragmatic hernia (CDH) continues to be one of the more challenging diagnoses of pediatric surgery (Fig. 9). CDH occurs in 1:3000 births, with a slight female predominance (194). The issues of pulmonary complications continue to be a dilemma in the management of patients with CDH, maintaining a mortality rate as high as 60%, and significant morbidity in those who survive (195). There is a 10% incidence of other congenital abnormalities, primarily chromosomal, cardiac, and neurological defects. It is the presence of these abnormalities that are responsible for the high mortality seen immediately after birth in some of these patients. Familial cases have also been reported, although the vast majority of the cases appear to be spontaneous. Our understanding of how and why this defect develops during embryogenesis remains quite obscure. Traditionally, it was believed that the pulmonary complications of

Figure 9 A typical chest radiograph in a newborn with left congenital diaphragmatic hernia. Significant findings include mediastinal shift to the right (note the tracheal deviation identified by the endotracheal tube), bowel gas in the left chest, and the ‘‘classic’’ finding of the nasogastric tube looping upward into the left hemithorax.

Physiologic Problems in the Pediatric Surgical Patient

1121

CDH were a result of failure of the diaphragm to close as the midgut makes its normal return to the abdomen from the yolk sac, during the tenth week of gestation. The herniation of the abdominal viscera into the thorax was then thought to lead to compression of the lung impeding proper lung growth. This theory was supported by lamb animal model studies, where an artificial hernia created in the diaphragm led to similar pathologic findings seen in abnormal lungs of human neonates with CDH (196). Recent rodent model studies provide increasing evidence that the pulmonary hypertension and lung hypoplasia precede the development of the diaphragmatic defect (197–199). Observations from these studies have shown that almost all of the embryos appear to have some degree of pulmonary hypoplasia, with a diaphragmatic hernia occurring in only 40% to 60% of the treated embryos (199). This model also explains the lung hypoplasia seen in both the ipsilateral and contralateral lungs. The fact that there is more severe hypoplasia seen on the ipsilateral side may be explained by the presence of the abdominal contents in the chest, causing further compression of an already hypoplastic lung (196). Other studies have implicated defects in the molecular mechanisms FGF-10 and Shh of normal branching morphogenesis, as being responsible for the lung hypoplasia as an initial event (201,202). It has also been shown that the pulmonary vasculature, including the number of arteriole branches, as well as the arteriolar muscularization in CDH patients is distinctly abnormal. The left posterolateral diaphragm hernia (Bochdalek hernia) represents the most common site for CDH, and defects in this region represent 85% of all cases. The less common anterolateral defects (Morgagni hernias) present more commonly on the right side and represent about 15% of the hernias. At presentation, patients with CDH typically have varying degrees of hypoxia and acidosis. The lungs are physically small and functionally immature. Gas exchange is poor, resulting in worsening hypoxia after birth. The hypertrophied muscular layers of the pulmonary arterioles increase vascular resistance adding to the pulmonary hypertension. This vicious cycle of the hypoxia and acidosis, both contribute to the persistent pulmonary hypertension of the newborn. As a result, there is persistent fetal circulation with a right to left shift through the foramen ovale and the ductus arteriosus. The diagnosis of CDH is usually made before birth with the prenatal ultrasonography. The presence of polyhydramnios may prompt this study. A prenatal diagnosis allows for preparation of therapy and provision of perinatal counseling. After birth, respiratory distress is apparent with tachypnea and cyanosis, which may develop immediately after clamping the umbilical cord, or may not be obvious until several hours after birth. Typically, the degree of respiratory distress worsens as the infant continues to breathe. The swallowed air distends the gut, which due to its location in the chest makes lung expansion even more difficult. Prompt endotracheal intubation is required along with orogastric tube decompression of the gut in the chest. Masked ventilation should be avoided as it may distend the stomach further. Physical examination may reveal a scaphoid abdomen with an increased chest diameter. There may be decreased breath sounds bilaterally, with the presence of bowel sounds within the chest. A plain radiograph of the chest usually confirms the diagnosis via the presence of the gastric tube within the affected thorax. Once the diagnosis is made, an echocardiogram should be obtained to evaluate for the presence of congenital heart defects and to determine the degree of right-to-left shunting.

medwedi.ru

1122

Part Nine: Special Physiologic Considerations

The concept that all patients with CDH require immediate surgical repair is no longer the approach to the management of these patients. It appears that improving oxygenation, while avoiding barotrauma prior to surgical intervention has a better overall outcome (203). Aggressive resuscitation with fluids and electrolytes should be used to correct any underlying acidosis, with careful monitoring of the patient’s fluid status to provide adequate resuscitation and at the same time to avoid volume overloading. Cardiac dysfunction with hypotension may necessitate the use of ionotropes. The degree to which the pulmonary hypertension improves will determine the timing of surgery. In instances where the patient does not respond to conventional ventilation, high-frequency oscillatory ventilation and nitrous oxide administration may be used (204). Permissive hypercapnia has also been utilized to minimize the degree of barotrauma (205). The use of surfactant therapy has been suggested in the management of CDH, but its use has not been shown to improve overall survival in controlled clinical trials (206). If after all these efforts the patient still fails to respond, extracorporeal membrane oxygenation (ECMO) may be instituted. ECMO allows respiratory support without concerns of barotrauma or oxygen toxicity. Careful selection must be used in choosing patients for ECMO, as it carries significant morbidity and/or mortality. Systemic anticoagulation is necessary and any contraindication to heparin must be taken into consideration. In general, as the patient’s condition improves, he or she is weaned from ECMO and operative repair performed; alternatively, the repair can be performed while the patient remains on ECMO. The surgical repair of CDH is usually performed via a subcostal incision. A reduction of the hernia contents is performed, and if a hernia sac is present, it is excised. The defect in the diaphragm is repaired primarily if possible. If the defect is too large, a prosthetic material or muscle flap may be used. The abdominal incision can then be closed in the usual fashion. In some instances, the abdominal closure may create undue tension on the diaphragm, which may lead to impaired lung ventilation in the postoperative period. In such cases, the abdominal fascia can be closed using a prosthetic patch or the skin approximated with a ventral hernia repair performed at a later date. Alternatively, a ‘‘silo’’ can be used with sequential down sizing and delayed closure of the fascia once the tension is relieved. The postoperative management in these patients involves close ventilatory support and management with serial arterial blood gases. Particular attention is needed in the immediate postoperative period as the surgery may exacerbate pulmonary hypertension and further perpetuate the right-to-left shunting. ECMO may have to be reinstituted for severe cases. Although the overall mortality of CDH has improved with the institution of the various ventilation techniques described earlier, a single management strategy has yet to be clearly defined. In addition, several experimental techniques are under investigation to better manage this devastating congenital anomaly. Specifically, some fetal interventions have been attempted involving in utero tracheal occlusion surgery. The benefit of this technique has been shown in animal models, but has failed to show a survival advantage in human neonates (207,208). As the mortality rate continues to decline, the longterm complications of patients who survive CDH repair are becoming more apparent. Foregut dysmotility is increasingly being recognized. GER has been reported in as high as 50% of patients (209). Diaphragmatic hernia recurrence is

common, particularly in patients who required a synthetic patch to close the diaphragmatic defect (206). As our management techniques for CDH improves, the significance of the long-term complication will become more apparent. For this reason, extended close follow-up should be maintained in all patients surviving CDH repair.

Malrotation In the fifth week of gestation, the primitive gut elongates and opens ventrally into the yolk sac, where it remains until the 10th week. During this time, the midgut rotates approximately 270 degrees in a counterclockwise direction, along the superior mesenteric artery (SMA), with the omphalomesenteric duct at the apex (Fig. 10). The prearterial portion of the gut then elongates and forms the duodenum from its proximal portion, while the distal portion of the prearterial segment rotates behind the SMA, and becomes fixed at the ligament of Treitz. The proximal postarterial segment then rotates in a counterclockwise direction anterior to the SMA to end upon in the right lower quadrant. This portion of the gut gives rise to the terminal ileum and cecum, with its distal end extending to the level of the midtransverse colon. By the 12th week of gestation, portions of the gut become fixed to the posterior body wall. This fixation results in an oblique, broad-based small bowel mesentery, extending from the ligament of Treitz to the cecum. When the process of rotation and fixation does not occur properly, the midgut is at risk of forming a volvulus and producing intestinal ischemia (210). The diagnosis of malrotation refers to any abnormality that occurs in this developmental process of rotation and fixation. Nonrotation refers to the early arrest of rotation of the duodenojejunal loop, so that the segment of bowel remains on the right side of the abdomen. The result is that the small intestine remains on the right side of the abdomen, with the colon on the left, and the cecum near the midline. In contrast, ‘‘incomplete rotation’’ refers to an arrest of the duodenojejunal loop after it has partially rotated around the SMA but has yet to ascend to its normal position. The duodenojejunal junction resides to the right of the midline, and the cecum, which fails to rotate anterior to the SMA, usually remains to its left, in the upper abdomen. In both, nonrotation and incomplete rotation, the patient may present with symptoms that result from duodenal obstruction, which develops from the peritoneal attachments of the cecum, which cross over the duodenum and attach to the posterior abdominal cavity. These bands are the so-called Ladd’s bands. In addition, because the SMA vascular pedicle is narrow, a midgut volvulus may occur, with subsequent symptoms of intestinal ischemia (211,212). Typically, the diagnosis of malrotation is made in the first year of life, with males presenting slightly more often than females. However, patients may remain asymptomatic into adulthood, where the diagnosis is made incidentally during an evaluation for other reasons. Upon further questioning, these patients often reveal ongoing symptoms that may have gone unrecognized. Regardless of the age at presentation, it is generally accepted that all cases of malrotation should undergo correction despite the absence of symptoms (213). Correction of the malrotation will reduce the chance of midgut volvulus with subsequent intestinal ischemia or death. The duodenal obstruction resulting from the Ladd’s bands produces bilious vomiting. The main concern in the neonate with bilious emesis is the possibility of midgut

Chapter 59:

Physiologic Problems in the Pediatric Surgical Patient

1123

Figure 10 A diagrammatic representation of the embryonic rotational events of the intestine. (A) The duodenojejunal limb begins to the right of the superior mesenteric artery (SMA). (B) After completion of the 270 degrees counterclockwise rotation, the duodenojejunal limb now lies to the left of the midline and slightly higher than its starting point. (C) The cecocolic limb initially begins directly inferior to the SMA and with rotation (D) migrates counterclockwise to its normal position in the right lower quadrant. Abbreviation: SMA, superior mesenteric artery.

volvulus, and it is this diagnosis that requires an aggressive investigative approach. If the bowel supplied by the SMA is compromised, the patient may require an extensive resection of the infarcted segment, which often leads to an extremely high morbidity and mortality. Therefore, any infant that presents with bilious vomiting should be considered as having a diagnosis of malrotation until proven otherwise. Other symptoms that may be present include abdominal distention with pain, and guaiac-positive stools. In late stages of intestinal ischemia, metabolic acidosis with a coagulopathy and shock may ensue. The diagnosis of malrotation is usually made with an upper gastrointestinal contrast study. In patients with malrotation without midgut volvulus, the contrast study reveals that the duodenojejunal junction fails to cross the midline and lies lower than normal. When volvulus is present, a partial or complete obstruction of the second/third portion of the duodenum is seen. The duodenum may show a ‘‘corkscrew effect,’’ which represents the point of volvulus around the superior mesenteric vessels. In addition, plain films may show gastric and proximal duodenal distention with little or no air in the distal small bowel. A barium enema may demonstrate an abnormally positioned cecum. This finding may not be totally reliable in the infant, because the cecum usually occupies a higher position than in older children. In the symptomatic patient with a new diagnosis of malrotation, the management should be guided to prepare the infant for emergent operation. The patient should be resuscitated with IV fluids and given IV antibiotics. The stomach should be decompressed, urine output should be closely monitored, and electrolytes should be corrected. At laparotomy, a Ladd’s procedure is performed (214). This procedure includes the division of the Ladd’s bands causing obstruction of the duodenum, widening of the base of the mesentery, appendectomy, and placement of the duodenum into the right gutter of the abdomen and the cecum into the left upper quadrant. A laparoscopic approach to the

Ladd’s procedure has been described with some reported advantages. Some of these advantages include less postoperative pain, decreased postoperative ileus, and a shorter hospital stay. The laparoscopic approach should be limited to cases where there is no evidence of midgut volvulus, as ischemic bowel is extremely friable and requires gentle manipulation of the involved segments (215). The volvulus is usually a result of a clockwise twisting of the bowel, so the reduction of the bowel should be performed in a counterclockwise direction. Once this is complete and the Ladd’s bands are divided, the duodenum should drop inferiorly toward the right lower quadrant, and the cecum falls to the left. The appendix is removed to avoid confusion in the event that appendicitis should develop later in life. In situations where the bowel is infarcted, a resection of the involved intestine should be performed. If there is concern for bowel viability after detorsion, a second look operation can be planned 24 hours later. If the patient is diagnosed prior to bowel ischemia, the prognosis is excellent with a normal life expectancy. In contrast, infants that require extensive bowel resection have a significantly higher mortality rate, and may suffer from the horrible consequences of a short bowel syndrome.

SUMMARY This chapter has attempted to show that ‘‘children are not little adults’’ but present unique challenges in perioperative management should a surgical procedure become necessary. These challenges are related to the specific changes that occur in physiology, thermoregulations, biochemistry, and nutrition, which commence at both following the in utero state and continue into the newborn period and throughout later stages of development. Common problems that occur in the pediatric populations have been discussed with these considerations in mind. A thorough understanding of these

medwedi.ru

1124

Part Nine: Special Physiologic Considerations

pathophysiologic perturbations and their clinical presentations not only is critical to enabling early diagnosis but also is likewise crucial, if correct and expeditions treatment is to be employed with an acceptable morbidity and a negligible mortality.

REFERENCES 1. Garg R, Agthe AG, Donohoe PK, Lehman CU. Hyperglycemia and retinopathy of prematurity in very low birth weight infants. J Perinatol 2003; 23:186–194. 2. Lorenz JM, Kleinman LI, Kotagal UR, et al. Water balance in very low birth weight infants: relationship to water and sodium intake and effect on outcome. J Pediatr 1982; 101:423–432. 3. Aperia A, Broberger O, Herin P, et al. Postnatal control of water and electrolyte homeostasis in pre-term and full-term infants. Acta Paediatr Scand 1983; 305:61–65. 4. Marian M. Pediatric nutritional support. Nutr Clin Pract 1993; 8:199–200. 5. Rose J, Gibbons K, Carlson SE, Koo WWK. Nutrient needs of the preterm infant. Nutri Clin Pract 1993; 8:226–232. 6. Heird W, Driscoll J, Schullinger J. Intravenous alimentation in pediatric patients. J Pediatr 1972; 80:351–355. 7. Letton RW, Chwals WJ, Jamie A, et al. Early postoperative alterations in infant energy use increases the risk of overfeeding. J Pediatr Surg 1995; 30:988–993. 8. Pang KY, Bresson JL, Walker WA. Development of the gastrointestinal mucosal barrier. Evidence for structural differences in microvillous membranes from newborn and adult rabbits. Biochim Biophys Acta 1983; 727:201–208. 9. Kudsk KA, Croce M, Favian T, et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992; 215:503–511. 10. Moore FA, Moore EE, Kudsk KA, et al. Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding. J Trauma 1994; 37:607–615. 11. Haumont D, Deckelbaum RJ, Richelle M, et al. Plasma lipid and plasma lipoprotein concentration in low birth weight infants given parenteral nutrition with twenty or ten percent lipid emulsion. J Pediatr 1989; 115:787–793. 12. Hirschprung H. Falle von angeborener pylorus stenose. Jb Kinderheilk 1888; 27:61–62. 13. Ramstedt C. Zur operation der angeboren pylorus stenose. Med Klinik 1912; 8:1702–1704. 14. Takahashi T. Pathophysiological significance of neuronal nitric oxide synthease in the gastrointestinal tract. J Gastroenterol 2003; 38:421–430. 15. Subramaniam R, Doig CM, Moore L. Nitric oxide synthase is absent in only a subset of cases of pyloric stenosis. J Pediatr Surg 2001; 36:616–619. 16. Wallgren A. Preclinical stage of infantile hypertrophic pyloric stenosis. Am J Dis Child 1946; 72:371–374. 17. Rollins MD, Shields MD, Quinn RJ, et al. Pyloric stenosis: congenital or acquired? Arch Dis Child 1989; 64:138–139. 18. Keller H, Waldermann D, Greiner P. Comparison of preoperative sonography with intraoperative findings in congenital hypertrophic pyloric stenosis. J Pediatr Surg 1987; 22: 950–952. 19. Benson CD, Alpern EB. Preoperative and postoperative care of congenital pyloric stenosis. Arch Surg 1957; 75:877–879. 20. Hulka F, Harrison MW, Campbell TJ, et al. Complications of pyloromyotomy for infantile hypertrophic pyloric stenosis. Am J Surg 1997; 1173:450–452. 21. Royal RE, Linz DN, Gruppo DL, et al. Repair of mucosal perforation during pyloromyotomy: surgeon’s choice. J Laparoendosc Surg 1995; 30:1430–1432. 22. Gross RE. A new method for surgical treatment of large omphalocele. Surgery 1948; 24:277–292.

23. Snyder CL. Outcome analysis for gastroschisis. J Pediatr Surg 2000; 35:1253–1256. 24. Hoyme HE, Jones MC, Jones KL. Gastroschisis: abdominal wall disruption secondary to early gestational interruption of the omphalomesenteric artery. Semin Perinatol 1983; 7:294–298. 25. DeVries PA. The pathogenesis of gastroschisis and omphalocele. J Pediatr Surg 1980; 15:245–251. 26. Swartz KR, Harrison MW, Campbell TJ, et al. Selective management of gastroschisis. Ann Surg 1985; 203:214–218. 27. Grosfeld JL, Weber TR. Congenital abdominal wall defects: gastroschisis and omphalocele. Curr Prob Surg 1982; 19:157–213. 28. Knight PJ, Buckner D, Vassey LE. Omphalocele: treatment options. Surgery 1981; 89:332–336. 29. Duhamel B. Embryology of exomphalos and allied malformations. Arch Dis Child 1963; 38:142–147. 30. Drongowski RA, et al. Contribution of demographic and environmental factors to the etiology of gastroschisis: a hypothesis. Fetal Diagn Ther 1991; 6:14–27. 31. Pokorny WJ, Garcia-Prats JA, Barry YN. Necrotizing enterocolitis: incidence, operative care, and outcome. J Pediatr Surg 1986; 21:1149–1154. 32. Kliegman RM, Fanaroff AA. Neonatal necrotizing enterocolitis: a nine-year experience. Am J Dis Child 1981; 135:603–607. 33. Wiswell TE, Robertson CF, Jones T, et al. Necrotizing enterocolitis in full-term infants. A case control study. Am J Dis Child 1988; 142:532–535. 34. Caplan MS, Hedlund E, Adler L, Hsueh W. Role of asphyxia and feeding in a neonatal rat model of necrotizing enterocolitis. Pediatr Pathol 1994; 14:1017–1028. 35. Read MA, Whitley MZ, Gupta S, et al. Tumor necrosis factor alpha-induced E-selectin expression is activated by the nuclear factor-kappa B and c-JUN N-terminal kinase/p38 mitogen-activated protein kinase pathways. J Biol Chem 1997; 272:2753–2761. 36. Shu HB, Agranoff AB, Nabel EG, et al. Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-kappa B subunits in endothelial and epithelial cells. Mol Cell Biol 1993; 13:6283–6289. 37. Mannick E, Udall JN Jr. Neonatal gastrointestinal mucosal immunity. Clin Perinatol 1996; 23:287–304. 38. Udall JN Jr. Gastrointestinal host defense and necrotizing enterocolitis. J Pediatr 1990; 117:S33–S43. 39. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336:1519–1523. 40. Kosloske AM. Breast milk decreases the risk of neonatal necrotizing enterocolitis. Adv Nutr Res 2001; 10:123–137. 41. Caplan MS, Amer M, Jilling T. The role of human milk in necrotizing enterocolitis. Adv Exp Med Biol 2002; 503:83–90. 42. Kelleher SL, Lonnerdal B. Immunological activities associated with milk. Adv Nutr Res 2001; 10:39–65. 43. McGuire W, Anthony MY. Donor human milk versus formula for preventing necrotising enterocolitis in preterm infants: systematic review. Arch Dis Child Fetal Neonatal Ed 2003; 88:F11–F14. 44. Robel-Tillig E, Vogtmann C, Bennek J. Prenatal hemodynamic disturbances—pathophysiological background of intestinal motility disturbances in small for gestational age infants. Eur J Pediatr Surg 2002; 12:175–179. 45. Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F. Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 2003; 6:6–23. 46. Sechi LA, Valentin JP, Griffin CA, Schambelan M. Autoradiographic characterization of angiotensin II receptor subtypes in rat intestine. Am J Physiol 1993; 265:G21–G27. 47. Bailey RW, Bulkley GB, Hamilton SR, Morris JB, Haglund UH. Protection of the small intestine from nonocclusive mesenteric ischemic injury due to cardiogenic shock. Am J Surg 1987; 153:108–116. 48. Hsueh W, Gonzalez-Crussi F, Arroyave JL. Platelet-activating factor: an endogenous mediator for bowel necrosis in endotoxemia. FASEB J 1987; 1:403–405.

Chapter 59: 49. Gonzalez-Crussi F, Hsueh W. Experimental model of ischemic bowel necrosis. The role of platelet-activating factor and endotoxin. Am J Pathol 1983; 112:127–135. 50. Kliegman RM, Fanaroff AA, Izant R, Speck WT. Clostridia as pathogens in neonatal necrotizing enterocolitis. J Pediatr 1979; 95:287–289. 51. Mollitt DL, Tepas JJ III, Talbert JL. The microbiology of neonatal peritonitis. Arch Surg 1988; 123:176–179. 52. Rotbart HA, Nelson WL, Glode MP, et al. Neonatal rotavirusassociated necrotizing enterocolitis: case control study and prospective surveillance during an outbreak. J Pediatr 1988; 112:87–93. 53. Mollitt DL, String DL, Tepas JJ III, Talbert JL. Does patient age or intestinal pathology influence the bacteria found in cases of necrotizing enterocolitis? South Med J 1991; 84:879–882. 54. Peter CS, Feuerhahn M, Bohnhorst B, et al. Necrotising enterocolitis: is there a relationship to specific pathogens? Eur J Pediatr 1999; 158:67–70. 55. Flick MR, Perel A, Staub NC. Leukocytes are required for increased lung microvascular permeability after microembolization in sheep. Circ Res 1981; 48:344–351. 56. Weiss SJ, Curnutte JT, Regiani S. Neutrophil-mediated solubilization of the subendothelial matrix: oxidative and nonoxidative mechanisms of proteolysis used by normal and chronic granulomatous disease phagocytes. J Immunol 1986; 136: 636–641. 57. Baird BR, Cheronis JC, Sandhaus RA, Berger EM, White CW, Repine JE. Oxygen metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. J Appl Physiol 1986; 61:2224–2229. 58. Caplan MS, Sun XM, Hsueh W. Hypoxia causes ischemic bowel necrosis in rats: the role of platelet-activating factor (PAF-acether). Gastroenterology 1990; 99:979–986. 59. Zhang C, Hsueh W, Caplan MS, Kelly A. Platelet activating factor-induced shock and intestinal necrosis in the rat: role of endogenous platelet-activating factor and effect of saline infusion. Crit Care Med 1991; 19:1067–1072. 60. Hsueh W, Caplan MS, Sun X, Tan X, MacKendrick W, Gonzalez-Crussi F. Platelet-activating factor, tumor necrosis factor, hypoxia and necrotizing enterocolitis. Acta Paediatr Suppl 1994; 396:11–17. 61. Colletti LM, Kunkel SL, Walz A, et al. The role of cytokine networks in the local liver injury following hepatic ischemia/ reperfusion in the rat. Hepatology 1996; 23:506–514. 62. Remick DG, Colletti LM, Scales WA, McCurry KR, Campbell DA Jr. Cytokines and extrahepatic sequelae of ischemiareperfusion injury to the liver. Ann N Y Acad Sci 1994; 723: 271–283. 63. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 1995; 9:899–909. 64. Read MA, Whitley MZ, Williams AJ, Collins T. NF-kappa B and I kappa B alpha: an inducible regulatory system in endothelial activation. J Exp Med 1994; 179:503–512. 65. Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K. Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol 1990; 10:561–568. 66. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995; 270:283–286. 67. Kanto WP Jr, Wilson R, Breart GL, et al. Perinatal events and necrotizing enterocolitis in premature infants. Am J Dis Child 1987; 141:167–169. 68. Wilson R, Kanto WP Jr, McCarthy BJ, et al. Epidemiologic characteristics of necrotizing enterocolitis: a population-based study. Am J Epidemiol 1981; 114:880–887. 69. Wilson R, Kanto WP Jr, McCarthy BJ, Burton A, Lewin P, Feldman RA. Age at onset of necrotizing enterocolitis: an epidemiologic analysis. Pediatr Res 1982; 16:82–85.

Physiologic Problems in the Pediatric Surgical Patient

1125

70. De Curtis M, Paone C, Vetrano G, Romano G, Paludetto R, Ciccimarra F. A case control study of necrotizing enterocolitis occurring over 8 years in a neonatal intensive care unit. Eur J Pediatr 1987; 146:398–400. 71. Yu VY, Joseph R, Bajuk B, Orgill A, Astbury J. Perinatal risk factors for necrotizing enterocolitis. Arch Dis Child 1984; 59:430–434. 72. Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 2001; 107:E1. 73. Uauy RD, Fanaroff AA, Korones SB, Phillips EA, Phillips JB, Wright LL. Necrotizing enterocolitis in very low birth weight infants: biodemographic and clinical correlates. National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1991; 119:630–638. 74. Ryder RW, Shelton JD, Guinan ME. Necrotizing enterocolitis: a prospective multicenter investigation. Am J Epidemiol 1980; 112:113–123. 75. Stoll BJ, Kanto WP Jr, Glass RI, Nahmias AJ, Brann AW Jr. Epidemiology of necrotizing enterocolitis: a case control study. J Pediatr 1980; 96:447–451. 76. Covert RF, Neu J, Elliott MJ, Rea JL, Gimotty PA. Factors associated with age of onset of necrotizing enterocolitis. Am J Perinatol 1989; 6:455–460. 77. Snyder CL, Gittes GK, Murphy JP, et al. Survival after necrotizing enterocolitis in infants weighing less than 1000g: 25 years’ experience at a single institution. J Pediatr Surg 1997; 32:434–437. 78. Rowe MI, Reblock KK, Kurkchubasche AG, Healey PJ. Necrotizing enterocolitis in the extremely low birth weight infant. J Pediatr Surg 1994; 29:987–990. 79. Fasching G, Hollwarth ME, Schmidt B, Mayr J. Surgical strategies in very-low-birthweight neonates with necrotizing enterocolitis. Acta Paediatr Suppl 1994; 396:62–64. 80. McElhinney D, Hedrick H, Bush D, et al. Necrotizing enterocolitis in neonates with congenital heart disease: risk factors and outcomes. Pediatrics 2000; 106:1080–1087. 81. Bunton GL, Durbin GM, McIntosh N, et al. Necrotizing enterocolitis. Controlled study of 3 years’ experience in a neonatal intensive care unit. Arch Dis Child 1977; 52:772–777. 82. Davey AM, Wagner CL, Cox C, Kendig JW. Feeding premature infants while low umbilical artery catheters are in place: a prospective, randomized trial. J Pediatr 1994; 124: 795–799. 83. Lopez SL, Taeusch HW, Findlay RD, Walther FJ. Time of onset of necrotizing enterocolitis in newborn infants with known prenatal cocaine exposure. Clin Pediatr (Phila) 1995; 34: 424–429. 84. Hein HA, Lathrop SS. Partial exchange transfusion in term, polycythemic neonates: absence of association with severe gastrointestinal injury. Pediatrics 1987; 80:75–78. 85. Carmi D, Wolach B, Dolfin T, Merlob P. Polycythemia of the preterm and full-term newborn infant: relationship between hematocrit and gestational age, total blood solutes, reticulocyte count, and blood pH. Biol Neonate 1992; 61: 173–178. 86. Werner EJ. Neonatal polycythemia and hyperviscosity. Clin Perinatol 1995; 22:693–710. 87. Davis JM, Abbasi S, Spitzer AR, Johnson L. Role of theophylline in pathogenesis of necrotizing enterocolitis. J Pediatr 1986; 109:344–347. 88. Grosfeld JL, Dalsing MC, Hull M, Weber TR. Neonatal apnea, xanthines, and necrotizing enterocolitis. J Pediatr Surg 1983; 18:80–84. 89. Zanardo V, Trevisanuto D, Cagdas S, Grella P, Cantarutti F. Prenatal theophylline and necrotizing enterocolitis in premature newborn infants. Pediatr Med Chir 1997; 19: 153–156. 90. Milner ME, de la Monte SM, Moore GW, Hutchins GM. Risk factors for developing and dying from necrotizing enterocolitis. J Pediatr Gastroenterol Nutr 1986; 5:359–364.

medwedi.ru

1126

Part Nine: Special Physiologic Considerations

91. Santulli TV, Schullinger JN, Heird WC, et al. Acute necrotizing enterocolitis in infancy: a review of 64 cases. Pediatrics 1975; 55:376–387. 92. Frantz ID III, L’heureux P, Engel RR, Hunt CE. Necrotizing enterocolitis. J Pediatr 1975; 86:259–263. 93. Buch NA, Ahmad SM, Ali SW, Hassan HM. An epidemiological study of neonatal necrotizing enterocolitis. Saudi Med J 2001; 22:231–237. 94. Tam AL, Camberos A, Applebaum H. Surgical decision making in necrotizing enterocolitis and focal intestinal perforation: predictive value of radiologic findings. J Pediatr Surg 2002; 37:1688–1691. 95. Fasoli L, Turi RA, Spitz L, Kiely EM, Drake D, Pierro A. Necrotizing enterocolitis: extent of disease and surgical treatment. J Pediatr Surg 1999; 34:1096–1099. 96. Ade-Ajayi N, Kiely E, Drake D, Wheeler R, Spitz L. Resection and primary anastomosis in necrotizing enterocolitis. J R Soc Med 1996; 89:385–388. 97. O’Connor A, Sawin RS. High morbidity of enterostomy and its closure in premature infants with necrotizing enterocolitis. Arch Surg 1998; 133:875–880. 98. Griffiths DM, Forbes DA, Pemberton PJ, Penn IA. Primary anastomosis for necrotising enterocolitis: a 12-year experience. J Pediatr Surg 1989; 24:515–518. 99. Kliegman RM, Fanaroff AA. Necrotizing enterocolitis. N Engl J Med 1984; 310:1093–1103. 100. Ladd AP, Rescorla FJ, West KW, Scherer LR III, Engum SA, Grosfeld JL. Long-term follow-up after bowel resection for necrotizing enterocolitis: factors affecting outcome. J Pediatr Surg 1998; 33:967–972. 101. Stanford A, Upperman JS, Boyle P, Schall L, Ojimba JI, Ford HR. Long-term follow-up of patients with necrotizing enterocolitis. J Pediatr Surg 2002; 37:1048–1050. 102. Weber TR, Lewis JE. The role of second-look laparotomy in necrotizing enterocolitis. J Pediatr Surg 1986; 21:323–325. 103. Sugarman ID, Kiely EM. Is there a role for high jejunostomy in the management of severe necrotising enterocolitis? Pediatr Surg Int 2001; 17:122–124. 104. Luzzatto C, Previtera C, Boscolo R, Katende M, Orzali A, Guglielmi M. Necrotizing enterocolitis: late surgical results after enterostomy without resection. Eur J Pediatr Surg 1996; 6:92–94. 105. Vaughan WG, Grosfeld JL, West K, Scherer LR III, Villamizar E, Rescorla FJ. Avoidance of stomas and delayed anastomosis for bowel necrosis: the ’clip and drop-back’ technique. J Pediatr Surg 1996; 31:542–545. 106. Demestre X, Ginovart G, Figueras-Aloy J, et al. Peritoneal drainage as primary management in necrotizing enterocolitis: a prospective study. J Pediatr Surg 2002; 37:1534–1539. 107. Ahmed T, Ein S, Moore A. The role of peritoneal drains in treatment of perforated necrotizing enterocolitis: recommendations from recent experience. J Pediatr Surg 1998; 33: 1468–1470. 108. Cass DL, Brandt ML, Patel DL, Nuchtern JG, Minifee PK, Wesson DE. Peritoneal drainage as definitive treatment for neonates with isolated intestinal perforation. J Pediatr Surg 2000; 35:1531–1536. 109. Rovin JD, Rodgers BM, Burns RC, McGahren ED. The role of peritoneal drainage for intestinal perforation in infants with and without necrotizing enterocolitis. J Pediatr Surg 1999; 34:143–147. 110. Noble HG, Driessnack M. Bedside peritoneal drainage in very low birth weight infants. Am J Surg 2001; 181:416–419. 111. Cheu HW, Sukarochana K, Lloyd DA. Peritoneal drainage for necrotizing enterocolitis. J Pediatr Surg 1988; 23:557–561. 112. Wang YH, Su BH, Wu SF, et al. Clinical analysis of necrotizing enterocolitis with intestinal perforation in premature infants. Acta Paediatr Taiwan 2002; 43:199–203. 113. Camberos A, Patel K, Applebaum H. Laparotomy in very small premature infants with necrotizing enterocolitis or focal intestinal perforation: postoperative outcome. J Pediatr Surg 2002; 37:1692–1695.

114. Moss RL, Dimmitt RA, Henry MC, Geraghty N, Efron B. A meta-analysis of peritoneal drainage versus laparotomy for perforated necrotizing enterocolitis. J Pediatr Surg 2001; 36:1210–1213. 115. Nadler EP, Upperman JS, Ford HR. Controversies in the management of necrotizing enterocolitis. Surg Infect (Larchmt) 2001; 2:113–119. 116. Masumoto K, Suita S, Taguchi T. The occurrence of unusual smooth muscle bundles expressing alpha-smooth muscle actin in human intestinal atresia. J Pediatr Surg 2003; 38: 161–166. 117. Roberts HE, Cragan JD, Cono J, Khoury MJ, Weatherly MR, Moore CA. Increased frequency of cystic fibrosis among infants with jejunoileal atresia. Am J Med Genet 1998; 78: 446–449. 118. Snyder CL, Miller KA, Sharp RJ, et al. Management of intestinal atresia in patients with gastroschisis. J Pediatr Surg 2001; 36:1542–1545. 119. Werler MM, Sheehan JE, Mitchell AA. Maternal medication use and risks of gastroschisis and small intestinal atresia. Am J Epidemiol 2002; 155:26–31. 120. Danismend EN, Frank JD, Brown S. Morbidity and mortality in small bowel atresia. Jejuno-ileal atresia. Z Kinderchir 1987; 42:17–18. 121. Kullendorff CM. Atresia of the small bowel. Ann Chir Gynaecol 1983; 72:192–195. 122. Touloukian RJ. Diagnosis and treatment of jejunoileal atresia. World J Surg 1993; 17:310–317. 123. Rescorla FJ, Grosfeld JL. Intestinal atresia and stenosis: analysis of survival in 120 cases. Surgery 1985; 98:668–676. 124. Waldhausen JH, Sawin RS. Improved long-term outcome for patients with jejunoileal apple-peel atresia. J Pediatr Surg 1997; 32:1307–1309. 125. Festen S, Brevoord JC, Goldhoorn GA, et al. Excellent longterm outcome for survivors of apple peel atresia. J Pediatr Surg 2002; 37:61–65. 126. Tam PK, Nicholls G. Implications of antenatal diagnosis of smallintestinal atresia in the 1990s. Pediatr Surg Int 1999; 15:486–487. 127. Louw JH. Resection and end-to-end anastomosis in the management of atresia and stenosis of the small bowel. Surgery 1967; 62:940–950. 128. Nixon HH. Intestinal obstruction in the newborn. Arch Dis Child 1955; 13–22. 129. Takahashi A, Tomomasa T, Suzuki N, et al. The relationship between disturbed transit and dilated bowel, and manometric findings of dilated bowel in patients with duodenal atresia and stenosis. J Pediatr Surg 1997; 32:1157–1160. 130. Sheth NP, Chainani M. Deflating proximal enterostomy for jejunoileal atresia. Pediatr Surg Int 1998; 13:455–456. 131. Turnock RR, Brereton RJ, Spitz L, Kiely EM. Primary anastomosis in apple-peel bowel syndrome. J Pediatr Surg 1991; 26:718–720. 132. de Lorimier AA, Harrison MR. Intestinal plication in the treatment of atresia. J Pediatr Surg 1983; 18:734–737. 133. Weber TR, Vane DW, Grosfeld JL. Tapering enteroplasty in infants with bowel atresia and short gut. Arch Surg 1982; 117:684–688. 134. Takahashi A, Tomomasa T, Suzuki N, et al. Gastrointestinal manometry findings in a case with dilated small bowel and disturbed transit treated successfully with bowel plication. Neurogastroenterol Motil 1995; 7:97–100. 135. Takahashi A, Suzuki N, Ikeda H, et al. Results of bowel plication in addition to primary anastomosis in patients with jejunal atresia. J Pediatr Surg 2001; 36:1752–1756. 136. De Lorimier AA. The letter to the editor. J Pediatr Surg 1998; 33:950. 137. Alexander F, Babak D, Goske M. Use of intraluminal stents in multiple intestinal atresia. J Pediatr Surg 2002; 37:E34. 138. Elhalaby EA. Tube enterostomy in the management of intestinal atresia. Saudi Med J 2000; 21:769–770. 139. Hatch EI Jr, Schaller RT Jr. Surgical management of multiple intestinal atresias. Am J Surg 1986; 151:550–552.

Chapter 59: 140. Soutter AD, Askew AA. Transumbilical laparotomy in infants: a novel approach for a wide variety of surgical disease. J Pediatr Surg 2003; 38:950–952. 141. Rothenberg SS. Laparoscopic duodenoduodenostomy for duodenal obstruction in infants and children. J Pediatr Surg 2002; 37:1088–1089. 142. Bax NM, Ure BM, van der Zee DC, van Tuijl I. Laparoscopic duodenoduodenostomy for duodenal atresia. Surg Endosc 2001; 15:217. 143. Fujimoto T, Hata J, Yokoyama S, Mitomi T. A study of the extracellular matrix protein as the migration pathway of neural crest cells in the gut: analysis in human embryos with special reference to the pathogenesis of Hirschsprung’s disease. J Pediatr Surg 1989; 24:550. 144. Rosenfield NS, Ablow RC, Markowitz RI, et al. Hirschsprung disease: accuracy of the barium enema examination. Radiology 1984; 150:393–400. 145. Alizai NK, Batcup G, Dixon MF, Stringer MD. Rectal biopsy for Hirschsprung’s disease: what is the optimum method? Pediatr Surg Int 1998; 13:121–124. 146. Park WH, Choi SO, Kwon KY, Chang ES. Acetylcholinesterase histochemistry of rectal suction biopsies in the diagnosis of Hirschsprung’s disease. J Korean Med Sci 1992; 7: 353–359. 147. So HB, Becker JM, Schwartz DL, Kutin ND. Eighteen years’ experience with neonatal Hirschsprung’s disease treated by endorectal pull-through without colostomy. J Pediatr Surg 1998; 33:673–675. 148. Cilley RE, Statter MB, Hirschl RB, Coran AG. Definitive treatment of Hirschsprung’s disease in the newborn with a onestage procedure. Surgery 1994; 115:551–556. 149. Wilcox DT, Bruce J, Bowen J, Bianchi A. One-stage neonatal pull-through to treat Hirschsprung’s disease. J Pediatr Surg 1997; 32:243–245. 150. Mir E, Karaca I, Gunsar C, Sencan A, Fescekoglu O. Primary Duhamel–Martin operations in neonates and infants. Pediatr Int 2001; 43:405–408. 151. van der Zee DC, Bax KN. One-stage Duhamel–Martin procedure for Hirschsprung’s disease: a 5-year follow-up study. J Pediatr Surg 2000; 35:1434–1436. 152. Teitelbaum DH, Cilley RE, Sherman NJ, et al. A decade of experience with the primary pull-through for Hirschsprung disease in the newborn period: a multicenter analysis of outcomes. Ann Surg 2000; 232:372–380. 153. Georgeson KE. Laparoscopic-assisted pull-through for Hirschsprung’s disease. Semin Pediatr Surg 2002; 11:205–210. 154. Georgeson KE, Cohen RD, Hebra A, et al. Primary laparoscopicassisted endorectal colon pull-through for Hirschsprung’s disease: a new gold standard. Ann Surg 1999; 229:678–682. 155. Rothenberg SS, Chang JH. Laparoscopic pull-through procedures using the harmonic scalpel in infants and children with Hirschsprung’s disease. J Pediatr Surg 1997; 32:894–896. 156. Gao Y, Li G, Zhang X, et al. Primary transanal rectosigmoidectomy for Hirschsprung’s disease: preliminary results in the initial 33 cases. J Pediatr Surg 2001; 36:1816–1819. 157. Albanese CT, Jennings RW, Smith B, Bratton B, Harrison MR. Perineal one-stage pull-through for Hirschsprung’s disease. J Pediatr Surg 1999; 34:377–380. 158. Shankar KR, Losty PD, Lamont GL, et al. Transanal endorectal coloanal surgery for Hirschsprung’s disease: experience in two centers. J Pediatr Surg 2000; 35:1209–1213. 159. Teeraratkul S. Transanal one-stage endorectal pull-through for Hirschsprung’s disease in infants and children. J Pediatr Surg 2003; 38:184–187. 160. Van Leeuwen K, Geiger JD, Barnett JL, Coran AG, Teitelbaum DH. Stooling and manometric findings after primary pull-throughs in Hirschsprung’s disease: perineal versus abdominal approaches. J Pediatr Surg 2002; 37: 1321–1325. 161. Carcassonne M, Guys JM, Morrison-Lacombe G, Kreitmann B. Management of Hirschsprung’s disease: curative surgery before 3 months of age. J Pediatr Surg 1989; 24:1032–1034.

Physiologic Problems in the Pediatric Surgical Patient

1127

162. Ikeda K, Goto S. Total colonic aganglionosis with or without small bowel involvement: an analysis of 137 patients. J Pediatr Surg 1986; 21:319–322. 163. Bickler SW, Harrison MW, Campbell TJ, Campbell JR. Longsegment Hirschsprung’s disease. Arch Surg 1992; 127: 1047–1050. 164. Ikawa H, Masuyama H, Hirabayashi T, Endo M, Yokoyama J. More than 10 years’ follow-up to total colonic aganglionosis— severe iron deficiency anemia and growth retardation. J Pediatr Surg 1997; 32:25–27. 165. Coran AG, Teitelbaum DH. Recent advances in the management of Hirschsprung’s disease. Am J Surg 2000; 180:382–387. 166. Endo M, Watanabe K, Fuchimoto Y, Ikawa H, Yokoyama J. Long-term results of surgical treatment in infants with total colonic aganglionosis. J Pediatr Surg 1994; 29:1310–1314. 167. Fouquet V, De Lagausie P, Faure C, et al. Do prognostic factors exist for total colonic aganglionosis with ileal involvement? J Pediatr Surg 2002; 37:71–75. 168. Rescorla FJ, Morrison AM, Engles D, West KW, Grosfeld JL. Hirschsprung’s disease. Evaluation of mortality and longterm function in 260 cases. Arch Surg 1992; 127:934–941. 169. Levy M, Reynolds M. Morbidity associated with total colon Hirschsprung’s disease. J Pediatr Surg 1992; 27:364–366. 170. Sarioglu A, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Clinical risk factors of Hirschsprung-associated enterocolitis. I. Preoperative enterocolitis. Turk J Pediatr 1997; 39:81–89. 171. Sarioglu A, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Clinical risk factors of hirschsprung-associated enterocolitis. II. Postoperative enterocolitis. Turk J Pediatr 1997; 39(1): 91–98. 172. Elhalaby EA, Coran AG, Blane CE, Hirschl RB, Teitelbaum DH. Enterocolitis associated with Hirschsprung’s disease: a clinicalradiological characterization based on 168 patients. J Pediatr Surg 1995; 30:76–83. 173. Blane CE, Elhalaby E, Coran AG. Enterocolitis following endorectal pull-through procedure in children with Hirschsprung’s disease. Pediatr Radiol 1994; 24:164–166. 174. Yoo SY, Jung SH, Eom M, Kim IH, Han A. Delayed maturation of interstitial cells of Cajal in meconium obstruction. J Pediatr Surg 2002; 37:1758–1761. 175. Neal MR, Seibert JJ, Vanderzalm T, Wagner CW. Neonatal ultrasonography to distinguish between meconium ileus and ileal atresia. J Ultrasound Med 1997; 16:263–266. 176. Burke MS, Ragi JM, Karamanoukian HL, et al. New strategies in nonoperative management of meconium ileus. J Pediatr Surg 2002; 37:760–764. 177. Rescorla FJ, Grosfeld JL. Contemporary management of meconium ileus. World J Surg 1993; 17:318–325. 178. Harberg FJ, Senekjian EK, Pokorny WJ. Treatment of uncomplicated meconium ileus via T-tube ileostomy. J Pediatr Surg 1981; 16:61–63. 179. Steiner Z, Mogilner J, Siplovich L, Eldar S. T-tubes in the management of meconium ileus. Pediatr Surg Int 1997; 12:140–141. 180. Nguyen LT, Youssef S, Guttman FM, Laberge JM, Albert D, Doody D. Meconium ileus: is a stoma necessary? J Pediatr Surg 1986; 21:766–768. 181. Mak GZ, Harberg FJ, Hiatt P, Deaton A, Calhoon R, Brandt ML. T-tube ileostomy for meconium ileus: four decades of experience. J Pediatr Surg 2000; 35:349–352. 182. Myers NA. The early history of oesophageal atresia and tracheoesophageal fistula. In: Beasley SW, Myers NA, Auldist AW, eds. Oesophageal Atresia. London: Chapman and Hall Medical, 1991:1–16. 183. Merei JM, Hutson JM. Embryogenesis of tracheo esophageal anomalies: a review. Pediatr Surg Int 2002; 18:319–326. 184. Crisera CA, Connelly PR, Marmureanu AR, et al. Esophageal atresia with tracheoesophageal fistula: suggested mechanism in faulty organogenesis. J Pediatr Surg 1999; 34:204–208. 185. Spilde TL, Bhatia AM, Marosky JK, et al. Complete discontinuity of the distal fistula tract from the developing gut: direct histologic evidence for the mechanism of tracheoesophageal fistula formation. Anat Rec 2002; 267:220–224.

medwedi.ru

1128

Part Nine: Special Physiologic Considerations

186. Ioannides AS, Henderson DJ, Spitz L, et al. Role of sonic hedgehog in the development of the trachea and oesophagus. J Pediatr Surg 2003; 38(1):29–36. 187. Crisera CA, Maldonado TS, Longaker, MT, et al. Defective fibroblast growth factor signaling allows for nonbranching growth of the respiratory-derived fistula tract in esophageal atresia with tracheoesophageal fistula. J Pediatr Surg 2000; 35:1421–1425. 188. Spilde TL, Bhatia AM, Ostlie D, et al. A role for sonic hedgehog signaling in the pathogenesis of human tracheoesophageal fistula. J Pediatr Surg 2003; 38:465–468. 189. Langer JC, Hussain H, Khan A, et al. Prenatal diagnosis of esophageal atresia using sonography and magnetic resonance imaging. J Pediatr Surg 2001; 36:804–807. 190. Rothenberg SS. Thorascopic repair of tracheoesophageal fistula in newborns. J Pediatr Surg 2002; 37:869–872. 191. Little DC, Rescorla JL, Grosfeld KW, et al. Long-term analysis of children with esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2003; 38:852–856. 192. Romeo C, Bonanno N, Baldari S, et al. Gastric motility disorders in patients operated on for esophageal atresia and tracheoesophageal fistula: long-term evaluation. J Pediatr Surg 2000; 35(5):740–744. 193. Filston HC, Shorter NA. Esophageal atresia and tracheoesophageal malformations. In: Ashcraft KW, Murphy JP, Sharp RJ, eds. Pediatric Surgery. 3rd ed. Philadelphia: WB Saunders, 2000. 194. Torfs CP, Curry CJ, Bateson TF, et al. A population-based study of congenital diaphragmatic hernia. Teratolog 1992; 46: 555–565. 195. Katz AL, Wiswell TE, Baumgart S. Contemporary controversies in the management of congenital diaphragmatic hernia. Clin Perinatol 1998; 25:219–248. 196. deLorimer AA, Tierney DF, Parker HR. Hypoplastic lungs in fetal lambs with surgically produced congenital diaphragmatic hernia. Surgery 1967; 62:12–17. 197. Keijzer R, Liu J, Deimling J, et al. Dual-hit hypothesis explains pulmonary hypoplasia in the Nitrofen model of congenital diaphragmatic hernia. Am J Pathol 2000; 156:1299–1306. 198. Guilbert TW, Gebb SA, Shannon JM. Lung hypoplasia in the nitrofen model of diaphragmatic hernia occurs early in development. Am J Physiol Lung Cell Mol Physiol 2000; 279: 1159–1171. 199. Kluth D, Tenbrinck R, von Ekesparre, et al. The natural history of congenital diaphragmatic hernia and pulmonary hypoplasia in the embryo. J Pediatr Surg 1993; 28:456–463. 200. Iritani I. Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol 1984; 169:133–139.

201. Acosta JM, Thebaud B, Castillo C, et al. Novel mechanisms in murine nitrofen-induced pulmonary hypoplasia: FGF-10 rescue in culture. Am J Physiol Lung Cell Mol Physiol 2001; 281:250–257. 202. Unger S, Copland I, Tibboel D, et al. Down-regulation of sonic hedgehog expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia. Am J Pathol 2003; 162:547–555. 203. Hirschl R. Innovative therapies in the management of newborns with congenital diaphragmatic hernia. Semin Pediatr Surg 1996; 5:256–265. 204. Reyes C, Chang LK, Waffarn F, et al. Delayed repair of congenital diaphragmatic hernia with early high frequency oscillatory ventilation during preoperative stabilization. J Pediatr Surg 1998; 33:1010–1016. 205. Boloker J, Bateman DA, Wung JT, et al. Congenital diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnea/spontaneous respiration/elective repair. J Pediatr Surg 2002; 37:357–366. 206. Lally KP. Congenital diaphragmatic hernia. Curr Opin Pediatr 2002; 14:486–490. 207. Hedrick MH, Estes JM, Sullivan KM, et al. Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J Pediatr Surg 1994; 29:612–617. 208. Flake AW, Crombleholme TM, Johnson MP, et al. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol 2000; 183:1059–1066. 209. Kamiyama M, Kawahara H, Okuyama H, et al. Gastroesophageal reflux after repair of congenital diaphragmatic hernia. J Pediatr Surg 2002; 37:1681–1684. 210. Skandalakis JE, Gray SW, Ricketts R, et al. The small intestines. In: Skandalakis JE, Gray SW, eds. Embryology for Surgeons. Baltimore: Williams & Wilkins, 1994:184–189. 211. Clark LA, Oldham KT. Malrotation. In: Ashcraft KW, Murphy JP, Sharp RJ, eds. Pediatric Surgery. 3rd ed. Philadelphia: WB Saunders, 2000. 212. Mehall JR, Chandler JC, Mehall RL, et al. Management of typical and atypical intestinal malrotation. J Pediatr Surg 2002; 37:1169–1172. 213. Prasil P, Flageole H, Shaw KS, et al. Should malrotation in children be treated differently according to age? J Pediatr Surg 2000; 35:756–758. 214. Ladd WE, Gross RE. Intestinal obstruction resulting from malrotation of the intestines and colon. In: Abdominal Surgery of Infancy and Childhood. Philadelphia: WB Saunders, 1941. 215. Bass KD, Rothenberg SS, Chang JHT. Laparoscopic Ladd’s procedure in infants with malrotation. J Pediatr Surg 1998; 33:279–281.

60 Physiologic Considerations in the Elderly Surgical Patient Ronnie Ann Rosenthal and Melissa F. Perkal

INTRODUCTION Physicians and surgeons have long understood that the physiological and pathological processes characteristic of the neonatal period are considerably different from those of the mature adult. The same is true of physiological and pathological characteristics at the other extreme of life. Although internists have recognized the need to provide special ‘‘geriatric’’ care for more than four decades, the adjustment of surgical practice to meet the specific needs of the elderly has only recently begun in a programmatic way. The ‘‘graying’’ of the population has created the need to provide surgical care to an ever-increasing number of older patients, and the technological explosion has provided the means to do so safely. In the next 25 years, the portion of the population over the age of 65 is expected to grow from the present 12.4% to nearly 20%, or over 70 million people. Persons over the age of 85 comprise the most rapidly growing segment of this population. Their number is expected to increase fivefold, to over 20 million, by 2050 (Fig. 1) (1). As the number of elderly persons continues to grow, so does the average life expectancy at all ages. At present, life expectancy for a male at age 65 is 16.6 years and at age 85 is 5.7 years. For a female, life expectancy at 65 and 85 years of age is 19.5 years and 6.9 years, respectively (2). The rise in the number of surgical procedures performed on older patients is, in part, a reflection of this aging population. In 1980, 19% of all operations performed in

nonfederally funded, short stay hospitals were on patients over 65 years of age. By 2002, this portion reached 36%, and if obstetrical procedures are excluded, this portion was 43% (3). In federally funded hospitals, this proportion is even higher. For example, in 2002, in the General Surgical Service at the Veterans Affairs Medical Center in West Haven, Connecticut, 83% of patients having major abdominal operations were over the age of 60, and 53% were over the age of 70. This increase is not, however, only a reflection of the increased number of older people, but also of the growing awareness that older patients can truly benefit from such surgical intervention. Although age was previously a contraindication to operations such as pancreaticoduodenectomy, major hepatic resection, major cardiac revascularization, and transplantation, these and other major procedures are now performed routinely on older patients with results that are comparable to those in younger patients. The indication for surgical treatment in the elderly, therefore, is increasingly determined by the need to provide maximal disease management rather than the desire to avoid surgical risk. It is important, however, to remember that the elderly surgical patient is frequently not physiologically equivalent to the younger patient and that comorbid illnesses can impact enormously on the surgical outcome. Understanding the physiological and pathological differences and adjusting care accordingly is essential for successful management.

PHYSIOLOGY AND PATHOLOGY OF AGING The processes of maturation, aging, and senescence describe the life cycle of most living organisms, including man. Aging and senescence are commonly used interchangeably to refer to the myriad molecular and cellular events that eventually lead to the demise of the organism. These terms are not necessarily synonymous, although in clinical medicine the aging process is believed to incorporate predetermined or programmed cellular events that inevitably contribute to a limitation of longevity. The development of some diseases in the elderly patient may be directly linked to cellular events related to senescence, whereas the clinical presentation of others may be altered by aging-related changes in the physiological milieu. Cristafalo et al. (4) have identified five attributes that characterize the human aging process, which are as follows: Figure 1 Projected population growth of persons over the age of 65 in the United States. Source: From Ref. 1.

&

&

An increase in mortality with increasing age (after maturation) A change in the biochemical composition of the body

medwedi.ru 1129

1130

Part Nine: Special Physiologic Considerations

Figure 2 Life expectancy in the United States, 1900 to 1988. Source: From Ref. 2.

& & &

A decline in physiological function A decreased ability to adapt to the environment An increased susceptibility to disease

Although the elucidation of molecular and cellular events is necessary for a complete understanding of the process of aging and senescence, an awareness of the clinical manifestations of the characteristics listed above is essential for the provision of appropriate care to the elderly patient.

Increasing Mortality with Age The risk of death increases exponentially with increasing age, as described initially in 1825 by Gompertz (5). The relationship between age and survival is frequently shown as a Gompertzian function. Figure 2 shows the average or median survival of a population (the age at which 50% of the population is alive) (2). In the past century, there has been a rectangularization of the survival curve with a larger and larger percentage of the population living into old age. Although the median survival of man has more than doubled since the time of Hippocrates, the maximum lifespan potential (MLSP) has remained essentially constant at 100 to 115 years. The dramatic shift in median survival has been attributed to an elimination of the causes of early mortality and an improvement in sanitation and nutrition. Although these changes have paralleled the expansion of medical knowledge, no modern medical breakthrough has impacted greatly on median survival or altered MLSP. Recently, the National Institute on Aging (NIA) has begun a new effort to increase life expectancy and longevity by challenging investigators to make novel proposals with this goal (6). Under the auspices of the NIA’s Interventions Testing Program, several compounds are presently being tested for their effects on prolonging life (7). The above observations suggest that survival in all species may be limited in a predetermined way, and experimental observations support this concept (Fig. 3). Human fibroblasts maintained in culture undergo a predictable number of proliferative cycles, or doublings, before dying. This number is many times greater than the number of doublings for mouse fibroblasts maintained in identical culture (8). In intact animals, the only intervention that consistently increases median survival and MLSP is caloric restriction (CR). This effect was first described by McCay in 1935 (9). In 1985, Yu et al. (10) showed that rats fed a diet containing

only 60% of the calories consumed by ad libitum fed littermates had a 50% higher median survival and MLSP than the animals receiving the full caloric load (Fig. 4). Over the past two decades, there has been a great increase in interest in the molecular explanation for the benefit of CR. Many theories have been proposed but two have gained widespread recognition. The first attributes the benefit to a decrease in oxidative damage caused by a decrease in intracellular accumulation of reactive oxygen species. The second credits the improvement in glucose and insulin metabolism associated with CR (11). Recently, there is growing opinion that the effects of CR are mediated through the stress response genes. The Hormesis Hypothesis, as it is called, suggests that a low intensity stressor, such as CRs, stimulates a survival response

Figure 3 Correlation between PDL and MLS potential. Fibroblasts from longer-lived species undergo more cell divisions before senescence than cells derived from shorter-lived species. Abbreviations: MLS, maximal life span; PDL, population-doubling capacity. Source: From Ref. 8.

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

Figure 4 Survival curve for ad libitum fed (solid circles) and calorically restricted (open circles) rats. Restriction of calories to 60% of ad libitum–fed levels results in a dramatic increase in life span and maximum life-span potential. Source: From Ref. 10.

characterized by metabolic changes and augmented host defenses (12). This theory provides a unifying framework for many of the observations made about oxidative damage and glycemic modulation. Although CR has been shown to increase MLSP in experimental animals, longitudinal studies in humans show a small survival advantage for the elderly who are slightly ‘‘overweight’’ (body composition below) (13). Whether or not human life-span potential is actually increasing, the elderly now represent the fastest growing segment of our population. The number of persons reaching their 100th birthday has increased so greatly that their names can no longer be read on the morning television programs. The number reaching their 110th birthday, however, is still quite small.

Changes in Body Composition Aging is associated with specific biochemical, anatomical, and functional changes in virtually all body tissues and

1131

organs. Age-related effects have been documented at the chromosomal level, at the protein-processing level, and at the level of catabolism. Changes in molecular structure may be expressed in a tissue-specific manner, however, and organ systems must be evaluated individually to assess how age-related changes in composition are manifested in any single patient. Compositional changes contribute to changes in organ function, such as the deposition of lipofuscin or ‘‘age pigment’’ in Purkinje cells, which results in conduction disturbances and altered cardiac contractility (14). Increased cross-linking of matrix molecules such as collagen (15) or the accumulation of increased amounts of protein due to impaired protein catabolism (16) can also alter the function of specific organs. An explanation for the increased occurrence of cross-linking of nucleic and matrix molecules is the age-related increase in oxidative damage to proteins due to excess free-radical formation (17). Impaired metabolism of reactive oxygen species may cause extensive damage to proteins, which in turn provides a favorable site for glucose moieties to bind to amino acids. This glycation reaction may promote the cross-linking of proteins such as osteocalcin and the lens protein crystalin, which may result in altered bone density or cataract formation (4). Alterations in musculoskeletal tissues account for the physiognomic changes associated with aging, including shortened stature, impaired ambulation, and decreased chest wall excursion (Fig. 5) (18). These changes impact greatly on the postoperative recovery of elderly patients by increasing susceptibility to complications such as atelectasis, pneumonia, and pulmonary embolism. However, because tissue composition is not uniformly affected in all elderly patients, it is inappropriate to institute compensatory measures, such as prolonged endotracheal intubation, based only upon older age. Nutritional effects account for some of the most important changes in body composition in the elderly (19). A significant prevalence of undernutrition has been documented in noninstitutionalized, free-living elderly, and reduced protein intake is common even among affluent

Figure 5 Four randomly selected patients from the ambulatory section of a nursing home, illustrating short stature, osteoporotic kyphosis, and relatively long extremities. Ages from left to right: 82, 78, 79, and 94 years. Source: From Ref. 18.

medwedi.ru

1132

Part Nine: Special Physiologic Considerations

older persons (19–21). These dietary changes are multifactorial (Table 1), but are thought to contribute to the significant loss of lean body mass (muscle) in elderly subjects. This loss translates into reduced strength and mobility, as well as a decline in creatinine excretion. The shift from lean body mass to increase adipose tissue may also be mediated in part through an age-related decline in pituitary growth hormone (GH) activity (22). Within the aging muscle, the synthesis of contractile proteins declines, as does the number of actual muscle fibers. Declining metabolic activity of the muscles combined with alterations in the neuromuscular junctions results in less efficient muscular activity and easy fatigability (23). In addition to impairing the strength and mobility of the elderly patient, the decrease in muscle mass results in a smaller pool of amino acids available for the synthesis of other body proteins. Protein intake, therefore, must be maintained at levels sufficient to prevent further muscle mass losses. Decreased levels of exercise further exacerbate the loss of muscle mass, and together with a relative increase in percent body fat, contributes to progressive insulin resistance and a lower basal metabolic rate (24,25). Reduced calcium and vitamin D intake contributes to osteoporosis and loss of bone mass, which is further compounded by reduced levels of 25-hydroxyvitamin D due to reduced exposure of the skin to sunshine. The shift in body mass from muscle to adipose tissue is complicated by the use of inaccurate methods to assess obesity in older persons (26), and by the metabolic consequences of increased adipose tissue. The standard comparisons of height to weight is an unreliable method to measure obesity in the elderly, due to both the shift in body mass from muscle to fat and the changes in skeletal configuration. Because weight generally increases linearly with the square of body height, the computation of a body mass index (BMI ¼ wt/ht2), using metric units of measurement, partially corrects weight for height and affords a better estimate of obesity. The computation of BMI must be corrected for age, however, to normalize indices of obesity in the elderly. The establishment of ‘‘normal’’ ranges of BMI for the elderly still ignores the effects of the increased ‘‘fatness’’ on metabolism and mortality. A comprehensive analysis of 4.2 million insurance policy holders indicates that the lowest mortality risks are associated with a progressive rise in BMI with age (27). The BMI associated with the lowest mortality increases from 21.4 in the 20- to 29-year-old group, to 22.9 in the 40- to 49-year-old group, and to 26.6 in the 60- to 69-year-old group. This roughly corresponds to an increase

Table 1 Findings in the Medical History Suggesting Increased Risk for Nutrient Deficiency Recent weight loss Restricted dietary intake (limited variety and food avoidances) Psychosocial situation (depression, cognitive impairment, isolation, and economic difficulties) Problems with eating, chewing, and swallowing Previous surgery Increased losses resulting from gastrointestinal disorders such as malabsorption and diarrhea Systemic disease interfering with appetite or eating (chronic lung, liver, heart, and renal disease, abdominal angina, and cancer) Excessive alcohol use Medications that interfere with appetite and/or nutrient metabolism Source: From Ref. 21.

Figure 6 The decrease in relative anesthetic requirement with age in unsedated humans. Abbreviations: C, cyclopropane; H, halothane; I, isoflurane; T, thiopental. Source: From Ref. 30.

of about 10 pounds per decade in the weight of the best survivors. Recent data from the National Health and Nutrition Examination Survey (NHANES I, II, III) confirmed that mildly increased BMI (25 to < 30) in persons over the age of 70 is not associated with increased risk of death, whereas underweight (BMI < 8.5) and obesity (BMI > 30) are (15). In addition to a progressive loss of lean body mass, and a corresponding increase in adiposity, aging is also associated with a decrease in total body water. Red cell mass is usually maintained in healthy individuals, but circulating plasma volume is reduced, particularly in debilitated patients (28). This decreased volume of distribution can result in higher than expected concentrations of administered drugs, and a correspondingly exaggerated drug effect. For example, the initial volume of distribution of thiopental in 20 to 40 year old subjects is 15 to 30 L, although in 60 to 90 year olds, it is 3 to 7 L (29). This fact dictates a reduction in dosing levels of many anesthetic drugs (Fig. 6) (30). The increase in relative body fat also has significant pharmacological implications for surgical management, due to an increased distribution compartment for lipid-soluble drugs. The increase in the reservoir of lipid-soluble agents can result in a lower than expected plasma concentration of the agents initially, with a longer drug effect due to protracted clearance (30). These changes in body composition, together with changes in the functions of organs responsible for the clearance of drugs, mandate more careful anesthetic management and closer postoperative surveillance of elderly surgical patients.

Decline in Physiologic Function With increasing age, there is a clear decline in physiologic function, although the rate and significance of the decline may vary considerably among individuals and among organ systems. In the resting state, these changes may have minimal consequences, but when physiological reserves are needed to respond to a stress such as surgery, overall performance may deteriorate.

Cardiovascular Function Morphological changes in the myocardium, conducting pathways, valves, and vasculature of the heart accompany advancing age, although it is often difficult to separate the

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

changes associated with aging from those caused by disease. The functional implications of many of these changes are also variable and frequently not well defined (Table 2). The overall weight of the heart increases slightly in females but not in males, whereas the thickness of the ventricular septum increases significantly regardless of gender (31). There is also an increase in the fat content of the epicardium overlying the right ventricle. The number of myocytes declines whereas the size of the cells and the content of lipofuscin, the degenerative pigment, increases. The deposition of amyloid protein increases significantly with age, and some form of the protein can be found in the hearts of nearly half of the persons over the age of 70 (32). Collagen and elastin content also increases and fibrotic areas may appear throughout the myocardium. Whereas any one of these features alone may be of limited functional significance, the sum of these changes is a decline in ventricular compliance (33). In the conducting system, the most pronounced change is the replacement of nearly 90% of the autonomic cells in the sinus node by fat and connective tissue (34). There is also a less impressive increase in fibrosis in the intranodal tracts and partial loss of proximal bundle fascicles between the left bundle and the bundle of His. These changes may contribute to the high incidence of sick sinus syndrome, atrial arrhythmias, and bundle branch blocks. Valvular anatomy is also altered with aging. Sclerosis and calcification of the aortic valve is most common, but is usually of little functional importance (35). Calcification and sclerosis occurs less frequently in the mitral valve, but because of the juxtaposition of the valve to the artrioventricluar (AV) node and conducting bundles, calcification at this location may be responsible for AV nodal and bundle branch blocks. Progressive dilation of all four valvular annuli has also been described (36). It is thought that this dilation may be responsible for the multivalvular regurgitation frequently demonstrated in healthy older people. Lastly, morphological changes can be seen in both the coronary and peripheral vessels. The endothelial cells lining the vessels change size and shape and flow may become more turbulent. The subendothelial and medial layers thicken, and calcification in these layers increases independent of atherosclerosis. As a result, the vessels become progressively more rigid and less distensible (37). These

Table 2 Age-Related Changes in the Heart and Great Vessels Morphologic changes # Number of myocytes " Interstitial collagen content " Amyloid deposition " Ventricular septal thickness " Myocardial fibrosis # Elasticity # Atrial pacemakers Replacement of autonomic tissue Fibrosis of the cardiac skeleton Calcification at base of aortic valve " Stiffness of the great vessels and outflow tract # Reactivity of baroreceptors

Functional significance # " " "

Ventricular compliance Diastolic pressure Diastolic relaxation time End diastolic volume

Bundle of His damage " Bundle branch blocks AV conduction abnormalities " Atrial arrhythmias " Afterload on the LV Compensatory LVH " Systolic blood pressure

Abbreviations: LVH, left ventricular hypertrophy; AV, Atrioventricular.

1133

changes in the peripheral vasculature probably contribute to an increase in systolic blood pressure, an increased resistance to ventricular emptying, and a compensatory loss of myocytes with thickening of the ventricular wall (38). These degenerative changes in the coronary vessels may appear as calcifications on radiographs and, therefore, may be mistaken for the calcifications caused by atherosclerotic disease. The functional implications of aging on the heart have been difficult to accurately assess because alterations in body composition, metabolic rate, general states of fitness, and underlying disease all influence cardiac performance (37). It is now generally accepted that systolic function, both at rest and in response to exercise, does not change with age. Cardiac output and ejection fraction at rest are maintained in spite of the increased afterload imposed by the stiffening of the outflow tract (39). In younger persons, cardiac output during periods of increased demand is maintained by increasing heart rate. With aging, the heart becomes less responsive to catecholamines, possibly secondary to changes in receptor function, and thereby loses the ability to augment cardiac output by increasing rate (37). Maintenance of cardiac output, therefore, becomes more dependent on ventricular filling (preload). Because of this dependence on preload, even minor hypovolemia may result in severe compromise in cardiac performance. Diastolic function, which depends on myocardial relaxation rather than contraction, is more significantly affected by aging. In 50% of patients over the age of 80 with heart failure, systolic function is preserved whereas diastolic function is impaired (40). Because relaxation requires greater energy expenditure and, therefore, more oxygen consumption than does contraction, it is more susceptible to declining oxygen availability. With age, there is a progressive decrease in the partial pressure of arterial oxygen. As a consequence, relaxation is prolonged and even mild additional hypoxia from stress can result in significant diastolic dysfunction (41). This prolongation of relaxation, combined with the decreased ventricular compliance that results from progressive fibrosis, leads to decreased ventricular filling and higher diastolic pressures. This in turn can result in pulmonary vascular congestion and signs of heart failure. As a result of impaired early diastolic filling, maintenance of adequate preload becomes more dependent on the contribution of the atrium. Loss of this atrial contraction or even minor hypovolemia can, therefore, result in significant impairment of cardiac function (41). Alterations at the cellular level have also been implicated in the diastolic dysfunction that accompanies aging. A decline in the rate of calcium sequestration by the sacroplasmic reticulum following myocardial excitation and an increase in net calcium influx across the sacroplasmic reticulum (42) have both been suggested as possible etiologic factors. Distinguishing systolic from diastolic dysfunction may be difficult. Systolic failure is usually gradual in onset and progressive, whereas diastolic failure is abrupt and the decline is rapid. Some distinguishing features are listed in Table 3 (43). The treatment is also different. Although digitalis and diuretics are indicated in systolic failure, the use of these agents in diastolic dysfunction may exacerbate the derangement. Diastolic abnormalities are treated with agents that improve preload and ventricular relaxation, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and beta-adrenergic antagonists (Table 4) (43,44).

medwedi.ru

1134

Part Nine: Special Physiologic Considerations

Table 3 Clinical Differentiation of Diastolic Vs. Systolic Dysfunction in Patients with Heart Failure Systolic dysfunction Past history

Presentation

Physical examination Radiographic findings Electrocardiogram Echocardiogram

Diastolic dysfunction

Hypertension Myocardial infarction Diabetes Chronic valvular insufficiency disorders Younger than 65 yrs Progressive shortness of breath Displaced PMI S3 gallop Pulmonary congestion Cardiomegaly Q waves Decreased LVEF

Hypertension Renal disease Diabetes Aortic stenosis 65 yrs or older Acute pulmonary edema Sustained PMI S4 gallop Pulmonary congestion Normal sized heart LVH Normal or increased LVEF

Abbreviations: LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; PMI, point of maximal impact. Source: From Ref. 43.

It is also important to remember that the manifestation of cardiac diseases in the elderly may be nonspecific and atypical. Whereas chest pain is still the most common symptom of myocardial infarction, as many as 40% of older patients will present in a nonclassical manner with symptoms such as shortness of breath, syncope, acute confusion, or stroke (45). Cardiac complications are the most common cause of death in the postoperative period. Identification of patients at risk for postoperative cardiac events is the basis for most preoperative evaluation strategies (Table 1).

Respiratory Function The normal decline in respiratory function that accompanies aging can be attributed to changes in the chest wall and the lung (Table 5) (46). There is a decline in chest wall compliance secondary to changes in structure caused by kyphosis and exaggerated by vertebral collapse. There is decreased

Table 5 Age-Related Changes in the Chest Wall and Lung Morphologic change

Functional significance

Thorax Calcification of bronchial and costal cartilage " Costovertebral stiffness " Rigidity of chest wall " Anteroposterior diameter (kyphosis) Wasting of respiratory muscles Lung Enlarged alveolar ducts # Supporting duct frame work, enlarged alveoli Thinning, separation of alveolar membrane " Mucous gland " Number, thickness of elastic fibers (?) " Tissue extensibility (alveolar wall) # Pulmonary capillary network " Fibrosis of pulmonary capillary intima

" Resistance to deformation of chest wall " Use of diaphragm in ventilation " Tidal volume Response to exercise hyperpnea # Maximal voluntary ventilation # Surface area for gas exchange " Physiologic dead space # Lung elastic recoil VC, RV/TLC # Ventilatory flow rate # Ventilation distribution " Resistance to flow in small airways # Ventilation: blood flow equality

Abbreviations: RV, residual volume; TLC, total lung capacity; VC, vital capacity. Source: From Ref. 46.

mobility of the ribs caused by calcification of the costal cartilage and contractures of the intercostal muscles (12). There is also a progressive decrease in the strength of the respiratory muscles (47), which leads to as much as a 50% decline in the maximum inspiratory and expiratory force generated, and easy fatigability. In the lung, the major change with age is the loss of elastic recoil in the alveoli. The elastic properties of the lung are responsible for maintaining the patency of the small airways. Loss of elasticity leads to increased alveolar compliance with collapse of these airways and subsequent uneven alveolar ventilation and air trapping (48). Uneven alveolar ventilation leads to ventilation–perfusion

Table 4 Pharmacologic Management of Heart Failure Secondary to Diastolic Dysfunction Therapeutic agents

Goals of therapy

Diuretics

Decrease in blood volume Decrease in ventricular filling pressure

ACE inhibitors

Decrease in afterload Regression of LVH Regression of myocardial interstitial fibrosis Enhanced ventricular relaxation Decrease in afterload Regression of LVH Relief of myocardial ischemia Slow heart ratea Enhanced ventricular relaxation Decrease in afterload Regression of LVH Relief of myocardial ischemia Slow heart rate Enhance ventricular relaxation

Calcium channel blockers

b-Blockers

a

Considerations Abrupt reduction in volume may produce hypotension and decreased CO; close monitoring for hypotension and renal dysfunction necessary; no effect on regression of LVH Agents with most marked effect on regression of LVH; acute unloading effects may produce hypotension and decreased CO; close monitoring of BP and renal function necessary Acute unloading effects may produce hypotension and decreased CO; antiischemic effects are beneficial in patients with CAD; may be detrimental when both systolic and diastolic dysfunction present and beneficial in slowing heart rate in patients with atrial fibrillationa; combination with bblockers may cause severe bradycardiaa Limited effect on LVH regression; anti-ischemic effect beneficial in patients with CAD; beneficial in slowing heart rate in patients with atrial fibrillation

Verapamil and diltiazem. Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CAD, coronary artery disease; CO, cardiac output; LVH, left ventricular hypertrophy. Source: From Ref. 43.

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

mismatches, which in turn cause a decline in arterial oxygen tension of approximately 0.3% or 0.42 mmHg/yr. Although there is a decline in the partial pressure of oxygen, the partial pressure of CO2 does not change, in spite of an increase in the dead space or wasted ventilation. This may be due, in part, to the decline in the production of CO2 that accompanies the falling basal metabolic rates. Air trapping is also responsible for an increase in the residual volume (RV) or the volume remaining after maximal expiration. The loss of support of the small airways also leads to compression during forced expiration, which limits dynamic lung volumes and flow rates. Forced vital capacity (VC) decreases by 14 to 30 cc/yr and one second forced expiratory volume decreases by 23 to 32 cc/yr (in males) (48). The overall effect of loss of elastic inward recoil is balanced somewhat by the decline in chest wall outward force. Total lung capacity (TLC), therefore, remains unchanged, and there is only a mild increase in resting lung volume or functional residual capacity. Because TLC remains unchanged, the increase in RV results in a decrease in VC (Fig. 7) (46). Changes in the control of ventilatory responses with age are not yet fully clarified. Older data in men describe a fall in response to hypoxia and hypercapnia by 50% and 40%, respectively (49). Recent studies in healthy women show no change in hypoxic response with age (50). In addition to these intrinsic changes, pulmonary function is affected by alterations in the ability of the respiratory system to protect against environmental injury and infection. There is a progressive decrease in T-cell function (see below) and a decline in mucociliary clearance. The loss of cough reflex secondary to neurologic disorders may predispose one to aspiration (51). The increased frequency and severity of pneumonia in older persons has been attributed to these factors and to an increased incidence of oropharyngeal colonization with gram negative organisms. This colonization correlates closely with comorbidity and with the ability of older patients to perform activities of daily living (ADL). This fact lends support to the idea that functional capacity is a crucial factor in assessing the risk of pneumonia in older patients (52).

1135

Renal Function Morphologic and functional changes also occur in the kidney and lower urinary tract with aging (Table 6). Between the ages of 25 and 85, there is a progressive decrease in kidney size, length, and volume. The majority of the tissue loss is in the cortex where approximately 40% of the nephrons become sclerotic and the remaining functional units hypertrophy in a compensatory manner. Sclerosis of the glomeruli is accompanied by atrophy of the afferent and efferent arterioles, and by a decrease in renal tubular cell number. Renal blood flow also falls by approximately 50%. This decline is thought to be secondary to changes in the vessels supplying the kidneys or to increased renal vascular resistance (53). The functional result of these changes is a fall in glomerular filtration rate (GFR) by approximately 45% at the age of 80. This fall in GFR is reflected in a decline in creatinine clearance of 0.75 mL/min/yr in healthy elderly men. Serum creatinine, however, remains unchanged, because there is a concomitant decrease in lean body mass and, thus, a decrease in creatinine production. Estimates of creatinine clearance in the healthy aged can be made from the serum creatinine by using the formula derived by Cockcroft and Gault (54): [(140 age in years) (weight in kg)] / [72 (serum creatinine in mg/dL)]. Caution must be exercised when applying this formula to critically ill patients or those on medications that directly affect renal function. Renal tubular function also declines with advancing age. The ability to conserve sodium and excrete hydrogen ion falls, resulting in a diminished capacity to regulate fluid and acid–base balance (55). Dehydration becomes a particular problem, because losses of sodium and water from nonrenal causes are not compensated for by the usual mechanisms: increased renal sodium retention, increased urinary concentration, and increased thirst. The inability to retain sodium is thought to be due to a decline in the activity of the renin–angiotensin system (56). The increasing inability to concentrate the urine, which has been well documented (57), is related to changes in antidiuretic hormone (ADH). Measurements of ADH indicate that with advancing age there is a normal or exaggerated ADH response to a variety of stimuli. The defect in concentrating ability, therefore, is probably secondary to a decline in end organ responsiveness to ADH rather than a change in hormone

Table 6 Age-Related Changes in the Kidney and Lower Urinary Tract Morphologic changes

Figure 7 Changes in lung volumes with aging. Note the decrease in VC and increase in RV. Abbreviations: RV, residual volume; VC, vital capacity; IRV, inspiratory reserve volume; VT, tidal volume; ERV, expiratory reserve volume; TLC, total lung capacity. Source: From Ref. 46.

# Kidney size, length, volume " Sclerosis of nephrons " Sclerosis of glomeruli Atrophy of afferent/efferent arterioles # Renal blood flow # Renal tubular cell number # Renal tubular function # Renin–angiotensin system # Responsiveness to ADH " Collagen content of bladder " Detrusor activity " Prostatic hypertrophy # Estrogen responsiveness

Functional significance # GFR # Creatinine clearance

# Ability to conserve sodium # Ability to excrete hydrogen # Ability to concentrate urine # Ability to excrete free water # Bladder distensibility Impaired emptying " Incontinence " Urinary tract infections

Abbreviations: GFR, glomerular filtration rate; ADH, antidiuretic hormone.

medwedi.ru

1136

Part Nine: Special Physiologic Considerations

production. The marked decline in the subjective feeling of thirst is also well documented (58), but not well explained. Alterations of osmoreceptor function in the hypothalamus may be responsible for the failure to recognize thirst in spite of significant elevations in serum osmolality (59). In the perioperative period, the decline in renal function combined with the changes in cardiovascular compensatory mechanisms leaves older patients at increased risk from both hypovolemia and fluid overload: Postural instability and syncope results when cardiovascular reflexes and tubular function cannot compensate for even minor volume depletion (42), whereas congestive heart failure and pulmonary edema result when excess fluid cannot be excreted rapidly enough, due to the inability to augment cardiac output, improve renal perfusion, and increase GFR. Alterations in renal function also have great impact on the types and doses of drugs used in older patients. Although drugs are handled by the kidney in several different ways, most changes in renal drug processing parallel the decline in GFR. Therefore, creatinine clearance can be used to determine the appropriate clearance of most agents processed by the kidney (60). Changes also occur in the lower urinary tract with aging. In the bladder, increased collagen content leads to limited distensiblity and impaired emptying (61). Overactivity of the detrusor secondary to neurological disorders or idiopathic causes has also been identified (62). In women, decreased circulating levels of estrogen and decreased tissue responsiveness to this hormone cause changes in the urethral sphincter, which predispose the person to urinary incontinence. In males, prostatic hypertrophy impairs bladder emptying. Together, these factors lead to urinary incontinence in approximately 10% to 15% of elderly persons living in the community and 50% of those in nursing homes (63). There is also an increased prevalence of asymptomatic bacteriuria with age, which varies from 10% to 50% depending on gender, level of activity, underlying disorders, and place of residence. Urinary tract infections alone are responsible for 30% to 50% of all cases of bacteremia in older patients (64). Alterations in the local environment and declining host defenses are thought to be responsible. Because of the lack of symptoms in elderly patients with bacteriuria, preoperative urinalysis becomes increasingly important.

Hepatobiliary Function Morphological changes in the liver with age include a decrease in overall weight and size, and a decrease in the number of hepatocytes. There is, however, a compensatory increase in cell size and increase in binucleated cells with

a proliferation of bile ducts. Functionally, hepatic blood flow falls by approximately 1% per year to about 40% of earlier values, after the age of 60 (65). Although the synthetic capacity, as measured by the standard test of liver function, remains unchanged (66), the metabolism of and sensitivity to certain kinds of drugs is altered. Drugs requiring microsomal oxidation (Phase I reactions) prior to conjugation (Phase II reactions) may be metabolized more slowly whereas those requiring only conjugation may be cleared at a normal rate (67). Drugs that act directly on hepatocytes, such as coumadin, may produce the desired therapeutic effects at lower doses in the elderly due to an increased sensitivity of the cells to these agents (68). The most significant correlate of altered hepatobiliary function in the aged is the increased incidence of gallstones and gallstone-related complications. Gallstone prevalence rises steadily with age, although there is variability in the absolute percentages, depending on the population studied (Table 7) (69–71). Stones have been demonstrated in as many as 80% of nursing home residents over the age of 90 (72). Biliary tract disease is the single most common indication for abdominal surgery in the elderly population (Table 8) (3). Although pigment gallstones are found with more frequency in older people (73), cholesterol stones have also been shown to increase with advancing age (74). The formation of all types of gallstone first requires a change in the bile itself that promotes stone formation. This lithogenic bile is necessary but not sufficient for stone formation. Factors that promote nucleation and allow stone growth (stasis) are also necessary. Included in these factors is the glycoprotein mucin, which serves as a nidus for stone formation and forms a gel layer lining the gallbladder mucosa, which provides the environment for stone growth. The formation of this mucin gel precedes the development of both types of stones and is closely related to gallbladder stasis. The increased development of gallstones in the elderly is thought to result from both changes in the composition of bile and impaired biliary motility. Alterations in the composition of bile with advancing age include an increase in the activity of 5-hydroxy3-methylglutaryl-coenzyme A (the rate-limiting enzyme in the synthesis of cholesterol), and a decrease in the activity of 7a-hydroxylase (the rate-limiting enzyme in the synthesis of bile salts from cholesterol) (75). This results in supersaturation of the bile with cholesterol and a decrease in the primary bile salt pool (76). The ratio of secondary to primary bile salts also increases. It is postulated that these secondary bile salts promote cholesterol gallstone formation by enhancing cholesterol synthesis, increasing protein content of the bile, decreasing nucleation time, and increasing

Table 7 Prevalence of Gallbladder Disease (%) Pima Indians (70) (cholecystography) Age 15–24 25–34 35–44 45–54 55–64 > 65

New Haven, Connecticut (71) (necropsy)

Rome (72) (ultrasound)

Male

Female

Male

Female

Age

Male

Female

0 4 11 32 66 68

13 73 71 76 62 90

7 2 9 13 18 22

4 5 10 16 20 28

20–29 30–39 40–49 50–59 60–69

0 1 4 11 10

2 4 6 12 23

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

Table 8 Distribution of Abdominal Operations Per Year in the United States (2002)

Cholecystectomy Lysis of adhesions Appendectomy (planned) Partial excision of large intestines

Total

Age > 65 yr

436 342 329 263

151 93 25 145

(35%) (27%) (8%) (55%)

Source: Data from Ref. 3.

the production of specific phospolipids that are thought to effect the production of mucin (77). It has also been suggested that the increase in secondary bile salts in the aged may promote a recycling of bilirubin, which in turn leads to the unconjugated bilirubin supersaturation necessary for pigment stone formation. Alterations in gallbladder motility and bile duct motility are thought to be central to the development of cholesterol stones and brown pigment stones, respectively. The role of motility in black pigment formation, however, is less clear (77). Biliary motility is a complex interaction of hormonal and neural factors; however, the major stimulus of gallbladder emptying is cholecystokinin (CCK). The sensitivity of the gallbladder wall to CCK has been shown to decrease with increasing age in animal models (78). Exogenous administration of CCK to animals fed a lithogenic diet inhibits the age-dependent development of cholesterol gallstones (79). In humans, gallbladder sensitivity to CCK is also decreased. However, there is a compensatory increase in the production of CCK in response to stimuli, which results in normal gallbladder contraction (80). The production of the hormone pancreatic polypeptide, which inhibits gallbladder contraction and promotes relaxation, has also been shown to increase with increasing age in humans (81,82). The significance of this observation with regard to gallstone formation, however, is unknown. Further studies to elucidate changes in biliary motility with age are necessary. Regardless of the pathogenesis, gallstones are associated with complications in 40% to 60% of older patients requiring treatment for the disease, as compared to less than 20% of younger patients (83). In a study of over 20,000 open cholecystectomies in the elderly, nearly two-thirds of patients required emergency operation (84). The increased rate of complicated disease seen in older patients may be directly attributable to the increased severity of the disease or to increased prevalence of comorbid illnesses like atherosclerosis and diabetes mellitus. It is more likely, however, a result of delays in diagnosis and treatment, caused by the frequent absence of typical biliary tract symptoms. Biliary colic, or episodic right upper quadrant pain radiating to the back, precedes the development of a complication only half as often in older than younger patients (85). Even in the presence of acute cholecystitis, one-quarter of older patients may have no abdominal tenderness, one-third will have no elevation in temperature or white blood cell count, and as many as one-half will have no peritoneal signs in the right upper quadrant (86). Unfortunately, mortality in the emergent setting is at least three times the elective mortality (83). Until predictors of impending complications other than symptoms are identified, improving the outcome of biliary tract disease in the elderly will be difficult. Until that time, increased awareness of the atypical presentation of gallstone-related illness in this age group is essential.

1137

Hematopoietic Function Long-term culture studies of bone marrow reveal that the maintenance of in vitro hematopoiesis varies inversely with the age of the donor (87). Additional studies corroborate the observation that the ability of progenitor spleen–colonizing stem cells to replicate is an age-dependent process (88,89), probably analogous to the species-dependent limits on cell replication. The replicative capacity of spleen-colonizing stem cells far exceeds the life span of the host, however, making it unlikely that exhaustion of erythroid precursor proliferation accounts for the diminished hematopoietic reserve seen in the elderly. In addition, marrow taken from young donors and transplanted into elderly recipients proliferates at a rate that is indicative of the recipient, not the donor (90). Erythropoiesis is dependent upon the stimulation of erythroid progenitor replication by erythropoietin. Under basal conditions, the rate of erythroid turnover and erythroid kinetics are essentially normal in healthy elderly subjects. Under the condition of increased demand, as in the response to hemorrhage, however, the elderly patient has a delayed or absent erythroid response. Diminished erythropoiesis in the elderly is, therefore, due to a combination of inherent and environmental factors that alter the erythroid response to increased demand and result in a loss of functional reserve. The reasons for altered red cell responses to stress are not well defined, but insufficient levels of erythropoietin, and/or other growth factors, or decreased sensitivity to these factors may contribute. Inflammatory cytokines have also been implicated as the mediators of this declining sensitivity (91). Neutrophils form the first line of defense by their role in phagocytosis and bacterial killing. The bactericidal action of neutrophil superoxides and lysosomal enzymes is dependent upon the neutrophil response to a series of stimuli. When young and old neutrophils are compared in their basal and stimulated responses, basal rates of enzyme release are similar whereas the response to a challenge is measurably impaired in the old neutrophils. The diminished response may be associated with an age-related but reversible alteration in the lipid composition of neutrophil plasma membranes (92). Clinically, the neutrophil response to bacterial invasion in elderly patients is generally intact if drugs, metabolic stress, or concurrent disease do not supervene. However, nutritional deficiency is an important variable, because the bactericidal function of neutrophils is significantly impaired by relatively short-term malnutrition of the host. However, protein-calorie repletion by the intravenous route carries its own risk of infectious problems, so the selection of treatment strategies that minimize the risk of ileus followed by an early enteral feeding is the best support for the aged leukocyte system.

Metabolic and Endocrine Function The regulation of intermediary metabolism and the neurocrine–paracrine–endocrine mediation of cellular events are complex processes with multiple potential points of failure. The age-related loss of functional reserve of endocrine responsiveness or the changes in nutrient metabolism seen commonly in elderly patients have multiple causes. Age-related alterations in hormone levels are inconsistent, with some being quite elevated and others nearly absent. For example, plasma levels of CCK are elevated in elderly patients, although levels of gastrin are reduced. Gallbladder CCK receptor function is depressed in elderly subjects, however, as is parietal cell gastrin receptor function (83,93).

medwedi.ru

1138

Part Nine: Special Physiologic Considerations

Therefore, diminished cholecystokinesis in the elderly is probably a result of receptor loss or dysfunction, but hypochlorhydria appears to be a consequence of primary hormone insufficiency. Altered endocrine function may result from changes at several points in the pathway—alterations in hormone (or receptor) gene expression, in protein processing within the cell of origin (including protein assembly, storage, or vesicle trafficking), in hormone release due to stimulus–secretion–coupling abnormalities, in hormone distribution due to circulatory dysfunction or vascular occlusion, and in target cell responsiveness (due to impaired receptor binding, faulty ligand internalization, or diminished target cell postreceptor activation). Studies of endocrine dysfunction in the elderly are further confounded by the use of reference measurements originally made in hospitalized patients. The hypothalamic-pituitary-adrenal axis is the classical neuroendocrine feedback loop. Subtle and varied age-related changes have been described in the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids, but the loop appears to remain essentially intact despite advanced age. Glucocorticoid inhibition of CRH and ACTH release has been documented to be impaired (94), which suggests that the central neuroendocrine response to stress is actually prolonged in elderly surgical patients. The release of GH from the anterior pituitary declines progressively with increasing age, and is associated with lower levels of insulin-like growth factor-I (IGF-I). GH stimulates IGF-I production by the liver, the replacement of which in aging animals has been shown to reverse agerelated defects in gene expression and immune function, and to prolong life expectancy (95,96). Protein catabolism has been shown to be reversed in critically injured patients by GH replacement therapy, and the role of GH in the treatment of impaired wound healing in the elderly is currently under study. The adrenal glands undergo gradual changes with aging, which include fibrosis or nodular hyperplasia. Glucocorticoid or mineralocorticoid excess is unusual, but can result from a functional adrenal adenoma or adrenocortical carcinoma. Deficiency of mineralocorticoid or glucocorticoid is more common, but is usually apparent in the setting of increased demand. Loss of adrenal reserve may result from hemorrhage, infection, infiltrative or metastatic disease, or autoimmune destruction. Unexplained hemodynamic instability or frank shock in an elderly patient should be treated with a trial of glucocorticoids, in addition to other necessary agents. Thyroid diseases are common in elderly patients, and are often insidious in their presentation. Fibrosis, decreased follicle size, and atrophy are frequently seen, and hypothyroidism occurs in up to 4% of the elderly population (97). Nonspecific symptoms, such as constipation, lethargy, and dry skin, are frequent and may be confused with constitutional complaints attributed to ‘‘aging.’’ Hyperthyroidism is fairly common among older patients as well, and some studies suggest it may be more prevalent in the elderly than in younger patients (98). Thyroid enlargement, commonly observed in younger hyperthyroid patients, may be absent in elderly. Older hyperthyroid patients also lack the exophthalmos seen in younger patients, and nodular goiter, rather than Graves’ disease, is the most frequent cause of thyroid hyperfunction. The presenting symptoms are also disturbingly misleading—weight loss, tremor, muscle weakness, anorexia, and arrhythmias may easily be mistaken for

signs of ‘‘aging.’’ Masked and apathetic hyperthyroidism, terms originally used to describe advanced cardiac and toxic forms of hyperthyroidism, are now used to describe the typical presentation of the disease in the elderly. Thyroid nodules and degenerative cysts occur with increased frequency in the elderly. Sonographic imaging is helpful to identify those cystic lesions that require only aspiration. Solid lesions, however, need to be evaluated with thyroid function studies and fine needle aspiration (FNA), because of the substantial risk of malignancy. Of the 20% to 25% of euthyroid patients with ‘‘suspicious’’ FNA cytology of a discreet nodule, a final pathologic diagnosis of malignancy will be observed in 11% to as many as 71% of cases (99), with the majority of these being papillary or follicular carcinoma. Hyperparathyroidism is more prevalent in the elderly as well, and is frequently unsuspected at diagnosis. Automated blood chemistry–screening accounts for most newly diagnosed cases, and in the elderly, the sporadic or nonfamilial forms of the disease is most common. With persistence of the disease, nephrocalcinosis, bone demineralization, mental status changes, and constitutional symptoms may develop, but many patients remain seemingly asymptomatic despite elevated calcium levels. This has resulted in controversy over whether or not to advocate parathyroidectomy in elderly patients with few or no symptoms. A National Institute of Health (NIH) consensus conference held in 1990 recommended that only patients with overt signs and symptoms of known target organ complications be managed surgically (100). At a more recent NIH workshop in 2002, a panel reconsidered therapy for asymptomatic primary hyperparathyroidism (101). The threshold for parathyroidectomy was reduced to include patients with a serum calcium greater than 1 mg/dL above the upper limits of normal. This definition still leaves uncertain whether ‘‘weakness’’ and ‘‘depression’’ indicate symptomatic disease, although roughly 40% of patients with hyperparathyroidism have one or both complaints. Furthermore, in a recent case–control study, only 4.6% of hyperparathyroid patients were found to be truly asymptomatic, and the majority of patients felt better overall, after surgery (102). Because there is no medical treatment of hyperparathyroidism, there is no means of predicting when or if severe complications of the disease, such as nephrocalcinosis or bone disease, will develop. Because the morbidity and mortality risk of surgery is low even in older patients, parathyroidectomy remains the treatment of choice unless other comorbid conditions preclude surgery (103) (see ‘‘Preoperative Evaluation, Risk Assessment, and Outcome’’). Diabetes and changes in glucoregulatory hormones constitute a common set of concerns in elderly surgical patients. Hyperglycemia after carbohydrate ingestion or glucose administration is so common in the elderly that age-adjusted nomograms are used in standardized glucose tolerance testing. Glucose homeostasis is the net result of the interactions of a series of interrelated systems or processes: (i) gastric emptying of nutrients, (ii) enteric nutrient absorption, (iii) insulin release by elevated circulating glucose levels, (iv) the potentiating effect of enteric hormones, called incretins, which augment the insulin response, (v) the distribution of insulin to visceral and peripheral tissues, (vi) insulin actions including receptor binding, glucose transport, and inhibition of glucose production, and (vii) metabolism of glucose by insulin-dependent and insulin-independent tissues. Abnormalities in one or more of these processes may lead to impaired glucose tolerance

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

or frank diabetes, and it should be apparent that multiple etiologies of abnormal glucose metabolism are possible. The most common abnormality in glucose metabolism with aging is an increased insulin resistance. Even in healthy elderly elderly volunteers, enteral glucose stimulates an exaggerated insulin response accompanied by higher glucose levels than those found in younger controls (Fig. 8) (104). The higher degree of body fat in the elderly may contribute to this insulin resistance. Hyperglycemia is common in elderly patients who receive intravenous alimentation, and insulin therapy is commonly, albeit transiently, required in many sick elderly patients. Avariety of abnormalities are apparent in gastroenteropancreatic function in older patients, and may contribute to surgical disease in the elderly. Altered esophageal motility and sphincter function results in an increased incidence of reflux and aspiration (105). Hypochlorhydria and diminished gastric emptying are common (106), but there is a paradoxical increase in the incidence of peptic ulcer disease in the elderly (107,108). This may be secondary to an age-related decrease in duodenal bicarbonate secretion (109), and a breakdown in mucosal defense mechanisms. Small bowel absorption of fat and carbohydrates is basically unaltered in healthy aging (110), and the enteric hormonal response to nutrients is essentially intact. Serum levels of some hormones actually rise with aging, including CCK and pancreatic polypeptide, probably in response to declining end organ sensitivity (81). Absorption of calcium is significantly impaired in aging secondary to decreased renal production of 1,25-hydroxycholecalciferol, as well as to a decrease in the amount and/or sensitivity of intestinal mucosal calcium-binding proteins (110). Mucosal changes are seen in the aging colon, where progressive loss of muscularis propria function and increased thickness of the colon wall contribute to the age-related incidence of diverticular disease. Exocrine pancreatic secretion appears to change minimally with advancing age, although duct ectasia and dilatation of acini are seen (111). Lipase deficiency may contribute to altered fat absorption, but secretory function of the gland remains intact (112). The incidence of nonalcoholic pancreatitis increases in the elderly, due to the increased incidence of gallstones and the increased incidence of acute idiopathic pancreatitis. This entity is disproportionately present in the elderly, and carries a mortality risk of 25% or more (113). The age-related increase in the death risk due to pancreatitis may result from a higher likelihood of

1139

coexisting diseases, but is also a reflection of an altered presentation as well as an altered response to the disease process in the older patient.

Decreased Ability to Adapt to Changes in the Environment Altered Response to Stress Alterations in the neuroendocrine response(s) to stress in the elderly may account for some aspects of the ‘‘diminished reserve,’’ which characterizes many aging effects on organ systems. Catecholamine responses to a variety of stressors are altered in aging, although it has been difficult to achieve consensus on age-related effects on the actual levels of the catecholamines. Considerable evidence demonstrates a decline in the beta-adrenergic regulation of arterial and venous dilatation and myocardial contractility (114,115). These effects are thought to be related to altered beta-adrenergic receptor function, rather than changes in catechol levels, per se (116,117). Adrenocortical responses to stress are retained in most studies, but the anterior pituitary response to surgical stress is greatly diminished in the elderly, and is virtually eliminated when spinal analgesia is used (118). It remains unknown whether the loss of this neuroendocrine response contributes to the risk of hemodynamic instability in elderly patients undergoing operation. Surgical stress is usually accompanied by catabolism and protein loss. The administration of appropriate nutritional support is, therefore, an important part of the care of the critically ill patient. Elderly patients are particularly vulnerable in the postoperative period, because subtle preoperative malnutrition, usually secondary to poor nutrient intake and concomitant disease, is so common in this age group. In addition, compensatory protein synthesis is impaired in older persons secondary to the shrinking amino acid reservoir that results from the replacement of lean muscle mass with fat (119). However, elderly patients also have a significant intolerance for protein administration despite standard calculation of their needs (120). The inaccuracy in standard formulae probably arises from the relatively lower lean body mass, and calculation of the basal energy expenditure (BEE) should be modified to compensate for the age-related changes. The Harris–Benedict equation, which does incorporate an age factor, accurately predicts BEE when a correction factor of 1.75 is used for trauma, or 1.5 for general surgery patients.

Altered Response to Pain and Temperature (A)

(B)

Blood glucose

Plasma insulin

12

200

10

160

8

120

6

80

mmol/L

4

40

2 0

0 b1 40 60 80 100 120 140 Young

b1

40 60 80 100 120 140 Time (mins) Old

Figure 8 Serum glucose and insulin response to an enteric glucose load in old and young healthy subjects. Source: From Ref. 104.

Neurosensory responses to stress are also altered in elderly patients, and this is particularly evident in the perception of pain and in the maintenance of body temperature. Although the data are somewhat conflicting, elderly patients appear to have a higher threshold for pain perception (121), which complicates the diagnosis of abdominal surgical disease. Peptic ulcer disease, for example, may be associated with diminished or even absent pain in as many as a third of elderly patients (122). Moreover, when analgesics are given, a lowered dose is frequently required (see section ‘‘Changes in Body Composition’’), because the unwanted effect of respiratory depression is not reduced (123). Pulse-oximetry is always an appropriate monitoring aide when narcotic analgesic agents are used in older patients. Diminished sensation of cold and an impaired sensitivity to temperature changes are causes of altered thermoregulation in the elderly (124). Altered autonomic

medwedi.ru

1140

Part Nine: Special Physiologic Considerations

vasoconstrictor responses to cold may contribute to a basal core temperature as low as 35 C in older individuals. Decreased thermogenesis secondary to reduced lean body mass with concomitant decreased basal metabolic rate, and a variety of coexisting endocrine and metabolic conditions including hypothyroidism and hypoglycemia, may also increase the risk of hypothermia. In the operating room, the use of body warmers, head covers, and warmed irrigation fluids are helpful to avoid the risk of hypothermia in elderly patients. The most significant immediate complications of severe hypothermia (below 32 C) are arrhythmias and cardiorespiratory arrest. The electrocardiogram may show a characteristic ‘‘J’’ wave or Osborn wave following the QRS complex, which disappears when the hypothermia is reversed (125). Hypothermia has also been implicated as a contributing factor to postoperative wound infections (126). Just as hypothermia represents a failure to compensate for ambient low temperatures in the elderly, hyperthermia may reflect an inability to increase evaporative heat loss in the setting of high external temperature. The inability to generate a fever in response to a serious infection or injury is another manifestation of altered thermoregulation in the older patient (127). Whereas younger individuals can mount a fever in response to relatively minor infections or inflammatory processes, the elderly patient may lack a febrile response to even suppurative peritonitis (128). When fever does occur in an elderly patient, it usually implies a significant pathologic process and should never be ignored.

Altered Wound Healing The response to a wound is also a form of reaction to the environment, and represents an attempt to preserve or restore physical homeostasis. This response involves the complex interaction of systemic and local immune processes as well as tissue repair processes, and both sets of events can be impaired in elderly patients (129). In addition, impaired wound healing is associated with nutritional deficiencies and other disease states that cause tissue hypoxia, all of which occur with increasing frequency in older persons. Unfortunately, because normal wound healing requires such a complex constellation of coordinated events, actual data confirming the changes associated with increased aging, per se, are few. In one study of experimental wounding in healthy volunteers, epithelialization was delayed in older patients compared to younger patients, but collagen content of the wounds appeared equal. The accumulation of noncollagenous proteins, however, was decreased in the older group (130). In another study, the rate of healing of ischemic wounds in old animals was impaired by 40% to 65% compared to that of younger animals (131). More recent studies suggest that impaired wound healing in the elderly is associated with an exaggerated inflammatory response and excess matrix degradation. Matrix production is also reduced secondary to altered cytokine-mediated fibroblast function (132). When immune responsiveness is enhanced in elderly subjects, as with the oral administration of arginine, cellular and chemical parameters of wound healing are also enhanced (133). Other strategies to enhance wound healing in the elderly are presently under investigation. These include the restoration of protein–calorie balance, and the induction of endogenous growth factor synthesis, such as IGF-I, by GH administration.

Increased Vulnerability to Disease Alterations in the Immune System Immune competence, like other physiologic parameters, declines with advancing age. This immunosenescence is characterized by an increased susceptibility to infections, an increase in autoantibodies and monoclonal immunoglobulins (Igs), and an increase in tumorogenesis. Also, like other physiological systems, this decline may not be apparent in the nonchallenged state. For example, there is no decline in neutrophil count with age, but the ability of the bone marrow to increase neutrophil production in response to infection may be impaired (134). Elderly patients with major infections frequently have normal WBC counts, but the differential count will show a profound shift to the left, with a large proportion of immature forms. Although the study of immunosenescence in humans is complicated by the increasing prevalence of other diseases, the inability to effectively sample all of the elements of the immune system, and the inability to separate environmental effects from biological effects, several specific changes have been defined. The most consistent of the changes in the immune system with age is the involution of the thymus gland and the decline in the production of thymic polypeptide factors such as thymosin a-1 (135). This and other thymic hormones control the differentiation and proliferation of thymocytes into mature T-lymphocytes. T-cell proliferation (136) and IL-2 production (137) in response to stimulation have been shown to decrease with increasing age, and diminished T-cell responsiveness to a variety of antigens has been demonstrated in studies using skin tests (138). B-cell defects have not been as clearly established, although it is thought that the functional deficits are related to altered T-cell regulation (134) rather than to intrinsic B-cell changes. The mix of Igs, however, does change— IgM levels decrease whereas IgG and IgA levels increase slightly. There is also a significant rise in the prevalence of monoclonal Igs to more than 10% in the population of people over the age of 80 (139). There is also an increase in the prevalence of autoantibodies, but this does not appear to correlate with overt clinical disease. Changes in the immune system with aging are similar to those seen in chronic inflammation and cancer. In addition to the reduced mitogenic responses of T-cells, there is an increase in the levels of ‘‘acute phase’’ proteins. It is hypothesized that persistently elevated levels of inflammatory cytokines may be responsible for downregulation of IL-2 production by chronically stimulated T-cells (134). The clinical manifestations of these changes are difficult to ascertain, because the increased susceptibility to many infectious agents is more likely a result of comorbid disease than of physiologic decline. There is no good evidence to support the contention that immunosenescence alone is responsible for the observation that older patients are more likely to contract an infectious illness and less able to eradicate it quickly. However, the decline in physiologic reserve of other organ systems combined with comorbid illnesses may make recovery prolonged and more difficult.

Oncogenesis There is a clear increase in most common cancers in people over the age of 65 and two-thirds of all cancer deaths occur in this age group. The increased incidence of cancer in the elderly is related to several biological factors including longer exposure to environmental carcinogens, increased

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

susceptibility of cells to carcinogens, decreased immune surveillance of abnormal cells, and abnormalities in the rate of occurrence or repair of acquired DNA damage. Alterations in the expression or amplification of oncogenes or tumor suppressor genes may play a role in oncogenesis as well as in the aging process itself. The biological basis for both oncogenesis and aging may be more closely related than was previously realized (140). Aging is characterized by a general decrease in cellular proliferative capacity, as discussed earlier. Some age-related illnesses, including prostatic hypertrophy and early atherosclerosis, may represent disease processes characterized by hyperproliferation of certain cells types. This altered control of cell-specific proliferation may be genetically programmed or acquired, but contributes to the limits of life span for that species. Although neoplasia frequently occurs in actively dividing cells, it also occurs in nonreplicating tissues. This suggests that factors that determine replicating capacity (and life span) may be directly and indirectly linked to those processes that regulate oncogenesis. Experimental evidence for this proposal is still incomplete, but interesting evidence for a reciprocal relationship between cellular aging and oncogenesis is found in animal studies of CR. In this model of maximal life-span prolongation in mammalian species, the extension of average life span is accompanied by a decrease in the occurrence of neoplasia (141). The control of proliferation at the molecular level is the subject of great interest in both aging and oncology circles. The end of each chromosome is capped by a telomere, a nucleoprotein structure with tandem repeating six nucleotide sequences. This structure protects the chromosomal DNA from degradation and fusion, and has multiple functions in cell division and nuclear spatial organization (142). With each cell division, the telomere is shortened until a critical length is reached at which point proliferation ceases and the cell enters replicative senescence. It is postulated that in tissue, changes in gene expression in senescent cells may cause alterations in adjacent cells, which effect overall homeostasis and facilitate the processes of aging and tumor development (143). Physiological evidence of this, however, is lacking. The enzyme telomerase, not normally found in most somatic cells, can restore telomere length and allow for continuing replication. Although telomerase expression has been identified in the great majority of tumor cells tested, it does not cause malignant transformation, but rather permits proliferation (142). As the gene pool represented by the older population continues to enlarge, the increased occurrence of late programmed events may result in a greater than expected incidence of cellular alterations (malignancy) linked to the end to the predetermined replicative cycle. This may explain the disproportionate increase in malignant diseases in older persons. In addition, there are several specific mechanisms whereby the aging process may contribute to malignant transformation. First, it is possible that aging or the passage of time simply allows the accumulation of a required sequence of cellular events to transform cells. Second, there may be increased susceptibility in aging to exposure to carcinogens (144). Third, it has been shown that DNA damage once incurred is repaired less efficiently or less completely in aged cells. This may explain why increased karyotypic abnormalities are seen in both normal elderly subjects and in patients with malignancies. Fourth, activation or amplification of oncogenes may be greater in the older subject. An increased amplification of protogenes has been documented in aging

1141

fibroblasts (145), and c-myc transcript levels are increased in aging mouse livers (146). Alternatively, cancer suppressor genes may be inactivated, because p53 has been shown to be altered in both tumorogenesis and in senescence (147). Fifth, although a loss of immune surveillance has been implicated in some tumors, it remains uncertain whether this is a common aging effect that facilitates tumorogenesis. Finally, in addition to specific effects of cellular aging on oncogenesis, other aspects of the aged host may alter the natural history of the tumor or the response to specific therapy. Although there is no evidence that cancers in older people respond differently to treatment than those in younger people (144), the presence of significant comorbid illness in the aged may require that treatment protocols be adjusted to avoid severe side effects and complications. Unfortunately, data defining appropriate drug regimens and dosing schedules for elderly patients with most types of cancer are lacking because, until recently, elderly patients have been excluded from most clinical trails of cancer treatments.

PREOPERATIVE EVALUATION, RISK ASSESSMENT, AND OUTCOME In keeping with previous discussions of risk assessment, we will refer to risk primarily as the chance of postoperative mortality and morbidity. Risk in the elderly, however, should also be assessed in terms of restoration of preoperative functional status and quality of life, because survival is not necessarily the only important issue for patients in this age group. Preoperative assessment of risk in the elderly must provide an accurate assessment of the extent of physiological decline and the presence of other coexisting disease processes. This does not necessarily require an extensive evaluation of each separate system. An assessment of functional status, nutritional status, cognitive function, and level of psychosocial support is frequently all that is necessary to evaluate risk and formulate a postoperative recovery plan. Although the physiological changes that accompany aging are myriad, the impact of these changes on the outcome of uncomplicated elective surgery in otherwise healthy, functional older patients is minimal. As a result of these physiological alterations, however, the response to the surgical disease in the elderly is frequently ‘‘atypical.’’ The lack of the classical signs and symptoms of disease often leads to delays and errors in diagnosis, which result in the increased need for ‘‘acute’’ surgical intervention. In one series of patients over the age of 70, emergency operation carried a 10-fold higher mortality rate than the elective rate of 1.9% (148). Almost regardless of the type of procedure, emergency surgery is associated with at least a threefold increase in mortality and morbidity. It is also associated with a higher rate of long-term hospital stay ( > 30 days), greater need for postoperative intensive care, and larger decline in functional status with consequent increase in the need for nursing home placement (149).

Assessment of Comorbid Illnesses Although physiologic decline may impair the ability of the elderly patient to compensate appropriately for the additional stress of complicated or emergency surgery, it is the presence of comorbid illnesses, or pathological processes other than the primary surgical disease, that is the most important determinant of surgical outcome. Comorbidity has been implicated both in the development of acute

medwedi.ru

1142

Part Nine: Special Physiologic Considerations

disease and in increased surgical mortality and morbidity. For example, Boyd et al. studied the impact of comorbidity on the mortality from colon surgery in 357 patients over the age of 50 (150). The preoperative incidence of additional pathologic conditions other than the primary surgical disease rose steadily with age, such that by age 80, only 5% of patients had no comorbid illnesses (Table 9). In patients over the age of 70, the mortality rate rose, in association with the number of comorbid conditions, from 1.5% with zero to one conditions to 16% with two or more. A similar increase in mortality was observed in patients younger than 70 years of age, and age as an isolated factor was seen to have no effect on mortality. In a more recent Veterans Affairs study, which included 26,648 patients over the age of 80 (5% of total subjects), both age and comorbidity were found to be independent predictors of postoperative mortality, but 10 other patient characteristics were better predictors than age. These included American Society of Anesthesiologists classification, low albumin, emergency surgery, impaired functional status, elevated blood urea nitrogen, disseminated cancer, do not resuscitate order, history of weight loss, elevated liver enzymes, and complexity of the operation (151). Unfortunately, as is the case with the surgical disease itself, the manifestations of these comorbid illnesses in the elderly are frequently less specific and less ‘‘typical’’ than they are in younger patients. Silent myocardial infarction, apathetic hyperthyroidism, moderate cognitive impairment, and malnutrition are among the many disorders that may not be apparent from initial history and physical examination. The search for comorbid illness must, therefore, be diligent. In one study of hospitalized patients over 70 years of age, 60% of moderate to severe cognitive deficits and 42% of nutritional deficits had been previously unrecognized by the primary caregiver (152). The identification of cardiac comorbidity is most important in the elderly surgical patient, because cardiac events are the leading cause of perioperative complications and death. For this reason, preoperative evaluation of ‘‘cardiac risk’’ has been extensively studied. The American College of Cardiology and the American Heart Association Task Force on Practice Guidelines has recently published an in depth set of guidelines for perioperative cardiovascular evaluation, which addresses all the major concerns (153). Stratification of risk based on clinical factors and operative factors is discussed. More detailed applications of these strategies are discussed elsewhere in the text, and for elderly patients with known cardiac disease, rigorous workup may be necessary. For most other elderly patients, however, assessments of functional status and exercise tolerance are accurate predictors of outcome (see section ‘‘Assessment of General Health and Functional Status’’).

Table 9 Prevalence of Preoperative Pathologic Conditions (%) Age (yr) Condition Cardiovascular Pulmonary Renal Hepatic Nutritional Other

50–59

60–69

70–79

> 80

Total

36 8 5 7 2 13

52 17 8 10 7 18

57 20 24 16 10 21

85 17 15 20 22 20

53 16 13 12 8 18

Source: From Ref. 150.

Assessment of General Health and Functional Status For decades, anesthesiologists have successfully predicted postoperative mortality in patients of all ages using the Dripp’s American Society of Anesthesiology Physical Status Scale. This scale assigns patients to one of five categories, depending on extent of underlying systemic disease. Using this scale Djokovic and Hedley-White studied mortality in 500 consecutive surgical patients aged more than 80 years (154). No patient in this study was classified as Class 1, because an age of 80 or more is an exclusion criterion for this category. Mortality rate correlated well with the severity of illness, increasing from less than 1% in Class 2 patients (mild systemic disease) to 25% in Class 4 patients (incapacitating systemic disease). For each and every class, the figures are similar to those seen in younger patients. These data support the concept that severity of illness and comorbidity rather than age alone are the significant factors in postoperative mortality. Standard measures of functional status have also proven to be predictive of postoperative outcome. The ability to perform the ADL or the simple tasks of life like feeding, continence, transferring, toileting, dressing, and bathing has been correlated with operative mortality and morbidity. In one study, patients identified as inactive (defined as unable to leave their homes on of their own efforts at least twice a week) were shown to have a higher incidence of all major surgical complications (155). In another study of noncardiac surgical cases, mortality in patients with severely limited activity (defined as bedridden or only able to transfer from bed to chair) was 9.7 times higher than in active patients. Of the risk factors studied, inactivity was found to be the single strongest predictor of death (156). Even for patients with less obvious limitations, functional capacity or exercise tolerance is the single most important predictor of cardiac complications following noncardiac surgery. In a study comparing Dripps Criteria and Goldman Clinical Criteria (noninvasive ventricular functional assessment and exercise tolerance), Gerson et al. (157) demonstrated that the inability to raise the heart rate to 99 beats/min while doing two minutes of supine bicycle exercise was the most sensitive predictor of postoperative cardiac complications and death. The physiologic basis for this finding has been further clarified by a study in which patients performed supine ergometry while being connected by mouthpiece to a metabolic cart (158). The authors identified an anaerobic threshold, defined as the level of oxygen consumption above which circulatory supply could not meet metabolic demand, and correlated this threshold with surgical outcome. For those patients able to reach an anaerobic threshold of 11 mL/kg/min or more, the mortality was 0.8%, compared to 18% for those unable to reach this threshold. Even in patients with preoperative ischemia identified at the time of exercise testing, this threshold level was highly predictive of postoperative mortality (Table 10). Should all preoperative elderly patients, therefore, be subjected to this type of exercise testing? Clearly this is neither practical nor necessary. The metabolic requirements for many routine activities have already been determined and are quantitated as metabolic equivalents (METs). One MET, 3.5 mL/kg/min, is basal oxygen consumption or that amount of oxygen consumed by a 70 kg, 40-year-old man at rest. Estimated energy requirements for various activities are shown in Table 11. By asking appropriate questions

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

Table 10 Anaerobic Threshold and Postoperative Mortality AT (mL/min/kg) All patients < 11 > 11

No. of pts.

No. of CVS deaths

% Mortality

55 132

10 1

18 0.8

8 1

42 4

Patients with preoperative ischemia < 11 19 > 11 25

p < 0.001. p < 0.01. Abbreviations: AT, anaerobic threshold, CVS, cardiovascular system. Source: From Ref. 158.

about the level of activity, or by using a standardized selfassessment tool such as the Duke’s Activity Status Index (159), the functional status can be determined. The inability to function above 4 METs has been associated with increased perioperative cardiac events and long-term risk (153). Diminished preoperative functional capacity may be the result of chronic anemia. The prevalence of anemia rises steadily after the age of 65 and more sharply after the age of 80. World Health Organization defines anemia as the hemoglobin (Hgb) levels less than 13 in men, and less than 12 in women (91). Anemia in older people, whether of known etiology (80%) or undefined, is a strong predictors of both disability in the community and in the hospital (160). Studies of elderly disabled women show women with Hgb levels of 13–14 have the best results on mobility test, whereas those with Hgb < 12 have the worst (161). In a study of patients with hip fracture repair, mobility, as measured in the distance walked, rose steadily with rising Hgb (Fig. 9) (162). Other nonspecific indices have recently been shown to predict poor outcome and mortality in elderly patients with a wide variety of medical and surgical illnesses. Among these, low levels of serum albumin have emerged as an independent and sensitive predictor of increased length of stay, increased rates of readmission, unfavorable disposition, and increased all cause mortality (163). Whether this finding is related to poor nutritional status or unidentified complex chronic illness has not been clarified. In a large study of surgical patients, low preoperative serum albumin was shown also to be an independent and sensitive predictor of both operative mortality and morbidity (164). Preoperative cognitive impairment has been shown to have a similar, although far less well defined, negative

1143

impact on many surgical outcomes. It has been suggested that the increased operative mortality seen in this group of patients is related, in part, to delays in diagnosis (165). In addition, preoperative cognitive dysfunction is a major cause of postoperative delirium. Postoperative delirium has significant impact on all other surgical outcomes including mortality, major morbidity, length of stay, and discharge to long-term care or rehabilitation facilities (166). Delirium in the ICU is also associated with higher mortality and prolonged length of stay (167). Persistent cognitive dysfunction can occur in the postoperative period, even in the patients without preexisting deficits. This dysfunction has been shown to persist for as long as three months after operation in a significant percent of elderly patients (168). Following cardiac bypass surgery, early cognitive deficits are common and persist at six months (169).

Overall Outcome Over the past 30 years, there has been a clear decline in the overall surgical mortality in older age groups (170), even for the highest risk operations like aneurysmorraphy and major cancer resections. Overall, long-term survival does not appear to be adversely affected by the need for surgical intervention, even in patients over the age of 90 (Fig. 10) (171). However, because of comorbidity and declining physiologic reserves, older patients are less able to tolerate postoperative complications. In the VA study mentioned earlier, mortality in patients over the age of 80 increased from 3.7% in patients without complications to 26% in patients with one or more complications (151). Data regarding the functional outcome and return to the same (or better) preoperative status are available primarily for procedures that directly address improving these outcomes, such as total joint replacement and aortic valve replacement. For other procedures, the data are less clear. In the SUPPORT study (Study to Understand Prognoses and Preferences for Treatment), designed to develop a model to predict outcome in seriously ill medical and surgical patients, prior ability to perform the ADL was the most important predictor of functional outcome (172). In a more recent study of functional recovery after major elective open abdominal operations, better recovery and short time to recovery of ADLs and instrumental ADL was nearly always predicted by a better preoperative physical performance status, as measured by three simple tests of strength and mobility (173). Minimal access techniques, which have been shown to limit postoperative pain and promote a more rapid return

Table 11 Estimated Energy Requirements for Various Activities 1 MET

| | | | | | | | | | | # 4 METs

Can you take care of yourself? Eat, dress, or use the toilet? Walk indoors around the house?

Walk a block or two on level gound at 2–3 mph or 3.2–4.8 km/h? Do light work around the house like dusting or washing dishes?

4 METs

| | | | | | | | | | | # 10 METs

Abbreviation: MET, metabolic equivalent. Source: From Ref. 153.

medwedi.ru

Climb a flight of stairs or walk up hill? Walk on level ground at 4 mph or 6.4 km/h? Run a short distance? Do heavy work around the house like scrubbing floors or lifting or moving heavy furniture? Participate in moderate recreational activities like golf, bowling, dancing, doubles tennis, or throwing a baseball or football? Participate in strenuous sports like swimming, single tennis, football, basketball, or skiing?

Actual and predicted mean number of feet

1144

Part Nine: Special Physiologic Considerations

100 90 80 70 60 50 40 7

8

9

10

11

12

Average Hb level (g/dL)

Figure 9 Functional recovery after hip fracture. The distance walked at discharge increases with increasing hemoglobin concentration. Source: From Ref. 162.

to normal function in younger patients, may also improve functional outcome in older patients. However, the advanced nature of the pathology frequently found in the aged often complicates or even precludes the laparoscopic approach. Studies do show that when laparoscopic techniques are possible, mortality and morbidity are comparable to open procedures (174). Further clarification of the factors that may have an impact on the outcomes of death, nursing home placement, and total hospital days in patients with medical or surgical illnesses can be found in a study of 12 conditions common in the geriatric population (175). These ‘‘geriatric-targeting criteria’’ include socioeconomic problems, vision impairment, hearing impairment, appetite loss, weight loss, incontinence, confusion, depression, dementia, falls, and prolonged bed rest. In this prospective study of 507 acutely ill male veterans, over 65 years of age, only confusion was associated with all three negative outcomes. Weight loss was the strongest predictor of death, although appetite loss, depression, falls, and socioeconomic problems were also significantly associated. Polypharmacy and prolonged bed

Figure 10 Postoperative survival in patients aged 90 years and older. Source: From Ref. 171.

rest predicted nursing home placement, and falls and prolonged bed rest were associated with increased total hospital days. The elderly are also more susceptible to the sequela of the surgical intervention that may not be directly related to the operative procedure itself. Bed rest, for example, is associated with a variety of physiological changes that can have a great impact on an elderly patient’s ability to recover from the surgical insult. In addition to the well-known sequela such as pressure ulcers, deep venous thrombosis, and muscle wasting, inactivity can quickly lead to deconditioning, which by itself can be considered an illness different from the original surgical disease. The deconditioned patient will demonstrate changes in multiple organ systems: depression and lethargy; anorexia and dehydration; neuromuscular instability, decreased bone density, muscular weakness, and incoordination; altered bladder and bowel function with retention and constipation; and urinary and fecal incontinence. Once these changes occur, the road back to independent functioning is all uphill. It is estimated that in severely deconditioned patients, the time to recovery can be three times the length of the period of inactivity (176). In a study of hospitalized elderly medical patients, initial admission to a special care unit, which emphasized a multidisciplinary approach to assessment and treatment, was found to have a positive effect on the outcomes of maintenance of independence and discharge to home (177). Similar studies of surgical patients are not yet available. It is likely, however, that careful attention to the assessment and treatment of elderly surgical patients in a multidisciplinary manner that emphasizes early recognition of surgical disease and comorbidity and addresses deficits appropriately will have equally beneficial results.

SUMMARY In the next 50 years, the portion of the population older than 65 years is expected to grow from the present 12.4% to 20% or more, encompassing nearly 80 million people. This being the case, it is incumbent on the surgeon to have a comprehensive understanding of the physiologic changes that occur with aging and how these could potentially impact on the outcome from a surgical procedure. Several important changes occur in body composition, including a reduction in lean body mass and the expansion of the extracellular compartment. Recognizing these body compositional changes ensures the appropriate use of drugs and fluids. Aging is also associated with specific changes in cellular function affecting cardiac, pulmonary, and renal responses to stress, which could impact adversely on perioperative management. Recognition of these changes enables appropriate risk assessment preoperatively. Altered responses to pain and temperature control and wound healing are likewise commonly encountered in elderly patients and can influence both preoperative diagnosis of surgical disease and postoperative complications. Accordingly, knowledge of this information in the older patient pays rich dividends in ensuring appropriate risk assessment preoperatively, precise management intraoperatively, and a smooth postoperative course. Although postoperative recovery and rehabilitation may sometimes be prolonged in elderly patients, returning these individuals to a functioning state after being subjected to surgical illness is an achievable goal.

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

REFERENCES 1. U.S. Census Bureau. U.S. Interim Projections by Age, Sex, Race and Hispanic Origin, 2004. http://www.census.gov/ipc/ www/usinterimproj/. Internet release date: March 18, 2004. 2. Arias E. United states life tables, 2002. National Vital Statistics Reports. Vol. 53, Number 6, November 2004. 3. DeFrances CJ, Hall MJ. 2002 National hospital discharge survey. CDC Advanced Data from Vital and Health Statistics. Number 342, May 2004. 4. Cristafalo VJ, Gerhard GS, Pignolo RJ. Molecular biology of aging. In: Zenilman ME, Roslyn JJ, eds. Surgery in the Elderly Patient. Surg Clin North Am 1994; 74:1. 5. Gompertz B. On the nature of the function expressive of the law of human mortality and on a new mode of determining life contingencies. Philos Trans R Soc Lond 1825; 115:513. 6. Warner HR, Ingram D, Miller RA, et al. Program for testing biological interventions to promote healthy aging. Mech Ageing Dev 2000; 115:199–207. 7. Beckman M. Placing bets, National Institute on Aging Committee chooses three compounds for the definitive longevity testing. Sci Aging Knowledge Environ 2004:14. 8. Rhome D. Evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc Natl Acad Sci USA 1981; 78:5009. 9. McCay, Cromwell M, Maynard L. The effect of retarded growth upon the length of life and upon ultimate size. J Nutr 1935; 10:63. 10. Yu BP, Masoro EJ, McMahon CA. Nutritional influences in aging of Fischer 344 rats. I. Physical, metabolic and longevity characteristics. J Gerontol 1985; 40:664. 11. Masoro EJ. Caloric restriction and aging: an update. Exp Gerontol 2000; 35:299. 12. Sinclair DA. Toward a unified theory of caloric restriction and longevity regulation. Mech Aging Dev 2005; 126:987–1002. 13. Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess death associated with underweight, over weight and obesity. JAMA 2005; 293:1861–1867. 14. Goldman R. Decline in organ function with aging. In: Rossman I, ed. Clinical Geriatrics. 2nd ed. Philadelphia: Lippincott, 1979. 15. Reiser KM, Hennessey SM, Last JA. Analysis of age-associated changes in collagen cross linking in the skin and lung in monkeys and rats. Biochem Biophys Acta 1987; 926:339. 16. Bjorksten J. Cross linkage and the aging process. In: Rothstein M, ed. Theoretical Aspects of Aging. New York: Academic Press, 1974. 17. Harman D. Aging: A Theory Based on Free Radical and Radiation Chemistry. J Gerontol 1956; 11:298. 18. Rossman I. Anatomy of aging. In: Rossman I, ed. Clinical Geriatrics. 2nd ed. Philadelphia: Lippincott, 1979. 19. Elahi VK, Elahi D, Andres R, Tobin JD, Butler MG, Norris AH. A longitudinal study of nutritional intake in man. J Gerontol 1983; 38:162. 20. Vin SC, Love AGH. Nutritional status of institutionalized and non-institutionalized aged in Belfast, Northern Ireland. Am J Clin Nutr 1979; 32:1934. 21. Rosenberg IH. Nutrition and aging. In Hazzard WR, ed. Principles of Geriatric Medicine and Gerontology, 3rd ed; New York: McGraw-Hill, 1994. Reprinted with permission of The McGraw-Hill Companies. 22. Rudman, et al. Effect of human growth hormone in men over 60 years old. N Engl J Med 1990; 323:1. 23. Trmiras P. Aging of the skeleton, joints and muscles. In: Timiras PS, ed. Physiological Basis of Aging and Geriatrics. Boca Raton: CRC Press, Inc., 1994. 24. Tzankoff SP, Norris AH. Effect of muscle mass decrease on age-related BMR changes. J Appl Physiol 1977; 43:1001. 25. Shock NW. Energy metabolism, caloric intake, and physical activity in the aging. In: Carlson LA, ed. Nutrition in Old Age, Symposia of the Swedish Nutrition Foundation.

1145

Uppsala: Almquist and Wiksell, 1972. 26. Shimokata H, et al. Studies on the distribution of body fat: I. Effects of age, sex, and obesity. J Gerontol 1989; 44:M66. 27. Andres R. Mortality and obesity: the rationale for age-specific height-weight tables. In: Hazzard WR, Bierman EL, Blass JP, Ettinger WH Jr, Halter JB, eds. Principles of Geriatric Medicine and Gerontology. 3rd ed. New York: McGraw-Hill, 1994. 28. McLeskey CH. Anesthesia for the elderly patient. In: Barash PG, Cullen BF, Stoelting RK, eds. Clinical Anesthesia. 2nd ed. Philadelphia: JB Lippincott, 1992. 29. Homer TD, Stanski DR. The effect of increasing age on the disposition and anesthetic requirement. Anesthesiology 1985; 62:114. 30. Buxbaum JL, Schwartz AJ. Perianesthetic consideration for the elderly patient. In: Zenilman ME, Roslyn JJ, eds. Surgery in the Elderly Patient. Vol. I. Surg Clin North Am 1994; 74:41–58. 31. Kitzman DW, Edwards WD. Minireview: age-related changes in the anatomy of the normal human heart. J Gerontol 1990; 45:M33. 32. Lakatta EG, et al. Human aging: changes in structure and function. J Am Coll Cardiol 1987; 10:42A. 33. Nixon JV, et al. Ventricular performance in human hearts aged 61–73 years. Am J Cardiol 1991; 56: 932. 34. Davies MJ. Pathology of the conducting system. In: Caird FL, Dalle JLC, Kennedy RD, eds. Cardiology in Old Age. New York: Plenum Press, 1976. 35. Sahasakul Y, et al. Age-related changes in aortic and mitral valve thickness: implications for two-dimensional echocardiography based on an autopsy study of 200 normal human hearts. Am J Cardiol 1988; 62:424. 36. Kitzman, et al. Age-related changes in normal human hearts during the first ten decades. Part II (Maturity): A quantitative anatomic study of 765 specimens from subjects 20–99 years old. Mayo Clin Proc 1988; 63:137. 37. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993; 73:413. 38. Yin FCP. The aging vasculature and its effect on the heart. In: Weisfeldt ML, ed. The Aging Heart: Its Function and Response to Stress. Aging. 12. Vol. 12. New York: Raven Press, 1980. 39. Lewis JF, Maron BJ. Cardiovascular consequences of the aging process. In: Lowenthal DT, ed. Geriatric Cardiology. Cardiovascular Clinics. Vol. 22. Philadelphia: FA Davis Co, 1992. 40. Lachi RJ, et al. Left ventricular function in hospitalized geriatric patients. J Am Geriatr Soc 1982; 30:700. 41. Manning WJ, et al. Reversal of changes in left ventricular diastolic filling associated with normal aging using diltiazem. Am J Cardiol 1991; 67:894. 42. Wei JY. Age and the cardiovascular system. N Engl J Med 1992; 327:1735. 43. Tresch DD, McGough MF. Heart failure with normal systolic function: a common disorder in older people. J Am Geriatr Soc 1995; 43:1035. 44. Wei JY. Use of calcium entry blockers in elderly patients: special considerations. Circulation 1989; 80(suppl IV):171. 45. Wenger NK. Cardiovascular disease. In: Cassel CK, Riesenberg DE, Sorensen LB, Walsh JR, eds. Geriatric Medicine. 2nd. New York: Springer-Verlag, 1990. 46. Timiras PS. Aging of the respiration, erythrocytes, and the hematopoietic system. In: Timiras PS, ed. Physiological Basics of Aging and Geriatrics. Boca Raton: CRC Press, 1988. 47. Pfitzenmeyer P, et al. Lung function in advanced age: study of ambulatory subjects aged over 75 years. Gerontology 1993; 39:267. 48. Tockman MS. Aging of the respiratory system. In: Katlic MR, ed. Geriatric Surgery. Baltimore: Urban & Schwarzenberg, 1990. 49. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia in with aging in men. J Clin Invest 1973; 52:1812. 50. Pokorski M, Walski M, Dymecka A, Marczak. The aging carotid body. J Physiol Pharm 2004; 55(suppl 3):107–113. 51. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001; 344:665–671.

medwedi.ru

1146

Part Nine: Special Physiologic Considerations

52. Bartlett JG. Pneumonia. In: Andres R, Bierman EX, Hazzard WR, eds. Principles of Geriatric Medicine. 1st. New York: McGraw-Hill, 1985. 53. Lindeman RD. Overview: renal physiology and pathophysiology of aging. Am J Kidney Dis 1990; 16:275. 54. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31. 55. Macias Nunez JF, et al. Physiology and disorders of water balance and electrolytes in the elderly. In: Macias Nunez JF, Cameron JS, eds. Renal function and Disease in the Elderly. Stoneham, MA: Butterworth, 1987. 56. Tsundo K, et al. Effect of aging on the renin-angiotensinaldosterone system in normal subjects: simultaneous measurement of active and inactive renin, renin substrate and aldosterone in plasma. J Clin Endrocrinol Metab 1986; 62:384. 57. Rowe JW, et al. The influence of age on urinary concentrating ability in man. Nephron 1976; 17:270. 58. Phillips PA, et al. Reduced thirst after water deprivation in healthy elderly men. N Engl J Med 1984; 12:753. 59. Mukherjee AP, Coni NK, Davidson W. Osmoreceptor function among the elderly. Gernotol Clin 1973; 15:227. 60. Lindeman RD. Changes in renal function with aging: implications for treatment. Drugs & Aging 1992; 2:423. 61. Susset JG, et al. Collagen in 155 human bladders. Invest Urol 1978; 16:204. 62. Brocklehurst JC, Dilane JB. Studies of the female bladder in old age: I. Cystometricograms in non-incontinent women. Gerontol Clin 1968; 10:242. 63. Mohide EA. Prevalence and scope of urinary incontinence. Clin Geriatr Med 1986; 2:639. 64. Esposito AL, et al. Community acquired bacteremia in the elderly: analysis of one hundred consecutive episodes. J Am Geriatr Soc 1980; 28:315. 65. Mooney H, et al. Alterations in the liver with aging. Clin Gastroenterol 1985; 14:757. 66. Kampmann JP, Sinding J, Moller-Jorgenson L. Effect of age on liver function. Geriatrics 1975; 30:91. 67. Schmucker DL. Aging and drug disposition: an update. Pharmacol Rev 1985; 37:133. 68. Shepherd MM, et al. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 4:315. 69. Sampliner RE, et al. Gallbladder disease in Pima Indians. Demonstration of prevalence and early onset by cholecystography. N Engl J Med 1979; 283:1358. 70. Simonivis NJ, Wells CK, Feinstein AR. In-vivo and postmortem gallstones: support for the validity of the ‘‘epidemiologic necropsy’’ screening technique. Am J Epidemiol 1991; 133:922. 71. The Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO). The epidemiology of gallstone disease in Rome, Italy, Part 1. Prevalence in men. Hepatology 1988; 8:904. 72. Ratner J, et al. The prevalence of gallstone disease in very old institutionalized persons. JAMA 1991; 265:902. 73. Trotman BW, Sotoway RD. Pigment vs cholesterol cholelithiasis: clinical epidemiological aspects. Dig Dis 1975; 20:735. 74. Bateson MC. Gallbladder disease and cholecystectomy are independently variable. Lancet 1984; 2:621. 75. Bowen JC, et al. Gallstone disease: pathophysiology, epidemiology, natural history, and treatment options. Med Clin North Am 1992; 76:1143. 76. Einarsson K, et al. Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. N Engl J Med 1985; 313:277. 77. Carey MC. Pathogenesis of gallstones. Am J Surg 1993; 165:410. 78. Khalil T, et al. Decreased gallbladder responsiveness to CCK-8 in aged rabbits. Gastroenterology 1984; 86:1134. 79. Poston GJ, et al. Effect of age and sensitivity to cholecystokinin on gallstone formation in the guinea pig. Gastroenterology 1990; 98:993.

80. Khalil T, et al. Effects of aging on gallbladder contraction and release of cholecystokinin-33 in humans. Surgery 1985; 98:423. 81. Berger D, et al. Effects of age on fasting plasma levels pf pancreatic polypeptide in man. J Clin Endocrinol Metab 1978; 47:1183. 82. Brunicardi FC, et al. Regulation of pancreatic polypeptide secretion in the isolated perfused human pancreas. Am J Surg 1988; 155:63. 83. Rosenthal RA, Andersen DK. Surgery in the elderly: observations on the pathophysiology and treatment of cholelithiasis. Exp Gerontol 1993; 28:459. 84. Escarce JJ, et al. Outcomes of open cholecystectomy in the elderly: a longitudinal analysis of 21,00 cases in the prelaparoscopic era. Surgery 1995; 117:156. 85. Wenckhert A, Robertson B. The natural history of gallstone disease. Gastroenterology 1966; 50:376. 86. Morrow DJ, Thompson J, Wislon SE. Acute cholescystitis in the elderly. A surgical emergency. Arch Surg 1978; 113:1149. 87. Lipschitz DA, et al. The use of long term marrow culture as a model for the aging process. Age 1983; 6:122. 88. Reincke U, et al. Proliferative capacity of murine hematopoietic stem cells in vitro. Science 1982; 215:1619. 89. Albright JA, Makinodan T. Decline in the growth potential of spleen-colonizing bone marrow stem cells of long lived aging mice. J Exp Med 1976; 144:1204. 90. Lipschitz DA. Aging of the hematopoietic system. In: Hazzard WR, Bierman EL, Blass JP, Ettinger WH Jr, Halter JB. Principles of Geriatric Medicine and Gerontology. 3rd ed. New York: McGraw Hill, 1994. 91. Balducci L. Epidemiology of anemia in the elderly: information on diagnostic evaluation. J Am Geriatr Soc 2003; 51(suppl):S2-S9. 92. Lipschitz DA, et al. Evidence that microenvironmental factors account for the age-related decline in neutrophil function. Blood 1987; 70:1131. 93. Evers BM, Townsend CM, Thompson JC. Organ physiology of aging. In: Zenilman ME, Roslyn JJ, eds. Surgery in the Elderly Patient. Vol. I. Surg Clin North Am 1994; 74:23–39. 94. Simpkins JW, Millard WJ. Influence of age or neurotransmitter function. Endocrinol Metab Clin North Am 1987; 16:893. 95. Khansari DN, Gustad TV. Effect of long term, low dose growth hormone therapy on immune function and life expectancy of mice. Mech Aging Dev 1991; 57:87. 96. Forster JA, et al. Effect of age and IGF-I administration on elastin gene expression in rat aorta. J Gerontol 1990; 45: B113. 97. Burrows V, Shenkman L. Thyroid function in the elderly. Am J Med Sci 1982; 283:8. 98. Ronnov V, Kirkegaard C. Hyperthyroidism—A disease of old age? Br Med J 1973; 1:41. 99. Norton JA, Levin B, Jensen RT. Cancer of the endocrine system. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia: JB Lippincott, 1993. 100. Potts JT, Ackerman IP, Barker CF, et al. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991; 114:593. 101. Bilezikian JP, Potts JT, Fuleihan GH. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin End & Metab 2002; 87(12):5353–5361. 102. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. Ann Surg 1995; 222:402. 103. Chen H, Parkerson S, Udelsman R. Parathyroidectomy in the elderly: Do the benefits outweigh the risks? World J Surg 1998; 22:533–536. 104. Macintosh CG, Horowitz M, Verhagen MA, et al. Effect of small intestinal nutrient infusion on appetite, gastrointestinal

Chapter 60: Physiologic Considerations in the Elderly Surgical Patient

105. 106.

107. 108.

109. 110. 111. 112.

113.

114.

115.

116. 117.

118.

119. 120.

121. 122. 123.

124. 125. 126.

127.

128. 129.

130.

hormone release, and gastric myoelectrical activity in young and older men. Am J Gastroenterol 2001; 96:997–1007. Soergel K, Zboralske F, Amberg J. Presbyesophagus: esophageal motility in nonagenarian. J Clin Invest 1964; 43:1472. Khalil T, Poston GJ, Thompson JC. Effects of aging on gastrointestinal hormones. In: Prinsley DM, Shustead HH, eds. Progress in Clinical and Biological Research, Nutrition, and Aging. Vol. 326. New York: Alan R. Liss, 1990. Bonnevie O. The incidence of duodenal ulcer in Copenhagen County. Scand J Gastroenterol 1975; 10:385. Kurata JH, Honda GD, Frankl H. The incidence of duodenal and gastric ulcers in a large health maintenance organization. Am J Public Health 1985; 75:625. Kim SW, Parekh K, Townsend CM, et al. Effect of aging on duodenal bicarbonate secretion. Ann Surg 1990; 212:332. Russel RM, Koruda MJ. The aging process as a modifier of metabolism. Am J Clin Nutr 2000; 72:529s-532s. Kreel L, Sandlin B. Changes in pancreatic morphology associated with aging. Gut 1973; 14:962. McEvoy A. Investigation of intestinal malabsorption in the elderly. In: Evans J, Caird F, eds. Advanced Geriatric Medicine. London: Pittman, 1982. Browder W, Patterson MD, Thompson JL, Walters DN. Acute pancreatitis of unknown etiology in the elderly. Ann Surg 1993; 217:469. Pan HY, et al. Decline in beta adrenergic receptor-mediated vascular relaxation with aging in man. J Pharmacol Exp Ther 1986; 239:802. Lakatta EG. Altered autonomic modulation of cardiovascular function with adult aging: perspectives from studies ranging from man to cell. In: Stone HL, Weglicki WB, eds. Pathobiology of Cardiovascular Injury. Boston: Nojhoff, 1985. Vestal RE, et al. Reduced beta-adrenoreceptor sensitivity in the elderly. Clin Pharmacol Ther 1979; 26:181. Feldman RD, Limbird LE, Nadeau J, Robertson D, Wood JJ. Alteration in leukocyte b-receptor affinity with aging: a potential explanation for altered b-adrenergic sensitivity in the elderly. N Engl J Med 1984; 310:815. Arnetz BB. Endocrine reactions during standardized surgical stress: the effects of age and methods of anesthesia. Age Aging 1985; 14:96. Rolandelli RH, Ulrich JR. Nutritional support of the frail elderly surgical patient. Surg Clin North Am 1994; 74:79. Clevenger FW, Rodriguez DJ, Demarest GB, Osler TM, Olson SE, Fry DE. Protein and energy tolerance by stressed geriatric patients. J Surg Res 1992; 52:135. Gibson SJ, Helme RD. Age-related differences in pain perception and report. Clin Geriatr Med 2001; 17:433–456. Clinch D, Banerjee AK, Ostick G. Absence of abdominal pain in elderly patients with peptic ulcer. Age Aging 1984; 13:120. Moore AK, et al. Differences in epidural morphine requirements between elderly and young patients after abdominal surgery. Anesth Analg 1990; 70:316. Collins KJ, Exton-Smith AN. Thermal homeostasis in old age. J Am Geriatr Soc 1983; 31:519. Wongsurwat N, et al. Thermoregulatory failure in the elderly. J Am Geriatr Soc 1990; 38:899. Kurz A, Sessler DI, Lenhardt R. Perioperative normaothermia to reduced the incidence of surgical wound infection and shorten hospitalization: study of wound infection and temperature group. N Engl J Med 1996; 334:1209–1215. Frankenfiled D, Cooney RN, Smith JS, Rowe WA. Age-related differences in the metabolic response to injury. Trauma 2000; 48:49–62. Norman DC, et al. Fever and aging. J Am Geriatr Soc 1985; 33:859. Mikinodan T, Kay MMB. Age influences the immune system. In: Kunkel HG, Dixon FJ, eds. Advances in Immunology. New York: Academic Press, 1980. Holt DR, et al. Effects of age on wound healing in healthy human beings. Surgery 1992; 112:293.

1147

131. Quirina A, Viidik A. The influence of age on the healing of normal and ischemic incisional skin wounds. Mech Ageing Dev 1991; 58:221–232. 132. Ashcroft GS, Mills SJ, Ashworth JJ. Ageing and wound healing. Biogerontology 2002; 3:337–345. 133. Kirk SJ, et al. Arginine stimulates wound healing and immune function in elderly human beings. Surgery 1993; 114:155. 134. Currie MS. Immunosenescence. Comprehensive Ther 1992; 18:26. 135. Lewis VM, et al. Age, thymic involution and circulating thymic hormone activity. J Clin Endocrinol Metab 1978; 47:145. 136. Hefton JM, et al. Immunologic studies of aging. V. Impaired proliferation of PHA responsive human lymphocytes in culture. J Immunol 1980; 125:1007. 137. Ershler WB, et al. IL-2 and aging: decrease IL-2 production in healthy older people does not correlate with reduced helper cell numbers or antibody response to influenza vaccine and is not corrected in vitro by thymosinal. Immunopharmacology 1985; 10:11. 138. Roberts-Thomson JC, et al. Aging, immune response and mortality. Lancet 1974; 2:368. 139. Crawford J, Eye MK, Cohen HJ. Evaluation of monoclonal gammopathies in the well elderly. Am J Med 1987; 82:39. 140. Cohen HJ. Biology of aging as related to cancer. Cancer 1994; 74:2092. 141. Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, II: Chas. C. Thomas, 1988. 142. Urquidi V, Tarin D, Goodison S. Role of telomerase in senescence and oncogenesis. Ann Rev Med 2000; 51:65–79. 143. Shay JW, Wright WE. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 2005; 26:867–874. 144. Ershler WB, Longo DL. Aging and cancer. Issues of basic and clinical science. J Natl Cancer Inst 1997; 89:1489–1497. 145. Srivastava A, et al. C-Ha-ras-1 protooncogenes amplification and over expression during the limited replicative lifespan of normal fibroblasts. J Biocommun 1985; 260:6404. 146. Matocha MF, et al. Selective elevation of c-myc transcript leels in the liver of the aging Fischer-344 rat. Biochem Biophys Res Commun 1987; 147:1. 147. Shay JW, Pereora DM, Wright WE. A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 1991; 196:33. 148. Keller SM, et al. Emergency and elective surgery in patients over age 70 years. Am Surg 1987; 53:636. 149. Zenilman ME. Considerations in surgery in the elderly. In: Andersen DK, ed. Master Series in Surgery. 2. Advances in Surgery in the Elderly. New York: World Medical Press, 1993. 150. Boyd BJ, et al. Operative risk factors pf colon resection in the elderly. Ann Surg 1980; 192:743. 151. Hamel MB, Henderson WG, Khuri SF, Daley J. Surgical outcomes for patients age 80 and older: morbidity and mortality from noncardiac surgery. J Am Geriatr Soc 2005; 53: 424–429. 152. Pinholt EM, et al. Functional assessment of the elderly. A comparison of standard instruments with clinical judgement. Arch Intern Med 1987; 147:484. 153. Eagle KA, et al. ACC/AHA Task Force Report. Guidelines for perioperative evaluation for noncardiac surgery. Circulation 1996; 93:1279. 154. Djokovic JL, Hedley-White J. Prediction of outcome of surgery and anesthesia in patients over 80. JAMA 1979; 242:2301. 155. Seymour DG, Pringle R. Post-operative complications in the elderly surgical patient. Gerontology 1983; 29:262. 156. Browner WS, Mangano DT. In hospital and long-term mortality in male veterans following noncardiac surgery: the study of perioperative ischemia research group. JAMA 1992; 268:228. 157. Gerson MC, et al. Cardiac prognosis in noncardiac geriatric surgery. Ann Intern Med 1985; 103:832. 158. Older P, et al. Preoperative evaluation of cardiac function and ischemia in elderly patients by cardiopulmonary exercise testing. Chest 1993; 103:701.

medwedi.ru

1148

Part Nine: Special Physiologic Considerations

159. Hlatky MA, et al. A brief self-administered questionnaire to determine functional capacity (the Duke’s Activity Status Index). Am J Cardiol 1989; 64:651. 160. Lipschitz D. Medical and functional consequences of anemia in the elderly. J Am Geriatr Soc 2003; 51(S):S10-S13. 161. Chaves P, Ashar T, Guralnik JM, et al. Looking at the relationship between hemoglobin concentration and previous mobility difficulty in older women. Should criteria used to define anemia in older people be changed? J Am Geriatr Soc 2002; 50:1257–1264. 162. Lawrence VA, Silverstein JH, Cornell JE, et al. Higher Hb level is associated with better early functional recovery after hip fracture repair. Transfusion 2003; 43:1717. 163. Corti M, et al. Serum albumin level and physical disability as predictors of mortality in older persons. JAMA 1994; 272:1036. 164. Gibbs J, Cull W, Henderson W, et al. Preoperative serum albumin level as a predictor of operative mortality and morbidity. Arch Surg 1999; 134:36–42. 165. Berstein GM, Offenbartl SK. Adverse surgical outcomes among patients with cognitive impairments. Am Surg 1991; 57:682. 166. Marcantonio ER, et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994; 271(2):134. 167. Ely EW, Shintani A, Bernadrd G, et al. Delirium in the ICU is associated with higher mortality and prolonged length of stay. J Am Geriatr Soc 2002; 50(suppl):S166.

168. Moller JT, et al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCDl study. Lancet 1998; 351(9106): 857. 169. Newman MF, Kirchner JL, Philips-Bute B, et al. For the Neurological Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators. Longitudinal assessment of neurocognitive function after coronaryartery bypass surgery. N Engl J Med 2001; 344; 395. 170. Thomas DR, Ritchie DS. Preoperative assessment of older adults. J Am Geriatr Soc 1995; 43:211–215. 171. Hosking MP, et al. Outcomes of surgery in patients 90 years of age and older. JAMA 1989; 261:1909. 172. Wu AW, et al. Predicting future functional status for seriously ill hospitalized adults. The SUPPORT prognostic model. Ann Intern Med 1995; 122:342. 173. Lawrence VA, Hazuda HP, Cornell JE, et al. Functional Independence after major abdominal surgery in the elderly. J Am Coll Surg 2004; 199:762–772. 174. Effron DT, Bender JS. Laparoscopic surgery in older adults. J Am Geriatr Soc 2001; 49:658–663. 175. Satish S, et al. Geriatric targeting criteria as predictors of survival and health care utilization. J Am Geriatr Soc 1996; 44:914. 176. Rader MC, Vaughen JL. Management of the frail and deconditioned patient. Southern Med J 1994; 87:61. 177. Landefeld CS, et al. A randomized trial of care in a hospital medical unit especially designed to improve the functional outcome of acutely ill older patients. N Engl J Med 1995; 332:1338.

61 Surgery for Morbid Obesity Eric J. DeMaria, Ramzi Alami, and Robert E. Brolin

INTRODUCTION At the present time, it is estimated that more than 40% of the population of the United States is clinically overweight (1). A 1999 report in JAMA indicated that the prevalence of obesity in the 18- to 29-year-old group had increased from 12.0% in 1991 to 18.9% in 1999 (2). It is not surprising, therefore, that most centers across the United States now offer some form of surgical therapy for morbid obesity. Obesity is currently reported in terms of body mass index (BMI), which is expressed as body weight in kilograms divided by the height in meters squared. Obesity is defined as a BMI of 30 kg/m2 or greater. Morbid obesity is defined as a BMI of 40 kg/m2 or greater or a BMI of 35 kg/m2 with associated comorbidities. Since the recognition by the 1985 National Institutes of Health (NIH) Consensus Development Panel that obesity is a disease that adversely affects health and longevity (3), there has been a growing interest in the pathology and treatment of morbid obesity. This culminated in the 1991 NIH Consensus Development Conference that set forth guidelines for the surgical treatment of clinically severe obesity (4). The definition of ‘‘morbid’’ obesity evolved in conjunction with the introduction of surgery as a viable treatment alternative for the massive overweight. Minimum weight limits for morbid obesity were initially established in the range of 100 pounds or 100% above ideal body weight. After the NIH Consensus Development Conference, morbid obesity was redefined as a minimum BMI of 40 kg/m4. Obesity of this magnitude is surprisingly common in the United States. One estimate suggests that between 6 and 10 million Americans are more than 100 pounds overweight. Even two decades ago in 1980, Abraham and Johnson (5) estimated that 7.2% of American women and 5% of American men were morbidly obese. The concept of superobesity has gradually evolved to describe a group of patients whose weight far exceeds the minimum weight criteria required for surgical treatment (6,7). Several definitions have been used to describe this magnitude of overweight including more than 225% of ideal body weight, a weight greater than 200 pounds overweight or a BMI greater than 50 kg/m2. Individuals in this extreme category frequently do not live longer than 45 years unless substantial weight loss is achieved. Apart from the excessive weight, morbid obesity carries a constellation of other life threatening syndromes including hypertension, diabetes mellitus, hyperlipidemia, cardiovascular atherosclerosis, cardiomyopathy, and sleep apnea. Morbid obesity has also been clearly linked with several other conditions including degenerative arthritis, cholelithiasis, pseudotumor cerebri, varicose veins, venous stasis ulcers, gastroesophageal reflux, urinary incontinence,

dysmenorrhea, infertility, and all types of hernias. Morbidly obese individuals also face social prejudice and discrimination often resulting in depression or low self-esteem. The initial approach to the morbidly obese individual focuses on nonsurgical therapy. Although it is widely accepted that most of the patients that fit the morbidly obese profile will fail this approach, it is recommended that attempts at dietary changes as well as lifestyle changes be made before consideration for surgery. Once patients have failed nonsurgical management, the 1991 panel recommended that gastric restrictive or bypass procedures be considered for patients that meet the criteria (4). Over the years, the surgical approach to morbid obesity has undergone several changes with many of the initial procedures being abandoned in favor of other operations and with the application of new technologies as they evolve. Over the last decade, the biggest change has been the adaptation of laparoscopic techniques to bariatric surgery.

ETIOLOGY AND PATHOPHYSIOLOGY An excess of calorie intake in comparison with reduced energy expenditure results in gradual expansion of the body’s primary energy storage depot, which is fat. In normal weight humans, the percentage of body weight as fat varies from 15% to 25%. The majority of excess fat is usually found in subcutaneous tissues. However, in men the intra-abdominal storage depot is occasionally larger than the subcutaneous depot. As the magnitude of obesity increases, the weight of the lean body mass, particularly bone and skeletal muscle, is also increased. A greater lean body mass is probably necessary to provide adequate structural support for the obese. During the past two decades, it has been learned that the distribution of body fat is of greater importance in terms of health risk than the weight of the fat mass per se. The risks of cardiovascular complications are significantly greater in patients with a preponderance of abdominal fat (so-called central or android obesity) as opposed to individuals with a gluteal preponderance [so-called peripheral or gynoid obesity (8)]. The gluteal fat distribution pattern is more prevalent in women. However, there is considerable heterogeneity of body fat distribution patterns in both sexes. There is also considerable variability in the size of fat cells from specific depots in both men and women. Women typically have larger fat cells in the gluteal region, whereas men tend to have their largest fat cells in the mesentery and omentum (9). The fat distribution pattern is commonly expressed in terms of waist-to-hip ratio (WHR) measurements, although other anthropomorphic measurements such as sagittal diameter or neck-to-thigh ratio may be more predicitive of cardiovascular risk.

medwedi.ru 1149

Part Nine: Special Physiologic Considerations

The precise mechanisms that explain the relationship between increased abdominal fatness and morbidity are not well understood. Furthermore, the biochemical and genetic mechanisms that result in deposition of excess fat in abdominal or gluteal depots are also incompletely explained. The primary mechanism for weight fluctuation in adults is change in fat cell size. However, fat cells may continue to increase in number throughout early adult life, particularly in individuals who are substantially overweight. Once formed, fat cells do not undergo involution. The failure of fat cells to undergo involution provides one explanation for the failure of postoperative morbidly obese patients to reach ideal weight even with a remarkably low level of daily calorie intake. There is convincing evidence that the development of obesity has a strong genetic component. Children of normal weight parents have only a 10% chance of becoming obese, whereas the children of obese parents have an 80% to 90% probability of developing obesity in early adulthood. There is also a strong correlation between the weight of adopted children and that of their biologic parents (10). Studies comparing the degree of fatness in monozygotic versus dizygotic twins have shown a considerably stronger correlation in the monozygotic group (11). Other studies have shown a close correlation of basal metabolic rate, body fat distribution pattern, and energy expenditure among family members. There is also a growing body of evidence that obese patients have lower levels of thermogenesis, which is a major component of the body’s means of energy expenditure. Several studies comparing thermogenesis in obese and lean subjects have shown that the obese have substantially lower levels of thermogenesis in comparison with the lean subjects. Conversely, the resting metabolic rate of obese patients is remarkably similar to that of normal weight patients. Although it is generally conceded that environmental factors also contribute to the development of obesity, there is little hard scientific data that confirm this relationship. Morbid obesity is predominantly an American disease, suggesting that the American diet and culture play an important role in its development. In the United States, morbid obesity is generally recognized as a disease of lower socioeconomic groups. Lack of good nutrition education and diets with high-fat content are two frequently cited causes for the preponderance of severe obesity in lower class people in the United States. Recent studies in animals and man have suggested that a disproportionately high intake of fat in the diet contributes to development of obesity. It has been estimated that the percentage of dietary fat consumed by Americans has increased by 10% in the past 50 years. Because dietary fat is converted to body fat with nearly 25% greater efficiency than carbohydrate, weight gain is promoted by a high-fat diet. A greater consumption of fast foods, which are notoriously high in fat, is also cited as a major factor contributing to the increased prevalence of obesity in the United States. Physical exercise is an extremely important means of energy expenditure and weight control. Because physical activity in morbidly obese patients is severely limited by their weight, they are notoriously sedentary. Poor diet habits and a sedentary lifestyle coupled with an inherently reduced capability of energy expenditure make morbid obesity a disease that is highly resistant to nonsurgical treatment.

RISKS AND COMPLICATIONS OF SEVERE OBESITY The relationship of body weight to mortality and other medical illnesses is shown in Figure 1. The prevalence of

Figure 1 The estimated relative risk of medical illnesses and complications in relation to percentage above desirable weight. Source: From Ref. 12.

complications related to severe obesity increases sharply at a level corresponding to approximately 60% above desirable weight (12,13). At that level there is a twofold increase in morbidity and mortality. However, the slope of the ‘‘risk curve’’ rises almost exponentially above the 60% overweight level, so that the complication rate corresponding to 100% above ideal weight is in the range of 13 to 14 times normal. Unfortunately, there is a paucity of life table statistics for adults who are more than 100 pounds overweight. These data are particularly lacking among women who are the most common subjects of obesity operations. The 1980 study of Drenick et al. (14) of mortality in 200 morbidly obese men, which is shown in Figure 2, is the only clinical series in which all the patients were heavy enough to qualify for surgical treatment. The most striking finding in the study was the 12-fold increase in mortality in the youngest age group. The most common causes of death among the overweight men in Drenick’s study were myocardial infarction and stroke. A list of medical problems and other illnesses that have been associated with severe obesity is shown in Table 1.

1,100 Excess Mortality, % (Obese Men)

1150

900

700

500

300

100 Normal Men

25-34

35-44 45-54 55-64 Age Intervals, yr

65-74

Figure 2 Comparison of excess mortality in men with morbid obesity (light shaded bars) vs. normal weight men (black boxes) by age interval. Source: From Ref. 15.

Chapter 61:

Table 1 Diseases Associated with Severe Obesity Comorbidity Hypertension Cholelithiasis Degenerative osteoarthritis Hyperlipidemia Diabetes mellitus Asthmatic bronchitis Coronary artery disease Heart failure (right ventricular and/or left ventricular) Stasis ulcers/venous insufficiency Gastroesophageal reflux Stress overflow urinary incontinence Obesity hypoventilation/sleep apnea syndrome Pseudomotor cerebri Sexual hormone imbalance/infertility Malignancy (uterine, colon, gallbladder) Pulmonary embolism/thrombophlebitis Necrotizing subcutaneous infections Mental depression

Incidence (%)a 20–55 25–45 20–35 15–25 10–25 10–15 5–15 5–15 5–15 5–15 5–15 5–12 1–2 –b –b –b –b –b

a

There is considerable variability in the reported incidence of nearly all the diseases that have been associated with morbid obesity. b Statistical data relative to the incidence of these conditions in patients 100 pounds overweight are absent.

Many of these conditions can be controlled or eliminated with substantial weight loss. It is generally acknowledged that there is an inverse relationship between the magnitude of overweight and the age of onset of many of these comorbid conditions. Problems such as sleep apnea and cardiovascular disease are frequent causes of premature death in the morbidly obese. Congestive heart failure is generally a consequence of left ventricular or biventricular hypertrophy caused by a combination of increased demand for blood flow through the excess adipose tissue and increases in both systemic and pulmonary artery blood pressure. The obesity hypoventilation syndrome is caused by the increased weight placed on the chest wall and diaphragm, which results in restricted breathing. Systemic hypoxemia and hypercarbia gradually ensue. Gradual desensitization of the central chemoreceptors to carbon dioxide may result in daytime somnolence. The obstructive sleep apnea syndrome is caused by fat deposition in the hypopharynx, which results in constriction of the upper airway. During sleep, the narrowed upper airway produces loud snoring and can become completely obstructed, resulting in episodic apnea and cardiac arrhythmias. Sudden wakening is caused by hypoxic stimulation of the desensitized chemoreceptors. Prolonged hypoxia also can result in cardiac arrest, which is the usual cause of death in these patients. Necrotizing subcutaneous infections can be life threatening in morbidly obese patients. These infections are usually polymicrobial, and typically develop in the perineum or the underside of a large abdominal paniculus. Diabetes frequently is an associated factor. The infections are extremely difficult to treat because the affected tissue has an inherently poor blood supply. Extensive soft tissue debridement is frequently necessary. Diabetes, hypertension, and atherosclerosis typically occur in patients with an ‘‘abdominal’’ fat distribution pattern, which is characterized by a WHR of 0.9 or greater (8). Diabetes associated with severe obesity almost invariably begins in adulthood and is typically resistant to insulin due a marked downregulation of insulin receptors. Oral hypoglycemic

Surgery for Morbid Obesity

1151

agents are also usually ineffective in controlling serum glucose levels. Coronary artery disease is usually found in patients with either diabetes or hyperlipidema. Approximately 20% of morbidly obese patients have elevated serum levels of total cholesterol and triglycerides (15). However, angina in these patients is relatively uncommon, probably because they are only capable of low levels of physical exertion. Other conditions such as degenerative arthritis, venous stasis, and urinary incontinence frequently result in serious long-term disability in the morbidly obese. Many orthopedic surgeons consider morbid obesity to be a contraindication for both prosthetic joint replacement and lower back operations, because of the likelihood of a poor result. Urologists and gynecologists are reluctant to attempt surgical correction of urinary continence problems for the same reason. This attitude creates a ‘‘catch-22’’ for the morbidly obese, in that the immobility resulting from both degenerative arthritis and massive overweight also contributes to their difficulty in losing weight. There are a number of other diseases that are increasingly prevalent in severely obese patients, including gastroesophageal reflux, sex hormone imbalance, pseudotumor cerebri, and several types of malignancy. Morbidly obese women of childbearing age are known to have a high incidence of infertility and other menstrual and hormonal problems. Grace et al. (16) and Deitel (17) have independently reported preoperative abnormalities in sex hormone– binding globulin (SHBG) in infertile morbidly obese women who were attempting pregnancy. An epidemiologic study conducted by the American Cancer Society has shown an increased risk for colon cancer in men 40% overweight and an increased incidence of uterine cervix and gallbladder neoplasms in women 40% overweight. Many of the morbidly obese suffer from low selfesteem and mental depression. The social stigma associated with severe obesity is apparent in a number of areas. Discrimination in obtaining employment is common particularly when the job requires some degree of public exposure. Fat people are often the objects of ridicule and unkind jokes. Their social activity is restricted by the inability to buy clothes at conventional clothing stores or to sit in airplane and theater seats. The most severely obese often have problems maintaining an acceptable level of personal hygiene. Morbid obesity is commonly associated with problematic marriages. Often obesity in one spouse is a ‘‘trade off’’ for a serious problem such as alcohol or drug addiction in the other. Many of the most severely obese become reclusive and housebound as a consequence of both the inability to ambulate and the embarrassment over their weight.

TREATMENT OF SEVERE OBESITY Morbid obesity has been notoriously refractory to virtually every method of nonoperative treatment. The failure rate of diet and behavior modification treatment at two years in the morbidly obese approaches 100% (18). Likewise, the results of jaw wiring in this group of patients have been disappointing. Many morbidly obese patients gain substantial amounts of weight after unsuccessful attempts at dieting. The socalled yo-yo theory of dieting, namely transient weight loss followed by greater weight gain, is gaining popularity among many health professionals who provide nonsurgical treatment for obesity. The gist of this theory is that chronic dieters experience a diminished capability to lose regained weight after each successive weight fluctuation. However,

medwedi.ru

1152

Part Nine: Special Physiologic Considerations

the primary premise and justification for surgical treatment of morbid obesity has been the compelling evidence that severe obesity is associated with a shortened life span and a variety of other serious medical problems.

Early Obesity Operations Kremen et al. (19) introduced the concept of surgery for morbid obesity in 1954, when they reported that resection of a large percentage of the small intestine resulted in massive weight loss. Kremen’s concept of malabsorptioninduced weight loss was later applied in the form of jejunoileal (intestinal) bypass as treatment for morbid obesity (20–22). Weight loss following jejunoileal bypass results entirely from malabsorption of ingested food. After experimenting with various lengths of jejunum and ileum, it was determined that the best weight loss occurred in patients with a functional intestinal length of approximately 18 in. Scott et al. (22) and Salmon (21) independently described a modification of jejunoileal bypass (Fig. 3) in which 12 in. of the proximal jejunum was anastomosed end-to-end to 6 in. of distal ileum. During the 1960s and 1970s, thousands of intestinal bypasses were performed for treatment of morbid obesity. However, as more of these operations were done, reports of serious late sequelae, including hepatic failure, urinary calculi, arthritis, and vitamin deficiencies appeared in the literature (24,25). In 1975, Passaro et al. (26) described the bypass enteritis syndrome, an entity characterized by intermittent episodes of abdominal pain, bloating, and diarrhea, which occasionally was mistaken for peritonitis or intestinal obstruction. Many patients with bypass enteritis went on to develop arthralgias, skin rashes, and cachexia. Drenick et al. (27) later incriminated bacterial overgrowth of the distal bypassed bowel as a cause for the syndrome.

The first public repudiation of jejunoileal bypass was delivered by Ravitch and Brolin (28) in 1979. During the next several years, many other prominent surgeons abandoned intestinal bypass as treatment for severe obesity (29,30). Today, jejunoileal bypass is no longer recommended for treatment of morbid obesity. The concept of gastric restriction as treatment for morbid obesity was introduced by Mason and Ito (31) in 1967. At that time, Mason’s operations received little support from the surgical community both because they were technically difficult to perform and because weight loss was less consistent than with jejunoileal bypass. Moreover, the early gastric restrictive operations were associated with a high incidence of postoperative complications. Complication rates with gastric bypass decreased after Alden (32) introduced the concept of stapling the stomach in continuity rather than dividing it. In addition, use of the Roux-en-Y technique eliminated problems with bile reflux esophagitis that were common after loop gastric bypass. In 1979 Pace et al. (33) introduced stapled gastric partitioning, touting its technical ease in performance and low incidence of operative complications relative to gastric bypass. However, an unacceptably high incidence of early staple-line breakdown subsequently led to a proliferation of modifications using this approach. Many of these stapling techniques were performed in an uncontrolled manner. However, during the 1980s two gastric restrictive operations, vertical banded gastroplasty (VBG) and Roux-en-Y gastric bypass (RYGB), have become recognized as procedures that have produced satisfactory weight loss in patients at 5 to 10 years postoperatively.

Current Open Operations As obesity surgery gained more acceptance and its role in the treatment of morbid obesity became better recognized and defined, the gastric restrictive procedures became the most popular method of surgical treatment. All the current gastric operations are designed to restrict oral intake. The less than 50 mL capacity upper gastric pouch and the calibrated less than 12 mm diameter outlet effectively limit the quantity of solid food that can be consumed at one time. Conversely, intake of liquids is not limited by these operations. There are three basic categories of gastric restrictive operations: (i) gastroplasty in which the stomach is partitioned close to the gastroesophageal junction, creating a small upper gastric pouch with a small calibrated outlet leading from the upper pouch to the remainder of the digestive tract; (ii) gastric banding in which a calibrated piece of prosthetic material is wrapped around the upper portion of the stomach; and (iii) gastric bypass in which the upper stomach is closed off, thereby excluding more than 95% of the stomach, all of the duodenum, and 10 to 15 cm of proximal jejunum, from digestive continuity.

Gastroplasty

Figure 3 Jejunoileal bypass in which a 12-in. segment of jejunum is anastomosed end-to-end to 6 in. of the terminal ileum. The remainder of the small bowel (dark shaded area) is totally excluded from digestive continuity. The distal end of the excluded bowel is anastomosed to the transverse colon. Source: From Ref. 24.

There is no malabsorption associated with gastroplasty operations. Weight loss results exclusively from reduced calorie intake. Current techniques have evolved in favor of stapling in a vertical direction along the lesser curvature of the stomach, which has facilitated reinforcement of the outlet with prosthetic materials to prevent progressive stomal dilation. Horizontal gastroplasty techniques have now been largely abandoned because of an unacceptably high incidence of staple-line disruption and stomal dilation. The two most popular techniques of gastroplasty are VBG and vertical silicone elastomer (Silastic) ring

Chapter 61:

Surgery for Morbid Obesity

1153

gastroplasty (SRG), which are shown in Figs. 4 and 5. The stoma located at the distal end of a vertically oriented staple-line is reinforced with prosthetic material to prevent gradual dilation. VBG was first described in detail by Mason (34) in 1982. SRG was first described by Laws (35) in 1981 and has since been refined by others (36,37). The incidence of transmural erosion of the Silastic ring has been greatly reduced by not covering it with the surrounding stomach as Laws had originally described. Morbidity and mortality rates with both VBG and SRG have been low. Mason et al. (38) have reported an overall morbidity rate of under 10% and a mortality rate of 0.25% in a series of more than 1200 VBGs. In 1987, Willbanks (37) reported a 3% complication rate with no deaths in a series of 305 SRG patients.

Gastric Banding Gastric banding is a technique that has enjoyed popularity in Europe, but has not received much attention in the United States. The majority of techniques of gastric banding employ a premeasured strip of prosthetic material to restrict oral intake (Fig. 6). The circumference of the band is generally in the range of 5 cm, similar to the measurement used in VBG. Most techniques of gastric banding lack precision in measuring the volume of stomach above the band. With some techniques, the band is sutured to both itself and the stomach to prevent ‘‘slipping.’’ Kuzmak (39) introduced the concept of an inflatable silicone band in which the diameter of the band can be adjusted by infusion of saline through a subcutaneous reservoir. Kuzmak’s reported that weight loss results and complication rates are better than those observed after other banding techniques in which strips of polypropylene or Teflon are used.

Figure 5 Vertical Silastic ring gastroplasty in which the 15 to 20 mL capacity upper gastric pouch empties through a 5 cm circumference Silastic ring. The ring is secured at the distal end of the vertical staple-line using a heavy suture of either nylon or polypropylene. Source: From Ref. 24.

Complication rates with the European techniques of gastric banding have been relatively high with morbidity and mortality rates in the range of 30% and 3%, respectively. Stenosis and/or erosion of the band have been reported in 10% to 30% of cases. Stenosis and erosion can result in leaks and stomal obstruction, which frequently require reoperation. Kuzmak has not reported erosion of his inflatable silicone band. However, problems with the subcutaneous reservoir are common.

Gastric Bypass Gastric bypass combines gastric restriction with a small amount of malabsorption. However, malabsorption of protein, carbohydrate, and fat has not been reported after

Figure 4 Vertical-banded gastroplasty in which the upper gastric pouch, measured at 15 to 20 mL capacity, empties into the remainder of the stomach through a calibrated stoma. The stoma is reinforced with a strip of polypropylene (Marlex) mesh measuring 5 cm in circumference resulting in a 1.6 cm internal diameter stoma. The mesh is placed around the stoma through a ‘‘window’’ created by firing a circular stapling instrument alongside a No. 32 French diameter bougie. The mesh is sutured to itself rather than the stomach, a modification that has reduced the incidence of outlet stricture and leaks. Source: From Ref. 24.

Figure 6 Gastric banding in which the upper portion of the stomach is encircled by a calibrated prosthetic band. The volume of the stomach above the band is crudely estimated by most surgeons who perform this operation. Source: From Ref. 24.

medwedi.ru

1154

Part Nine: Special Physiologic Considerations

conventional gastric bypass. The anatomic parameters required for successful weight loss with gastric bypass were defined by Mason et al. (40) in 1975 and include a small 50 mL capacity upper gastric pouch and a 1.2 cm diameter gastrojejunostomy stoma. The RYGB, shown in Figure 7, is currently the preferred method of almost every surgeon who performs gastric bypass. Further, a number of surgeons are now transecting the upper stomach rather than stapling it in continuity. The postoperative complication rates and weight loss observed with current modifications of RYGB improved substantially during the 1980s. In 1984, Flickinger et al. (42) reported a 10% complication rate and two deaths (1%) in a series of 210 consecutive RYGB patients. Sugerman et al. (43) reported a 5% morbidity rate and no mortality in their series of 182 patients who had RYGB. Yale (44) reported two deaths (0.8%) and a 10% incidence of major early postoperative complications in a series of 251 gastric bypass operations. Gastric bypass occasionally produces symptoms of the ‘‘dumping syndrome,’’ which include nausea, bloating, diarrhea, and colic. Dumping is thought to be due to rapid emptying of the small gastric pouch directly into the small bowel. Symptoms of ‘‘late’’ dumping such as lightheadedness, palpitations, and sweating also occur in a smaller percentage of patients. These vasomotor symptoms are the consequence of rebound hypoglycemia and typically occur one to two hours after ingestion of a carbohydrateladen meal. After gastric bypass, the incidence of dumping is variable with some patients reporting no symptoms, others having symptoms associated with eating specific foods such as milk products or sweets, and a few patients who report troublesome symptoms after almost every meal.

Biliopancreatic Bypass

gastric restriction with a substantial amount of malabsorption. The concept of BPB was introduced by Scopinaro in the late 1970s. An early modification of this procedure is shown in Figure 8. The technique includes performance of a subtotal gastrectomy leaving an approximately 250 to 500 mL capacity gastric remnant, which is anastomosed to the proximal ileum. All the jejunum is excluded from digestive continuity and is anastomosed end to side to a ‘‘common channel’’ of ileum at a point between 50 and 100 cm proximal to the ileocecal junction. Because this degree of malabsorption predisposes to cholelithiasis, cholecystectomy is also an integral part of the operation. Scopinaro et al. (45) have modified his original operation several times to further reduce gastric capacity to 200 mL in superobese patients (the so-called very little stomach modification) and has lengthened the ‘‘common channel’’ in less obese patients to reduce the incidence of malabsorption-related sequelae. Sugerman et al. (46) suggested that there is no need to perform gastrectomy as part of BPB, and recommended stapling the stomach in continuity. The incidence of early postoperative complications after BPB has been in the range of 10% to 15% with a 1% mortality rate (45,47). However, the incidence of metabolic complications within the first postoperative year has been high, including a 30% incidence of anemia, an 8% to 10% incidence of marginal ulcers, and a 20% incidence of hospitalization for treatment of protein-calorie malnutrition (45). As malabsorption is the primary source of both weight loss and weight maintenance, diarrhea and foul-smelling stools are common in patients after BPB has been performed. An operation that was initially described for the management of duodenogastric reflux has been adapted for the

Biliopancreatic bypass (BPB), also known as distal gastric bypass, is an operation that combines a modest amount of

Figure 7 Roux-en-Y gastric bypass in which the TA 90B stapler (U.S. Surgical Corp., Norwalk, Connecticut, U.S.) is fired across the cardia of the stomach creating a 255 mL upper pouch. The jejunum is divided approximately 15 cm distal to the ligament of Treitz with the distal end anastomosed to the upper stomach using a circular stapler to create a 1.1 cm diameter anastomosis. The proximal end of jejunum is then anastomosed 50 cm below the gastrojejunostomy. Source: From Ref. 42.

Figure 8 Biliopancreatic bypass in which the small bowel below the ligament of Treitz is bisected with the distal end of transected bowel anastomosed to the upper stomach and the proximal end anastomosed end to side to the ‘‘common channel’’ of distal ileum 50 cm proximal to the ileocecal junction. The distal stomach (shaded in black) is either resected (Scopinaro technique) or stapled in continuity. Source: From Ref. 24.

Chapter 61:

treatment of morbid obesity by Marceau et al. (48) This modification shown in Figure 9 combines a ‘‘parietal’’ gastrectomy with biliopancreatic diversion. Because the functional portion of the duodenum is diverted from digestive continuity, this procedure has been dubbed the ‘‘duodenal switch.’’ The primary goal of this modification is reduction in the incidence of the serious metabolic sequelae that are associated with BPB. The so-called ‘‘parietal’’ gastrectomy preserves the pylorus and the vagal innervation along the lesser curvature, which in theory would facilitate both gastric emptying and vitamin B12 absorption. Elimination of the gastroenteric anastomosis might be expected to reduce the incidence of marginal ulcers. As one-third of the stomach is left intact, restriction of oral intake does not play a prominent role in postoperative weight loss. Of the open procedures listed above, gastric bypass gained the most popularity in the United States. It was favored mostly because of the maintained weight loss that patients achieved long term. A study by Sugerman et al. (49) comparing gastric bypass with VBG showed significantly superior results from bypass surgery. The results revealed an average of 37% weight loss among the banding population compared to 64% among the bypass population at three years (49). Furthermore, a study from the Mayo Clinic looking at long-term results of VBG showed only a 26% success rate at 10 years follow-up (50). It is not surprising, therefore, that in a survey of the membership of the

Surgery for Morbid Obesity

1155

Table 2 Common Surgeries for Morbid Obesity Operation RYGB Biliopancreatic diversion VBG Gastric banding Silastic ring gastroplasty Laparoscopic bariatric surgery

Frequency performed (% of total) 70 12 7 5 4 3

Abbreviations: VBG, vertical banded gastroplasty; RYGB, Roux-en-Y gastric bypass. Source: Courtesy of American Society of Bariatric Surgery, 1999.

American Society of Bariatric Surgery in 1999, 70% chose RYGB, while only 7% performed VBG (Table 2).

Laparoscopic Operations The application of laparoscopic techniques to bariatric surgery is, by far, the most important advancement over the last decade. Laparoscopic approaches to bariatric surgery emerged in the early to mid-nineties. Because of the inherent technical difficulties of the procedures, especially gastric bypass, they did not gain widespread acceptance until the latter part of the decade. In fact, most centers where laparoscopic procedures are now common place went through a transition period using such bridging procedures as handassisted laparoscopic gastric bypass. Mirroring the results of the open techniques, lap gastric bypass, and lap gastric banding have emerged as the two most popular operations. Interestingly, lap gastric banding is the preferred operation among most European centers, whereas lap gastric bypass has emerged as the operation of choice in the United States. Regardless of the choice of operation, laparoscopic surgery lends itself ideally to the morbidly obese population. In terms of technical difficulty, there is a long learning curve, especially for gastric bypass. Schauer et al. reported the learning curve as being 100 cases (51). Once the learning curve is overcome, the results from laparoscopic gastric bypass have so far been shown to be equivalent to those obtained with the open technique, which is the established gold standard. Moreover, with the minimally invasive approach, some of the short- and long-term complications associated with RYGB, most notably wound infections and incisional hernias, are diminished.

Laparoscopic Gastric Banding

Figure 9 In a duodenal switch, two-thirds of the stomach is excised along the greater curvature using linear staplers. The duodenum is dissected from the head of the pancreas for a distance of 5 cm beyond the pylorus and stapled in continuity at that point. The ileum is then transected at a point 250 cm proximal to the ileocecal junction. The distal end of the transected ileum is anastomosed to the proximal duodenum using two layers of sutures. The remainder of the duodenum and proximal small bowel (unshaded portion) is diverted from the digestive stream. The distal end of the bypassed segment is reanastomosed to the ileum 100 cm proximal to the ileocecal junction to create the common channel.

Much like the open procedure, laparoscopic gastric banding is a purely restrictive procedure that involves the creation of a gastric pouch using an inflatable band with an adjustable subcutaneous reservoir buried in the abdominal wall. The reservoir is accessed and inflated with saline. Adjustments in the reservoir lead to tightening or releasing of the band, allowing adjustment of the luminal diameter of the band to decrease side effects or enhance weight loss. Again, this procedure is ideally suited for the minimally invasive approach in that it is technically easy and circumvents the complications associated with the open technique. In addition, one of its features is that it is totally reversible. This is currently the favored procedure in Europe and Australia where published series have shown comparable results to open banding (52–55). In the United States, the experience is much more limited with the Food and Drug Administration (FDA) approving the LAP-BAND in June 2001. The initial FDA-approved trials could not reproduce the data from studies elsewhere in the world (56). However, in a review by Ren et al. (57) of 500 LAP-BAND cases not

medwedi.ru

1156

Part Nine: Special Physiologic Considerations

included in the FDA trials, the percent excessive weight loss at nine months was 35.6% and at 12 months it was 41.6%. The study also had similar complication rates to those cited in the world literature (57). The general consensus is that laparoscopic gastric banding is a safe and effective procedure, though it fails at achieving the weight loss seen with gastric bypass.

Laparoscopic Gastric Bypass As opposed to lap gastric banding, there is a lot of data from the United States on laparoscopic bypass. This is the procedure that has gained the widest acceptance in the circles of U.S. bariatric surgery. The operation itself is an adaptation of the open RYGB with minor modifications. The initial results from lap gastric bypass have shown a steep learning curve with higher complication rates. However, with time, the complication rates have been reduced to those seen in open gastric bypass. This is clearly demonstrated in several studies, an example of which was published by Demaria et al. of their first 281 consecutive laparoscopic gastric bypasses (58). In that series, the overall mortality was 0, with a leak rate of 5.1%. However, the leak rate for the last 164 patients and after modification of the gastrojejunostomy technique was only 1.8% (comparable to open RYGBP). The results of laparoscopic gastric bypass have been very promising. The average excess weight loss is around 65% to 80% for most large series, which is comparable to the open technique. Improvement in comorbidities is most notable among type 2 diabetics, with resolution in about 85% of the patients. Anastomotic leak rate is around 2%, which again compares well to open gastric bypass. The reported mortality rate is around 0.2%. The most commonly reported complications were bowel obstruction and stomal stenosis in 3.1% and 4.7%, respectively. Wound complications of open gastric bypass, including wound infection and hernias, have been virtually eliminated by the laparoscopic technique (59). Conversion to open gastric bypass occurs in about 1.5%. Hospital stay is in the range of two to three days. The operation is performed through five ports, and is essentially the same as the open procedure except that the stomach is usually divided and the jejunal limb is brought up in a retrocolic, retrogastric fashion. The gastrojejunostomy can be done with either a circular stapling device or can be performed in two layers, with an inner linear staple layer and an outer suture layer. The jejunojejunostomy is a stapled anastomosis.

PATIENT MANAGEMENT Preoperative Patient Selection All candidates for obesity operations should be interviewed in an outpatient setting prior to operation. During that interview, the surgeon should provide prospective patients with a clear understanding of the risks and goals of the operation as well as explain the mechanism by which the procedure produces weight loss. At the same time, the surgeon should obtain a complete medical history and make a preliminary assessment of a patient’s operative risk. Psychologic stability should also be evaluated, particularly in terms of the patient’s willingness to adjust to the permanent postoperative side effects of gastric restriction and malabsorption. At the conclusion of the interview, the patient should have obtained sufficient information to give informed consent. Standard criteria used in selecting patients for obesity operations are shown in Table 3. Minimum weight limits for

Table 3 Criteria for Patient Selection 1. Weight a. 100 pounds or 100% above desirable weight b. BMI 40 kg/m2 c. BMI 35 kg/m2 with coexisting medical problems 2. Failure of nonsurgical methods of weight reduction 3. Absence of endocrine disorders that can cause massive obesity 4. Psychologic stability a. Basic understanding of how surgery causes weight loss b. Realization that surgery itself cannot guarantee a good result c. Absence of alcohol and drug abuse Abbreviation: BMI, body mass index.

surgical treatment of severe obesity were traditionally established in the range of 100 pounds or 100% above desirable weight as defined by standard life insurance tables. The 1991 NIH Consensus Development Panel (4) on gastrointestinal surgery for severe obesity suggested using the BMI rather than absolute body weight in evaluation of potential surgical candidates. The panel recommended that surgical treatment be considered for any patient with a BMI of 40 kg/m2, who had failed serious attempts at nonsurgical treatment (4). The panel also recommended that surgery be considered for patients with a BMI of 35 kg/m2, who have serious coexisting medical problems such as diabetes, hypertension, hyperlipidemia, or sleep apnea (4). There are relatively few endocrine disorders that cause massive obesity. Although hypothyroidism is associated with both a decreased metabolic rate and obesity, it is virtually never the sole cause of morbid obesity. Hence, hypothyroidism is not a contraindication for obesity surgery. Conversely, Cushing’s disease may occasionally cause massive obesity. Because successful treatment of Cushing’s disease likely results in substantial weight loss, patients with untreated Cushing’s disease should not undergo operations designed for treatment of morbid obesity. Adult-onset diabetes mellitus (AODM) is almost invariably associated with obesity. However, unlike Cushing’s disease, AODM is effectively treated by weight reduction. Hence, AODM is considered an indication for obesity surgery. Although patients with morbid obesity have been shown to have similar psychologic profiles to their normal weight counterparts, the psychologic stability of surgical candidates should be considered prior to operation. Although standardized psychologic tests and separate screening interviews with psychologists or psychiatrists have not proven useful in predicting postoperative outcome of obesity operations, a formal psychologic evaluation of patients with a documented history of mental illness is recommended. Patients should also be carefully queried regarding abuse of addictive drugs and alcohol prior to operation. All patients who undergo surgical treatment of obesity should be admonished that sustained long-term weight loss is not guaranteed merely by having an operation. This understanding is particularly important for patients who have gastric restrictive operations, which can be defeated by consuming large quantities of high-calorie liquids and soft junk foods.

Preoperative and Postoperative Care Routine preadmission tests include a complete blood count, chem-21 screen, urinalysis, blood typing, chest X ray, electrocardiogram, and ultrasound of the gallbladder. An active peptic ulcer represents an absolute contraindication for

Chapter 61:

bariatric surgery. It used to be routine to perform an upper gastrointestinal study to rule out ulcers. The current standard however is to screen for Helicobacter pylori and irradicate it if present. Because the incidence of cholelithiasis is 15% to 25% in morbidly obese patients, preoperative or intraopertaive screening for gallstones is recommended in all patients who have not had cholecystectomy. Ultrasonography is the most popular method of evaluation. Intraoperative ultrasonography is considered to be more sensitive than transabdominal examination in the morbidly obese. We recommend concomitant cholecystectomy for all patients with cholelithiasis. The association of obesity with sleep apnea also requires some attention. A room air arterial blood gas is therefore obtained in the clinic from all patients who are at high risk for having concomitant sleep apnea. Patients who are scheduled to have gastric bypass or BPB operations should also have serum iron, iron-binding capacity, vitamin B12, and folate levels determined prior to operation. Baseline serum levels of fat-soluble vitamins should be obtained in patients prior to BPB. All patients who are scheduled to have revision of a failed bariatric procedure should have blood cross-matched for possible transfusion. Blood transfusion is necessary in nearly 50% of patients who undergo revision of failed gastric restrictive operations. Preoperative preparation of patients for bariatric operations varies according to the underlying health of individual patients. Many young patients with no associated illnesses can be admitted to the hospital on the day of operation. Conversely, patients with severe sleep apnea syndrome or congestive heart failure require hospitalization for two or three days prior to operation to optimize their cardiopulmonary condition. Insertion of a Swan-Ganz catheter on the day prior to operation is advisable in many of these patients. All patients should be given intravenous prophylactic antibiotics in the perioperative period. Morbidly obese patients tolerate general anesthesia remarkably well. However, endotracheal intubation may be difficult, particularly in patients who weigh more than 400 pounds. Awake intubation using intravenous sedation and topical pharyngeal anesthesia is often the safest way to establish an airway in the heaviest patients. Although an arterial line is not required during most bariatric operations, it is useful in some patients both for intraoperative blood pressure monitoring and for drawing blood for blood gases both during and following the operation. A Foley catheter and nasogastric tube are inserted in all patients after induction of anesthesia. The Foley catheter is generally removed on the first postoperative day in all patients who spend their first night in the hospital. The nasogastric tube is helpful in identifying the gastroesophageal junction intraoperatively and is now routinely removed during the end of the case except in rare situations. Less than 10% of patients require admission to the intensive care unit postoperatively. However, all patients with sleep apnea, congestive heart failure, and severe asthmatic bronchitis should spend one or two nights in the intensive care unit for close monitoring of their cardiopulmonary status. Many of these patients require overnight intubation. Incentive spirometry is used routinely for several days after extubation. Clinically significant atelectasis is remarkably uncommon in these patients postoperatively. Obesity has traditionally been considered as a risk factor for postoperative pulmonary embolism. Hence, a variety of methods of prophylaxis have been employed toward prevention of this feared complication. These include subcutaneous low-dose heparin, pneumatic compression of the legs,

Surgery for Morbid Obesity

1157

elastic stockings or bandages, intravenous low-molecular weight dextran, and use of the Trendelenburg position intraoperatively. None of these methods have been proven to decrease the incidence of postoperative venous thromboembolism in bariatric surgical patients. Early postoperative ambulation is strongly encouraged and almost certainly contributes toward the low incidence of postoperative venous thromboembolism that has been reported in these patients. Patients are assisted in getting out of bed on the night of their operation and are walked on the first postoperative day. It is interesting to note that many of these patients move remarkably well. Incisional pain is moderately severe during the first 48 to 72 hours postoperatively. This is obviously less severe with laparoscopic procedures. Nonetheless, patients are routinely maintained on narcotics via a patient-controlled analgesia pump in the first 24 hours. Oral narcotics are usually begun on the second or third postoperative day after intravenous fluids have been stopped. All pills and tablets are crushed and administered as a slurry with a liquid beverage. Patients are instructed not to swallow whole pills during the first four weeks postoperatively. Ice chips and sips of water are given orally on postop day 1. Intravenous fluids are usually discontinued after clear liquids are tolerated without difficulty. A low calorie (maximum 1000 cal) pureed consistency diet is given on the next day and is continued until the time of discharge. Patients are usually discharged on the third postoperative day. Hospitalization for more than seven days is unusual in the absence of major complications. A limited upper gastrointestinal tract contrast study previously was routinely performed shortly before discharge, to examine the integrity of the staple-line and outlet stoma. This is only performed in cases with a high index of suspicion for a leak, or those who manifest signs and symptoms of a leak.

Postoperative Dietary Management and Follow-Up Postoperative dietary counseling is essential in the longterm success of gastric restrictive operations. Patients are instructed to follow a modified liquid diet for four weeks after discharge. The modified liquid diet consists of liquids, pureed foods, and several soft solid foods such as mashed potatoes and cottage cheese. A liquid or chewable multivitamin supplement is taken during this phase of the diet. The purpose of the modified liquid diet is twofold: (i) to allow time for patients to adjust to their tremendously restricted stomach capacity by consuming foods that are relatively easy to chew and swallow and (ii) to minimize the likelihood of vomiting in the early postoperative period. Repeated episodes of vomiting in the early postoperative period have been associated with staple-line disruption and leaks. Patients are given a soft solid diet at the fourweek visit and then gradually progress to a normal diet. Patients can resume swallowing whole pills and tablets after solid food is well tolerated. Postoperative follow-up is extremely important in bariatric surgical patients. All patients should have easy access to the operating surgeon and a clinical nutritionist. During the first year visits are scheduled at four weeks postoperatively and then at three-month intervals thereafter. Two follow-up visits are scheduled at six-month intervals during the second year. After the second year, all bariatric surgical patients should be followed indefinitely by annual physician office visits. However, some patients may require more frequent follow-up. Weight and blood pressure should be recorded at each visit along with the laboratory studies,

medwedi.ru

1158

Part Nine: Special Physiologic Considerations

which are needed to check for postoperative metabolic sequelae and to follow up preoperative medical problems such as diabetes or hyperlipidemia. Patients who have malabsorptive operations require periodic blood tests postoperatively to check for possible metabolic and nutritional deficiencies. These patients should take a daily multivitamin supplement with minerals for the rest of their lives. Menstruating women who have had gastric bypass or BPB should also take a prophylactic iron supplement postoperatively. After BPB, many patients require additional protein and other nutritional supplements.

RESULTS OF SURGICAL TREATMENT Weight Loss Early weight loss results with both VBG and SRG have been generally acceptable. Mason et al. (38) reported a mean loss of 62% of excess weight in a series of 226 patients followed for a mean five years after VBG. MacLean et al. (7) reported a mean 60% excess weight loss in 57 patients followed for five years after VBG. However, a substantial number of their patients required surgical revision for either complications or inadequate weight loss during the five-year study period. Willbanks (37) reported a mean 61% excess weight loss in his series of 305-SRG patients who were followed for a minimum of two years. Weight loss maintenance after VBG and SRG has been somewhat problematic, in that many patients regain at least 15% to 20% of their lost weight between three and five years postoperatively. Open gastric banding has given way to laparoscopic gastric banding. Most large series are reported from Europe and reveal a 40% to 60% mean EWL over three to five years (52–55). The U.S. experience with LAP-BAND is much more limited and has not consistently reproduced the results seen in the larger European trials (56). Weight loss results with RYGB have been generally superior to those observed after other gastric restrictive operations. Studies over the last two decades regarding open gastric bypass have consistently shown a better maintained weight loss with most large series showing an average of 49% to 80% EWL over 5 to 15 years (60–66). Weight loss results with BPB have been almost uniformly good. Scopinaro et al. (45) reported a mean loss of 75% of the preoperative weight in a series of 916 patients followed for a mean five years with excellent weight maintenance after stabilization. Sugerman et al. (46) reported a mean 71% excess weight loss at one year in their series of 25 superobese patients. Early weight loss results with the ‘‘duodenal switch’’ have been comparable to those reported after BPB. Over the years, there have been several prospective comparisons of bariatric procedures that have shown significant differences between operations both in terms of weight loss outcome and in terms of the incidence of postoperative complications. Pories et al. (66), Naslund et al. (67), and Lechner and Callender (68) independently performed prospective randomized comparisons of horizontal gastroplasty with gastric bypass and reported significantly better weight loss after gastric bypass and no difference in the early complication rate between the two procedures. Sugerman et al. (69) prospectively compared VBG with RYGB and again found that gastric bypass resulted in significantly greater weight loss. Surgeons from Adelaide, Australia prospectively compared gastrogastrostomy, vertical gastroplasty, and RYGB in 310 patients (70). At five

years postoperatively, weight loss after gastric bypass was significantly greater than with either gastroplasty or gastrogastrostomy. The early postoperative complication rates were similar among the three procedures. These prospective studies clearly show that gastric bypass is a better weight loss– producing operation than any modification of gastroplasty. Sugerman et al. (46) prospectively compared conventional RYGB with Scopinaro’s BPB in a group of superobese patients and found that weight loss was significantly better at one year after BPB. However, because the incidence of serious complications was considerably higher after BPB, Sugerman et al. concluded that BPB was too risky to be recommended as a primary procedure for treatment of morbid obesity (46). Successful weight loss in superobese patients has generally been problematic after conventional gastroplasty and gastric bypass procedures. Two reports have described modifications of conventional operations with the goal of improving long-term weight loss (6,71). One study employed a ‘‘long-limb’’ modification of RYGB in which the Roux limb length was measured at 150 cm. The long-limb modification was prospectively compared with a standard technique of gastric bypass and resulted in significantly greater weight loss versus the conventional method after 12 months postoperatively (6). Another investigator proposed a two-stage approach consisting of a jejunocolic bypass at the outset, which was subsequently converted to a VBG after weight stabilization (71). This two-stage method resulted in excellent weight loss in a group of eight superobese patients. It appears that some degree of intestinal malabsorption is necessary to achieve satisfactory weight loss in these extremely heavy patients. The results from laparoscopic RYGBP have been just as good as those obtained from open gastric bypass. The largest series so far by Higa et al. (72) reports an excess weight loss of 70% at 12 months. These figures are reproduced in all the large series so far published (58,59,73,74). These results are shown in Table 4.

Amelioration of Comorbidities Amelioration of obesity-related medical problems is a primary goal of all bariatric operations. Improvement or resolution of morbid obesity-associated diabetes, including a significant decrease in insulin resistance after weight reduction surgery, has been reported by many investigators (63,75–77). Pories et al. (63,76) have extensively studied postoperative changes in glucose metabolism in morbidly obese patients with diabetes. In 1995, they reported that 121 of 146 (82.9%) patients with overt type 2 diabetes became euglycemic after RYGB (63). Moreover, 98.7% (150 of 152 patients) with glucose impairment maintained normal levels of blood glucose, glycosylated hemoglobin, and insulin (63). Weight reduction surgery also has salutary effects on obesity-related hypertension and cardiovascular dysfunction. Table 4 Weight Loss Results Using Laparoscopic Gastric Bypass Author Demaria (59) Higa (73) Schauer (74) Wittgrove (75)

N

BMI (mean)

Follow-up (months)

Excess weight loss (%)

281 1040 275 500

48 46 48 NI

12 12 30 60

70 70 77 73

Abbreviation: BMI, body mass index.

Chapter 61:

Alpert et al. (78) used echocardiography to measure a number of parameters of ventricular function in 62 morbidly obese patients and found that surgically induced weight loss was associated with significant improvement of left ventricular ejection fraction and lesser, but measurable improvements in mean blood pressure, cardiac chamber size, and ventricular wall thickness. Sugerman et al. (77) queried their database of 1025 patients between 1981 and 2000. They showed a 69% resolution of hypertension at one year and 66% at five to seven years. The response of hypertension to weight loss following gastric restrictive operations was also reported by two other groups of investigators (79,80). Each group defined hypertension as a blood pressure reading 160/90 and noted improvement or resolution of hypertension in approximately 70% of patients at four years postoperatively. However, there were conflicting results regarding the relationship between blood pressure reduction and weight loss, with one group showing a correlation between blood pressure improvement and the amount of weight loss (79) and the other reporting a significant correlation between improved blood pressure and proximity to ideal weight after weight stabilization (80). The beneficial effects of weight reduction surgery on obesity-related hyperlipidemia have been documented by a number of investigators. Gleysteen et al. (81), Rucker et al. (82), Nanji and Freeman (83), and Gonen et al. (84) independently reported significant decreases in both total cholesterol and triglyceride levels after gastric restrictive operations for morbid obesity. They also showed a favorable increase in the high-density lipoprotein/low-density lipoprotein ratio after gastric bypass, suggesting that the risk of atherosclerosis may be decreased by weight loss in this group of patients. Gleysteen et al. (81) have shown that these lipid reductions persist for as long as weight loss is satisfactorily maintained. Conversely, patients who regain a substantial portion of their lost weight tend to have concomitant regression of the salutary changes in lipid profile. The obesity hypoventilation syndrome probably poses the greatest immediate risk to life of any of the obesityrelated medical illnesses. Following gastric restrictive operations, Sugerman et al. (85) and Charuzi et al. (86) have independently reported complete resolution of sleep apnea symptoms and significant improvements in both arterial blood gases and polysonmographic studies. Sugerman et al. (85) also reported significant reductions in mean pulmonary artery pressures in patients with obesity hypoventilation syndrome between three and nine months after RYGB. Many patients in these reports were incapacitated by their condition preoperatively, but after losing weight were able to lead normal and productive lives. Weight loss has a salutary effect on sex hormone balance and fertility in women. After gastroplasty-induced weight loss, Grace et al. (16) and Deitel (17) independently reported significant improvement in SHBG levels and a significantly decreased incidence of irregular menses. Both androgen levels and hirsutism decreased with substantial weight loss. A number of previously infertile women became pregnant and delivered normal babies, following surgically induced weight loss. Printen and Scott (87) reported similar results after gastric bypass. Although these women are able to eat only small amounts, adequate nutritional status can be maintained for both the mother and the developing fetus. Pregnancy is not recommended during the first postoperative year in which the great majority of weight loss occurs

Surgery for Morbid Obesity

1159

Postoperative Complications In experienced hands, bariatric operations can be performed with anticipation of a perioperative morbidity rate of under 10% and a mortality rate of approximately 1%. The advent of laparoscopic techniques was at first faced with a higher incidence of complications due to the learning curve, especially with gastric bypass. With time and experience, the laparoscopic approach has proven superior as it is associated with fewer wound-associated complications (58,59,72–74).

Early Complications The most serious early complications are gastrointestinal tract anastomotic leak and pulmonary embolism. Fortunately, the incidence of these two serious problems is reported in the range of 1% to 2% in most large series of bariatric operations (41,43,44,88–90). The incidence of pulmonary embolism does not seem to be altered by the routine use of intermittent decompression stockings or subcutaneous heparin. However, nearly all bariatric surgeons use some method of deep venous thrombosis prophylaxis in the perioperative period. Early postoperative ambulation is always emphasized and is surprisingly well tolerated by most patients. Gastrointestinal tract leaks can be difficult to recognize after gastric restrictive procedures, because fever and abdominal tenderness are frequently absent during the first 48 hours after a leak has occurred. Persistent tachycardia and progressive tachypnea are the most common early signs. Hence, it is not unusual to initially suspect pulmonary embolism in a patient with a gastric leak. However, a ventilation-perfusion scan is generally interpreted as ‘‘low probability’’ for pulmonary embolism. An isolated left-sided pleural effusion is a common finding on the plain chest radiograph. Most surgeons initially attempt to identify leaks using radiographic gastrointestinal tract contrast studies. However, a normal result from contrast study by no means excludes the diagnosis, because leaks from the gastric staple-line are usually not identified by upper gastrointestinal tract contrast studies. Because failure to recognize a leak can result in death, exploratory laparotomy should be empirically performed in patients with progressive tachypnea and tachycardia in whom pulmonary embolism has been ruled out. This approach has been modified in the laparoscopic population in whom a drain is routinely placed posterior to the anastomosis, with one-third of these patients not requiring any further intervention, one-third undergoing laparoscopic drainage and one-third undergoing laparotomy (58). Although severe obesity is reported to be associated with a high incidence of postoperative wound problems, in experienced hands, the incidence of major wound infection after gastric restrictive operations is reported in the range of 1% to 3% (41,43,44). The potential for wound dehiscence after bariatric operations is increased because of the great tension placed on the wound closure by massive overweight. Hence, the abdominal fascia should be closed with heavy absorbable or nonabsorbable suture. Again, this has not been a problem with the laparoscopic techniques.

Late Complications Previous studies have documented a high incidence of gallstone formation following rapid weight loss in obese patients. The incidence of symptomatic gallbladder disease reported after gastric restrictive operations varies from 3% to greater than 30% (91). Hence, removing the gallbladder

medwedi.ru

1160

Part Nine: Special Physiologic Considerations

‘‘prophylactically’’ at the time of gastric restrictive surgery is a controversial issue among bariatric surgeons. Several surgeons who have recommended prophylactic cholecystectomy report histologic evidence of gallbladder pathology in nearly 90% of cases. Other surgeons believe that the incidence of symptomatic cholecystitis after gastric restrictive operations is not high enough to justify routine removal of the gallbladder in patients who do not have gallstones. Scopinaro et al. (45) have recommended cholecystectomy as an integral part of BPB, because more than 50% of the patients in his early experience developed symptomatic gallstones. The risks of adding cholecystectomy to an elective gastric restrictive procedure are negligible. A multicenter, randomized, double-blind, prospective trial evaluated three oral doses of ursodiol (Actigall) versus placebo during the first six months after RYGB (92). Of 233 patients who had postoperative ultrasonography, gallstones formed in 32% of the placebo group versus 4% of the higherdose treatment groups. The investigators concluded that ursodiol at doses of 600 and 1200 mg/day was effective in preventing cholelithiasis during the rapid weight-loss phase after gastric bypass. Although vomiting is a common side effect of most gastric restrictive operations, severe, intractable vomiting is quite rare. Most cases of severe vomiting have followed banded gastric restrictive operations and are usually caused by stenosis of the outlet stoma. Patients with vomiting who cannot tolerate liquids should be hospitalized and given intravenous fluids. In most cases, the stomal edema that results from protracted vomiting resolves without further intervention. Patients who cannot tolerate liquids after several days of nothing by mouth and intravenous fluids should undergo upper endoscopy and stomal dilation using balloon-tipped catheters. Stomal dilation is almost always successful in patients after RYGB, but is more problematic in patients with prosthetic stomal reinforcement. Many patients report great difficulty with eating meat and fresh fruit and vegetables after banded gastric restrictive operations. Hence, these patients often consume large quantities of soft high-calorie foods such as cookies, chips, and ice cream. Incisional hernia is a common late complication after gastric restrictive operations, with an incidence ranging from 10% to 15%, in most large series of open RYGB. Again, this is a rarely encountered complication after laparoscopic RYGB. The incidence of marginal ulcer in patients after RYGB and BPB ranges from 3% to 10%. These ulcers typically develop on the jejunal side of the gastroenterostomy and are caused by excessive production of gastric acid. Serum gastrin levels are normal or subnormal. This potentially serious complication has been associated with breakdown of the gastric staple-line after RYGB (89). Marginal ulcers that are not associated with disruption of the stapled gastric partition almost always respond to H2 blocking drugs or pump inhibitors. Conversely, ulcers that occur in patients with staple-line breakdown are often intractable to medications and require operative treatment.

Patients who have either RYGB or BPB are at risk for developing metabolic sequelae as a consequence of malabsorption. Table 5 shows the incidence of metabolic complications typically associated with gastric bypass (15,90,93). Because iron absorption occurs primarily in the duodenum, malabsorption of ingested iron is the primary cause of iron deficiency after gastric bypass. Smith et al. (94) demonstrated that vitamin B12 deficiency after gastric bypass is the result of failure to cleave food-bound vitamin B12 in the upper gastric pouch. Conversely, crystalline vitamin B12 is absorbed normally in the distal ileum. The cause of folate deficiency after gastric bypass is not known. Deficiencies in each of these micronutrients can result in anemia. Because these deficiencies are relatively common, daily prophylactic multivitamin/mineral supplements are recommended for all patients. However, the efficacy of multivitamin supplements alone in prevention of these deficiencies has not been clearly established. In our experience, a daily multivitamin supplement does not consistently prevent development of iron deficiency and anemia in women who have had gastric bypass. Fortunately, the majority of vitamin and mineral deficiencies after gastric bypass are mild and easily corrected with oral supplements of the deficient micronutrients. Injection therapy is rarely required in patients who are willing to take oral supplements. Hospitalization for treatment of these deficiencies is extremely uncommon. Due to the fact that fat malabsorption is a primary component of both the BPB and the duodenal switch, patients who have these procedures are prone to develop deficiencies in fat-soluble vitamins. Sugerman et al. (46) reported a 50% incidence of serious complications, metabolic sequelae, and two deaths during the first year after BPB in a series of 25 superobese patients. More than half of Sugerman’s patients had deficiencies in fat-soluble vitamins after BPB. Calcium deficiency and hypoproteinemia have been noted in 10% to 20% of patients after BPB (47). Moreover, approximately 3% of the lighter patients ( < 220% overweight) in Scopinaro’s series (45) became ‘‘underweight’’ with gross manifestations of malnutrition. Marceau et al. (48) reported a comparative study of the duodenal switch versus conventional BPB, which disclosed significant reductions in the incidence of hypocalcemia, hypoalbunlinenemia, anemia, and malodorous flatus in patients who had the duodenal switch.

Revision Operations Occasionally, bariatric operations require revision for either inadequate weight loss or late complications. The incidence of major postoperative complications following revision of bariatric procedures is high, with reports ranging from 15% to 60%. The mortality rate reported after revision operations ranges from 5% to 30%. Undoing an original bariatric operation without conversion to another weight reduction procedure is invariably associated with prompt regaining of the lost weight. The indication for revision (unsatisfactory weight loss or complications) generally dictates the planned approach.

Table 5 Metabolic Deficiencies after Gastric Bypassa Report/year Halverson (1981) (91) Amaral (1985) (94) Brolin et al. (1990) (16) a

Iron

Vitamin B12

Folate

Anemia

Follow-up

20%/17 mo 49%/15.6 mo 33%/13.4 mo

26%/20 mo 70%/13 mo 37%/12.8 mo

9%/13 mo 18%/– 16%/10.7 mo

18%/– 35%/20 mo 22%/12 mo

20 mo 33.2 mo 24.2 mo

The mean incidence and time of deficiency recognition reported in each series are listed in columns 2 through 5 with the mean follow-up shown at far right.

Chapter 61:

Patients who undergo revision operations for complications frequently have lost a sufficient amount of weight after their initial procedure. These patients should generally be offered a gastric restrictive rather than a malabsorptive procedure. Patients who require takedown of an intestinal bypass for metabolic complications and are no longer overweight are best suited by conversion to a banded gastroplasty for weight maintenance. Conversely, patients who remain substantially overweight after intestinal bypass are best converted to RYGB with the hope of providing further weight loss. Gastroplasty patients with stornal stenosis and an intact staple-line may initially undergo stomal dilation via upper endoscopy. Unfortunately, because less than 50% of patients with stomal stenosis have permanent relief with dilation, operative revision is frequently required. Revision should include removal of the reinforcing band and conversion to RYGB. Patients with staple-line disruption after gastroplasty or RYGB need only to have the stomach restapled. After observing a high incidence of subsequent disruption in patients who had restapling in continuity, MacLean et al. (89) recommended transection of the stomach between staple-lines in patients who require reoperation for staple-line breakdown. Patients with unsatisfactory weight loss after gastroplasty are best converted to PYGB or, in some cases, BPB. Patients with anatomically intact operations and unsatisfactory weight loss after gastric bypass have almost certainly ‘‘outeaten’’ the operation. These patients may be converted to a BPB with anticipation of further weight loss. Unfortunately, patients with intact gastric restrictive operations who are converted to BPB frequently suffer severe metabolic complications. At present, many surgeons believe that BPB should only be used in revision of patients with unsatisfactory weight loss after an anatomically intact banded gastroplasty or gastric bypass (95,96). There are also a small number of morbidly obese patients who outeat any bariatric operation or die trying. Whenever a patient has failed a second technically sound and intact operation, surgeons should approach the prospect of a further revision with considerable caution and skepticism. Rejection of such patients for another operation is frequently a prudent decision.

Quality of Life Changes Nearly all morbidly obese patients with satisfactory postoperative weight loss experience substantial improvement in their overall lifestyle. Health status is generally markedly improved as characterized by increased exercise tolerance and improvement or resolution of obesity-related comorbidities. Patients’ abilities to interact with others in social situations are also enhanced. They are delighted to be able to buy clothes at major department stores, sit comfortably in an airplane seat, or even climb a flight of stairs. Employment opportunities also increase. Approximately 75% of patients who were receiving public assistance prior to gastric restrictive surgery were able to find full-time jobs at two years postoperatively. Other patients have received promotions in the same workplace, which seemed unattainable prior to losing weight. Weight loss can suddenly make a patient attractive to the opposite sex. However, increased self-esteem and sexual awareness probably results in divorce as often as marriage. Generally, divorce can be viewed as a positive step for these patients, because they are usually leaving a pathologic marriage in which they were ‘‘trapped’’ by their severe obesity.

Surgery for Morbid Obesity

1161

SUMMARY As stated at the beginning of this chapter, it is estimated that more than 40% of the U.S. population is clinically overweight. Many of these individuals are clearly obese, and of this subset a substantial number are morbidly obese. Despite attempts at dietary changes as well as lifestyle modifications, the ability to successfully lose weight and keep it lost once morbid obesity has occurred is virtually impossible. Thus, surgery has evolved as an effective treatment option. In the early history of surgical intervention for morbid obesity, jejunoileal bypass was the most popular operation. Although effective in eliciting weight loss, problems with severe malabsorption and metabolic complications quickly demonstrated that it was more harmful than beneficial. At the same time that jejunoileal bypass was falling into disfavor, a variety of gastric restrictive or bypass procedures were demonstrating their ability to initiate weight loss and keep this loss maintained with an acceptable complication rate, most of which were easily managed. As operative strategies have been refined and new technological approaches have evolved, it is now possible to manage morbid obesity using laparoscopic techniques. The minimal complication rates associated with these new procedures have made surgical management of morbid obesity the treatment of choice.

REFERENCES 1. Popkin BM, Udry JR. Adolescent obesity increases significantly in second and third generation US immigrants: The National Longitudinal Study of Adolescent Health. J Nutr 1998; 128:701. 2. Mokdad AH, Serdula MK, Deitz WH, et al. The spread of the obesity epidemic in the United States 1991–1998. JAMA 1999; 282:1519. 3. National Institutes of Health Consensus Development Panel. Health implications of obesity. Ann Intern Med 1985; 103:1073. 4. National Institutes of Health Consensus Development Panel. Gastrointestinal surgery for severe obesity. Am J Clin Nutr 1992; 55(suppl):615. 5. Abraham S, Johnson CL. Prevalence of severe obesity in adults in the United States. Am J Clin Nutr 1980; 33:364. 6. Brolin RE, et al. Long-limb gastric bypass in the super-obese: a prospective randomized study. Ann Surg 1992; 215:387. 7. MacLean LD, Rhode BM, Forse RA. Late results of vertical banded gastroplasty for morbid and super obesity. Surgery 1990; 107:20. 8. Larsson B, et al. Abdominal adipose tissue distribution, obesity and risk of cardiovascular disease and death, 13 year follow up of participants in the study of men born in 1913. Br Med J 1984; 288:1401. 9. Fried SK, Krai JG. Sex differences in regional distribution of fat cell size and lipoprotein lipase activity in morbidly obese patients. Int J Obes 1987; 11:129. 10. Stunkard AJ, et al. An adoption study of human obesity. N Engl J Med 1986; 314:193. 11. Stunkard AJ, Foch TT, Zdenek H. A twin study of human obesity. JAMA 1986; 256:51. 12. Kral JG. Morbid obesity and health risks. Ann Intern Med 1985; 103:1043. 13. Van Itallie TB. Health implications of over-weight and obesity in the United States. Ann Intern Med 1985; 103:983. 14. Drenick EJ, et al. Excessive mortality and causes of death in morbidly obese men. JAMA 1980; 243:443. 15. Brolin RE, et al. Serum lipids after gastric bypass surgery for morbid obesity. Int J Obes 1990; 14:939. 16. Grace DM, Nisker JA, Hammond GL. Changes in menstrual cycle pattern and sex hormone binding after gastroplasty. Abstract presented at the Second Annual Meeting of the American Society for Bariatric Surgery, Iowa City, June 13, 1985.

medwedi.ru

1162

Part Nine: Special Physiologic Considerations

17. Deitel M. Gynecologic-obstetrics changes after massive weight loss. Abstract presented at the Third Annual Meeting of the American Society for Bariatric Surgery, Iowa City, June 19, 1986. 18. Anderson T, et al. Randomized trial of diet and gastroplasty compared with diet alone in morbid obesity. N Engl J Med 1984; 310:352. 19. Kremen AJ, Linner JH, Nelson CH. An experimental evaluation of nutritional importance of the proximal and distal small intestine. Ann Surg 1954; 140:439. 20. Payne JH, DeWind LT. Surgical treatment of obesity. Am J Surg 1969; 118:141. 21. Salmon PA. The results of small intestinal bypass operations for the treatment of obesity. Surg Gynecol Obstet 1971; 132:965. 22. Scott HW Jr, et al. Results of jejunoileal bypass in two hundred patients with morbid obesity. Surg Gynecol Obstet 1977; 145:661. 23. Brolin RE. In: Levine BA, et al., eds. Current Practice of Surgery. Vol. 3. New York: Churchill Livingstone, 1993. 24. Halverson JD, et al. Jejunoileal bypass. Late metabolic sequelae and weight gain. Am J Surg 1980; 140:347. 25. Starkloff GB, et al. Metabolic intestinal surgery: its complications and management. Arch Surg 1975; 110:652. 26. Passaro E Jr, Drenick EJ, Wilson SE. Bypass enteritis. Am J Surg 1976:131. 27. Drenick EJ, et al. Bypass enteropathy. JAMA 1976; 236:269. 28. Ravitch MM, Brolin RE. The price of weight loss by jejunoileal shunt. Ann Surg 1979; 190:382. 29. Griffen WO Jr, Bivens BA, Bell RM. The decline and fall of the jejunoileal bypass. Surg Gynecol Obstet 1983; 157:301. 30. Hocking MP, et al. Late hepatic histopathology after jejunoileal bypass for morbid obesity. Am J Surg 1981; 141:159. 31. Mason EE, Ito C. Gastric bypass in obesity. Surg Clin North Am 1967; 43:1345. 32. Alden JE. Gastric and jejunoileal bypass: a comparison in the treatment of morbid obesity. Arch Surg 1977; 112:799. 33. Pace WG, et al. Gastric partitioning for morbid obesity. Ann Surg 1979; 190:392. 34. Mason EE. Vertical banded gastroplasty for obesity. Arch Surg 1982; 117:701. 35. Laws HL. Standardized gastroplasty orifice. Am J Surg 1981; 141:393. 36. Eckhout GV, Willbanks OL, Moore JT. Vertical ring gastroplasty for morbid obesity: five year experience with 1463 patients. Am J Surg 1986; 152:713. 37. Willbanks OL. Long-term results of silicone elastomer ring vertical gastroplasty for the treatment of morbid obesity. Surgery 1987:606. 38. Mason EE, et al. Vertical banded gastroplasty (VBG) for treatment of obesity: an eight year review. Abstract presented at the 75th Clinical Congress of the American College of Surgeons, Atlanta, October 17, 1989. 39. Kuzmak LL. Gastric binding. In: Dietel M, ed. Surgery for the Morbidly Obese Patient. Philadelphia: Lea & Febiger, 1989:225. 40. Mason EE, et al. Optimizing results of gastric bypass. Ann Surg 1975; 182:405. 41. Brolin RE, et al. The dilemma of outcome assessment after operations for morbid obesity. Surgery 1989; 105:337. 42. Flickinger EG, et al. The Greenville gastric bypass: progress report at 3 years. Ann Surg 1984; 157:93. 43. Sugerman HJ, et al. Weight loss with vertical banded gastroplasty and Roux-en-Y gastric bypass for morbid obesity with selective versus random assignment. Am J Surg 1989; 157:93. 44. Yale CE. Gastric surgery for morbid obesity: complications and long term weight control. Arch Surg 1989; 124:941. 45. Scopinaro N, et al. Evolution of biliopancreatic bypass. Clin Nutr 1985; 5(suppl):137. 46. Sugerman HJ, et al. Conversion of failed standard to distal gastric bypass for superobesity. J Gastrointest Surg 1997; 1:167. 47. Scopinaro N, et al. Biliopancreatic diversion for obesity. Probl Gen Surg 1992; 9:362. 48. Marceau P, et al. Biliopancreatic diversion with a new type of gastrectomy. Obes Surg 1993; 3:29.

49. Sugerman HJ, Starley JV, Birkenhauer R. A randomized prospective trial on gastric bypass vs vertical banded gastroplasty for morbid obesity and their effects on sweets vs non sweets eaters. Ann Surg 1987; 205:613. 50. Balsiger BM, Poggio JL, Mai J, et al. Ten and more years after vertical banded gastroplasty as primary operation for morbid obesity. J Gastrointest Surg 2000; 4:598. 51. Schauer P, Ikramuddin S, Hamad G, Goursh W. The learning curve for laparoscopic roux en y gastric bypass is 100 cases. Surg Endosc 2003; 17:212. 52. Fielding GA, Rhodes M, Nathanson LK. Laparoscopic gastric banding for morbid obesity: surgical outcomes in 335 cases. Surg Endosc 1999; 13:550. 53. Belachew M, Legrand M, Vincent V, et al. Laparoscopic adjustable gastric banding. World J Surg 1998; 22:995. 54. Dargent J. Laparoscopic adjustable gastric banding: lessons from the first 500 patients in a single institution. Obes Surg 1999; 9:446. 55. O’Brien PE, Brown WA, Smith A, et al. Prospective study of a laparoscopically placed adjustable gastric band in the treatment of morbid obesity. Br J Surg 1999; 86:113. 56. Rubenstein RB. Laparoscopic adjustable gastric banding at a U.S. center with up to 3-year follow-up. Obes Surg 2002; 12: 380–384. 57. Ren CJ, Horgan S, Ponce J. US experience with the LAP-BAND system. Am J Surg 2002; 184:46S. 58. Demaria EJ, Sugerman HJ, Kellum JM, Meador JG, Wolfe LG. Results of 281 consecutive total laparoscopic Roux-en-Y gastric bypasses to treat morbid obesity. Ann Surg 2002; 235:640. 59. Pondos YD, Jiminez JC, Wilson SE, Stevens CM, Nguyen NT. Complications after laparoscopic gastric bypass: a review of 3464 cases. Arch Surg 2003; 138:957. 60. Linner JH. Comparative effectiveness of gastric bypass and gastroplasty. Arch Surg 1982; 117:695. 61. Sugerman HJ, Londrey GL, Kellum JM, et al. Weight loss with vertical banded gastroplasty and Roux -en-Y gastric bypass for morbid obesity with selective vs. random assignment. Am J Surg 1989; 157:93. 62. Brolin RE, Kenler HA, Gorman JH, et al. Long limb gastric bypass in the superobese: a prospective randomized trial; Ann Surg 1991; 215:387. 63. Pories WJ, Swanson MS, Mac Donald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995; 222:339. 64. Capella JF, Capella RF. The weight reduction operation of choice: vertical banded gastroplasty or gastric bypass. Am J Surg 1996; 171:74. 65. Fobi MAL, Lee H, Holness R, et al. Gastric bypass operation for obesity. World J Surg 1998; 22:925. 66. Pories WJ, et al. The effectiveness of gastric bypass over gastric partition in morbid obesity. Ann Surg 1982; 196:389. 67. Naslund I, et al. A prospective randomized comparison of gastric bypass and gastroplasty: complications and early results. Acta Chir Scand 1986; 152:681. 68. Lechner GW, Callender K. Subtotal gastric exclusion and gastric partitioning: a randomized prospective comparison of one hundred patients. Surgery 1981; 90:637. 69. Sugerman HJ, Starkey JV, Birkenhauser R. A randomized prospective trial of gastric bypass vs. vertical banded gastroplasty for morbid obesity and their effect on sweets vs. nonsweets eaters. Ann Surg 1987; 205:613. 70. Hall JC, et al. Gastric surgery for morbid obesity. The Adelaide Study. Ann Surg 1990; 211:419. 71. Grant JR. Duke procedure for super-obesity: preliminary report with 3.5 year follow-up. Surgery 1994; 115:718. 72. Higa KD, Boone KB, Ho T. Complications of the laparoscopic Roux-en-Y gastric bypass: 1,040 patients—what have we learned? Obes Surg 2000; 10:509. 73. Schauer PR, Ikramuddin S, Gourash W, Ramanthan R, Luketich J. Outcomes after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Ann Surg 2000; 232:515.

Chapter 61: 74. Wittgrove AC, Clark GW. Laparoscopic gastric bypass: a five year prospective study of 500 patients followed from 3 to 60 months. Obes Surg 1999; 9:123. 75. Herbst CA, et al. Gastric bariatric operation in insulin-treated adults. Surgery 1984; 95:209. 76. Pories WJ, et al. The control of diabetes mellitus (NIDDM) in the morbidly obese with the Greenville gastric bypass. Ann Surg 1987; 206:316. 77. Sugerman HJ, Wolfe LG, Sica DA, Clore JN. Diabetes and hypertension in severe obesity and effects of gastric bypassinduced weight loss. Ann Surg 2003; 237:751. 78. Alpert MA, Terry BE, Kelly DL. Effect of weight loss on cardiac chamber size, wall thickness and left ventricular function in morbid obesity. Am J Cardiol 1985; 56:783. 79. Foley EF, et al. Impact of gastric restrictive surgery on hypertension in the morbidly obese. Am J Surg 1992; 163: 294. 80. Carson JL, et al. The effect of gastric bypass surgery on hypertension in morbidly obese patients. Arch Intern Med 1994; 154:193. 81. Gleysteen JJ, Barboriak JJ, Sasse EA. Sustained coronary-risk factor reduction after gastric bypass for morbid obesity. Am J Clin Nutr 1990; 51:774. 82. Rucker RD, et al. Lipid effects of obesity operations. J Surg Res 1981; 30:229. 83. Nanji AA, Freeman JB. Rate of weight loss after vertical banded gastroplasty in morbid obesity.Relationship to serum lipids and uric acid. Int Surg 1985; 70:323. 84. Gonen B, Halverson JD, Schonfeld G. Lipoprotein levels in morbidly obese patients with massive surgically induced weight loss. Metabolism 1983; 32:492.

Surgery for Morbid Obesity

1163

85. Sugerman HJ, et al. Hemodynamic dysfunction in obesityhypoventilation syndrome and the effects of treatment with surgically induced weight loss. Ann Surg 1988; 207:604. 86. Charuzi I, et al. The effect of surgical weight reduction on sleep quality in obesity-related sleep apnea syndrome. Surgery 1985; 97:535. 87. Printen KJ, Scott DS. Pregnancy following gastric bypass for the treatment of morbid obesity. Am Surg 1982; 48:363. 88. Benotti PN, et al. Gastric restrictive operations for morbid obesity. Am J Surg 1989; 157:150. 89. MacLean LD, et al. Results of the surgical treatment of obesity. Am J Surg 1993; 65:155. 90. Halverson JD, et al. Gastric bypass for morbid obesity: a medical-surgical assessment. Ann Surg 1981; 194:152. 91. Amaral JF, Thompson WR. Gallbladder disease in the morbidly obese. Am J Surg 1985; 149:551. 92. Sugerman HJ, et al. Prophylactic ursodiol acid prevents gallstone formation following gastric bypass induced rapid weight loss: a multicenter, placebo controlled, randomized, doubleblind, prospective trial. Am J Surg 1994; 169:91. 93. Amaral JF, et al. Prospective hematologic evaluation of gastric exclusion surgery for morbid obesity. Ann Surg 1985; 201:186. 94. Smith CD, et al. Gastric acid secretion and vitamin B-12 absorption after vertical Roux-en-Y gastric bypass for morbid obesity. Ann Surg 1993; 218:91. 95. Linner JH. Comparative effectiveness of gastric bypass and gastroplasty. Arch Surg 1982; 117:695. 96. Flanigan L. Does initial pouch volume influence weight loss results in the Roux-en-Y gastric bypass procedure? Abstract presented at the 6th Annual Meeting of the American Society for Bariatric Surgery, Nashville, 1989.

medwedi.ru

Index

Abdominal aortic aneurysms (AAAs), 387 Abdominal pain anatomy and physiology of, 539 with AIDS, 551 chronology and pattern of, 542 films, 488 types of, 539 Abdominal straining (valsalva), 787 Abdominal wall defects, 1111–1112 ABI. See Ankle-brachial index Abnormal cardiac contractility, 665 Abnormal circulatory congestion, 668 Abnormalities of acid–base, fluid, and electrolyte, 747 of calcium, phosphate, and bone metabolism, 743 of carbohydrate and lipid metabolism, 746 Absorptive fillers, 1041 Accelerated rejection, 110 Accessory molecules, 98 Acetaldehyde, 472 Acetaminophen, 432 Acetylcholine, 336 Acetylcholinesterase inhibitors, 748 Achalasia, 318 Acid reflux, patterns of, 304 Acid suppression, physiology of, 306 Acid/base abnormalities, 38 balance, 37 disorders, 45 fluid and electrolyte abnormalities, 754 Acidosis metabolic, 43 respiratory, 42 Acinar cells, 469 Acini, secreting units, 469 Acinus cells, 469, 470 Acontractile/hypocontractile detrusor, 781 Acquired autoimmune hemolytic anemias, 510 Acquired immunodeficiency syndrome (AIDS), 7, 289, 539 Acromegaly, 957 ACTH. See Adrenocorticotropic hormone Actin filaments, 649 myosin cross-bridge, 649 Action potential (AP), 650 Activated partial thromboplastin time (aPTT), 161 Acute aortic dissection, 901 Acute appendicitis due to inflammation, 547 history of, 547 Acute embolus, 398 Acute heart failure, treatment of, 669 Acute kidney failure (AKF), 728, 735 classification of, 736

Acute kidney failure (AKF), (Contd.) common causes of, 736 diagnosis, 737 Acute lung injury (ALI), 129, 637 Acute mesenteric embolus history of, 548 pathophysiology of, 548 Acute mesenteric ischemia after aortic surgery, 401 Acute mesenteric thrombosis, 401 Acute myocardial infarction, 669 Acute Physiologic and Chronic Health Evaluation (APACHE), 474 Acute rejection, histologic features of, 111 Acute respiratory distress syndrome (ARDS), 129, 632, 637–638 Acute tubular necrosis (ATN), 111, 282, 734 Acute tubulointerstitial nephritis (ATIN), 734, 736 Acute viral hepatitis, 280 Addison’s disease, 949 A-delta fibers, myelinated nerves, 539 Adenohypophysis, hormones of, 948 Adenomatous polyposis coli (APC) protein, 555 Adenosine potent vasodilator, 699 1 receptors, 727 Adenosine diphosphate (ADP), 9, 157 Adenosine triphosphate (ATP), 9, 33, 186, 649, 700, 727 Adequate hemostasis, 288 ADH. See Antidiuretic hormone Adhesion molecules, 101 Adjusted body weight (ABW), 52 Adjuvant chemotherapy, 579 Adjuvant local therapy, 1061 Adjuvant systemic therapy, 1060–1061 Adjuvant therapy, 326 Adrenal anatomy, 907 Adrenal catecholamine production, 909 Adrenal cortex, 968 malignant neoplasms, 974 steroidogenesis in, 966–968 Adrenal corticocarcinoma, 974 adjuvant treatment, 976 epidemiology and natural history of, 974 molecular pathogenesis of, 974 surgical treatment of, 975 Adrenal disease and hypertension, 907 Adrenal gland embryology, anatomy, and histology, 965–966 neoplasms of, 968 physiology of, 966 Adrenal incidentaloma, 980 treatment of, 975

medwedi.ru I-1

Adrenal insufficiency, 237, 983–984 causes of, 983 morbidity of, 982 Adrenal medulla, 968 neoplasms of, 968 Adrenal medullary cells, 965 Adrenal medullary hyperfunction, 909 Adrenal metastases, 981 Adrenal tumors, biochemical diagnosis of, 970 Adrenalectomy, laparoscopic, 971, 983, 1031 Adrenergic receptor system, 16 Adrenocortical carcinoma, 908 Adrenocorticotropic hormone (ACTH), 15, 20, 185, 284, 947, 1027, 1094, 1138 Adrenogenital syndrome–producing tumors, 974 Adson maneuver, 879 Adult respiratory distress syndrome (ARDS), 53, 56, 186, 242 Adult-onset diabetes mellitus (AODM), 1157 Advanced cardiac life support (ACLS), 671–672 AF. See Atrial fibrillation Afterload, evaluation of, 193 Agency for Healthcare Research and Quality (AHRQ), 221 Aging, physiology and pathology of, 1129 Agkistrodon rhodostoma, 173 Aiding bladder emptying, 788 Airway resistance, 633 Alanine aminotransferase (ALT), 437, 488 Alcock’s canal, 601 Alcoholic liver disease, 280 Aldosterone, 907, 965, 967, 968 Aldosterone secretion, 666 regulation of, 967 Aldosterone-producing adrenal adenoma (APA), 969, 970 Aldosteronoma, 968 Alemtuzumab, 118 Alkaline phosphatases (ALP), 437 Alkalosis, metabolic or respiratory, 42–43 Allogeneic blood transfusion, reduction in, 247 Allograft rejection, 91, 755 pathways for, 109 Allograft survival, 79 Allorecognition, 107 Alpha-adrenergic blockade, 1031 Alpha-1 antitrypsin deficiency, 437 Alpha-2-antiplasmin, 159 Alpha-granule, 161 a Smooth muscle actin (a-SMA), 474 a-Thalassemia, 510 Alteplase (rTPA). See Thrombolytic agent Alveolar cells, 632 Alveolar ventilation (VA), 634 Amaurosis fugax, 872

I-2

Index

Ambulatory (24-hour) esophageal pH monitoring, 302 Amenorrhea, 1053 American Association for the Surgery of Trauma (AAST), 516 American Joint Committee on Cancer (AJCC), 1060 American Society for Gastrointestinal Endoscopy (ASGE) survey, 349 American Society of Anesthesiologists (ASA), 136, 213 American Society of Hematology, 507 American Spinal Injury Association (ASIA), impairment scale, 805 Amine precursor uptake and decarboxylase (APUD), 1006, 1016, 1020 Amino acid deamination, carbon skeletons of, 12 Aminoglycosides clinical use of, 147 pharmacodynamic properties of, 146 Anal canal, anatomy of, 600 Anal sphincter mechanism, 601 Analgesia, 219 Anaphylaxis, 72 Anaplastic carcinoma, 1002 Anastomosis diamond-shaped, 1116 end-to-end, 859, 1117, 1120 colorectal, 1118 end-to-side, 705 proximal, 859 graft-to-artery, 706 microlymphatic venous, 894 primary, 1115, 1120 pull-through coloanal, 1118 side-to-side, 706 colorectal, 1118 Anastrazole, 1061 Anatomy biliary, 431 functional, 429 internal surface, 429 vascular, 429–430 Androgens, 968 Android or central obesity, 1149 Anemia, 283 pernicious, 563 types of, 619 Anesthesia cardiovascular effects of, 275 maintenance of, 215 peripheral nerve or plexus regional, 214 physiology of, 213 types of neuraxial regional, 225 Anesthetic drugs, volatile, 747 Aneurysm dissecting, 901 false, 852 true, 852 Aneurysmal disease, 866 Aneurysms asymptomatic, 862 cause of aortic, 862 diagnosis of, 863 femoral artery, 865 fusiform, 897 inflammatory, 898 popliteal, 865 ruptured, 863 saccular, 897 symptomatic, 862

Aneurysms, (Contd.) of thoracic aorta, 897 treatment for, 863–864 Angina description of, 701 pectoris, 688 postinfarction, 703 Prinzmetal’s or variant, 701 Angiogenesis, 201, 517, 558, 1036 Angiography, 517 catheter-based, 856 intra-arterial contrast, 854 magnetic resonance, 854 Angioplasty, balloon, 687 Angiotensin I, II, III, 914 Angiotensin converting enzyme (ACE) inhibitors, 36, 41, 276, 666, 703, 729, 907 polymorphism, 637 Angiotensin-mediated pathways, 1114 Anionic compounds, 731 Anions and cations (organic), secretion of, 731 Ankle-brachial index (ABI), 854 Ankle-brachial systolic pressure index (ABI), 839 Annuloaortic ectasia, 898 Anomalies, congenital, 1049 Anomalous maturation, 1049 Anorectal abscesses classification of, 607 diagnosis and treatment of, 607–608 Anorectal anatomy, 599 Anorectal angle, angulation of, 604 Anorectal sensibility, 604 Anorectum, physiology of, 604 Anorexia, 545 ANP. See Atrial natriuretic peptide Antacids, 355 Antenatal diagnosis, 1117 Anterior cord syndrome, 811 Antiarrhythmic therapy, 670 Antibiotic coverage, 494 Antibiotic prophylaxis, 272, 475 Antibiotic therapy, basic categories of, 151 Antibiotic-associated colitis (AAC), 128 Antibiotics clinical use of, 135 spectrum activity of, 135 Antibody-dependent cell-mediated cytotoxicity (ADCC), 69 Anticoagulation, 670–671, 745 Antidiuretic hormone (ADH), 34–35, 185, 730, 950, 1135 Antigen-independent stimulants, 91 Antigen-presenting cells (APCs), 66, 68, 91 Antigens (Ags), 95 Antihypertensive drugs, 919 Antilymphocyte globulin (ALG), 759 Antilymphocyte sera (ALS), 112 Antioxidant supplementation, 247 Antiplatelet agents, 173 Antireflux procedures, endoscopic, 307 Antireflux surgery, failure, 315 Antithrombin-III (AT-III), 160 Antithrombotic therapy, 170 Antithyroid drugs, 996 Aorta ascending, 899 descending, 900–901

Aortic arch aneurysms, treatment of transverse, 900 Aortic dissection criteria for, 902 diagnosis of, 902 pathophysiology of, 901–902 symptoms of, 902 treatment of, 902 Aortic insufficiency, 710–711 diagnosis of, 710-711 Aortic regurgitation, 278 Aortic stenosis, 278 subvalvular, 688 supravalvular, 688, 689 valvular, 688 Aortic valve area (AVA), 709 Aortic valve disease diagnosis and treatment of, 709–710 pathologic anatomy of, 709 Aortocaval fistula, 863 Aortocoronary anastomotic devices, 706 Aortography transbrachial, 856 translumbar, 856 APC. See Adenomatous polyposis coli (APC) protein Aphasia Broca’s, 872 Wernicke’s, 872 Aponeurosis, 1068, 1072, 1073 Apoptosis, 231, 266, 807 Apoptosis, proteins involved in, 266 Apoptosis-inducing factor (AIF), 266 Apoptotic death, 231 Appendicitis, 419–420 Apple-peel deformity. See Atresia, jejunoileal Aquaporins, 371 ARDS. See Acute respiratory distress syndrome Areas under the concentration curve (AUC), 114 Aredia1, 935 Arginine, semiessential amino acid, 54 Arginine vasopressin (AVP), 21, 950 Aromatase inhibitors, 1061 Arrhythmias, 42, 278, 670 prototypical, 672 Arterial aneurysm, 769 Arterial emboli, 852 Arterial fibrodysplasia, 915 Arterial flow patterns, 835–836 Arterial hemodynamics, 833 Arterial obstruction, acute, 852 Arterial pathology, 871 Arterial pressure direct measurement of, 838–839 indirect measurement of, 838–839 Arterial system, 667 Arterial wall, layers of, 832 Arteries pressure storer, 831 processes affecting lower extremity, 851 Arteriography, 533, 872 contrast, 916 coronary, 701–702 profunda femoris, 852 subclavian, 878 Arterioles, upper-extremity, 876 Arteriovenous fistula (AVF), 750 Arteriovenous malformations (AVMs), 533 Artery, innominate, 877–878

Index Artificial urinary sphincter (AUS), 790 Artrioventricluar (AV) node, 1133 ASD. See Atrial septal defect Aspartate aminotransferase (AST), 437, 488 Aspergillus flavus, 119 Aspergillus fumigates, 119 Aspiration, risk of, 54 Aspirin advantage of, 173 antiplatelet agent, 170 impact of, 165 Assist devices, ventricular, 678 Asymptomatic heart failure, 670 Asystole, 672 Atelectasis, 638 clinical manifestations of, 639 Atherogenesis, 744 Atherosclerosis, 398, 744, 1159 coronary risk factors of, 700 irreversible factors for, 849 reversible factors for, 849 Atherosclerotic lesions, 850–851 Atherosclerotic plaques, 849 Atresia duodenal, 1116–1117 diagnosis of, 1116 intestinal, 1116 jejunoileal, 1116–1117 types of, 1116–1117 tricuspid, 691–692 surgical treatment of, 691 Atrial fibrillation (AF), 278, 709 prevention of, 671 Atrial natriuretic peptide (ANP), 485, 666–667, 739, 767, 952 Atrial naturitic hormone (ANH), 185 Atrial septal defect (ASD), 691, 694 ostium primum, 689 ostium secundum, 689 sinus venosus, 689 Auerbach’s plexus, 337 Auscultatory (Riva–Ricci method) technique, 838 Austin flint murmur, 711 Autocannibalism, 1092 Autocrine signaling, 264 Autograft aorta, 695 Autonomic dysreflexia, symptoms, 782 Autonomic function, tests of, 823 Autonomic nervous system (ANS), 778 Autonomic neuropathy, 746 Autoregulation, impaired, 806 Autoregulatory homeostasis, loss of, 806 Autosplenectomy, 510 A-V graft dysfunction, management of, 751 Avian leukosis virus (ALV), 206 Axonal injury, 823 diffuse, 798 Axonal regeneration, stages of, 819–820 Axonotmesis, 817 Aza, limitations of, 115 Azathioprine, 115 Bacteremia, 130 Bacterial enterotoxins, 372 Bacteroides fragilis, 139 Baculovirus, 200 Balloon angioplasty, 687, 858–859 Balloon atrial septostomy, 694 Balloon dilatation catheter, 704 Bannayan–Zonana syndrome, 557 Barbiturate coma, 869

Bare-metal stents, 858 Bariatric operation, 1161 Bariatric surgery, 52 Barium enema, 1119, 1123 Barium esophagogram, 315 Barium radiology, 297 Barrett’s esophagus, 312, 1121 Barrett’s mucosa, ablation of, 313 Barrett’s ulcers, 312 Basal energy expenditure (BEE), 51 Basal glucagon level, 1009 Base excess, negative, 191 Baseline NO, physiologic role of, 188 Bassini repair, 1073 Batista and Dor procedures, 715 BCS. See Breast-conserving surgery Beckwith–Weidemann syndrome, 1114 Belly cleft. See Gastroschisis defects Benediction sign, 822 Benign bile duct strictures, 495–497 Benign breast disease, categories of, 1057 Benign breast pathology, treatment of, 1057 Benign disease, 495 Benign prostatic hyperplasia (BPH), 771 Benign tumors of spleen, 514 Bernard–Soulier disease (syndrome), 164 Bernoulli’s principle, 834 Beta-adrenergic blockade, 1031 Beta-adrenergic blocking agents, 670 Beta-blockade, 286, 996 Beta-blocking agents, 918 Beta-lactam antibiotics, 142 resistance to, 144 Beta-lactamases chromosomal, 144 inhibitors, 144 plasmid-mediated, 144 b-Receptors, types of, 659 b-Thalassemia, 510 Bicarbonate reabsorption/proton secretion, 731 Bifurcation graft, Dacron, 859 Bilateral ureteral obstruction vs. unilateral, 767 Bilateral ureteral occlusion (BUO), 767 Bile acids properties, 458 components of, 456 duct strictures, 495–497 monitoring of, 302 physiologic functions of, 455–456 reflux, 312 secretion, 456 Bile salt–dependent flow (BSDF), 456 Bile salt–independent flow (BSIF), 456 Biliary atresia, 121 Biliary colic, 543 Biliary motility, 1136 Biliary obstruction, 484 Biliary pancreatitis, 465 Biliary scintigraphy, 490 Biliary secretions, 372 Biliary sepsis, 494 Biliopancreatic bypass (BPB), 1154 Bilious emesis, 1115, 1117, 1122 Bilirubin impaired transport or excretion, 484 metabolism, 483 overproduction of, 483 Biliverdin, 435, 483 Biobreeding (BB) rat, 1011 Biochemical evaluation, 487–488

medwedi.ru

I-3

Biologic response modifiers (BRM), 85 Biomarkers, 474 Bioprosthetic valves, 711 Bishop–Koop procedure. See Enterostomy, distal chimney Biventricular pacing, 716 Bladder neck contracture (BNC), 771 Bladder outlet, anatomy and physiology of, 779 Bladder outlet obstruction (BOO), 771 Blalock–Taussig procedure, 691 Blalock–Taussig shunt, 694, 695 Bleeding duodenal ulcers, 353 history of, 161 gastric ulcers, 360 risks of, 161 Blockreplace regimen, 996 Blood flow, 665 collateral, 851 coronary, 699 myocardial, 699 viscous properties of, 833 Blood pressure, lowering of, 670 Blood urea nitrogen (BUN), 473, 735, 738 Blood–brain barrier, 817, 818, 869 Blue dye, 1060 Blue toe syndrome, 852, 887 B-lymphocyte, 65 B-mode ultrasound, 863 Bochdalek hernia, 1121 Body cell mass (BCM), 5–7 Body composition in adult man, 2 changes in, 1139 definition by Moore, 1 Body fluid compartments changes in, 189 electrolyte composition of, 3 measurement of, 1–2 Body mass index (BMI), 51–52 Body mass, lean, 5–7 Body’s glycogen, 5 Boerhaave’s syndrome, 589 Bombesin, 341 Bombina bombina, 341 Bone-marrow transplantation complications of, 123 indications for, 123 Boundary layer separation, 836–837 Bowel length, 1117, 1119 Bowel motility, 1117 Bowel obstruction, 1113, 1118 Bowel syndrome, factors of, 60 Bradycardia, chronic sinus, 717 Bradycardia–tachycardia syndrome, 717 Bradycardia, types of symptomatic, 716 Brain lesions, 780 Brain swelling, 798 Brainstem, 778 Branched-chain amino acids (BCAA), 435 Breast, development of, 1047 Breast abscess, 1053, 1057 Breast cancer, 1060, 1061 susceptibility genes, 269 Breast-conserving surgery (BCS), 158, 1058, 1061 Breast-feeding, 1053 Breast imaging, techniques of, 1056–1057 Breast, mammary gland, 1047 Breast mass, 1056 Brequinar (BQR), 116

I-4

Index

Bretscher and Cohn, signal model of, 103 Bridge-to-transplant (BTT) support, 678 Broad-spectrum antibiotics, 1114–1115 Bromocriptine, 1027 Bronchoalveolar lavage (BAL), 135 Bronchodilation therapy, 639 Brown-Sequard Syndrome, 811 Bruit characteristics of, 872 clinical sign of turbulence, 835 indicative of severe stenosis, 854 Brunner gland adenomas, 566 Budding stage, 1047 Buerger’s disease, 876 BUN. See Blood urea nitrogen Bundle of His, divisions of, 658 Burkitt’s lymphoma, 78 Burn wound, 1091 histopathology of, 1086 management of, 1099 pathophysiology of, 1086 Burning agent, 1085 Bypass enteritis syndrome, 1152 Bypass graft afemorofemoml, 860 aortofemoral, 859 axillofemoral, 860 femoral distal, 860–861 femorofemoral, 860 femoropopliteal, 860–861 in situ vein, 860 Bypass procedures, 859 Bypass surgery, long-term results of, 703 Bystander effect, 206 Cadaver grafts, 120 Caenorhabditis elegans, 199 Calcific uremic arteriolopathy (calciphylaxis), 743 Calcification, 850 Calcimimetics, 944 Calcineurins (CaN), 113 Calcitonin, 36, 930, 935, 944 role of, 929 Calcitriol deficiency, 743 Calcium abnormalities of, 42 hemostasis, 195 homeostasis, 927–928 metabolism disorders of hypercalcemia, 931 phosphate and bone metabolism, 743 replacement therapy, 943 Calcium channels blockers, 672 blocking agents, 670, 702 L-type, 650 Calcium–cyclic AMP interactions, 18 Calcium receptors (CaR), 36 Calcium-sensing receptor (CaSR), and calcium regulation, 930 Calculi, 768 Caliber tube thoracostomy treatment, 641 Calmodulin (CaM), 104 Caloric requirements, 51 Campylobacter pyloridis, 349 Canal of nuck, 1068, 1070 Canalization stage, 1047 Cancer biology principles, 197 chemotherapy, 85, 1040 gene therapy, 267

Cancer, (Contd.) periampullary, 497, 498 syndromes, 575–576 Candida albicans, 119 Candida globrata, 119 Candida infections, 84 Cantlie’s line, 429 Cantrell syndrome, 1113 Capillary filtration, 847 Capsaicin ointment, 824 Capsule endoscopy, 535 Carbapenems, 144 Carbohydrate, 5–6 absorption, 374 and lipid metabolism, 746 metabolism, 9–10 Carbohydrate antigen (CA), 497 Carbon monoxide poisoning, clinical symptoms of, 1096 Carcinoembryonic antigen (CEA), 1002 Carcinoid tumors, surgical resection of, 570 Carcinoma of the stomach, classification of, 565 Cardiac allotransplantation, 121 Cardiac contractility, abnormal, 665 Cardiac cycle, 654 Cardiac death rates, 744 Cardiac dysfunction, causes of, 663 Cardiac dysrhythmias, 716 Cardiac function, 651 Cardiac mucosa, 306 Cardiac muscle length-dependent properties of, 651 loss of, 663 mechanism, 651 Cardiac output (CO), causes of low, 706 Cardiac physiology, 1109 Cardiac stabilization devices, 706 Cardiac surgery, 273 Cardiac tamponade, 707 Cardiac transplantation, 669, 671 Cardiac tumors, diagnosis of, 721 Cardiac vein, 699 Cardiogenic shock, 702 Cardiomyocytes, 650 Cardioplegic solution, 705 Cardiopulmonary, 493 arrest, 671 following trauma, 673 Cardiopulmonary bypass (CPB) circuit, 677, 706, 899 Cardiopulmonary resuscitation (CPR), 672 monitoring the effectiveness of, 673 pathophysiology of, 671 Cardiovascular, 485 complications, 744 function, 1132 vascular system efficiency, 670 Cardiowest C-70 total artificial heart, 682 Carotid angioplasty, 875 Carotid artery disease extracranial, 872 symptomatic, 872 Carotid endarterectomy, indications for, 873 Carotid–subclavian artery bypass, 878 Caspases, 266, 1052 Catabolism, postinjury, 1092 Catecholamines, metabolism of, 909 Catheter, 59

Catheter, (Contd.) drainage, 787 related bacteremia, risk factors for, 750 Cationic liposomes, 268 Cationic organic molecules, 728 Cauda equina syndrome, 809 Causalgia, pathophysiology of, 821 C-cell, 990, 994 hyperplasia, 1029, 1030 CDH. See Congenital diaphragmatic hernia Celiac artery compression syndrome, 404 Cell communication pathways, 264 cycle, 265 death, 91 division stages, 198 fractionation of, 260 free radical–mediated injury of, 807 and human genome, 253 isolation and growth in culture, 259 migration, 266 molecular organization of, 263 proliferation, 260 signaling, 263 surface receptors, 264 therapy, 268 Cell-to-cell interactions, 1052 Cell-to-cell signaling, 264 Cell-mediated immunity (CMI), 68, 70 Cell-mediated lympholysis (CML), 76 Cellular alterations, 1088 Cellular biochemical mechanisms, 664 Cellular components, 65 Cellular dysfunction, 188–189 Cellular hypoxia, 190 Cellular infiltrate as a determinant of biologic priority, 26 Cellulitis, 130 Central cord syndrome, 807–809 Central neuroanatomy, 540 Central venous catheters (CVCs), 274, 749 Cephalic phase, 344 Cephalosporins, categories of, 143 Cephalothin, 143 Cerebral angiography cardiac complications of, 872–873 neurologic complications of, 873 Cerebral blood flow (CBF), 186, 672, 795 during cardiopulmonary resuscitation, 672 measurement of, 870 Cerebral circulation, 869 Cerebral perfusion pressure (CPP), 802 Cerebral protection devices, 875 Cerebral salt wasting, 40 Cerebral vascular accidents, 708 Cerebrospinal fluid (CSF), 800 Cerebrovascular accidents, 781 Cerebrovascular disease, 279, 869 definition of, 871 symptoms of, 871 types of, 872 CF. See Cystic fibrosis C-fibers, 539 Chagas’ disease, 318, 611 Chamber dilation, 660 Chediak–Higashi syndrome, 75 Chemokine cascade, 92 families, 82 receptors, 92 Chemotherapy, 202, 1002

Index Chenodeoxycholic acid (CDCA), 463 Chest CT diagnosing study, 640 pain, 318 radiograph, 299, 678, 686 roentgenogram, 713 trauma, 642 Child’s class, 446 Child–Pugh classification scheme, 436 score. See Child–Turcotte classification Child-Turcotte classification, 281, 446 Chloride, abnormalities of, 42 Cholangiocarcinoma, 498 Cholangitis, 494 Cholecystectomy, 461, 463, 1154 Cholecystectomy and common bile duct exploration (CBDE), 495 Cholecystokinin (CCK), 264, 456, 470, 1007, 1009, 1137 receptors, 475 Choledocholithiasis, 463, 495 diagnosis of, 463 Cholelithiasis asymptomatic, 461 symptomatic, 461–463 Cholescintigraphy, 490 Cholesterol saturation index (CSI), 459 Cholinergic agents, 470 Cholinergic receptor, 777 Christian Barnard, human cardiac transplant by, 120 Christmas tree deformity. See Atresia, jejunoileal Chromatin three-dimensional proteins, 203 tissue, 965, 979 types, 255 Chromatolysis, 817 Chronic active hepatitis, 281 Chronic ambulatory peritoneal dialysis (CAPD), 1070 Chronic constrictive pericarditis, 719 Chronic dialysis, indications for, 750 Chronic gastric retention, causes of, 587 Chronic heart failure, 663 hallmark of, 663 treatment of, 670–671 Chronic hepatitis, 280 Chronic hypertension, 278 Chronic intestinal ischemia, 402 Chronic kidney disease (CKD), 729, 740 anemia of, 743 clinical course of, 741 clinical manifestations of, 742 management of, 725, 747 pathophysiology of, 741 stages of, 742 Chronic kidney failure, causes of, 736 Chronic kidney rejection, 759 Chronic lymphocytic leukemia (CLL), 512 Chronic myelogenous leukemia (CML), 206, 513 Chronic obstructive pulmonary disease (COPD), 149, 271, 638 Chronic pancreatitis treatment of, 476–477 drainage procedure in, 477 duct drainage and resection procedures in, 478

Chronic pancreatitis, (Contd.) surgical therapy in, 477 Chronic rejection, 112 Chronic renal failure, 283 Chronic symptomatic heart failure, 670 Chronic wounds, 1038 treatment of, 1042–1043 Chronotropism, 832 Chvostek’s sign, 936 Chylothorax, 642 Cilostazol, phosphodiesterase inhibitor, 857 Cineangiography, 661 Cinedefecography, 605 Circle of Willis, 869 Circulatory function cellular reservoir, 505 erythrocyte destruction, 505 erythrocyte maturation, 505 intraerythrocytic inclusions removal, 505 Circumferential tension (T), 833 Cirrhosis, 281, 736 Cisterna chyli, 892 Claudication, 853 Claw hand deformity, 822 Clip and drop-back technique, 10 Cloacogenic zone, 601 Clopidogel versus aspirin in patients at risk of ischemic events (CAPRIE), 170 Clopidogrel (Plavix) antiplatelet agent, 703 advantage of, 174 Closing volume (CV), 635 Clostridium difficile colitis, 423 Cluster of differentiation (CD) antigens, 65 Coagulation, 485, 493 abnormalities of, 746 cascade, 158 defects, 288 factors synthesis, 431 zone of, 1100 Coagulation protein deficiency epidemiology of, 162 therapy of, 162 Coarctation of aorta, 686 Cocaine-associated mesenteric ischemia, 405 Coccidioides immitis, 119 Cockroft–Gault equation, 735 Codons, 257 Colitis, etiologies of, 534 Collagen metabolism, 1068 synthesis of, 1040 types of, 1036 Collateral beds, 851 Collateral circulation, 381 Colon, mechanical disorders of, 595 Colonic diverticular disease, 422 Colonic dysmotility, 611 diagnosis and treatment, 597 etiology and pathophysiology, 596 Colonic obstruction diagnosis and treatment, 595 etiology and pathophysiology, 595 Colonic surgery, bowel preparation for, 273 Colonic transit time, 605, 611 Colonoscopy, 533 Colony-stimulating factors (CSFs), 108 Color duplex ultrasonography, 839 Color flow Doppler (CFD), 111 Colorectal cancer classification of, 577

medwedi.ru

I-5

Colorectal cancer, (Contd.) diagnosis of, 579 prevention, 579–580 screening, 579 symptoms of, 579 Common bile duct (CBD) stones, 463 Common bile duct exploration (CBDE), 463 Comorbid illnesses, assessment of, 1137 Compensatory anti-inflammatory response syndrome (CARS), 50, 231 Complete lesions, abnormalities of, 822 Complex lipids, classifications of, 433 Complex neurohormonal interactions, 671 Computed tomographic arteriography (CTA), 917 Computerized axial tomography (CAT) scan, 81 Concanavalin A, 76 Cone stage, 1047 Congenital aganglionosis. See Hirschsprung’s disease Congenital diaphragmatic hernia (CDH), 1121 diagnosis of, 1121 surgical repair of, 1122 Congenital heart disease, 668 results of, 686 Congestive heart failure (CHF), 276, 685–686, 668, 703 medical therapy of, 715 Conscious sedation, 298 Constipation diagnosis and treatment of, 611 pathophysiology of, 610 Continuous ambulatory peritoneal dialysis (CAPD), 754 Continuous cyclic peritoneal dialysis (CCPD), 754 Continuous renal replacement therapy (CRRT), 748 complications of, 754 Continuous veno-venous hemodiafiltration (CVVHDF), 752 Continuous veno-venous hemofiltration (CVVHF), 752 Contractile system, 650 Contractility, evaluation of, 193 Conus medullaris syndrome, 809–810 Convective therapies, 753 Cooley’s anemia, 510 Coombs’ test, 511 Cooper’s ligament, 1054, 1074 COPD. See Chronic obstructive pulmonary disease Cord syndrome anterior, 811 posterior, 811 Coreceptors, 71 Cori cycle, 10, 190, 433 Corkscrew effect, 1123 Corneal grafting, 124 Coronary artery disease, 275, 664, 677, 744 left branches of, 1 Coronary blood flow during cardiopulmonary resuscitation, 672 Coronary bypass postoperative complications after, 707 surgery indications, 704

I-6

Index

Coronary circulation, unique features of, 660 Coronary flow, 660, 708 Cortical thick ascending limbs (cTAL), 726 Cortical-sparing adrenalectomy, 982 Corticosteroids, 112, 760 Corticotropin, 953 deficiency, 953 Corticotropin releasing factor (CRF), 20, 966 Corticotropin-releasing hormone (CRH), 949, 973, 1138 Cortisol, 20 deficiency, 953 metabolic dysfunction, 284 producing adenoma, 971 secretion, 284 secretion regulation, 966 systemic effects of, 967 Cosmid, 260 Costimulatory molecules, 98–100 Coughing, spasms of, 296 Couinaud’s liver segment classification, 429 Cowden’s disease, 557, 576, 999 Cox-Maze procedure, 718 Craniopharyngioma, 959 C-reactive protein (CRP), 50, 228 Creatinine, 731 Creatine kinase (CK), cardiac enzyme, 703 Creatine phosphokinase (CPK), 80 Cricomyotomy for pharyngoesophageal disorders, 317 Cricopharyngeal dysphagia, 297 Cricopharyngeal myotomy, technique of, 317 Cricopharyngeus muscle, 295 Crigler–Najjar syndromes, 484 Critical blood count (CBC), 73–74 Crohn’s disease (CD), 415 antigens, identification of, 65 Cullen’s sign, 472 Cultured epithelial autografts (CEA), use of, 1101 Curative surgery, principles of, 325 Cushing’s disease, 958, 1027 Cushing’s syndrome, 285, 958 causes of, 972 Cushing’s ulcer, 347 Cusps, 709 Cutaneous ulcers, 853 Cutaneous vesicostomy, 789 Cyanide, 1097 Cyanosis, 686, 692, 693 Cyclic adenosine monophosphate (cAMP), 15, 158, 456, 730, 932–933, 937, 949, 1010 Cyclin-dependent kinases (CDKs), 475 Cyclins activities of, 266 classes of, 266 Cyclooxygenase-2 (COX-2) pathway, 327, 561 Cyclosporine, 418, 759 Cystic fibrosis (CF) defect, 1117–1118 mutation, 1117 Cystic fibrosis transmembrane regulator (CFTR), 369, 371 Cystic medial necrosis, 710, 897 concept of, 898 Cytokines, 26–27, 108, 266, 1086 and chemokines, 757 Cytolysis, complement-mediated, 72 Cytolytic lymphocytes (CTL), 99

Cytomegalovirus (CMV), 116, 437, 551 infection, 759 Cytoskeletal proteins, 819 Cytotoxic T-cells (CTLs), 69, 99, 756 Cytotoxicity, CTL-mediated, 73 Da Nang Lung. See Adult respiratory distress syndrome (ARDS) Debridement autolytic, 1040 enzymatic, 1041 mechanical, 1040 sharp, 1041, 1043 Deep venous thrombosis (DVT), 272, 845, 884 complications of, 887 diagnosis of lower extremity, 885 upper extremity, 886, 892 Defecation obstructed, 611 reflex, 604 Deformity, posttraumatic, 813 Dehydration, 8 isotonic, 39 Dehydroepiandrosterone (DHEA), 968 Delayed graft function (DGF), 758 Delayed type hypersensitivity (DTH), 102 functions, 67, 73 Deleted in colon cancer (DCC), 556 Delorme procedure, 609 Delphian node, 993 Dendritic cell (DC), 69, 103, 231 Denervation phase, 826–827 Denonvilliers’ fascia, 599 Density-gradient centrifugation, 260 Depilatory agents, 272 1-Desamino-8-D arginine vasopressin (DDAVP), 283, 954 Detrusor areflexia, 779 overactivity, 781 Detrusor leak point pressure (DLPP), 786 Detrusor–external sphincter dyssynergia, 771 Detrusor–sphincter dyssynergia (DSD), 782 Dextran, 174 Diabetes, 283 complications of, 1012 diagnosis and treatment of, 1013 type II. See Diabetes mellitus, noninsulindependent Diabetes control and complications trial (DCCT), 1013 Diabetes insipidus (DI), 954 Diabetes mellitus, 84, 283, 1010 adult-onset or nonketogenic, 1012 anesthetic implications of, 217 insulinopenic type I, 1011 noninsulin-dependent, 1012 Diabetic cystopathy, symptoms, 783 Diabetic ketoacidosis, 284 Diabetic ulcers, treatment of, 1043 Diacylglycerol (DAG), 104, 157 Diagnostic peritoneal lavage (DPL), 516 Dialysate composition, 752 Dialysis adequacy, measurement, 752 therapies, 752 Dialyzer design, 749 membrane, 749

Diamond–Blackfan anemia, 123 Diamond-shaped anastomosis, 1116 Diarrhea and malabsorption, 378 Diastolic behavior, 656 Diastolic dysfunction, 666–667, 744 Diastolic filling, phases of, 655 Dicrotic notch, 837 Didronel1, 935 Dietary counseling, postoperative, 1158 Dietary fiber, 374 Dieting, yo-yo theory of, 1151 Dieulafoy lesion, 530 Differential-velocity centrifugation, 260 Digestion, overview of, 371 Digestive enzymes, 470 Digoxin, 670 therapy, 717 Dihydro-orotate dehydrogenase (DHODH), 116 Dihydrotestosterone (DHT), 771 Diiodothyrosines (DIT), 990, 991 Dinitrochlorobenzene (DNCB), 76 Disc stage, 1047 Disequilibrium syndrome, 746 Disseminated intravascular coagulation (DIC), 160, 288 Disturbed flow, categories of, 836 Diuretic action, sites and mechanisms of, 731 Diverticulitis, 422 etiology of, 533 DNA binding peptides, 268 chips, 268 and chromosomes, 254 cloning, 260 isolation, cloning, and sequencing, 260 libraries types complementary DNA (cDNA) library, 260 genomic DNA library, 260 protein complexes, 268 replication, repair, and recombination, 255 sequences, rearrangements of, 256 vectors (plasmids), 268 Dobutamine, 236 Donor grafts, types of, 120 Dopamine, 951 low-dose, 731 Doppler angle, 840 ankle pressure, 854 beam, 839 detectors, 855 echocardiography, 686, 714 equation, 840 probe, 854 shift, 854 signal, 839, 854 transducer, 838 ultrasound imaging, 855 velocity spectra pattern, 836, 839 waveform analysis, 855 Double-antibody immunoassays, 929 Double-edged sword, 667 Double product, 660 Double-stranded RNA (dsRNA), 207 Drainage, preoperative, 494 Dressings barrier-type, 1040 biologically active, 1044

Index Dressings, (Contd.) occlusive, 1041, 1042 semiocclusive, 1041 Dressler’s syndrome, 720 Drugs eluting stents, 858 principles for use of, 203 DSD with detrusor hyper-reflexia (DSD–DH), 783 Dubin–Johnson syndrome, 484 Duct of Santorini, accessory pancreatic duct, 469 Duct of Wirsung, main pancreatic duct, 469 Duhamel theory, 1113, 1118 Dukes’ method, 578 Dumping early, 617–619 late, 619 syndrome, 1154 Duodenal obstruction, 1116, 1122 diagnosis and treatment, 588 etiology and pathophysiology, 588 Duodenal switch, 1155 Duodenal ulcer clinical manifestations, 352 intractable, 353 pathophysiology, 352 perforated, 353 Duodenoduodenostomy, 1116, Duplex scanning, 393, 840, 855 Duplex venous ultrasound, 845 DVT. See Deep venous thrombosis Dynamic modules (Edyn), 833 Dysesthesias, 821 Dysphagia, 296 Dysplasia in Barrett’s esophagus, 325 Dyspnea, exertional, 709 EA. See Esophageal atresia EA/TEF, anatomic variants of, 1119 Early goal-directed therapy (EGDT), 236 protocol for, 237 Eastern Association for the Surgery of Trauma (EAST), 516 ECC. See Excitation-contraction coupling Echocardiography, 661 Ectasia, annuloaortic, 898 EDV. See End-diastolic volume Efferent limb, 109 Efferent loop obstruction, 621–622 Ehlers-Danlos syndrome, 710, 1040 Eicosanoids, 388, 1086 Eisenmenger’s syndrome, 690 Either-aminocaproic acid (EACA), 164 Ejection fraction (EF), 660 Elasticity, coefficient of (Young’s modulus), 656 Elastin–collagen ratio, 832 Electrocautery, 719 Electrolyte, 1108 abnormalities, 740, 1111, 1116 correction, 1111 disorders pathophysiology, 33 homeostasis abnormalities, 38 management, 1107 normalization, 1120 serum, 1111 Electromechanical dissociation, 672 Electromyography (EMG), 604, 771, 821 Embden–Meyerhof pathway, 9 Embryonic stem (ES) cell lines, 260

Embryonic venous system, 428 Empty sella syndrome, 960 Emptying phase, 780 End systolic volume (ESV), 660 End-diastolic volume (EDV), 656 Endarterectomy, 859, 921 Endocardial cushion defect, 689 Endocarditis prophylaxis and dental procedures, 279 Endocrine cells patterns, 1006 disease diabetes mellitus, 283 function, 1005 neoplasia syndromes, 944 neoplasia type-II syndrome, 268 signaling, 264 Endopelvic fascia, layers of, 599 Endoplasmic reticulum (ER), 93 positive tumors, 1060 positive women, 1060 Endoscopic retrograde cholangiography (ERC), 491–492 Endoscopic retrograde cholangiopancreatography (ERCP), 463, 490 Endoscopic sphincterotomy (ES), 492 Endoscopic therapy, 446 Endoscopic ultrasound (EUS), 490, 564, 1027 Endoscopic variceal banding (EVB), 445 Endoscopic variceal sclerotherapy (EVS), 445 Endoscopy, technique of, 298 Endothelial cell NOS (ecNOS), 188 Endothelial cell protein C receptor (EPCR), 159 Endothelial dysfunction, 806 Endotoxin, 485 Endotracheal intubation, 672, 720 Endovascular therapy, 858 End-stage liver disease (ESLD). See Liver transplantation, indications for End-vesicle stage, 1047 Energy metabolism, 9–10 storage depot, 1149 Enteral access gastric, 55 jejunal, 55 Enteral nutrition, 247 benefits of, 53 complications of, 55 indications and contraindications for, 54 Enterochromaffin-like (ECL) cells, 338 Enterocutaneous fistula, 628 Enterohepatic circulation, 372 Enterostomy distal chimney, 1119 double-barreled, 1119 proximal, 1115–1116 proximal chimney, 1119 side-by-side, 1119 Enzyme replacement therapy (ERT), 514 Enzyme-linked immunoabsorbent assay (ELISA), 75, 169 Enzyme-linked immunospot (ELISPOT), 75–76 Enzyme-linked receptors, 265 Eosin staining, 1118 Eosinophil, 70 protein X, 70

medwedi.ru

I-7

Eosinophilic esophagitis, 316 Epidermal growth factor (EGF), 264, 438, 555, 1049, 1051 Epidermal growth factor receptors (EGFrs), 197 Epidural hematomas, 800 Epinephrine, 20 lipolytic effect of, 967 norepinephrine fractionation, 285 Epithelial barrier, 346 Epithelial transport mechanisms, 729 Epithelial–mesenchymal crosstalk, 559 Epithelialization, 1036 Epstein–Barr virus (EBV), 78, 118, 437, 761 disease, 132 protein, 200 Erosette formation, 75 receptor, 67 Erythropoiesis, 1137 Erythropoietin (EPO), 260 deficiency, 743 Escherichia coli, 80, 127 Esmarch bandage, 888 Esophageal acid exposure, 302 Esophageal and gastric function, tests of, 303 Esophageal atresia (EA), 1119–1121 diagnosis of, 1119–1120 Esophageal body function, 295, 300 Esophageal cancer chemoprevention of, 327 development of, 313 Esophageal carcinomas, types of, 323 Esophageal disease gastro esophageal reflux disease (GERD), 296 symptoms of, 296 Esophageal emergencies, 321 Esophageal histology, 299 Esophageal mobilization, 308 Esophageal motility, 299 Esophageal motor disorders, 316 Esophageal mucosa, 299 Esophageal shortening, 313 Esophageal sphincter, upper, 301 Esophageal stricture, 311 Esophageal tumors, leiomyoma, 323 Esophageal varices, etiology, 528 Esophagitis, 305 nonreflux, 315 Esophagus cancer of, 323 diseases of, 295 spans, 295 surgical anatomy, 295 Estradiol, 930 Estrogens and progestins, 944 Eukaryotes, 253 Eukaryotic genome, 253 Eupenicillum brefeldianum. See Mizorbine (MZB) European Cooperative Study, 705 Euthyroidism, 286 Evans blue dye, 642 Evening Primrose Oil. See Gamma-linolenic acid Everolimus, 114 Excitation, factors affecting, 658 Excitation–contraction coupling (ECC) system, 650–651

I-8

Index

Excitatory postsynaptic potentials (EPSPs), 819 Exocrine function, 1005 Expiratory reserve volume (ERV), function of, 632 External beam radiation therapy (EBRT), 973 Extracellular fluid (ECF), 1108 Extracellular matrix (ECM), 474, 776 Extracorporeal membrane oxygenation (ECMO), 1122 Extracorporeal shock wave lithotripsy (ESWL), 769 Extrahepatic biliary obstruction, malignant causes of, 492 Fahraeus–Lindqvist effect, 833 Familial adenomatous polyposis (FAP), 555, 575 Familial hyperaldosteronism type I (FH-type I), 969 Familial hypocalciuric hypercalcemia (FHH), 930, 941 Familial medullary thyroid carcinoma (FMTC), 1028, 1029 Fanconi–Bickel syndrome, 375 FAP. See Familial adenomatous polyposis Fascicular anatomy, 817 Fat (lipids), 3–5 absorption, 376 distribution pattern, 1150 free body, 6 necrosis, 472 Fatty acid metabolism, metabolic pathways of, 14 Fatty streak lesion, 849 Fc receptor (FcR), 94 Fecal continence diagnosis and treatment, 610 mechanical factor of, 603 neurologic factor of, 603 pathophysiology of, 609 Feedback inhibitor of lactation (FIL), 1052 Felty’s syndrome, 514 Fenoldopam, low-dose, 739 Ferguson technique, 606 Fiberoptic endoscopy, 355 Fibrillation potentials, 823 Fibrin sealant, hemostatic agent, 167 Fibrinolysis, 160 Fibroblast growth factor (FGF), 103, 1035, 1049, 1052, 1119, 1121 Fibrodysplasia, medial, 916 Fibronectin, 1095 Fibroplasia, 1036 intimal, 916 Fibrous cap, 850 Fibrous plaque, 850 Fight-or-flight reaction, 16, 20 Filaria bancrofti parasite, 893 Filling phase, 780 Filling pressures (FPs), 657 Fine needle aspiration (FNA), 490, 1138 Fine needle aspiration biopsy (FNAB), 994, 998, 999, 1002 Fine-tooth comb, 505 Finney-type pyloroplasty, 617 Fissures diagnosis and treatment of, 606–607 pathophysiology of, 606 Fistula-in-ano classification of, 607 diagnosis and treatment of, 607–608

Fistulogram, 608 Fitz-Hugh-Curtis syndrome, 543 FK778 (Fujisawa), 116 Flail chest, 643 Flavin adenine dinucleotide (FADH), 9 Fleeting blindness. See Amaurosis fugax Flow cytometry, 74–75 Fluid and electrolyte secretion and absorption, 369 energy types, 833 management, 1107, 1109, 1112 pathophysiology of, 33 resuscitation, 1095 sequestration, 473 therapy, 45 Fluorescence-activated cell sorter (FACS), 259 Fluorescent microscopy detection, 75 Fluoroquinolone, activities of, 147 5-Fluorouracil (5-FU), 558 Fogarty balloon catheter, 861 Foley catheter, 1158 Follicle-stimulating hormone (FSH), 948, 1048, 1048 Follicular carcinoma, 1002 Follicular lymphoma cells, 266 Follitropin (FSH), 950 Fontan procedure, 692, 695 Foramen of Bochdalek, 1081 Morgagni’s, 1082 of Winslow, 1068 Forced expiratory volume in one second (FEV1), 632 Forced vital capacity (FVC), 632 Force–velocity relations, 652 Foregut carcinoids, 1027 Forward versus backward heart failure, 667 Fox’s sign, 472 FP. See Filling pressures Fractional excretion of sodium (FENa), 738 Fragment antigen-binding (Fab), 174 Frameshift mutation, 256 Frank–Starling curve, 665 mechanism, 669, 832 relationship, 656–657 Free fatty acid (FFA), 239, 433 Fresh frozen plasma (FFP), 164 Friis–Hansen’s graph, 1108 Frykman–Goldberg procedure, 609 FTY720 (Novartis), as active metabolite, 116 Fuel metabolism in normal fasted man, 22 in starved man, 23 Functional residual capacity (FRC), 134, 632 Fundic mobilization, 309 Fundoplication, 297 Furosemide, 739 Fusiform aneurysms, 897 G protein–coupled receptors (GPCRs), 264, 562 G proteins, 264 Galactic band, 1047 Galactorrhea, 1053 Gallbladder cancer, 464–465 Gallbladder contractions, 457 Gallbladder dysfunction, 459–460

Gallbladder functions, 456 Gallbladder, porcelain. See Gallbladder cancer Gallium nitrate, 935 Gallstone disease, 455 clinical manifestations of, 461–463 history of, 462 Gallstone ileus, 464 Gallstones classification of, 455 pathogenesis of, 459 Gamma-aminobutyric acid type A (GABAA) receptor, 216–217 Gamma-glutamyl transpeptidase (GGTP), 437 Gamma-linolenic acid, 1056 Gamma scintillation counter, 885 Gangrene, dry, 853 Gangrene, wet, 853 Gardner’s syndrome, 575, 999 Gas analysis, metabolic, 51 Gasbloat syndrome, 311 Gastrectomy Billroth I, II, 617, 619 subtotal, 358 Gastric acid secretion, 303, 343 Gastric adenocarcinoma diagnosis of, 564 diffuse, 564 intestinal, 563 pathology of, 563 surgical procedures to, 564 Gastric anatomy blood supply, 333 divisions, 333 innervation, 335 lymphatic drainage, 334 Gastric banding, 1158 Gastric bypass, 1152 Gastric emptying, 303 Gastric feeding, 54 Gastric inhibitory peptide (GIP), 19 Gastric lymphoma, 564 Gastric microscopic organization, 338 Gastric morphology, 337 Gastric motility diagnosis and treatment, 589–590 etiology and pathophysiology, 589 postprandial, 339 preprandial, 339 disorders of, 589–590 Gastric mucosal barrier, 345 Gastric mucosal blood flow, 346 Gastric mucus and bicarbonate, 345 Gastric neoplasms, 562 Gastric outlet obstruction, 361, 498 diagnosis and treatment, 587 etiology and pathophysiology, 587 Gastric phase, 345 Gastric physiology exocrine regulation, 342 hormonal/peptide regulation, 340 neural/electrical regulation, 339 Gastric restriction, 1152 Gastric restrictive operations, categories of, 1152 Gastric sarcomas, 566 Gastric tumors, benign, 562 Gastric ulcer, 353 giant, 361 intractable, 360 pathophysiology of, 352

Index Gastric ulcer, (Contd.) perforated, 360 type 4, 361 Gastric volvulus diagnosis and treatment, 589 etiology and pathophysiology, 589 Gastric-inhibitory peptide (GIP), 1007, 1019 Gastrin, 338 Gastrin-releasing peptide (GRP), 341 Gastrinoma, diagnosis of, 1026 Gastrinoma syndrome, 1018 Gastritis, stress, 346 Gastroepiploic artery, 334 Gastroesophageal (GE) junction, 296, 352 Gastroesophageal reflux (GER), 1111, 1120–1122 clinical measurement of, 735 physiology of, 304 physiology of surgical control of, 308 treatment of, 306 Gastroesophageal reflux disease (GERD), 296 clinical spectrum of, 305 complications of, 311 histologic changes of, 305 in morbidly obese patients, 314 tissue injury in, 305 Gastrografin, 1119 Gastrointestinal (GI) bleeding, upper, causes of, 529 Gastrointestinal (GI) blood flow, intrinsic factors regulating, 385 Gastrointestinal (GI) cancer, inflammatory response of, 559 Gastrointestinal (GI) carcinoid tumors foregut, 568 hindgut, 569 midgut, 569 Gastrointestinal (GI) complaints, 1026 Gastrointestinal (GI) hemorrhage, 527, 730 diagnostic step, 528 physiology of, 527 Gastrointestinal (GI) hormones, receptors for, 562 Gastrointestinal (GI) mucosal deterioration, 1115 Gastrointestinal (GI) mucosal wounds, 267 Gastrointestinal (GI) neoplasms, 565 Gastrointestinal (GI) radiography, upper, 354 Gastrointestinal (GI) stromal tumors (GISTs), 566–567 Gastrointestinal (GI) system, 341, 742 Gastrointestinal (GI) tract, 147, 445 cancers of, 555 regulation of, 378 Gastroparesis, diagnosis of, 624 Gastroplasty, 1152 Gastroschisis defects, 1111–1114 Gastrosplenic ligament, 337 Gaucher’s disease, 514–515 Gene expression, 262 control of, 257 and function, 262 Gene, structure, 259 Gene therapy, 267, 671 Gene transfer systems, nonviral, 268 Genetic code, 257

Genetic mutations, 259 Genetic polymorphism, 259 Genetic recombination, role in, 256 Genetic stability, 256 Genotype, 259 GH releasing hormone (GHRH), 949 Ghrelin, 341 GI. See Gastrointestinal Gilbert’s syndrome, 484 Glanzmann’s thrombasthenia, 164 treatment of, 164 Glasgow coma score (GCS), 799 Glenn procedure, 695 Glisson’s capsule, 429, 541 Globular stage, 1047 Globus sensation, 297 Glomerular filtration, 727, 731 Glomerular filtration rate (GFR), 282, 726, 1108, 1135 Glucagon, 19–20 Glucagonoma, 1018, 1027 Glucocorticoid resistance syndrome, peripheral, 237 Glucocorticoid response elements (GRE), 113 Glucocorticoid-remediable hyperaldosteronism (GRA), 969 Glucocorticoids, 930 Gluconeogenesis, 1010, 1011 Gluconeogenic pathway, 11 Glucose, catabolism of, 9–10 Glucose–alanine cycle, 12 Glucose–lactate (Cori) cycle, 12 Glucose homeostasis, 1138 Glucose monitoring, home, 1014, 1015 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 509 Glu-plasminogen, 160 Glutamate excitotoxicity, 807 Glutamine, 80 synthesis of, 434 Glycation reaction, 1131 Glyceryl trinitrate ointment (GTN, nitroglycerin), 606 Glycine, amino acid, 1036 Glycolytic enzyme abnormalities, 510 Glycolytic products, accumulation of, 670 Glycosuria, 734 Gnawing, 463 GnRH insufficiency, 1050 GnRH. See Gonadotropin-releasing hormone Goblet cells, 471 Goldberg graphs, 45 Goldie–Coldman hypothesis, 203 Golgi apparatus, 470 Gompertzian function, 1131 Gompertzian kinetics, 203 Gonadotroph adenomas, 958 Gonadotropin deficiency, 953 Gonadotropin-releasing hormone (GnRH), 1048, 1053 Gonadotropins, 951 Goniometer, 822 Goodsall’s rule, 607 Goretex or composix, 1081 Gore-Tex, 689, 690, 692 Gorlin formula, 712 Grade and Ransohoff studies, 461 Graft arterial, 705 destruction of, 758

medwedi.ru

I-9

Graft, (Contd.) free, 705 pedicle, 705 saphenous vein, 708 Graft alloantigen, 756 Graft destruction, 109 Graft dysfunction, late, 759 Graft function, diagnosis of, 758 Graft survival, 79 Graft-versus-host disease (GVHD) reaction, 123 Gram-negative organisms, 147 Gram-positive organisms, 147 Granulocyte, 70 Granulocyte-macrophage colonystimulating factor (GM-CSF), 86 Graves’ disease, 994, 995, 996 clinical features of, 995 treatment for, 996 Green fluorescent protein (GFP), 262 Green-field aspiration, 888 Greenfield filter, 170 Grey Turner’s sign, 472 Growth hormone (GH), 185, 930, 948, 1048 Growth hormone and vasopressin, 21–22 Growth-related oncogenes (GRO), 82 Grynfeltt’s triangle, 1080 Guanosine diphosphate (GDP), 264 Guanosine monophosphate (GMP), 101 Guanosine triphosphate (GTP), 9, 264 Gut-associated lymphoid tissue (GALT), 1091 Gut-derived cytokines, 187 Gut mucosal wounds and healing, 27 Gynecomastia, 1050 Gynoid or peripheral obesity, 1149 Haemophilus influenza, 133, 451 Haemophilus pylori infection, 354 treatment of, 355 Haemophilus pylori testing, 355 Hageman factor, 159 Hairy cell leukemia (HCL), 512 Halitosis, 297 Halsted mastectomy, 1058 Hammurabic code, 427 Harris–Benedict equation, 51, 1139 Hartmann’s pouch, 461 Hartmann’s procedure, 596 Hashimoto’s thyroiditis, 994, 995, 997 Head injury pathophysiology, 799 penetrating, 799 Head-injured patient, management of, 800 Health status, 1161 Healthcare associated pneumonia (HCAP), 133 Heart burn, 296 Heart disease, end-stage, 121 Heart failure, 660, 715–716 approach to asymptomatic, 670 biochemical derangements, 665 cardiac and systemic abnormalities resulting in, 664 clinical manifestations of, 667 diagnosis of, 669 etiology and natural history of, 663 events precipitating or exacerbating, 664 features of, 663 intrinsic myocardial abnormalities causing, 664 mechanical derangements, 665

I-10

Index

Heart failure, (Contd.) mechanical or anatomic abnormalities causing, 664 pathophysiology of, 664, 677 primary, 668 rhythm and conduction disturbances causing, 664 secondary, 668 symptoms of, 663 therapy of, 678 transient, 668 treatment of, 667, 669, 670, 671 vicious cycle of, 666, 667 Heart mate device, 681 Heart, mechanical properties of, 669 Heart muscle, 651, 656 Heart rate, determinant of the heart’s performance, 653 Heart replacement therapy, 716 Heat shock proteins (HSPs), 92 Helical CT, 533 Helicobacter pylori, 267, 346, 530, 560, 1157 Helicobacter pylori infection, 588 Hemangiosarcoma, 513 Hematologic disease, risks of, 286 Hematological disorders, 507 Hematoma, acute subdural, 795 Hematopoietic function, 506, 1137 Hematuria, 759 Hemiagenesis, 990 Hemobilia, 532 Hemodialysis, 752 Hemodialysis catheter-related infections, 750 Hemodialysis vascular access, 750 Hemodynamic monitoring, 669 Hemofiltration in sepsis, 242 Hemoglobin, disorders of, 510 Hemoglobinopathies, 123, 510 Hemoglobinuria, 282, 737 Hemoglobinuria and myoglobinuria, 737 Hemolytic anemias, congenital, 509 Hemophilia A, B, 161 Hemorrhage, 83 Hemorrhoidal artery, 602 Hemorrhoidectomies, technique, 606 Hemorrhoids pathophysiology of, 605 treatment for, 605 Hemosiderin-laden red blood cells, 888 Hemostasis, 431, 1035 acquired disorders of, 164 inherited disorders of, 161 mechanisms of, 157 regulation of, 159 Hemostatic system, activation of, 752 Hemothorax, 641 Henderson–Hasselbach equation, 37 Henle’s limb, 42 Heparin, 279 anticoagulant effect of, 171 complications of, 171 mast cell synthesis of, 171 Heparin therapy, 887 Heparin/antithrombin III (AT-III) complex, 158 Heparin-binding proteins, 92 Heparin-induced thrombocytopenia (HIT), 169, 886 Heparinoids, compositions of, 173 Hepatic arterial inflow, 443

Hepatic artery, 430 Hepatic bile formation, 456 Hepatic disease, 279 Hepatic dysfunction due to anesthetic agents, 279 Hepatic encephalopathy, 435–436 Hepatic enzymes, 429 Hepatic function tests, 436 Hepatic functions, 431 Hepatic glycogen, 6 Hepatic perfusion, 187 Hepatic regeneration, 438 Hepatobiliary, 484–485 Hepatobiliary function, 1136 Hepatoblasts, 427 Hepatocyte growth factor (HGF), 55, 429 Hepatofugal flow, 448 Hepatogenesis, 427–428 Hepatorenal syndrome, 737 Hereditary elliptocytosis (HE), 509 Hereditary nonpolyposis colorectal carcinoma (HNPCC), 558, 576 mechanism for, 576 Hereditary spherocytosis (HS), 509 Hereditary stomatocytosis, 509 Hernia diagnosis of, 1071 diaphragmatic, 1081 direct inguinal, 1068, 1070 epigastric, 1068, 1080 femoral, 1071 groin, 1068, 1070 anatomy of, 1072 anterior approach to, 1077 laproscopic approach to, 1077 posterior approach to, 1077 H, type I, III, 304 incisional, 1068, 1160, 1081 indirect inguinal, 1068, 1070 internal, 1068 irreducible. See Hernia, incarcerated Littre’s, 1068 lumbar or dorsal, 1080 oblique. See Hernia, indirect inguinal obturator, 1081 paraesophageal, 1082 parahiatal, 1082 parastomal, 1081 pathophysiology of, 1068 pelvic, 1081 perineal, 1081 Peterson, 1068 reducible, 1067 repair, 1067, 1077, 1079, 1080 retroanastomotic, 1068 Richter, 1068 sliding, 1068, 1071 Spigelian, 1068, 1080 types of abdominal wall, 1070 umbilical, 1068, 1079 ventral, 1068 Herniated disc, 781 Herniation, 796 oblique, 1073 transtentorial, 797 Herniorrhaphy, 1077 Herpes simplex virus (HSV) infections, 116, 762 Herpes simplex virus thymidine-kinase gene (HSV-tk), 206 Herpes zoster, 781

Hesselbach’s triangle, 1071, 1072, 1073 Heterotopic cardiac transplantation, 121 H-graft portacaval shunts (HGPCSs), 446, 450 Hiatal hernia, 304 Hibernating myocardium, ventricular dysfunction, 708 Hickman catheter, 1113 High-density lipoprotein (HDL), 434, 457, 700 High-energy phosphate (HEP), 9 High frequency oscillatory ventilation (HFOV), 1097 High-output vs. low-output heart failure, 667 Hinman syndrome, 776 Hippocrates, phenomenon of, 1, 8 Hirschsprung’s disease (HSCR), 596, 611, 1028, 1031, 1109 diagnosis of, 118 Hirschsprung’s-associated enterocolitis (HAEC), 1118 Hirudin, 173 anticoagulant, 173 Hirudo medicinalis, salivary gland, 169 Histamine, 341 Histocompatibility antigens, tests for, 756 Histones, 255 Histoplasma capsulatum, 119 HIT syndrome. See Heparin-induced thrombocytopenia syndrome HLA-identical siblings, 123 HLHS. See Hypoplastic left heart syndrome HNPCC. See Hereditary nonpolyposis colorectal carcinoma Hoarseness, 297 Hodgkin’s disease (HD), 511 Hodgkin’s lymphoma, 511 Ann Arbor classification of, 511 Hoffmann’s sign, 825 Holosystolic murmur, 714 Homans’ sign, 885 Homeostasis calcium, 36 potassium, 36 sodium and water, 35 Homocysteine, 168 Honeymoon phase, 1011 Hormesis hypothesis, 1130 Hormonal regulation of extracellular calcium concentration, 928–931 Hormonal regulation of metabolism, 18–19 Hormone secretion, regulation of, 950 Horner’s syndrome, 645, 875 Horseshoe kidney, 863 Hospital acquired-pneumonia (HAP), 133 Host defenses, 415 Hot belch or acid belch, 296 Houston, valves of, 603 Howship-Romberg sign, 1081 Hyperparathyroidism (HPT), clinical features of, 1026 H-type fistula. See EA/TEF, anatomic variants of Hu¨rthle cell carcinoma, 1002 Hu¨rthle cells, 998, 999 Human aging process, 1129 Human antimouse antibodies, 117 Human EGF 2 (HER-2), 1061 Human ES cells, 260 Human genome project, 261

Index Human immunodeficiency virus (HIV) infection, 289, 1040 Human leukocyte antigen (HLA), 69, 92, 758, 995 Human placental lactogen (HPL), 1051 Humoral hypercalcemia of malignancy (HHM), 932 Hyaluronan, 1042 Hybrid vectors, 268 Hybridoma technology, 117 Hydrocolloids, 1041 See Hereditary stomatocytosis Hydrogen ions, 1 Hydrophobic hormones, extracellular, 264 Hydroxyproline, amino acid, 1069 Hyperacute rejection, 95, 758 Hyperaldosteronism, 907–909, 968–969 Hyperbaric oxygen (HBO) therapy, 1042 Hyperbilirubinemia, 483, 487 Hypercalcemia, 36, 284 acute management of severe, 934 clinical manifestations of, 933 differential diagnosis of, 931 due to hyperthyroidism, 931 familial benign, 944 of malignancy, 931, 932, 935 mechanisms of, 931, 936 nonmalignant causes of, 931 severe, 934 Hypercarbia, 1150 Hypercoagulability, congenital disorders of, 167 Hyperemia, zone of, 1087 Hyperesthesia, 821 Hypergastrinemia, causes of, 341 Hyperglucagonemia resolution, 473 Hyperglycemia, 238, 799, 1138 effects of, 1011 Hyperglycemia resolution, 473 Hyperhomocysteinemia, 168 Hyperkalemia, 41 Hypermetabolic response, 1091 Hypernatremia, 41 Hyperparathyroidism (HPT), 1025, 1138 primary, 939 principles of treatment and prevention of, 743 Hyperphosphatemia, 929, 936, 937 Hyperplasia, four-gland, 1026 Hyperpolarization, 659 Hypersplenism, 506 Hypertension, 278, 744 control of, 874 renovascular, 916 Hypertensive urography, 918 Hyperthyroidism (thyrotoxicosis), 286, 995, 1138 causes of, 995 Hypertonic contrast enema, 1118 Hypertonic saline, 799 Hypertrophic cardiomyopathy, 671 Hypertrophy, 660, 663, 709 adolescent, 1050 juvenile, 1050 virginal, 1050 Hypoalbuminemia, 927, 937 Hypocalcemia, 740, 936, 1107, 1108 lack of PTH effect, 936 lack of vitamin D effect, 936 mechanisms of, 931, 936 Hypochlorhydria, 1138 Hypocontractile esophagus, 321

Hypoesthesia, 821 Hypoglycemia, 284, 1017 Hypokalemia, 42 Hypomagnesemia, 1108 Hypomotile esophagus, 314 Hyponatremia, 39–40 Hypophysial-hypothalamic axis, 1094 Hypopituitarism, 952 Hypoplasia, infundibular, 693 Hypoplasia, pulmonary valvular, 693 Hypoplastic left heart syndrome (HLHS), 695 Hyposplenism, 506–507 Hypothalamic-pituitary-adrenal axis (HPA), 983, 1047 Hypothermia, 1140 Hypothyroidism, 286, 993, 997 causes of, 997 Hypoventilation syndrome, 1159 Hypovolemia, 188, 801, 1094 renal dysfunction of, role in, 473 Hypoxemia, 473 systemic, 1150 Hypoxic pulmonary vasoconstriction, 634 IABP. See Intra-aortic Balloon Pump Iatrogenic factors, 1070 Ideal body weight (IBW), 52 Idiopathic myelofibrosis, 512–513 Idiopathic pulmonary fibrosis (IPF), diagnosis and treatment of, 639 Idiopathic thrombocytopenia purpura (ITP), 288, 507 IL-2 receptor (IL-2R) antagonists, 118 Ileal brake mechanism, 625 Ilioinguinal nodes, 118 Imipenem–cilastatin therapy, 144 Immune system, 92, 486 cellular components of, 65 functions of, 65 humoral, 71 innate, 70 nonspecific, 1095 specific, 1096 Immunoassays, double-antibody, 929 Immunodeficiency diseases, 77 Immunoglobulin (Ig) superfamily (IgSF), 96 Immunoglobulin G (IgG), 169 Immunoglobulin M (IgM), 169 Immunologic function, 506 Immunologic tests, 437 Immunologic tolerance, 112 Immunological synapse (IS), 104 Immunonutrition, 247 Immunoreceptor tyrosine-based activation motif (ITAM), 97 Immunosuppression antirejection, 119 risks of, 118 Immunosuppressive agents, 78, 760 Immunotherapy, 205 Implantable cardioverterdefibrillator (ICD), 719 Inducible costimulator (ICOS), 99 Inducible nitric oxide synthetase (iNOS), 54 Infant premature, 1108 Infantile pyloric stenosis (IPS), 1111 ultrasonic criteria for, 1111 Infants, preterm. See Salt wasters Infection prevention, principles of, 86

medwedi.ru

I-11

Inferior mesenteric artery (IMA), 381 Inferior vena cava (IVC), 428 Inferior vena cava (IVC ) filters, 813 Inflammation-dysplasia-carcinoma model, 560 Inflammatory bowel disease (IBD), 415, 560 clinical presentation, 416–417 dietary and environmental factors, 416 immunologic abnormalities in, 416 medical therapy, 417 surgical therapy, 418–419 Inflammatory lesions, 405 Infrarenal inferior vena cava (IVC), 768 Inguinal ligament, 1073 Inhibitors calcineurin, 113 lymphokine synthesis, 113 nucleoside synthesis, 115 Initial evaluation and management, 527 Injury, reperfusion, 1038 Injury response, acute, 38 Injury severity score (ISS), 81 Injury stress. See Metabolic response Innate immune system, 92 Inosine monophosphate dehydrogenase (IMPDH), 115 Inositol triphosphate (IP3), 470 Inspiratory capacity, 632 Inspiratory reserve volume (IRV), function of, 632 Inspiratory to expiratory (I:E) ratio ventilation, 638 Inspiratory–expiratory cycle. See Lung volumes Instability, management of, 813 Insulin, 19–20 and fluid administration, 284 and glycemic control, 238 maintenance of, 1014 Insulin-like growth factor I (IGF-I), 1095, 1138 Insulin-like growth factor–binding protein 5 (IGFBP-5), 1052, 1053 Insulin-like growth factors (IGF), 949 Insulinoma diagnosis of, 1017 symptoms of, 1017 treatment of, 1027 Insuloacinar axis, 1007 Intact heart, function of, 653 Integrilin, a synthetic peptide, 703 Integument, 272 Intensive care unit (ICU), 50, 80 Intercellular adhesion molecule (ICAM), 96 Interferon (IFN), 67, 740 Interleukin (IL), 67, 73 Intermediary metabolism, 1, 9, 15 Internal carotid artery (ICA), 947 Internal jugular (IJ), 749 Internal jugular lines, 85 Internal milieu, 33 International classification of diseases (ICD), 231 International normalized ratio (INR), 171, 887 International sensitivity index (ISI), 172 Interstitial cells of Cajal (ICCs), 337, 567, 1118 Interstitial fibrosis, 668 Interstitial fluid, 2

I-12

Index

Intestinal bleeding causes of, 532 diagnostic steps, 533 lower, 532 upper, 528 Intestinal blood flow, clinical evaluation of, 392 Intestinal circulation, physiology of, 384 Intestinal morphology, 387 Intestinal pathophysiology, 387 Intestinal phase, 345 Intestinal viability, intraoperative assessment of, 396 Intestine motility disorders of, 595 diagnosis and treatment, 595 etiology and pathophysiology, 595 reperfusion injury of, 386 Intestine bleeding, small, 534–535 Intra-aortic balloon pump (IABP), 669, 677–678, 704 Intra-aortic filters, 706 Intracellular body water (IBW), 1108 Intracellular signaling molecules, 264 Intracorporeal pump, 669 Intracranial hematomas, 795 Intracranial pressure (ICP), 795, 800 treatment of, 800 Intrahepatic, portal hypertension, 430 Intraluminal impedance, multilevel, 303 Intraoperative cholangiogram (IOC), 464 Intraoperative enteroscopy, 535 Intraperitoneal onlay of mesh (IPOM), 1077 Intrathoracic pressure, increase of, 671 Intrathyroid regulation, 993 Intravenous (IV), 1108 Intravenous immunoglobulins (IVIG), 508 Intravenous pyelogram (IVP), 768 Intravenous urography (IVU), 768, 785 Intrinsic renal azotemia, 737 Involution, 1150 endocrine control of, 1054 physiology of, 1053–1054 Iodine ablation, 1001 Iodine metabolism, 990 Ion-channel receptors, 265 Ion-channels, types of, 265 Ionic substances, 1 Iron deficiency, 743 Iron storage, 432 Irreversible heart failure, 668 Ischemia, 677, 797–798, 1038 arterial , 852 progressive, 1099 severe, 842 Ischemia–reperfusion injury, 91 Ischemic ATN, causes of, 282 Ischemic cardiomyopathy, 708 Ischemic heart disease, 716 clinical presentation of, 701 Ischemic ulcer, types of, 853 Islet amyloid polypeptide, 1012 Islets of Langerhans anatomy of, 1005–1007 embryology of, 1005–1007 physiology of, 1007 Isolated muscle, behavior of, 651 Isometric contractions, 652 Isosthenuria, 743 Isotonic contractions, 651

Isotopic renography, 918 Ito cells, 429 Jackson-Pratt drain, 301 Jaundice algorithm for evaluation of, 487 classification of, 483–484 clinical evaluation, 487 diagnostic approach, 487 mechanism of renal dysfunction in, 486 obstructive, 283 pathophysiology of, 484 Jaundiced patient, radiologic evaluation of, 488 Jejunogastric intussusception, 623 Jejunoileal bypass, 1152 Jejunoileal diverticuli, 421 Jobst intermittent pressure pump, 827 JunD-activated transcription, 1025 Juvenile-onset juvenile-onset. See Diabetes mellitus, insulinopenic type I Juvenile polyposis, 576 Juxtaglomerular, 726 Kaposi’s sarcoma, 78 of spleen, 513 Kasai procedure, 121 Kelly, pancreatic transplant by, 122 Keloids, 1038 Kent bundle, 718 Ketoacidosis, 1011, 1012, 1014 Ketoconazole, 958 Ketone bodies, 665, 734 Kidney disease, risks of, 282 Kidney, grafting of, 120 Kidney transplantation, 761 Kidney transplant recipients, evaluation of, 759 Knockout animals, 263 Knudson, two-hit hypothesis of, 199 Knudson two-hit model, 1025 Korotkoff sounds, 838 K-ras mutations, 555 Krebs citric acid cycle, 665 Krebs–Henseleit cycle, 432 Kremen’s concept, surgery for morbid obesity, 1152 Kupffer cells, 83, 429, 485 Kussmaul–Kien respiration, 1011 Laboratory assays, categories of, 436 Lacis cells, 912 Lactating adenoma, 1053 Lactation endocrine control of, 1052 physiology of, 1051 Lactogenesis, 1052 Lacunar ligament, 1073 Ladd’s bands, 1122 Ladd’s procedure, 1123 Laennec’s cirrhosis, 1079 Lagging strand, 255 Lamina propria, 337 Langerhans cells, 82 Laparoscopic splenectomy (LS), 508 Laparoscopic surgery, 273 Laparoscopic techniques, 1155 Laplace, law of, 596, 833, 852 Laplace relationship, 654 Larynx, 295 Leaflet anterior (aortic leaflets), 709 posterior (mural leaflet), 712

Lean body mass, 1149 Learning curve, 1155 Lectins, 75 Leeds/York trial, 623 Leflunomide, 115–116 Left anterior descending coronary artery (LAD), 699 Left circumflex coronary artery, 699 Left internal thoracic artery (LITA) graft, 699 Left ventricular assist device (LVAD), 669, 677, 682 Left ventricular (LV) support, 679 Left ventricular function, 665 Left ventricular hypertrophy (LVH), 742, 747 Leriche syndrome, 854 Leukocytes migration of, 757 Leukotrienes (LTs), 386 Lewis (Le) antigens, 95 Lichtenstein repair, 1073 Life threatening syndromes, 1149 Ligament of Berry, 899 hepatoduodenal, 427 hepatogastric, 427 of Treitz, 1117 Limb salvage rate, 861 Limiting dilution analysis (LDA), 75 Linker for activation of T-cells (LAT), 104 Linoleic acid, 1110 Lionheart system, 681 Lipid metabolism, 13–15 Lipid protein complex (LPC), 1089 Lipodermatosclerosis, 889 Lipofuscin or age pigment, 1131 Lipogenesis, 14, 20 Lipolysis, 14, 20 Lipopolysaccharide (LPS), 70, 76, 231 Lipoprotein lipase (LPL), 434 Lissauer’ stract, 540 Littre’s hernia, 421 Liver biopsy, 437, 492 Liver disease, 279 risks of, 279 Liver regeneration, phases in, 438 Liver transplantation, 446 indications for, 121 Living donor, evaluation and selection of, 758 LMWH. See Low-molecular-weight heparin Local osteolytic hypercalcemia (LOH), 932 Local wound metabolism, 25 Log-kill hypothesis, 203 Long-limb modification, 1159 Long-term Nonpulsatile Ventricular Assist Devices (LVADs), 681 Loss of heterozygosity (LOH), 199, 974 Low birth weight, 1107 Low-density lipoprotein (LDL), 434, 457, 856 Lower esophageal sphincter (LES), 295 relaxation, 300, 319 Low molecular-weight heparin (LMWH), 172, 289, 885 advantages of, 172 Lower motor neuron lesion (LMNL), 787 Lower urinary tract (LUT), 792 dysfunction, 776 pathophysiology of, 776 physiology of, 775

Index Lower urinary tract syndrome (LUTS), 770 L-type Ca channels, 650 Lugol’s solution, 996 Lumbar triangle, inferior, 1080 Lump, 1056 Lung physiology of, 632 segmental anatomy of, 631 tumors of, 644 Lung abscesses, treatment for, 640 Lung cancer, 644 diagnosis and staging of, 645 Lung disease, infectious, 639 Lung perfusion, 633-634 Lung volumes and capacities, measurement of, 632 Lung volumes, 632 Lupus anticoagulant, 288 Luteinizing hormone (LH), 948 Lutenizing hormone-releasing hormone (LHRH), 950 Lutropin (LH), 950 LV support. See Left ventricular LVADs. See Long-Term Nonpulsatile Ventricular Assist Devices LVAS Thoratec Heart Mate VE, 681 World Heart Novacor, 680 Lymph node biopsy, 1050, 1060 Lymph node status, 1060 Lymphangitis acute, 130 Lymphangitis suppurative, 130 Lymphatic drainage, 602 Lymphatic system deep, 846 functions of, 892 superficial, 846 Lymphatics, 736 Lymphedema complications of, 894 diagnosis of, 893 excisional operations for, 893 obstructive, 894 physiologic operations for, 12 primary, 847, 892 secondary, 847, 892 treatment for, 893 Lymphedema clinics, 847 Lymphedema prascox, 847, 892 Lymphedema tarda, 892 Lymphocyte function-associated antigen (LFA), 96 Lymphocytes, 92 Lymphocytic hypophysitis, 959 Lymphocytic infiltration, 995, 998 Lymphocytic leukemias, 512 Lymphokine-activated killer cells (LAKs), 205 Lymphokines, 73, 79 Lymphoproliferative disorders, 511 Lymphoscintigraphy, 893 Lynch syndrome. See Hereditary nonpolyposis colorectal carcinoma Lys-plasminogen, 160 Lytic granules, 69 Lytic mediators, 69 Macro and microcirculation, 725 Macrophage, 69 Magnetic moment or spin, 262 Magnetic resonance angiography (MRA), 395, 917

Magnetic resonance arteriography (MRA), 873 Magnetic resonance cholangiography (MRC), 498 Magnetic resonance cholangiopancreatography (MRCP), 490 Magnetic resonance imaging (MRI), 1027 Magnocellular neurons, 948 Maintenance fluid therapy, 1111 Major histocompatibility complex (MHC), 66, 69–70, 91, 756 Malabsorption, 1154 Malayan pit viper, 173 Malignant breast pathology, treatment of, 1058 Malignant causes of extrahepatic biliary obstruction, 492 Malignant disease, 497 Malignant hyperthermia (MH), 218 Malignant lung tumors, 644 Mallory–Weis tears, 444, 529–530 Malnutrition, 78, 493 Maloney dilator, mercury-weighted bougie, 624 Malrotation, diagnosis of, 1123 Mammary growth factor (Mgf), 1052 Mammary ridge, 1047 Mammography, 1056, 1057 Marcy repair, 1073 Marfan’s syndrome (MFS), 710, 897, 1040 Marfanoid habitus, 1025, 1028 Marjolin’s ulcer, 1044 Marlex mesh, 1077 Martin–Gruber anastomosis, 822 Mastalgia, 1055 Mastitis, 1053 acute, 1057 Maternal immunity, 1052 Matrix metalloproteinase (MMP), 474, 558, 1035 nonspecific inhibitor, 1038 specific inhibitor, 1038 Mature milk, 1052 Maximum lifespan potential (MLSP), 1131 McBurney’s point, 542, 548 Mean arterial pressures (MAP), 736 Meat intoxication syndrome, 436 Meckel’s diverticulum, 421, 1068 Meconium ileus, 1117 complicated, 1118 uncomplicated, 1118 Meconium obstruction, 1119 Meconium plug syndrome, 1118 Mediastinum masses, tumors of, 643–644 Medical and surgical treatment, comparison of, 307 Medullary thick ascending limb of Henle’s loop (mTAL), 727 Medullary thyroid carcinoma (MTC), 1002, 1025, 1028, 1029 bilateral, 1029 sporadic, 1029 Meglumine diatrizoate (Gastrograffin) swallow, 589 Meissner’s plexus, 337 MEN 1 gene, 1025 MEN 1, characteristics of, 1026 MEN 2 characteristics of, 1028 clinical features of, 1025 hallmark of, 1028

medwedi.ru

I-13

MEN 2, (Contd.) history and pathogenesis of, 1025 kindreds, 1032 syndromes, 1028, 1029, 1030 MEN 2A and 2B, nonendocrine features of, 1031 MEN syndromes, 1025 clinical features of, 1026 MEN type 1 (MEN 1), 1025 MEN type 2 (MEN 2), 1025 MEN. See Multiple endocrine neoplasia Menopausal regression, 1054 Menstrual cycle, histologic phases during, 1048 Mental depression, 1151 Mental obtundation, 667 Meropenem, 144 Mesenteric ischemia, radiologic evaluation of, 393 Mesenteric venous thrombosis, 399, 401 Messenger RNA (mRNA), 1007 Metabolic acidosis, cause of, 731 Metabolic alterations, 1091 Metabolic and endocrine function, 1137 Metabolic response, 21, 49 Metabolic theory, 385 Metabolism, 36–38 bile acid, 458 bile salt, 626 biliary, 435 calcium, 626 carbohydrate, 432 cholesterol, 457 lipid, 433 phosphatidylcholine, 457 protein, 434 Metallic taste, 297 Metastasis, models of, 201 Metastatic tumors, of spleen, 513 Methicillin-resistant staphylococcus aureus (MRSA), 146 Methotrexate (MTX), 116 Methylenetetrahydrofolate reductase (MTHFR), 168 Methyl tert-butyl ether (MTBE), 463 Metyrapone, 954 MI. See Myocardial infarction Micelle, 372 Microarray technology, using DNA chips, 268 Microbial metabolites, 70 Microbial virulence, 1039 Microcirculation changes in, 188 Microcirculatory effects, 188 Microminiaturization, 671 Microsatellite instability (MSI), 558 Microsomal enzyme, 483 Micturition cycle, 770–771 Migrating myoelectric complex (MMC), 339 Migration inhibitory factor (MIF), 561 Military antishock trousers (MAST), 812 Milk box, 1052 Milk hill stage, 1047 Milk proteins, 1052 Milroy’s disease, 892 Mineralocorticoid secretion, 953 Minimum inhibitory concentration (MIC), 133 Mirizzi syndrome, 462 Missense mutation, 256

I-14

Index

Mitogen-activated protein kinase (MAPK) activation, 475 Mitogens, 75 Mitral regurgitation, 278, 689 acute, 713 diagnosis of, 713 Mitral stenosis, 278 Mitral valve area (MVA), 712 Mitral valve disease, 712 Mixed lymphocyte culture (MLC), 108 Mixed lymphocyte reaction (MLR), 76, 107 Mixed venous oxygen saturation (MvO2), 191 Mizorbine (MZB), 115 MMP. See Matrix metalloproteinases Moberg pickup test, 827 Model for end-stage liver disease (MELD) scale, 436 Molecular clock. See Telomere shortening Monitoring fluid resuscitation, 1099 Monoclonal antibodies, chimeric, 117 Monocyte, 69 Monoiodothyrosines (MIT), 990–991 Montgomery glands, 1047 Morbid obesity and body mass index relationship, 1149 etiology and pathophysiology of, 1149 patient management of, 1156–1158 surgical treatment results of, 1158–1161 Morbidity, mortality, and prognosis, 673 Morgagni, columns of, 600 Morgagni hernias, 1121 Mortality and body weight relationship, 1150 increase with age, 1137 Motility alterations, 592 Motility disorders, 320 Motor disorders, 316 Motor unit action potentials (MUAPs), 824 mRNA processing in eukaryotic cells, 257 MTC. See Medullary thyroid carcinoma MUAPs. See Motor unit action potentials Mucosa-associated lymphoid tissue (MALT), 351, 564 Mucosal disease, 597 Mucosal injury, acute, 267 Mucous neck cells, 346 Mueller–Hinton agar plate, 133 Multidrug resistance (MDR), 202 pathogens, 134 Multiple endocrine neoplasia (MEN) syndromes , 993, 995, 997, 1025 Multiple endocrine neoplasia type 1 (MEN1), 939, 940, 944, 955 Multiple endocrine neoplasia type 2, 1028 Multiple organ dysfunction (MODS), 139, 238, 753 definition of, 244 incidence and outcome of, 244 pathophysiology of, 246 Multiple-organ failure (MOF), 50, 638 Multiple sclerosis (MS), 781 Multivitamin supplement, 1158 Mural thrombus, 852 Murine melanoma model, 203 Murphy’s sign, 463 Muscarinic receptors, 788 Muscle glycogen, 5–6 Muscular contraction, 665

Musculature, 601 Musset’s sign, 711 Mustard’s procedure, 694 Myasthenia gravis (MG), 644 Mycobacterium avium, 76, 551 Mycobacterium avium-intracellulare, drug resistant, 640 Mycobacterium paratuberculosis, 415 Mycophenolate Mofetil (MMF), 115, 760 Mycophenolic acid (MPA), 115 Myeloproliferative disorders, 512 Myocardial abnormalities, 664 Myocardial cells, 744 Myocardial compensatory mechanisms, 665 Myocardial contractility, 677 Myocardial cooling, 705 Myocardial fibrosis, 744 Myocardial infarction (MI), 274, 666, 669, 670, 702 diagnosis of, 703 indications for surgery, 703 transmural, 703 treatment of, 703 Myocardial irritability, 42 Myocardial necrosis, 668 Myocardial oxygen consumption, 660 Myocardial toxicity, 1088 Myocardial viability, 708 Myocardium, hibernating, 708 Myochosis, 422 Myogenic theory, 385 Myxoid degeneration, 710 N-Acetylcysteine, 738 Na–Ca exchanger, 650 NaCl and water reabsorption, 729 NAP. See Nerve action potential Naþ-taurocholatev cotransport polypeptide (NTCP), 458 National Acute Spinal Cord Injury Study (NASCIS), 813–814 National Health and Nutrition Examination Survey (NHANES), 217, 455 National Institute on Aging (NIA), 1130 National Nosocomial Infection Surveillance System (NNISS), 136 National Research Council (NRC), 136 National Surgical Breast and Bowel Project (NSABP) workshop report, 1059 Natural killer (NK) cells, 69, 92 Nausea, 297 NCSs. See Nerve conduction studies NEC. See Necrotizing enterocolitis Neck cells, 338 Necrolytic migratory erythema, 1019 Necrotizing enterocolitis (NEC), 1109 diagnosis of, 1115 pathogenesis of, 1114 Necrotizing subcutaneous infections, 1151 Needle catheter jejunostomy (NCJ), complications of, 55 Neonatal intensive care unit (NICU), 1112 Neoplasms of adrenal cortex-benign neoplasms, 968 of adrenal gland, 968 colorectal, 571 diagnosis of, 566 pathology of benign, 565 Nephron loss, physiological compensation for, 732 Nephron structure, 726 Nephrostomy, percutaneous, 769 Nephrotoxic injury, 737

Nerve action potential (NAP), 818 Nerve conduction studies (NCSs), 821 motor, 822 sensory, 822 Nerve gap, 826 Nerve injuries, neurophysiologic tests of, 822–824 Nerve paralysis, 317 Nerve stimulation, 605 Neural control, 659 Neurapraxia, 820 Neuroendocrine control, 1048 Neuroendocrine effectors, 18 Neuroendocrine reflexes, 15 Neuroendocrine regulatory mechanisms, 15–18 Neuroendocrine system, 15 Neurofibromatosis type 1 (NF1), 1032 Neurogenic bladder, 788 Neurogenic lower urinary tract dysfunction (NLUTD), 775 classification of, 783 diagnosis of, 783 management of, 787 pharmacologic therapy, 788, 790 Neurogenic voiding dysfunction, 789 Neurohumoral cascade, 185 Neurohumoral response, 185 Neurohypophysis, hormones of, 950 Neurologic complications, 746 Neurologic deficits, reversible ischemic, 871 Neurological lesions, 781 Neuroma-in-continuity, 817 treatment of, 825–826 Neuropathy, cause of, 1012 Neurosarcoidosis, 960 Neurotmesis, 817, 820 Neurotransmitter excitotoxicity, 806–807 Neurotrauma, 795 Neutral protamine Hagedorn (NPH) insulin, 1014 Neutropenia, 418 Neutrophils, 70, 391 phagocytic function of, 239 Newton’s law of motion, in wall force, 653 Newtonian fluid property, 833 Nicotinamide adenine dinucleotide (NADH), 9, 43 Nicotine, 1040 Nil per os (NPO), 1120 Ninhydrin sweat test, 821 Nipple-areolar complex, 1047, 1050, 1055, 1057 Nipple discharge, 1056 Nissen fundoplication, technique of, 297 Nitric oxide (NO) as chemical mediator, 188 forms of, 188 Nitric oxide synthase (NOS), 188 Nitroblue tetrazolium (NBT) test, 76 Nitrogen balance, 51, 1093 NK-cell receptors (NKR), 69 N-methyl-D-aspartate (NMDA), 802, 807 Nocardia asteroides, 119 Nociception projection of, 225 transmission of, 220 Nociceptors, types of, 220 Nodule hot, 997 thyroid, 998

Index Nonadrenergic, noncholinergic (NANC) system, 335 Non–B islet cell tumors, 1019, 1020 Nonerosive reflux disease (NERD), 305 Nonesophageal symptoms, important, 297 Non-Hodgkin’s lymphoma (NHL), 76, 512, 564 Noninvasive tests, direct, 872 Nonketotic hyperosmolar coma, 1012 Non-Newtonian character, of blood, 837 Nonobese diabetic (NOD) mice, 1010 Nonocclusive mesenteric ischemia (NOMI), 392, 399 Nonparasitic cysts, 514 Nonphagocytic basophils, 70 Nonsecretory adenoma, 955 Nonsense mutation, 256 Non–small cell lung cancer (NSCLC), 644 Nonspecific esophageal motor disorder (NEMD), 318 Nonsteroidal anti-inflammatory drugs (NSAIDs), 311, 346, 530, 998 Normal saline (NS), 1108 Norton–Simon approach, goals of, 203 Norwood procedure, 695 Nosocomial infection, 136 Nosocomial pneumonia types of, 133 NSCLC. See Non–small cell lung cancer N-type fistula. See EA/TEF, anatomic variants of Nuclear factor of activated T-cells (NFAT), 104 Nuclear factor-kB (NF-kB), 473, 561, 1115 Nuclear magnetic resonance (NMR) spectroscopy, 262 Nuclear renograms, phases of, 111 Nucleation, 459 Nucleotide scan, 533 Nutrition, 271 Nutritional assessment, 50–51 Obesity, 272 anesthetic implications of, 217 and body mass index relationship, 1149 morbid, 51 severe risks and complications of, 1150 surgical treatment of, 1151 Obesity operations, early, 1152 Obstructing colon cancer, 595 Obstruction extrinsic, 769 intrinsic, 769–770 Occlusive lesions distal. See Tandem lesions Occult bleeding, 535 Octreotide, 957 Octreotide therapy, 444 Odynophagia, 296 Off-pump coronary artery bypass grafting (OPCAB), 706 Ogilvie’s syndrome, 596 Okazaki fragments, 255 Oliguria, 733, 738 Oliguric renal failure, 1094 Olive, mobile firm mass, 1111 Omental bursa, 337 Omentum, 337 Omphalocele defects, 1113 epigastric, 1113

Oncogenesis, 1140 Oncological surgery, 268 Oncotic effect, 34 Oophorectomy, 1054, 1061 Opsonins, 72–73, 1095 Oral anticoagulation, 279 Oral glucose tolerance test (OGTT), 957 Oral warfarin (Coumadin) therapy, 887 Organ system alterations, 1093 Organic acid transporting protein (OATP) role of, 458 transporters, 458 Orphan annie cells, 1000 Osmolality, 34 Osmotic and ionic stability, 33 Ovalocytosis. See Hereditary elliptocytosis (HE) Overwhelming postsplenectomy infection (OPSI), 519 Oxaloacetate, 10 Oxandrolone, 1093 Oxygen-carrying capacity, 635 Oxidative deamination, 11–12 Oxygen debt, 182 Oxygen-derived free radicals (ODFRs), 388 Oxygen dissociation curve, 672 Oxygen–hemoglobin relationship, 635 Oxygen paradox, 1090 Oxyntic mucosa, 306 Oxytocin, 948, 1053 p16 tumor suppressor gene, 556 p53 tumor suppressor gene, 556 Pacemaker activity, factors affecting, 658 Pacemaker placement, approaches for, 717 Paget–Schroetter syndrome, 891 Paget’s disease, 1055 Pain, rest, 853 Palliative surgery, 498 for periampullary cancer, 497 Palliative therapy, 327, 983 Palpatory technique, 838 Pamidronate, 935 Pancoast’s syndrome, 645 Pancreas annular, 469 divisions of, 469 embryolgy, 469 gross anatomy, 469–470 Pancreatectomy, 475 Pancreatic A, and B cells, 19 Pancreatic cholera, 1019 Pancreatic endocrine tumors, types of, 1016 Pancreatic enzymes, 371 Pancreatic exocrine function, 470–471 Pancreatic fibrosis, 474 Pancreatic injury, 474 Pancreatic islet transplantation, 1015 Pancreatic polypeptide (PP), 1006, 1026 Pancreatic pseudocysts, 514 Pancreatic secretion, control of, 471 Pancreatic stellate cells (PSCs), 474 Pancreatic transplantation, 1016 Pancreaticoduodenal arcade, 383 Pancreaticoduodenal tumors, 1026 Pancreatitis, 61 acute, 470 causes of, 472 prognostic signs of, 474 severity of, 474 Panel reactive antibodies (PRAs), 758

medwedi.ru

I-15

Papilla of vater, 122 Papillary cancer, features of, 1000 Papillary carcinoma, 1000 Papillary muscle, 704 Papillary muscle infarction, 669 Papillary thyroid carcinoma (PTC) oncogene, 999 Paracrine control, 1049, 1051, 1052, 1054 Paracrine function, 1005 Paraesophageal hiatal hernia, 304 Paralytic agents, uses, 800 Paralytic ileus, 593 Paranodal demyelination, 821 Parasitic cysts, 514 Parasympathetic stimulation, 770 Parathormone (PTH), 36 Parathyroid adenoma, 939 Parathyroid cancer, 939–940 Parathyroid carcinoma, diagnosis of, 940 Parathyroid glands, 1026 anatomy of, 938 Parathyroid hormone (PTH), 729, 927, 928, 929, 930, 1026 Parathyroid hormone-related protein (PTHrP), 930 role of, 932 Parathyroid hyperplasia, 939 Parathyroid poisoning, 944 Parathyroidectomy, 932, 939, 941 indications and technique of, 942 Parathyromatosis, 940 Parenchymal rupture, 759 Paresthesias, 821 Parietal cell, 306, 338 Parietal cell vagotomy, 358 Parietal gastrectomy, 1155 Parkinson’s disease, 781 Partial pressure of oxygen (PO2), 685, 686 Parvocellular neurons, 948 Patent ductus arteriosus (PDA), 686, 691, 695 Patent foramen ovale (PFO), 685 Pathogen-associated molecular patterns (PAMPs), 70 Pathogens, 521 reservoir for , 50 Patientcontrolled analgesia (PCA) pump, 223 PBI. See Penile-brachial index PDA. See Patent ductus arteriosus PDA. See Posterior descending coronary artery PE. See Pulmonary embolism Pedialyte feeds, 1111 Pelvic surgery, 781 Pelvis, potential spaces in, 601-602 Penetrating keratoplasty, 124 Penicillin glaucum, 115 Penicillins classification of, 142 generations of, 142 Penile-brachial index (PBI), 855 Penile erection, 853 Pentoxifylline, xanthine derivative, 857 Pepsinogen, 342 Peptic ulcer disease, 530 epidemiology, 348 type of, 349 Peptide-binding groove, 93 Peptide hormones, mechanism of action of, 17

I-16

Index

Percutaneous arterial catheters, 275 Percutaneous endoscopic gastrostomy (PEG), 55, 311 Percutaneous transhepatic cholangiography (PTC), 491 Percutaneous transluminal angioplasty (PTA), 919 Percutaneous transluminal coronary angioplasty (PTCA), 703 Periampullary cancer, 498 palliative surgery for, 497 Periampullary carcinoma, 497 Periarteriolar lymphoid sheaths (PALS), 505 Pericardial disease, 719 Pericardial tamponade, 719 Pericarditis, 745 Perimedial dysplasia, 916 Perinuclear antineutrophil cytoplasmic antibody (pANCA), 416 Perioperative pain management, 222 Peripheral arterial occlusive disease (PAOD), lower extremity, 742 Peripheral blood mononuclear cells (PBMC), 69 Peripheral nerve, 779 injury, 781 lesions, 783 Peripheral occlusive disease clinical manifestation of, 853 treatment of, 856 Peripheral resistance units (PRU), 835 Peristalsis, 295 Peritoneal dialysis, 748, 754 peritoneal drainage, 1116 Peritoneal reflections and omentum, 337 Peritonitis, 131 Perthes test, 890 Petit’s triangle. See inferior lumbar triangle Peutz–Jeghers syndrome, 576 Peyer’s patches, 116 P-glycoprotein, 202 Phagocytosis, 72, 84 Pharyngeal anesthesia, topical, 1157 Phenoxybenzamine, 286 Phenylethanolamine N-methyltransferase (PNMT), 966, 968, 979 Pheochromocytoma, 285 clinical presentation, 909 diagnosis of, 1030 etiology and physiology, 977 extra-adrenal primary, 910 malignant, 911, 979 surgical management, 910 therapy, 911 treatment of, 1031 Phlebitis, 131 Phlebotomy, 287 Phlegmasia alba dolens, 885 Phlegmasia cerulea dolens, 885 Phophonacetyl-L-aspartate (PALA), 199 Phosphatase and tensin (PTEN), 557 Phosphate metabolism, 937 disorders of, 937 hyperphosphatemia, 937 hypophospatemia, 938 Phosphatidylcholine (PC), 457 Phosphatidylinositol-3 kinase (PI3K), 557 Phosphoenolpyruvate, 9–10 Phosphofructokinase (PFK), 9

Phosphoinositide-dependent kinase–protein kinase B (PKB), 105 Phospholipase C (PLC), 265 Phosphoribosyl pyrophosphate (PRPP), depletion of, 115 Physical exercise, 1150 Physicochemical effect, 930 Phytohemagglutinin (PHA), 76, 80 PI3K pathway, 561-562 Pigment gallstones classification of, 460 features of, 460 pathogenesis.of, 460 Pigmenturia, 734 Pituitary adenoma, 955 Pituitary apoplexy, 959 Pituitary dysfunction, diagnosis of, 947 Pituitary gland anatomy of, 947 physiology of, 948 Pituitary-luteinizing hormone (LH), 1048 Pituitary tumors, 1027 Plasma aldosterone concentration (PAC), 908, 969, 970 Plasma exchange, 508 Plasma renin activity (PRA), 907 Plasminogen activator inhibitor (PAI), 741 primary regulator, 160 Plastic repair, 1074 Platelet activation, 165 Platelet-activating factor (PAF), 388, 1115 Platelet aggregation, 164, 702 Platelet coagulant activity, 158 Platelet-derived growth factor (PDGF), 474, 476, 1035, 1045 Platelet disorders, 288, 507 inherited qualitative, 163 Platelet factor 4 (PF4), 157 Plethysmographic technique, 839, 845 Plethysmography gold standard measurement, 632 impedance, 885 Pleural disease, 641 Pleural effusion, 1160 Plicamycin (mithramycin), 935 Pneumococcal vaccine, 83 Pneumocystis carinii , 119, 140 Pneumonia clinical manifestations of, 639 recurrent, 296 treatment of, 639 Pneumothorax, 641 diagnosis and treatment of, 641 tension, 641, 642 PO2. See Partial pressure of oxygen Pognostic factors, 494 Poiseuille’s law, 834 Poland syndrome, 1049 Polyclonal antibodies, 116–117 Polycythemia or erythrocytosis, 287 Polymerase chain reaction, 259 Polymodal C fibers, 220 polymorphonuclear leukocyte (PMN), 70, 1097, 1115 Polyps adenomatous, 574 classification of, 577 nonadenomatous, 571 Polytetrafluoroethylene (Gore-Tex), 689, 690, 691

Polyunsaturated fatty acids (PUFA), 53–54 Polyurethane, 749 Polyuria, 748 Pontine micturition center (PMC), 778 Pop-off mechanism, 692 Porcine insulin, 1014 Portal hypertension causes of, 443 left-sided or sinisteral, 451 Portal venous inflow, 443 Portasystemic shunts, types of, 447 Portosystemic anastamoses, sites of, 430 Postantibiotic effect (PAE), 146 Posterior cord syndrome, 811 Posterior descending coronary artery (PDA), 713 Posterior urethral valves (PUV), 771 Postlactation involution, phases of, 1052 Post-obstructive diuresis (POD), 772 Postoperative infections, types of, 130 Postphlebitic syndrome, 888 diagnosis of, 889 treatment for, 889 Postrenal azotemia, 737 Postresuscitation hypertension, 672 Postsplenectomy infection, overwhelming, 521 Post-transplant lymphoproliferative diseases (PTLD), 117 Postvagotomy diarrhea, 623 Postvagotomy dysphagia, 624 Postvagotomy gastric atony, 624 Postvoid residual (PVR), 785 Potassium, abnormalities of, 41 Potassium handling, 730 Potts anastomoses, 691 Pouchitis, 627 Powered apicoaortic conduits, 682 PP. See Pancreatic polypeptide Ppomas, 1019 Prealbumin, 51 Precordial Dopplers. See Venous air embolism (VAE) Predisposition, infection, response, and organ dysfunction (PIRO) system, 227 for staging sepsis, 228 Pregnancy endocrine control during, 1051 mammary differentiation during, 1050–1051 Prehepatic, portal hypertension, 430 Preoperative preparation general aspects of, 271 specific aspects of, 273 Preoperative surgical evaluation, 436 Preproinsulin mRNA levels, 1007 Prerenal azotemia, 735 pathogenesis and etiologies of, 737 Pressure-flow autoregulation, 870 Pressure–flow relationships, 843–844 Pressure ulcers, 1043 Pressure–volume curve, 656 Pressure–volume loop, 183, 633 Primary active transport, 729 Primary adrenal hyperplasia (PAH), 969–971 Primary aldosteronism, causes of, 969 Primary heart failure, 669 Primary hyperaldosteronism, treatment of, 970

Index Primary hyperparathyroidism (pHPT), 929, 932, 933 bisphosphonate therapy of, 944 clinical and biochemical diagnosis of, 940 medical approaches to, 943 pathology of, 939 surgery for, 941 treatment of, 941 PRL. See Prolactin PRL-inhibiting factor (PIF), 1051–1053 Proapoptotic molecules, 242 Procalcitonin (PCT), 228 Proctosigmoidoscopy, 610 Profundaplasty, 859 Programmed cell death. See Apoptosis Proinsulin, 1007, 1016 Prokaryotes, 253 Prolactin (PRL), 951, 1048, 1051, 1052 Prolactinoma, 952, 1027 Prolene mesh, 1077 Prometheus, legend of, 438 Proopiomelanocortin (POMC), 949 Prophylaxis, 148 Prospective randomized controlled trials (PRCT), 50 Prostacyclin (PGI2), 1086 Prostaglandin E2 (PGE2), 79, 1086 Prostaglandins (PGs), 386 Prosthetic heart valves, 279 Proteases, 1038 Proteasome, 93 Protected specimen brash (PSB), 135 Proteins, 5 acute-phase, 50 body, 50 constitutive, 50 mutant, 555 synthesis of, 265 wild-type, 556 Protein absorption, 372–373 Protein and amino acid metabolism, 11–13 Protein C deficiency, 167 resistance to, 167 for severe sepsis, 240 Protein C activated, properties of, 240 Protein-calorie malnutrition, 49 Protein catabolism, 1131 Protein kinase C (PKC), 757 Protein malnutrition acute, 50 prevention of, 50 Protein S, deficiency, 167 Protein structure and function, analyses of, 261 Protein-sparing substrate, 1110 Protein tyrosine kinases (PTKs), 104 Proteinuria, 759 Proteoglycan matrix, 632 Proteolytic enzymes, 267 Prothrombin time (PT), 164, 279, 436, 445, 887 Proton pump inhibitor (PPI), 305, 341, 531 Proto-oncogenes, 267 abnormal induction of, 744 nuclear, 267 Protoporphyrin, as sensitizing agent, 313 Pruritus, 494 Psammoma bodies, 1000 Pseudoaneurysms, 865 traumatic, 902–903 Pseudocysts, 514

Pseudodiverticula, 301 Pseudomonas species, 494, 752 Pubertal development, abnormalities of, 1050 Puberty, precocious, 1049 Pulmonary and venous congestion, 667 Pulmonary artery catheterization, indications for , 275 Pulmonary artery, segmental anatomy of, 634 Pulmonary blood flow (Q), 634 Pulmonary capillary wedge pressure, 668, 671 Pulmonary complications, postoperative, 637 Pulmonary congestion, 667 Pulmonary disease, risks of, 273 Pulmonary disorders, 637 Pulmonary embolism (PE), 640, 884, 887, 1160 diagnosis of, 887 pathophysiology of, 887 treatment of, 888 Pulmonary function tests (PFTs), 274 Pulmonary injury, indirect, 1096 Pulmonary physiology, 1109 Pulmonary system, body’s gateway, 631 Pulmonary to systemic blood flow (Qp/Qs), ratio of, 689 Pulmonary vascular resistance (PVR), 685, 686, 690, 694 Pulmonary venous pressures (Pv), 634 Pulsatile flow, principles of, 837–838 Pulseless disease, 877 Pulseless stage, 877 Puncture, aspiration, injection, and reaspiration (PAIR) technique, 514 Purified protein derivative (PPD), 76, 80 Purine salvage, 115 Purkinje cells, 1131 Purkinje fibers, 215 Purkinje system, 658 Push enteroscopy, 534–535 PVR. See Pulmonary vascular resistance Pyloric relaxation, 588 Pyloromyotomy, 1111 Pyrosis, 296 Pyruvate kinase (PK) deficiency, 510 Quiescent cells, 266 Quincke’s sign, 711 Radiant warmers, 1109 Radiation enteritis, 423–424 Radical mastectomy. See Halsted mastectomy Radioactive iodine (RAI), 996 Radiopaque markers, 605 Radiotherapy, roles of, 204 Randle effect, 15 Ranson signs, 474 Rastelli procedure, 695 Rathke’s pouch, 1006 Raynaud’s disease, 857 Raynaud’s phenomenon, 877 Red blood cell membrane disorder, 509 metabolism disorder, 509 RCA. See Right coronary artery Reactive oxygen and nitrogen species (RONS), 561 Reactive oxygen species (ROS), 560

medwedi.ru

I-17

Rearranged during transfection (RET) proto-oncogene, 994, 999, 1025 Receptor–ligand interactions, 91 Recipient tissue, 1085 Recombinant DNA techniques, 260 Recombinant human erythropoietin (r-HuEPO), 743 Recovery phase, 827–828 Rectal prolapse, diagnosis and treatment of, 608–609 Rectoanal inhibitory reflex, 604 Rectopexy, 609 Rectosigmoid transition zone, 1118 Rectum, reservoir function of, 603 Recurrent strokes, 869 Red cell mass, 1132 Red pulp, 504 Reed–Sternberg cells, 511 Reepithelialization, 1086 Refeeding syndrome, 53 Reflex sympathetic dystrophy (RSD), 823 Reflux causing end-stage lung disease, 314 Reflux-induced lung disease, characteristic features of, 315 Refractory heart failure, therapy of, 671 Regulatory T-cells (Treg), 68 Regulatory.proteins, 73 Regurgitation, 296 Rehabilitation, 814 Relaxation, period of, 656 Renal anatomy and microanatomy, 725 Renal artery occlusive disease and hypertension, 912 stenoses development, 917 ultrasonography deep abdominal, 918 Renal blood flow (RBF), 725, 726, 767 clinical estimation of, 735 measurement of, 736 Renal failure, 84 acute, 282 Renal function, 1108, 1135 clinical assessment of, 733 tests, 734 Renal hyperparathyroidism, surgical treatment of, 942 Renal osteodystrophy, principles of treatment and prevention of, 743 Renal pelvis, physiology of, 725, 767 Renal systemic renin index (RSRI), 918 Renal transplantation, 485, 739 complications of, 760 Renal ultrasonography, 747, 768 Renal vasculopathy, 1013 Renal vein renin ratios (RVRRs), 918 Rendu-Osler-Weber disease, 566 Renin, 6 activity of peripheral and renal venous blood, 918 gene, 7 Renin–aldosterone axis, 667 Renin–angiotensin activity, 687 system, 677, 914 renal blood flow–mediated changes, 914 Renovascular hypertension treatment, 97, 919 antihypertensive drugs, 919 bypass procedures, 920 conventional surgical therapy, 921 endarterectomy, 921

I-18

Index

Renovascular hypertension treatment, (Contd.) ex vivo renal artery reconstruction, 921 percutaneous transluminal renal angioplasty, 919 renal artery fibrodysplasia PTA, 919 Reperfusion-induced tissue injury, mediators of, 388 Replication error–positive (RER+), 558 Residual volume (RV), function of, 632 Resistance to infection, 1095 Respiration, muscles of, 632 Respiratory failure, acute, 637 Respiratory function, 1134 Respiratory inversion point (RIP), 299 Resting energy expenditure (REE), 49 Resting force–length relationship, 653 Resting length–tension curves, 653 Resuscitation, 671 and hemodynamic support, 234 Rearranged during transfection (RET) activation, 999 mutation, 999, 1000, 1028, 1029 protein, 1028 RET. See Rearranged during transfection Reteplase. See Thrombolytic agent Retinoblastoma (Rb) protein, 558 molecular regulator, 198 Retrocaval ureter, 768 Retrograde axonal transport, 819 Retrograde filling test, 890 Retroperitoneal fibrosis (RPF), 768 Revascularization procedures, 745 Rexed lamina V, 540 Reynolds number (Re), 835 Rh null disease, 509 Rhabdomyolysis, 937 Rhabdosphincter or striated sphincter (SS), 775–776 Right coronary artery (RCA), 699 Right internal thoracic artery (RITA) graft, 705 Right ventricular infarction, 671 Right versus left ventricular failure, 667 Ringer’s lactate, 39 solution, 1040 Ripstein procedure, 609 RNA interference technique, 206, 263 Rome II criteria, 610 Rotor syndrome, 484 Rouleaux, 833 Routine chest roentgenography, 898 Roux-en-Y gastric bypass (RYGB), 1068, 1152, 1154 Roux-en-Y procedure, 619 Roux-en-Y reconstruction, 623 RSD. See Reflex sympathetic dystrophy Rugae, 337 Saccular aneurysms, 897 Sacral anterior root stimulation (SARS), 789 Sacral cord injury, 781 Sacral reflex center, 779 Sacral sparing, 807 Saline diuresis treatment, 36 Salt wasters, 1108 Sandwich technique, 929 Saphenofemoral junction, 890 Sarcoidosis, 90, 515 granulomatous disease, 639 Sarcolemmal excitation system, 650 Sarcomere, 649 Sarcoplasmic reticulum (SR) membrane, 650

Saturday night palsy, 820 SBS. See Short bowel syndrome Scarring/Fibrosis, 474–475 Scars contracture, 1038 hypertrophic, 1038 SC b. See Slow component b Schatzki’s ring, 311 Schilling test, 626 Schwann cells, 818, 820 Screening tests, 437 Secondary heart failure, 668 Secretin, 470 Segmentation, 422 Seldinger technique, 678 Selective IGA (SIGA) deficiency, 74 Sellar and parasellar lesions surgical approaches to, 960 Semi-Fowler’s position, 1120 Semmes–Weinstein Monofilament Test, 828 Sengstaken–Blakemore (SB) tube, 444 Senning procedure, 694 Sentinel lymph node, 1050, 1060 Sepsis caused by, 233 definition of, 227 genetic variability in, 232 hemofiltration in, 242 ICD-9 codes for, 230 incidence and outcomes of, 229 pathophysiology of, 230 protein C for, 240 putative markers of, 229 syndrome, 129 treatment strategies in, 234 Sepsisrelated organ failure assessment (SOFA), 234 Septic shock, definition, 227 Serotonin, vasoconstrictor, 1035 Serum albumin, 272 bilirubin concentration, 483 creatinine concentration and GFR, 734 endocrine profile, 1050 potassium levels, 740 proteins, 272 thyroglobulin, 994 Severe combined immunodeficiency disease (SCID), 74 Sex hormone balance, 1159 Sex hormone–binding globulin (SHBG), 1151 Small for gestational age (SGA) babies, 1107 SGA. See Small for gestational age Sheehan’s syndrome, 954, 1053 Shifting dullness, 1055 Shock cardiac compressive, 183 causes of, 193 classification of, 183 definition of, 181 pathophysiology of, 180 treatment of, 193 types of, 183 Shock lung. See Adult respiratory distress syndrome (ARDS) Short bowel syndrome (SBS), 625 pathogenesis of, 625–626 surgical and medical treatment to, 626–627 Short interfering RNAs (siRNAs), 207 Shouldice repair, 1079

Shunts failure, 449 left-to-right, 689 normal, 636 right-to-left, 691 types of, 450 Shutter mechanism, 1073 Shy–Drager syndrome, 780 SIADH, secretion of, 960 Sick euthyroid syndrome, 994 Sickle cell anemia, 510 disease, 545 Sigmoidoscopy, 595 Signal transducers and activators of transcription (STAT), 949 Signaling molecules, 264 Silastic stent, 1120 Silent mutation, 256 Silk deficiency, 166 Silo, 1112–1113 Single nucleotide polymorphism (SNP), 259 Single photon emission computed tomography (SPECT), 941 Single-nephron GFR, 729 Sinoatrial (SA) node, 657 Sinuses of Valsalva, 699 Sirolimus, 114, 760 Sjo¨gren’s syndrome, 997 Skin dimpling, 1054 harbors, 272 substitutes, 1042 Skin flaps axial-pattern, 1042 random-pattern, 1042 Skin grafts full-thickness, 1042 partial or split-thickness, 1042 Sleep apnea, 1150 symptoms of, 1159 Slicone elastomer (Silastic) ring gastroplasty (SRG), 1152–1153 Slow component b (SCb), 819 Slow continuous ultrafiltration (SCUF), 754 Small bowel, mechanical disorders of, 590 Small bowel obstruction (SBO), 543 diagnosis and treatment, 592 etiology, 590 Small bowel transplantation (SBT), 123 Small-cell lung cancer (SCLC), 645 Small for gestational age (SGA), 1107, 1112 Small interfering RNA (siRNA), 263 Smoke inhalation diagnosis, 1097 poisoning, 1097 toxicity, 1096 Sodium–glucose cotransporter gene (SGLT1), 375 Sodium-iodide symporter, 991 Somatic nervous system, 603 Somatomedins. See Insulin-like growth factors Somatoparietal pain clinical features of, 539 peripheral neural pathways for, 540 Somatostatin, 19–20, 386, 949, 1010, 1020 Somatostatinoma, pancreatic neuroendocrine tumor, 1027 Somatotropin, 950 deficiency, 953

Index Sonic hedgehog (Shh) signaling, 1119 Space of disse, 429 Spatial average velocity (Vsa), 840 Sphincter muscle, external, divisions of, 600 Sphincter of oddi, 456, 463 Sphincteroplasty, 610 Sphincterotomy, external, 789 Spinal cord injury (SCI), 790 advance therapies, 814 classic injury patterns, 807 epidemiology, 805 management of, 813 pathophysiology, 805–806 pharmacologic management, 813 primary mechanism, 805 secondary mechanism, 806 Spinal cord, 791 ischemia, 806 lesions of, 780, 790 regeneration, 814 Spinal shock, 807 Spirometry. See Lung volumes and capacities Splanchnic blood flow, 381 Splanchnic vascular bed, 386 Spleen dysfunction of, 506 embryology, 503 functions of, 505 gross anatomy, 503 histology of, 504 physiology and function of, 505 venous drainage of, 503 Spleen-colonizing stem cells, 1137 Splenectomy, 83, 506 accessory, 520 complications of, 520–521 laparoscopic, 520 open, 520 potential indications for, 507 preoperative preparation, 520 Splenic abscess, 513 Splenic artery aneurysms, 515 Splenic cysts, 513-514 Splenic infarct, 512 Splenic injury AAST classification of, 517 management of, 517–518 Splenic microcirculation, 504 Splenic neutropenia, 511 Splenic parenchyma, 504 Splenic salvage techniques, 518–519 Splenic trauma, 515 diagnosis, 516 Splenomegaly, 506 Splicing, differential, 253 Squamocolumnar junction, 312 Standardized incidence ratio (SIR), 78 Staphylococcus aureus, 80, 231, 750 Starling forces, 1101 Starling hypothesis, principles of, 847 Starling mechanism, 677 Starling’s law, 34 Statins, reductase inhibitors, 702 Steatorrhea, 372 Stellate cells, 474 Stem cell biology, 269 Stem cell factor (SCF), 567 Stenosis, 851, 1153 aortic, 709 coronary osteal, 709 critical arterial, 851

Stenosis, (Contd.) endstage aortic, 12 mitral, 709 diagnosis of, 710 treatment of, 710 rheumatic aortic, 709 silent mitral, 713 Stenting, 875 intraluminal, 857–858 Sternal infection, 708 Steroids, 540 hormones, 16 mechanism of action, 17 Stokes–Adams attacks, 716 Stomach and duodenum, mechanical disorders of, 587 Stomach embryology, 333 Strain-gauge transducers, 838 Streamline (laminar) flow, 835 Streptococcus pneumoniae, 80 Streptokinase (SK). See Thrombolytic agent Streptomyces hygroscopicus, 114 tsukubaensis, 114 Stress gastritis, 532 Stroke-in-evolution, 871 Stroke volume (SV), 657, 668 Stump pressure, 874 Stuttering stroke, 871 Subclavian lines, 85 Subclavian steal syndrome, 875 Sucralfate, 348 Suction rectal biopsy, 1118 Sulfasalazine (SASP), 417 Sumerian clay tablet, 427 Superior mesenteric artery (SMA) syndrome, 381, 543, 588, 1122 Superior vena cava (SVC) syndrome, 644 Suppurative anorectal infections, types of, 607 Suprahepatic, portal hypertension, 430 Supramolecular activation clusters (SMACs), 104 Surfactant, 1109 abnormalities in, 638 functions of, 632 lipoprotein complex, 632 proteins SP-A and SP-D, 632 Surgical consent, 271 Surgical infections definition of, 130 pathophysiology of, 127 Surgical-site infections (SSI), 130 Surgical stress, 285 Surviving sepsis campaign, 129 Sustained low-efficiency dialyis (SLED), 753 Sutures absorbable, 1041 nonabsorbable, 1041 Swan–Ganz catheters, 85, 720, 1157 Sweat secretion, 821 Symbion or Jarvik Total Artificial Heart, 682 Sympathectomy, lumbar, 861 Sympathetic renal compensatory mechanisms, 668 Symptoms cardiovascular, 617 gastrointestinal, 617 Synarchic, 17

medwedi.ru

I-19

Syndrome afferent loop causes of, 620-621 blind loop, 627–628 dumping, 617 retained antrum, 622 roux, 623 small stomach, 619 Syndrome of inappropriate antidiuretic hormone secretion (SIADH), 960 Syringomyelia, 811 Systemic antibiotic therapy, 234 Systemic blood circulation, 671 Systemic compensatory mechanisms, 666 Systemic inflammatory response syndrome (SIRS), 49–50, 128, 185, 227, 1091 Systolic dysfunction, 668 Systolic ejection, stimulation of, 668 Systolic pressure, 666, 671, 672 Systolic vs. diastolic dysfunction, 667 T helper (Th) cells, 67 Tabes dorsalis (Neurosyphilis), 783 Tachycardia, 275, 1160 supraventricular diagnosis of, 717 ventricular, 699 Tacrolimus, 114 Takayasu’s arteritis, types of, 877 Takayasu’s disease, 877 Tamoxifen, antiestrogen drug, 1059 Tandem lesions, 872 Target of rapamycin (TOR), 114 T-cell activation of signal hypothesis for, 103 anergic, 69 antigen recognition, processing, and signaling, 756 cytotoxic function, 67 helper function, 67 suppressor, 69 T-cell receptor (TCR), 66, 96, 756 Tracheoesophageal fistula (TEF) diagnosis of, 1120 N-type, 1120 TEF. See Tracheoesophageal fistula TENS. See Transcutaneous electric nerve stimulation Tension time index, 660 Tension-free repair. See Lichtenstein repair Tetraiodothyronine (T4), 990, 991 Tetralogy of Fallot, 692 TGA. See Transposition of the great arteries Thalassemia (Mediterranean anemia), 510 Thebesian veins, 699 Thelarche, 1049 Therapeutic anticoagulation, 279 Therapeutic genes, 206 Thermal injury biophysics of, 1092 pulmonary consequences of, 1096 Thermogenesis, 1150 Thiazide diuretics, 742 Thienopyridine derivatives, 170 Thiersch procedure, 609 Thoracic aneurysmal disease, 902 Thoracic aneurysms classification of, 897 clinical presentation and symptomatology of, 898 diagnosis of, 898–899 pathophysiology of, 897–898 treatment of, 899

I-20

Index

Thoracic aortic aneurysms, 897 disease, 897–902 Thoracic outlet syndrom, 878-879 complications of, 880 diagnosis of, 879 measures of, 879 Thoracotomy extra-pleural, 1120 trans-pleural, 1120 Thoratec device, 680 Three-Phase Desensitization Test, 827 Thrombectomy, surgical, 888 Thromboangiitis obliterans (Buerger’s disease), 405 Thrombocytopenia, 288, 521 conditions associated with, 508 HIV-related, 508–509 Thromboembolism prevention of, 671 prophylaxis against, 289 Thrombolytic agents, 703 Thrombolytic therapy, 888 Thrombomodulin (TM), 159 Thrombophlebitis, superficial, 891–893 Thromboregulation, 159 Thrombosis, acute, 852 Thrombotic thrombocytopenic purpura (TTP), 508 Thromboxane A2 (TXA2), 1086 Thyroglubulin hydrolyzation, 991 Thyroid agenesis (athyreosis), 990 artery inferior, 899 superior, 899 autoantibody tests, 994 cancer, 999 carcinoma differentiated, 999 cartilage, 318 disease symptoms, 993 dysfunction, 286 function regulation, 992 nodules evaluation, 998–999 storm, 996 tests, 994 Thyroid gland anatomy of, 899 histology of, 990 physiology of, 990 Thyroid hormones, 286, 930 action, 992 active, 990 administration, 1001 elimination, 992 receptors, 992 synthesis of, 990 Thyroid hormone binding globulin (TBG), 991 Thyroid hormone binding prealbumin (TBPA), 991 Thyroidectomy, 996, 1000 unilateral, 1001 Thyroiditis, 997 De Quervain’s, 998 giant cell, 998 Hashimoto’s, 997 Riedel’s, 997

Thyroiditis, (Contd.) subacute, 998 Thyroid-stimulating hormone (TSH), 185, 286, 948, 994, 1001 Thyrotoxicosis, 286 Thyrotropin, 949 Thyrotropinoma, 958 Thyrotropinreleasing hormone (TRH), 950, 993, 995, 1052 TIA. See Transient ischemic attacks Ticlopidine (Ticlid) advantage of, 170 antiplatelet agent, 703 Tidal volume (TV), function of, 632 Tissue engineering and transplantation, 269 Tissue factor pathway inhibitor (TFPI), 159 Tissue inhibitors of matrix metalloproteinase (TIMPs), 741 Tissue necrosis factor-alpha (TNF-a), 1115 Tissue plasminogen activator (TPA), 1098 Tissue-type plasminogen activator (t-PA), 160 T-lymphocyte cell, 66, 96 TNF-receptor (TNFR), 99 Toll-like receptor (TLR), 70, 91, 233 Tolypocladium Inflatum Gams, 113 Tonicity, 34 Tonometry gastric, 191 mucosal, 191 Total artificial heart (TAH), 671 Total body fat (TBF), 4 Total body nitrogen (TBN), 5 Total body potassium (TBK), 3 Total body proteins (TBPs), 5 Total body water (TBW) components, 1108 distribution of, 2 extracellular water (ECW), 1 intracellular water (ICW), 1 Total lung capacity (TLC), 632, 1135 Total lymphoid irradiation (TLI), 118 Total parenteral nutrition (TPN), 52, 79–80, 123, 626, 1107 components of, 57 indications for, 56 infectious complications of, 59 metabolic complications of, 59 monitoring of, 60 preventative measures of, 59 technical complications of, 59 Toxic multinodular goiter (Plummer’s disease), 996 Toxic products, effect of inhaled, 1097 Toxoplasma gondii, 140 TPN. See Total parenteral nutrition Trachea, 295 Tracheoesophageal fistula (TEF), 1119 Transcatheter therapy, 688 Transcellular fluids, 3 Transcellular space, 3 Transcutaneous electric nerve stimulation (TENS), 221, 827 Transepithelial water loss, 1108–1109 Transesophageal echocardiograms. See Venous air embolism (VAE) Transferrin, 50 Transforming growth factor-alpha (TGFalpha), 438 Transforming growth factor-b (TGF-b), 555, 1035, 474, 1049 Transgenic animals, 259 Transient cerebral ischemic attacks, 869

Transient heart failure, 668 Transient ischemic attacks (TIA), 869 Transient LES relaxations(TLESRs), 296 Transjugular intrahepatic portasystemic shunt (TIPS), 446, 529 advantages to, 450 Translation, 257 Transluminal balloon angioplasty, 857 Transmembrane segments (TMs), 265 Transmyocardial revascularization, 709 Transplant acute tubular necrosis (TxATN), 759 Transplantation bone-marrow, 123 cardiac, 120 corneal, 124 immunobiology, 755 lung, 122 pancreas, 122 renal, 120 xenograft, 91 Transporter in antigen processing (TAP), 93 Transposition of the great arteries (TGA), 693, 694 Transposon, 256 Transpulmonary thermodilution (TDD), 1098 Transurethral incision (TUI), 771 Transurethral microwave thermal therapy (TUMT), 771 Transurethral needle ablation (TUNA), 771 Transurethral resection of the prostate (TURP), 771, 782 Transventricular dilatation, 688 Transversalis fascia, 1067, 1069, 1072 Trastuzumab, antibody, 1061 Trauma, 403–404 Traumatic brain injury (TBI), 802 Traumatic degeneration, 819 Traumatic lung injury, 642 Traumatic pseudoaneurysms, 902–903 Trendelenburg test, 890 Tricarboxylic acid (TCA), 9, 13 Triiodothyronine (T3), 990, 991 Tropomyosin, 649 Troponin, subgroups of, 649 Trousseau’s sign, 936 Truncal vagotomy, 348, 470 and antrectomy, 359 Trypanosoma cruzi, 318 Trypsinogen, 470 Thyroid-stimulating hormone (TSH) deficiency, 953 receptor antibodies, 995 ultrasensitive, 997 TSH. See Thyroid-stimulating hormone Tubercle of zuckerkandl, 1001 Tuberculosis, 640 Tubular functions, 729 Tubuloglomerular feedback (TGF) system, 726 Tubulointerstitial fibrosis, 741 Tumor, 534 Tumor-infiltrating lymphocytes (TILs), 205 Tumor necrosis factor (TNF), 27–28, 67, 91, 491, 1087 alpha (TNF-a), 473, 561, 993, 995 classification, 1000 Tumor-node-metastasis (TNM), 324, 1060 Tumor suppressor proteins, 555 Tunica adventitia, 903 Tunnel technique, lateral, 692

Index Turbulent flow, 835 Turcot’s syndrome, 576 Turner syndrome, 1050 Tyrosine kinase inhibitors, 559 Ultrasonography, 488, 516, 1057 diagnostic tool, 547 food and drug administration, 971 sensitivity and specificity of, 547 Ulcerative colitis (UC), 415, 560 Ultrafiltration, 745 Unilateral ureteral obstruction (UUO), 767 Unilateral versus bilateral ureteral obstruction, 767 Unna’s boot, 889 UPJ (uretopelvic junction) obstruction (UPJO), 769 Upper esophageal sphincter (UES), 295 Upper GI bleeding, other sources of, 532 Upper motor neuron lesion (UMNL), 787 Upper tract obstruction, diagnosis of, 772 Urea breath test, 354 Urea cycle, 12 Uremia arthropathy, 743 associated immune deficiency, 746 cardiomyopathy, 744 complication of, 165 Uremic encephalopathy, 746 Uremic manifestations, 742 Uremic peripheral neuropathy, 746 Uremic toxins, 746, 752 Ureter, physiology of, 767 Ureteral obstruction, symptoms of, 767 Ureteral stricture, 769 Ureteropelvic junction (UPJ), 767 Urethra, anatomy of, 770 Urethral obstruction, 771 Urethral stricture, 771 Urinalysis, 759 Urinary bladder anatomy of, 770 innervation of, 776 wall, 775 Urinary diversion, 783 Urinary nitrogen, 22, 25 Urinary obstruction, causes of, 769 Urinary pH, 733 Urinary retention, 783 Urinary sphincter, external, 785 Urinary storage and micturition, CNS control of, 778 Urinary tract infections (UTI), 768, 784 Urinary tract obstruction, 767 diagnostic studies, 768 etiologies of, 2 Urinary tract infections, 131 lower, 768 upper, 767 Urinary urea nitrogen (UUN), 51–53, 60 Urine microscopic examination, 734 output, 738 specific gravity and osmolality, 733 volume of, 733 Urodynamic studies, 785 Urodynamic tests, 786 Uroflometry (UFR), 785 Urogenital short nervous system (USNS), 776 Ursodeoxycholic acid (UDCA), 372, 463

VACTERL (vertebral, anal, cardiac, tracheoesophageal, renal, and limb) association, 1119 Vagal-sparing esophagectomy, technique of, 325 Vagal transection, 623 Vagotomy, types of, 623 Vagus nerve, 295 origin, 335 Valsalva leak point pressure (VLPP), 786 Valsalva maneuver, 844, 890 Valvular heart disease, 278 Valvuloplasty, balloon mitral, 710 Vancomycin, 134 Vancomycin-resistant enterococci (VRE), 148 Vanillylmandelic acid (VMA), 978 Variceal bleeding, definitive therapy for, 446 Variceal hemorrhage, 443 Variceal rehemorrhage, 450 Varicose veins primary, 889 secondary, 889 Vasa recta, 725 Vasa vasorum, 850, 862 Vascular cell adhesion molecule (VCAM), 101 Vascular endothelial growth factor (VEGF), 201, 558 Vascular endothelial growth factor (VEGF) receptors (VEGF-R) types, 558 Vascular engorgement, 798 Vasculature bronchial, 633 pulmonary, 633 Vasculitis, 405 Vasoactive intestinal peptide (VIP), 336, 386, 1009, 1019, 1026, 1052 Vasodilator therapy, 660, 704 Vasopressin, 951 deficiency, 240, 954 therapy for septic shock, 240 Vasopressor agents, 235 therapy, 129, 238 Vecuronium, 801 Vein coronary, 705 perforating, 883 stripping, 891 thrombosis, 891 Venography, 885 Venous air embolism (VAE) detectors, 218 Venous anatomy, 841-842 Venous congestions, 686 Venous disorders lower extremity, 884 upper extremity, 891 Venous flow effects of respiration in, 844 gravitational effects, 844 Venous lakes, 842 Venous sclerotherapy, 890 Venous system deep, 883 features of, 841–842 perforating, 883 physiology of, 884 superficial, 883 Venous thromboembolism (VTE), 289 Venous thrombosis, acute, 845

medwedi.ru

I-21

Ventilation mechanical, 672 perfusion mismatch, 887 relationship, 636 scan, 887 Ventilator-associated pneumonia (VAP), 129 Ventricular assist device (VAD), 680, 707 Ventricular assist system (VAS), 679 Ventricular contractility, 659 Ventricular end-diastolic pressure, 668, 671 Ventricular end-diastolic volume, 667 Ventricular fibrillation, 670, 672 prolonged, 671 Ventricular filling pressure, 665, 667, 671 Ventricular function, left, 665 Ventricular geometry, 654 Ventricular infarction, right, 671 Ventricular septal defect (VSD), 686, 687, 690, 704 Ventricular septal rupture, 669 Ventriculography, 661 Ventriculostomy, 801 Verner–Morrison syndrome, 1020 diagnosis of, 1019 Vertebrobasilar disease, syndrome of, 875 Vertical banded gastroplasty (VBG), 1152 Very low birth weight (VLBW), 1107 Very low density lipoprotein (VLDL), 434, 457 Veterans affairs cooperative study, 711 Vibratory injury, 877 Vicious cycle of heart failure, 666, 667 Video-assisted thoracic surgery (VATS) treatment, 641 Video-assisted thoracoscopy, 691 Vigorous potassium replacement, 1014 Villous adenomas, 566 VIP. See Vasoactive intestinal peptide Vipomas, 1019 pancreatic neuroendocrine tumor, 1027 Viral infections, hepatitis C, 121 Viral vectors, 267 Virchow’s triad, 884–885 Visceral pain clinical features of, 539 peripheral neural pathways for, 540 Visceral pericardiectomy, 721 Visceral vessels, 397 operative interruption of, 398 Vitamin D, 929 Vitamin D–binding protein (VDBP), 929 Vitamin D receptor (VDR), 743 Vitamin K deficiency, 288 Vitamins and minerals, 377 VLBW. See Very low birth weight (VLBW) Voiding cystourethrogram (VCUG), 771, 785 Voiding studies, 785 von Hippel Lindau (VHL) disease, 1032 von Willebrand factor (vWF), 157, 431 qualitative deficiency of, 161 quantitative deficiency of, 161 types of, 161 von Willebrand’s disease, 289 VSD. See Ventricular septal defect Waist-to-hip ratio (WHR), 1149 Waldenstrom’s macroglobulinemia (WM), 512 Wall forces, 653

I-22

Index

Wall stress, 653 Wallerian degeneration, 818 Warfarin-induced skin necrosis, 171 Warfarin, vitamin K antagonist, 171 Warthin, HNPCC, 576 Water for dialysis, 752 hydrogen-bonding capacity of, 1 universal solvent, 33 Water balance, abnormalities of, 38 Water in various tissues, distribution of, 2 Waxes and wanes. See Stroke-in-evolution Weight fluctuation, primary mechanism for, 1150 Weight loss, 1152 Weir equation, 51 Wellington’s forces, 605 Wells procedure, 609 Westermark’s sign, 887 Whipple operation, 567 Whipple’s triad, 1017

White blood cells, disorders of, 287 White clot syndrome, 169 White pulp, 504 Wiggers, hemorrhagic shock by, 181 Williams syndrome, 689 Wilson’s disease, 437 Windkessel effect, 832 Wiskott–Aldrich syndrome, 77 Wnt pathway, 555 Wolff-Parkinson-White (WPW) syndrome, 718 World Health Organization (WHO), 560 definition anemia, 1143 Wound and soft tissue, infections, 136 Wound closure, 1041 vacuum-assisted, 1042 Wound complications, 1156 Wound edema, nonburn, 1090 Wound fluid shifts in, 1089 Wound healing, 486 altered, 1145

Wound healing, (Contd.) pathologies of, 1038 phases of, 1035 research in, 1044 Xenotransplantation, 269 Xeroradiography, 1056 Xigris, human-activated protein C, 129 X-ray crystallography, 262 Young’s modulus, 656 Zenker’s diverticulum, 296 transoral treatment of, 317 treatment of, 316 ZES. See Zollinger–Ellison syndrome Zeta-associated protein (ZAP), 104 Zidovudine, 508 Zollinger–Ellison syndrome (ZES), 340, 570, 1018, 1026 clinical manifestations of, 1026 medical management of, 1026

medwedi.ru